JP3187806B2 - External preparation for treating atopic dermatitis containing nitroimidazole compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for treating atopic dermatitis and / or its related skin diseases.

[0002]

2. Description of the Related Art Skin diseases are caused by various causes such as inflammation, urticaria, allergy represented by IgE, bacteria and viruses. For example, patients suffering from insect bites, hives, atopic dermatitis, etc. scratch their sites due to pruritus, discomfort or the like, so that the symptoms are often further worsened by bacteria or viruses. It is known that such a dermatitis group is caused not by one kind of bacteria and virus but various kinds of bacteria and viruses.
There are individual differences such as symptoms, and even the same person differs depending on the site and the like. In the skin where the symptoms have worsened, for example, typical ones are MRSA, MSS
Bacteria such as A, CNS, and M. Furfur (Pityrosporum), viruses, and the like are observed.

At present, corticosteroids are mainly used for the treatment of skin diseases, and various corticosteroids are used depending on the symptoms. However,
Although corticosteroids have excellent therapeutic effects, they have prominent side effects due to long-term use or discontinuation of use during treatment, and even when the therapeutic effects appear, they suffer from complicated side effects. That is the current situation.
On the other hand, it is known that when a small amount of a corticosteroid is applied due to concerns about side effects, the therapeutic effect is hardly exhibited.

[0004] For example, corticosteroids which are most used for atopic dermatitis and / or related skin diseases and other skin diseases, ie, steroidal anti-inflammatory drugs, have excellent therapeutic effects, Oral administration over a period of time can cause systemic side effects such as renal failure, diabetes, hypothalamus, pituitary, and suppression of adrenal cortical function. Even in the form of an external preparation, side effects such as exacerbation of skin infections and acne peculiar to corticosteroids often occur locally, and scars and melasma during the administration period or after discontinuation of administration. In addition, the problem of rebound after the administration has been pointed out as a social problem by the Ministry of Health, Welfare, the Medical Association, and the Pharmaceutical Association.

[0005] In particular, regarding atopic dermatitis, newspapers,
As described in social issues in magazines, etc., and problems with steroids in publications, patients with symptoms and their families with illness for which the cause has not been identified are subject to daily pruritus, pain, insomnia, etc. Suffered from the symptoms of
In fact, in addition to treatment at hospitals, they rely on private treatment and the like, and there is no established treatment method at universities, hospitals, and treatment institutions.

[0006] For example, in the use of steroids, "Guidelines for the treatment of atopic dermatitis" regarding the method of using the steroids (Ministry of Health and Welfare Long-term Chronic Disease Research Project Allergy Research and Ministry of Health and Welfare Science Research 1997 and 1998: Shared Research ""A guideline for the treatment of atopic dermatitis" (published in 1999) has been distributed to some medical institutions, but there is a research group, but there is a skin disease that is not cured by medical institutions. At present, there are a number of therapeutic problems that patients undergo in folk medicine and religion. For this reason, there has been a demand for rapid development of a more effective treatment for skin diseases such as atopic dermatitis without side effects.

[0007]

DISCLOSURE OF THE INVENTION In view of the above-mentioned current state of the treatment of skin diseases, the present invention provides an atopic dermatitis and / or a skin disease associated therewith capable of obtaining an excellent therapeutic effect without side effects. It is intended to provide an external preparation for treatment.

[0008]

Means for Solving the Problems The present inventor has conducted intensive studies for the treatment of atopic dermatitis and / or related skin diseases. As a result, the present inventor is a therapeutic agent for trichomoniasis and dysentery amoeba. It has been found that metronidazole, which has not been studied for any atopic dermatitis and / or its related skin diseases, has excellent therapeutic effects on atopic dermatitis and / or its related skin diseases. The present inventor further studied and found that the metronidazole-based compound was stably combined with another specific drug component such as a steroid to form a composite preparation, whereby the amount of other specific drug components used was reduced. Shows an effective therapeutic effect even in a very small amount (for example, about 10 to 20 times) as compared with the amount used as a single agent, and also has, for example, side effects as seen in conventional steroidal anti-inflammatory external preparations (Such as rebound after discontinuation of administration) was also found. As a result of the test or treatment, the present inventors have also found that pigmentation, scars, liver spots, sparrow eggs, etc. of the skin tissue scattered before the treatment are reduced or eliminated, and have completed the present invention.

