JPH0920680A - Antifungal agent - Google Patents

Abstract

PURPOSE: To obtain an antifungal agent capable of reducing an adverse effect and lowering appearing frequency of a resistant strain because of having a strong antifungal effect with a small amount application by incorporating an azole-based antifungal agent and lysozyme. CONSTITUTION: This antifungal agent contains an azole-based antifungal agent (preferably itoraconazole or miconazole) and lysozyme (preferably having >=95% purity). Lysozyme can be prepared from, e.g. egg-white, a milk or a lysozyme- homologous sample, etc., in human saliva generated by genetic engineering. The objective antifungal agent can be made as a preparation form of, e.g. an oral agent, an injection, a troche agent, an ointment or a lotion. The antifungal agent exhibits the sufficient effect in the amount of (1/3-1/10) of a conventional agent.

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]

BACKGROUND ART In superficial mycosis, invasion of the causative bacteria is caused by epidermis,
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.

Conventionally, as an antifungal agent for internal use, antifungal agents used for the treatment of mycoses include polyene amphotericin B, fluoropyridine flucytosine, imidazole (azole) miconazole, and triazole ( There were only four azole-based fluconazole agents, but in September 1993, the azole-based itraconazole was marketed.

The types of pathogenic fungi targeted by these antifungal agents and drug sensitivities differ depending on the respective antifungal agents. Candida, Cryptococcus, Aspergillus, Trichophyton, Malassezia, Kochidioides Etc.

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 highest occupancy rate has a lower efficacy rate for aspergillosis than 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, the appearance of side effects such as liver damage, renal damage, diarrhea, and vomiting due to long-term large-dose administration of such antifungal agents is a clinical problem, and further, fungal-causing bacteria caused by long-term administration. It is feared that drug resistance will become worse.

[0011]

Considering such circumstances, an antifungal agent having a bactericidal action even when used in a small amount, that is, an antifungal agent having few side effects and a strong antifungal action, or , The development of antifungal drug usage is desired.

[0012]

Means for Solving the Problems The present inventors have studied 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 the azole antifungal agent exerts a strong antifungal activity at a dose much smaller than the conventional dose. The 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 azole agent to be used in the present invention may be any one including conventionally used azole antifungal agents, but itraconazole or miconazole is particularly preferable.

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 higher, and particularly preferably 95% or higher.

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

[0017]

EXAMPLES 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 troche containing an azole antifungal agent, itraconazole, egg white lysozyme and other excipients was prepared.
The composition is shown in Table 1.

Table 1 Composition of 11 lozenges Itraconazole 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 model experiment was carried out 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. Itraconazole (alone) was used as a control drug. The results are shown in Table 2. That is, 2
The “75% growth-inhibiting itraconazole concentration (IC75)” after 4 hours of culturing was as follows when itraconazole and lysozyme were combined as compared to itraconazole alone.
A remarkable decrease was seen. The antibacterial activity when the culture was continued for 3 days under the same conditions was more remarkable in the latter case, and the antibacterial activity was bactericidal, and the minimum bactericidal concentration was remarkably lowered. In addition,
Lysozyme alone (4-100 μg / ml) had significantly lower antifungal activity.

Table 2 IC75 Minimum bactericidal concentration (ng / ml) (μg / ml) Itraconazole alone> 30 10 Mixing itraconazole with lysozyme 10 0.8

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.

[0024]

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 the front page (72) Inventor Shigeru Niu 5-37-3 Shiraitodai, Fuchu-shi, Tokyo Virana Nagakawa A-202 (72) Innovator Nobuo Suegara 1-25, Machiya, Shiroyama-machi, Tsukui-gun, Kanagawa Prefecture 22 No. (72) Inventor Hideyo Yamaguchi 2-15-5 Kuriya, Tama-ku, Kawasaki City, Kanagawa Prefecture

Claims (3)

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