JPH08198773A - Antifungal agent - Google Patents

Abstract

PURPOSE: To provide an antifungal agent which comprises an azole antifungal agent and lysozyme and manifests strong antifungal action with a reduced dose, thus is useful for therapy of superficial mycosis, particularly oral candidiasis or vaginal candidiasis of low incidence of resistant strain. CONSTITUTION: This antifungal agent comprises (A) an azole antifungal agent such as lanoconazole (A1 ) or clotrimazole (A2 ) and (B) a lysozyme such as an egg-white lysozyme (B1 ), milk lysozyme or a human saliva lysozyme- homologous lysozyme prepared by the genetic engineering. This antifungal agent is prepared typically by formulating A1 , B1 , NaHCO3 , powdery sucrose, arabic gum powdery, dextrin as an excipient into a troche or by formulating A2 , B1 , carbarsone, and macroglia as an excipient into a pessary.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antifungal agent characterized by containing an azole antifungal agent and lysozyme and showing a strong antifungal action at a low concentration.

[0002]

2. Description of the Related Art Superficial mycoses are caused by invasion of causative bacteria,
It is a disease limited to keratinized tissues such as hair and nails, and mucosal regions adjacent to the skin such as oral cavity and vagina, but the frequency of occurrence is highest.

The incidence of dermatophytosis (tinea), which is known as one of the typical superficial mycoses, reaches 10% or more of the total population, and there are many cases where recurrence and reinfection occur repeatedly. Ringworm has various pathological conditions such as tinea pedis, tinea corporis, and tinea cruris. Moreover, candidiasis is known as another typical superficial mycosis. Candidiasis is oral candidiasis,
Diseases such as esophageal / intestinal candidiasis and vulvovaginal candidiasis are caused by invasion of Candida fungi. Furthermore,
Pyelonephritis, interstitial rash, interdigital erosion, paronychia, cystitis,
There are also many candidiasis.

On the other hand, in recent years, serious deep-seated mycosis has rapidly increased. In the background, broad spectrum antibiotics, anticancer agents,
Administration of many drugs such as immunosuppressants and oral contraceptives in organ transplantation, use of high-calorie infusions, indwelling catheters, etc. Furthermore, there is a rapid increase in the number of patients with AIDS and other immunocompromised patients, which is a major clinical problem. Is.

The types of pathogenic fungi targeted by antifungal agents and drug sensitivities differ depending on the respective antifungal agents. is there.

The antifungal agents collectively referred to as azoles are
It has an azole ring or a triazole ring, and exhibits similar properties in biological activity. In particular, sterol / C-14 demethylation disorder in the ergosterol synthetic pathway localized in the endoplasmic reticulum of fungal cells is common in that it acts as an antifungal mechanism of action.

Looking at the current state of use of such an antifungal agent for internal use which is used as a single preparation, the occupancy rate of the azole agent is high. The reason why azole agents are commonly used is
Compared to amphotericin B and flucytosine, it has advantages such as high safety and resistance to resistant bacteria. However, it has been reported that fluconazole (an azole antifungal agent) having the largest occupancy rate has a lower efficacy rate for aspergillosis compared to the efficacy rate for candidiasis and cryptococcosis.

Since azole agents generally act only bacteriostatically, it is said that they are unlikely to be effective when the infection resistance of a patient is significantly reduced or when an invasive serious infection is established. There is. As described above, in the current use of the azole agent, since it has no bactericidal action, administration of a relatively large amount over a long period of time is required.

Therefore, such antifungal agents (among others,
The long-term large-dose administration of an internal antifungal agent causes clinical side effects such as side effects such as liver damage, renal damage, diarrhea, and vomiting, and drug resistance of fungal disease-causing bacteria caused by long-term administration. Is afraid.

[0010]

Considering such a situation, an antifungal agent having a bactericidal action even when used in a small amount, that is, an antifungal agent having less side effects and a strong antifungal action, Alternatively, there is a desire to develop methods of using antifungal agents.

[0011]

Lanoconazole is an azole compound having a broad antibacterial spectrum and high antifungal activity against dermatophytes (Trichophyton, etc.), Candida, Malassezia, and other fungi. It is an antifungal agent.

The present inventors have examined the enhancement of the antifungal action of azole antifungal agents, and as a result, by adding an appropriate amount of lysozyme to the azole antifungal agent, It was experimentally found that a strong antifungal activity was exerted at a dose far smaller than that of the above-mentioned, and the present invention was completed.