That is, the present invention provides: (A) Formula (I):

[0010]

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(Wherein R ¹ and R ² are each independently a linear or branched alkyl or alkyl alcohol group, such as a hydroxyl group, a benzyl group, a phenyl group,
It may have a cycloalkyl group, an ether group, and / or an amino group. A) a nitroimidazole derivative or a pharmacologically acceptable salt thereof, and (B)
It is a complex preparation containing as an active ingredient at least one drug component selected from an antifungal agent, a corticosteroid agent, an antibacterial agent or a sulfa agent, an antihistamine agent, an antiallergic agent, an antiinflammatory agent, an antibiotic and a local anesthetic. Provided is an external preparation for treating atopic dermatitis and / or its related skin diseases.

The compound represented by the formula (I) is 2- (2-
Methyl-5-nitroimidazol-1-yl) ethanol, ie, metronidazole.
Among the above external preparations, the drug component (B) is an antifungal agent and a corticosteroid, and an external preparation containing (A) metronidazole as an active ingredient, an antifungal agent and a corticosteroid is particularly preferable.

The content of the nitroimidazole derivative or the pharmaceutically acceptable salt (A) thereof is 0.1 to 0.1% in the preparation.
Desirably, it is 20% by weight.

(B) The content of each component in the preparation when formulated as a drug component is as follows. When the antifungal agent is contained, the amount is desirably 0.0005 to 2% by weight. When the corticosteroid is contained, the amount is desirably 0.0001 to 1% by weight. When the antibacterial agent or the sulfa agent is contained, the amount is desirably 0.001 to 5% by weight. The amount when the antihistamine is contained is 0.001 to 10
% By weight. When the antiallergic agent is contained, the amount is desirably 0.001 to 10% by weight. The amount when the anti-inflammatory agent is contained is 0.00
It is desirably 1 to 5% by weight. When the antibiotic is contained, the amount is desirably 0.0001 to 5% by weight. The amount when a local anesthetic is contained is 0.0
It is desirable that the content be from 0.01 to 5% by weight.

The pH of the preparation is preferably in the range of 3.0 to 9.0.

The external preparation as described above can be used for treating atopic dermatitis and / or its associated skin diseases.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, (A) the following formula (I)
A nitroimidazole derivative or a pharmacologically acceptable salt thereof, and (B) an antifungal agent, a corticosteroid agent, an antibacterial agent or a sulfa agent, an antihistamine agent, an antiallergic agent, an antiinflammatory agent, an antibiotic, and local anesthesia. The present invention provides an external preparation for treating atopic dermatitis and / or a related skin disease, comprising a composite preparation containing, as an active ingredient, one or more drug components selected from preparations.

(A) Metronidazole compounds

[0019]

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Here, R ¹ and R ² are each independently a linear or branched alkyl group or an alkyl alcohol group, such as an aromatic group such as a hydroxyl group, a benzyl group or a phenyl group, or a cycloalkyl group. , An ether group, and / or an amino group.

The substituents R ¹ and R ² are a linear or branched alkyl group or an alkyl alcohol group,
For example, alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butylene and the like, and alcohols thereof and the like.

In the present invention, among the nitroimidazole derivatives represented by the above formula (I), in particular, metronidazole (2- (2-methyl-5-nitroimidazole-1-)
Il) ethanol) is preferred. Metronidazole
It is represented by the following formula (II).

[0023]

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The nitroimidazole derivative represented by the above formula (I) may form a pharmacologically acceptable salt thereof. The salt is not particularly limited, but examples thereof include inorganic acid salts and organic acid salts, and the case where the hydroxyl group has another protecting group is also included in the present invention. For example, hydrohalic acid, hydrochloric acid, nitric acid,
Examples thereof include inorganic acids such as sulfuric acid and phosphoric acid, organic acids such as acetic acid, propanoic acid, benzoic acid, citric acid, and lactic acid, and salts thereof.

In the present invention, two or more selected from nitroimidazole derivatives and salts thereof may be used in combination as the active ingredient (A). In this specification, a nitroimidazole derivative and a salt thereof may be simply referred to as a “metronidazole-based compound”.

Compound metronidazole (2- (2-methyl-5-nitroimidazol-1-yl) ethanol)
Was synthesized by Jacob in Rhone-Poulenc Roller (France) in 1957. Among the nitroimidazole derivatives, metronidazole, as described above, has strong anti-trichomonas activity, as described in Cosar and Julo.
discovered by u. The fact that Trichomonas protozoa disappeared in 1959 using this drug for human trichomoniasis was reported by Du.
rel reported for the first time. It also shows a strong antibacterial activity against dysentery amoeba. Furthermore, it has been reported that oral administration and topical administration have a bactericidal action against other anaerobic bacteria. The mechanism of action is that the nitro group of metronidazole is reduced by microorganisms,
It is thought to cause dysfunctions such as double-strand breaks of, and control mitotic proliferation. However, it has not been studied so far for atopic dermatitis and / or its related skin diseases.

Investigation of the present invention revealed that metronidazole, even as a single agent, showed a mild therapeutic effect after application (if the patient suffers from mild atopic dermatitis, the effect is 1%). ２2 days later, but in severe patients, the effect can only be confirmed after about 3-7 days). However, the time to healing and the cure rate are not different from those of topical steroids, and side effects such as pigmentation, scarring, hardening of the stratum corneum and rebound after treatment with topical steroids, I can't see it.

The metronidazole compound is a substance having a low toxicity, but has a strong bactericidal action, and is a substance which is not toxicologically dermatological. That is, it is thought that the nitro group of metronidazole acts on the drug substance that causes atopic dermatitis and / or its associated skin disease, and improves human skin. Therefore, metronidazole, which has not been studied as an anti-allergic agent, including any atopic dermatitis and / or its related dermatitis, can be used as an essential component in an external preparation for treating dermatological diseases such as atopic dermatitis. The feature of the present invention lies in that it is included as one.

[Toxicity test] Metronidazole has a small number of side effects with conventional oral administration, but has hypersensitivity such as rash, tongue coating, anorexia, nausea, gastric discomfort, diarrhea, gastrointestinal symptoms such as abdominal pain, leukocyte,
Side effects such as dark red urine, rarely due to long-term administration, and peripheral neuropathy, and sometimes side effects such as local irritation such as pruritus and vaginal wall congestion when administered to the vaginal wall have been reported (references: 13th revision Japanese Pharmacopoeia commentary). The acute toxicity of metronidazole was reported to be 4,300 mg / kg in mice when administered orally (cited reference: metronidazole (Frazil (registered trademark)) vaginal tablet (Yoshio Shiono) 1
In June 1998, revised 2nd edition drug interview form), metronidazole was used in rats for subacute toxicity.
After oral administration of 5,50 mg / kg / day for 1 month, it was reported that there was no change in any of body weight curve, general condition, blood findings, liver / renal function, and histological findings as compared with the control group. (Cited document: Metronidazole (Frazil (registered trademark)) vaginal tablet (Yoshio Shiono) Second revised June 1998
Version of the medicinal product interview form) and for chronic toxicity, metronidazole was administered to rats at 75,150,300 mg /
Oral administration of kg / day for 18 weeks resulted in a weight gain of 30
Although suppression was observed in the 0 mg / kg / day group, blood findings were normal, and histological findings were all normal except that spermatogenesis was reduced in males in the 300 mg / kg / day group. (Cited document: Metronidazole (Frazil (registered trademark)) vaginal tablet (Yoshio Shiono) June 1998 revised second edition drug interview form). That is, it can be understood that metronidazole is a substance having low toxicity even in excessive oral administration. Furthermore, the present invention is extremely safe because it is an external preparation.