That is, the present invention relates to an antifungal agent characterized by adding lysozyme to a small amount of an azole agent to prepare a mixture.

The lysozyme used in the present invention may be egg white, milk, or one prepared from a genetically engineered lysozyme homologous sample in human saliva, or a salt thereof. The purity is preferably 90% or more, and particularly preferably 95% or more.

The antifungal agent of the present invention can be administered in the same manner as the antifungal agent contained therein. That is, oral preparations, injections, tablets, ointments, lotions,
An appropriate dosage form can be selected from lozenges and the like.
Also, the dose of the present invention may be 1/3 to 1/10 of the dose of a conventional antifungal agent, and has antifungal activity equal to or higher than that.

[0016]

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 A lozenge preparation comprising azo antifungal agent lanoconazole, egg white lysozyme and other excipients was prepared. The composition is shown in Table 1.

Table 1 Composition of 11 lozenges Lanoconazole 0.01 g Egg white lysozyme 1.0 g NaHCO ₃ 2.0 g Sucrose powder 4.0 g Arabic gum powder 3.0 g Dextrin 1.0 g

Example 2 A vaginal preparation comprising clotrimazole, an azole antifungal agent, egg white lysozyme, and other excipients was prepared. The composition is shown in Table 2.

Table 2 Composition of 11 vaginal agents Clotrimazole 0.01 g Egg white lysozyme 1.0 g Carvalzone 0.3 g Macrogol 1500 10.0 g Macrogol 4000 45.0 g

Example 3 A model experiment was conducted using the agent of the present invention as an agent for treating oral candidiasis which dissolves in the oral cavity.

The drug prepared in Example 1 was appropriately made into an aqueous solution, and the antibacterial activity against the pathogenic fungus, Candida albicans TIMM 1768 strain, was measured in vitro. Lanoconazole (alone) was used as a control drug. The results are shown in Table 3. That is, "75% stunting lanoconazole concentration (IC
75) ”markedly decreased when lanoconazole and lysozyme were combined as compared to lanoconazole alone. The antifungal activity of lysozyme alone (4 to 100 μg / ml) was remarkably low.

Table 3 IC75 (ng / ml) lanoconazole alone> 200 a mixture of lanoconazole and lysozyme 60

Example 4 A model experiment was carried out in which the agent of the present invention was applied as a therapeutic agent for vaginal candidiasis that dissolves in the vagina.

The drug prepared in Example 2 was appropriately made into an aqueous solution, and the antibacterial activity against the pathogenic fungus, Candida albicans TIMM 1768 strain, was measured in vitro. Clotrimazole (alone) was used as a control drug. The results are shown in Table 4. After culturing for 24 hours, "75% growth inhibitory clotrimazole concentration (IC7
5) ”markedly decreased when clotrimazole and lysozyme were combined, as compared to clotrimazole alone. In other words, it was revealed that this drug was sufficient to suppress the growth of Candida at a dose of about 1/5 of clotrimazole compared to clotrimazole alone. The antifungal activity of lysozyme alone (4-100 μg / ml) is
It was extremely low.

Table 4 IC75 (ng / ml) clotrimazole alone 50 a mixture of clotrimazole and lysozyme 10

Thus, it was revealed that the agent of the present invention has an antifungal effect at a much lower concentration than the conventional antifungal agent alone.

[0028]

INDUSTRIAL APPLICABILITY The antifungal agent of the present invention has a strong antifungal effect even in a small dose and is expected as a therapeutic agent for various fungal diseases. In addition, side effects are reduced and the frequency of appearance of resistant bacteria is reduced.

Continuation of front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display location A61K 31/415 ADZ 45/08 A61K 37/54 ACV (72) Inventor Hideyo Yamaguchi 2 Kuriya, Tama-ku, Kawasaki-shi, Kanagawa Chome 15 number 5

Claims (3)

[Claims] 1. An antifungal agent comprising an azole antifungal agent and lysozyme. 2. The antifungal agent according to claim 1, wherein the azole antifungal agent is lanoconazole or clotrimazole. 3. The antifungal agent according to claim 1, wherein the azole antifungal agent is lanoconazole or clotrimazole, and the target disease is oral candidiasis or vaginal candidiasis.