(B) Other Pharmaceutical Ingredients The external preparation according to the present invention comprises (A) a metronidazole compound as described above together with (B) an antifungal agent, a corticosteroid agent, an antibacterial agent or a sulfa agent, an antihistamine agent, an antiallergic agent. One or more drug components selected from agents, anti-inflammatory agents, antibiotics and local anesthetics are contained as active ingredients.

Examples of the antifungal agent include imidazole compounds including croconazole hydrochloride, neticonazole hydrochloride, clotrimazole, ketoconazole, isoconazole nitrate, econazole nitrate, oxyconazole nitrate, sulconazole nitrate, miconazole nitrate, thioconazole, bifonazole, and lanoconazole. And the like.

Examples of corticosteroids include amcinonide, oxymetholone, potassium canrenoate, prednisolone acetate valerate, diflucortron valerate, dexamethasone valerate, betamethasone valerate, hydrocortisone succinate, prednisolone succinate, chlormadinone acetate, Cortisone acetate, diflorazone acetate, hydrocortisone acetate, paramethasone acetate, fludrocortisone acetate, prednisolone acetate, metenolone acetate, difluprednate, betamethasone dipropionate, dexamethasone, triamcinolone, triamcinolone acetonide, halcinonide, hydrocortisone pivalate, flumethasone pivalate Prednisolone gel, budesonide, mometasone furoate, fluocinonide, fluocinolone aceto De, fluorometholone, fludoxycortide, prednisolone, alclomethasone propionate, clobetasol propionate, dexamethasone propionate, deprodone propionate, beclomethasone propionate, betamethasone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, hydrocortisone butyrate, propionate butyrate Corticosteroids (steroids) such as betamethasone acid, hydrocortisone sodium phosphate, betamethasone sodium phosphate or derivatives thereof.

Examples of the antibacterial agent or sulfa agent include enoxacin, methylrosaniline chloride, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, ofloxacin, sinoxacin, sparfloxacin, tosfloxacin tosylate, nalidixic acid, norfloxacin, pipemidic acid trihydrate, Pyromidic acid, fleloxacin, levofloxacin, acetylsulfamethoxazole, salazosulfapyridine, sulfadiazine, silver sulfadiazine,
Sulfadimethoxine, sulfathiazole, sulfafenazole, sulfamethoxazole, sulfamethoxypyridazine, sulfamethopyrazine, sulfamethomidine, sulfamethizole, sulfamerazine, sulfamonomethoxine, sulfisoxazole , Sulfisomidine, sodium sulfisomidine, homosulfamine or derivatives thereof.

Examples of antihistamines include cyproheptadine hydrochloride, diphenhydramine hydrochloride, triprolidine hydrochloride, hydroxyzine hydrochloride, promethazine hydrochloride, homochlorcyclidine hydrochloride, cimetidine, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teoclate, hydroxyzine pamoate, Famotidine,
Chlorpheniramine maleate, clemastine fumarate, mequitazine or derivatives thereof, and the like.

Examples of anti-allergic agents include astemizole, amlexanox, ibudilast, ebastine, azelastine hydrochloride, epinastine hydrochloride, ozagrel hydrochloride, cetirizine hydrochloride, oxatomide, sodium cromoglycate, seratrodast, tazanolast, terfenadine, suplatast tosilate, tranilast and fumaric acid. Anti-allergic compounds such as emedastine, ketotifen fumarate, pranlukast hydrate, pemirolast potassium, repirinast or derivatives thereof, and the like.

Examples of anti-inflammatory agents include Actarit,
Acemetacin, aspirin, alclofenac, aluminoprofen, ampenac sodium, ampiroxicam, ibuprofen, ibuprofen piconol, indomethacin, indomethacin farnesyl, ufenamate, etodolac, epilizol, emorfazone,
Tiaramid hydrochloride, Tinolizine hydrochloride, Buprenorphine hydrochloride, Pentazocine hydrochloride, Enfenam, Oxaprozin, Glycyrrhetinic acid, Crotamiton, Ketoprofen, Zaltoprofen, Diflunisal, Diclofenac sodium, Suprofen, Sulindac, Thiaprofen, Tenoxicam, Trimethine sodium, Nabumeton, Naproxime, Nipromexime , Phenacetin, phenylbutazone, fenoprofen calcium, felbinac, fenbufen, bucolome, bufexamac, pranoprofen, flurbiprofen,
Floctafenin, Dimethothiazine mesylate, Methiazine, Bendazac, Heparin analog, Proglumetacin maleate, Meclofenam, Mefenamic acid, Loxoprofen sodium, Robenzarit disodium,
Anti-inflammatory compounds such as vaccinia virus-inoculated rabbit inflamed skin extracts or derivatives thereof.

Examples of antibiotics include acetylkitasamycin, acetylspiramycin, amphotericin B, amoxicillin, ampicillin, kanamycin monosulfate, erythromycin ethylsuccinate, erythromycin, erythromycin espriate, aclarubicin hydrochloride, oxytetracycline hydrochloride, clindamycin hydrochloride Cefetamethopivoxil hydrochloride, cefotiamhexetil hydrochloride, cefcapen pivoxil hydrochloride, cefmenoxime hydrochloride, taranpicillin hydrochloride, tetracycline hydrochloride, demethylchlortetracycline, tetracycline hydrochloride, vancomycin hydrochloride, doxycycline hydrochloride, doxorubicin hydrochloride, bacampicin hydrochloride Clindamycin acid, vancomycin hydrochloride, pivmecillinam hydrochloride, bufo hydrochloride Omycin, minocycline hydrochloride, lincomycin hydrochloride, lenampicillin hydrochloride, carbenicillin sodium, kitasamycin, potassium clavulanate, clarithromycin, griseofulvin, cloxacin sodium, chloramphenicol, colistin sodium methanesulfonate, cycloserine, midecamycin acetate, cyclacillin , Dicloxacillin sodium, siccanin, josamycin, erythromycin stearate, sulbenicillin sodium, cefaclor, cefazolin, cephatrizine propylene glycol, cefadroxil, cefapirin, cefamandole sodium, cephalexin, cephalothin sodium, cephalorizine, cefixime, cefoxi Xitin sodium, cefotaxime sodium Cefotetan, cefoperazone sodium, cefditoren pivoxil, cefdinir, cefsulodin sodium, ceftizoxime sodium, ceftibutene, cefteram pivoxil, cefpyramid sodium, cefbuperazone sodium, cefpodoxime proxetil, cefmetazole sodium , Cefradine, cefloxazine, cefuroxime axetil, cefuroxime sodium, ticarcillin sodium, tetracycline, sultamicillin tosylate,
Tobramycin, Tricomycin, Nystatin, Variotin, Chloramphenicol palmitate, Piperacillin sodium, Pimaricin, Faropenem sodium, Josamycin propionate, Pheneticillin potassium, Phenoxymethylpenicillin potassium, Benzylpenicillin potassium, Benzylpenicillin benzathine,
Fosfomycin calcium, mitomycin C, midecamycin, tetracycline metaphosphate, latamoxef sodium, rifampicin, astromycin sulfate,
Amikacin sulfate, kanamycin sulfate, gentamicin sulfate, sisomicin sulfate, dibekacin sulfate, streptomycin sulfate, netilmycin sulfate, fradiomycin sulfate, bleomycin sulfate, bekanamycin sulfate, peplomycin sulfate, polymyxin sulfate B, micronomycin sulfate, ribostamycin sulfate, phosphorus Antibiotic compounds such as the acid clindamycin, roxithromycin, rokitamicin or derivatives thereof.

Examples of the local anesthetic include ethyl aminobenzoate, oxybuprocaine hydrochloride, dibucaine hydrochloride,
Local anesthetic compounds such as tetracaine hydrochloride, diethylaminoethyl parabutylamino hydrochloride, procaine hydrochloride, mepivacaine hydrochloride, lidocaine hydrochloride, oxesazein, lidocaine and derivatives thereof.

The external preparation of the present invention comprises, as a drug component (B), an antifungal agent, a corticosteroid agent, an antibacterial agent or a sulfa agent, an antihistamine agent, an antiallergic agent, an antiinflammatory agent, an antibiotic and a local anesthetic as described above. One kind selected from the agents may be contained, or two or more kinds may be contained.

<Composite> The external preparation of the present invention comprises a composite preparation containing the above-mentioned (A) metronidazole compound and (B) a drug component as active ingredients. The components other than (A) and (B) of this composite preparation (external preparation) will be described later. When the total weight of the composite preparation is 100% by weight, the above (A) in the preparation is used.
The content of the metronidazole-based compound is desirably 0.1 to 20% by weight, preferably 1 to 20% by weight, and more preferably 1.6 to 20% by weight. In addition, this upper limit is more preferably 10 from the viewpoint of the preparation of the external preparation.
% By weight, more preferably 5% by weight.

The compounding amount (content) of each drug component to be compounded as the drug component (B) in the preparation is determined based on the therapeutic effect of the metronidazole compound (A) and the bacteria or virus which cannot be covered by the metronidazole compound. Bactericidal action, etc.
It is an amount capable of assisting and enhancing the anti-inflammatory action and the like, and is determined based on the side effects of the drug component (B) and the findings of the pharmacological pharmacological effects.
Usually, the following amounts are preferred.

When the antifungal agent is contained, the amount is 0.0005 to 2% by weight, preferably 0.01 to 2% by weight in the preparation.
Desirably, it is 0.5% by weight. The amount of the corticosteroid when it is contained is 0.0001 to 1 in the preparation.
%, Preferably 0.001 to 0.1% by weight. When the antibacterial agent or the sulfa agent is contained, the amount is preferably 0.001 to 5% by weight, preferably 0.01 to 0.5% by weight in the preparation. The amount when the antihistamine is contained is 0.001 in the formulation.
It is desirably from 10 to 10% by weight, preferably from 0.01 to 5% by weight. When the antiallergic agent is contained, the amount is preferably 0.001 to 10% by weight, preferably 0.1% by weight in the preparation.
It is desirable that the content be from 0.01 to 5% by weight. When the anti-inflammatory agent is contained, the amount thereof is desirably 0.001 to 5% by weight, preferably 0.005 to 0.5% by weight in the preparation. The amount of antibiotics contained is 0.0
It is desirably 001 to 5% by weight, preferably 0.001 to 0.1% by weight. When the local anesthetic is contained, the amount is preferably 0.001 to 5% by weight, preferably 0.01 to 5% by weight in the preparation.

When the drug component (B) is contained in the above-mentioned amount (content) in the preparation, the intended pharmacological effect is sufficiently recognized. Moreover, the amount of the above-mentioned drug component (B) is extremely small as compared with the usual use amount of a single agent or the like. For example, the amount of corticosteroids
It is about 1/20 of the amount of the usual topical corticosteroid drug, but has the same pharmacological effect as shown in the test examples described later.

As a therapeutic agent for treating rosacea or removing odor, 0.8-1% by weight of a single metronidazole (eg, a hospital pharmacy preparation, 4th edition, Japan Hospital Pharmacists Association, 1% metronidazole (Fragil (registered trademark)) )) Ointment, 0.8
% Metronidazole gel) was tested, but did not show particularly good therapeutic effect.

It is also known that the drug component (B), ie, an antifungal agent, a corticosteroid agent, an antibacterial agent or a sulfa agent, an antihistamine, an antiallergic agent, an antiinflammatory agent, an antibiotic, or a local anesthetic is effective. This drug component (B) has almost no side effects if it is present in a smaller amount than currently available preparations or pharmacologically conceivable, but does not expect effective treatment for skin diseases. BEST MODE FOR CARRYING OUT THE INVENTION The present invention is most suitable for the treatment of various skin diseases without side effects by combining a metronidazole compound (A) as a main drug and the above-mentioned drug component (B) in a trace amount that is considered not to be effective. External preparations have been obtained.

As described above, by combining the metronidazole compound (A) with the drug component (B), even if the drug component (B) is extremely small in comparison with the usual use amount, it has excellent medicinal effects and has side effects. Is not found by the present inventors for the first time. In addition, even if (B) a drug component alone could not be expected to have much therapeutic effect, (A) a therapeutic agent can be obtained or a rapid effect can be obtained by forming a complex with a metronidazole compound. There is also an effect.

The effective skin diseases and the like of the composite agent (external preparation) of the present invention will be described later. The above-mentioned drug component (B) is appropriately selected and combined depending on the purpose and the degree of the symptoms. For example, for the treatment of severe or intractable skin diseases such as atopic dermatitis, it is preferable to add an antifungal agent and a trace amount of a corticosteroid,
At this time, (A) is particularly preferably metronidazole. That is, as an active ingredient, metronidazole,
A triple combination of an antifungal and a trace amount of corticosteroids is most suitable for the treatment.

To give another example, a complex containing an antibiotic as a drug component (B) is suitable for treating ulcerative skin disease. In addition, for example, the antihistamine in the drug component (B) was used as a complex with the metronidazole compound (A) to obtain a rapid anti-itch effect.

The external preparation comprising the composite agent of the present invention comprises (A)
And (B) do not combine, and show a more excellent therapeutic effect than an external preparation of metronidazole alone or an external preparation of the drug component (B). This is because skin diseases are caused by a variety of bacteria, viruses, etc., each of which has a limited anti-inflammatory effect against the bacteria, viruses, etc., and the use of a combination agent makes it possible to obtain the drug, bacteria, viruses, etc. It is considered to be a bactericidal effect on the antimicrobial or to suppress inflammation.

Therefore, a patient suffering from mild tinea pedis has a therapeutic effect by using, for example, an external preparation of metronidazole alone, but a patient having severe symptoms has a metronidazole compound of the present invention ( A) and antibacterial agent (B)
It is desirable to administer an external preparation, which is a combination with the above, because a more rapid and more effective therapeutic effect can be obtained than metronidazole alone.

In the present invention, the complex agent (external preparation) of the present invention can be used in combination with a single metronidazole as needed. For example, even in the same patient suffering from the same atopic dermatitis, an external preparation of the present invention, which is a combined preparation of metronidazole and an antibiotic, is administered to a site where purulence is caused by the affected site. On the other hand, an external preparation of metronidazole alone can be administered to a site where suppuration has not occurred.

It is desirable that the pH of the preparation of the present invention is in the range of 3 to 9, preferably 4 to 8. With such a pH, the active ingredient can be stably melted, dispersed, and compounded in the preparation. In addition, the expression of skin irritation varies among individuals and varies, but within the above pH range, patients suffering from skin diseases in general, damage to skin tissue, reduced function of skin tissue, etc. It can be used with less skin irritation.

In order to adjust the pH of the external preparation, an acid such as hydrochloric acid, citric acid and lactic acid, or an alkali such as sodium hydroxide, potassium hydroxide and triethanolamine may be blended.

The external preparation of the present invention comprises a complex preparation as described above, and the form may be any known or well-known form, and is not particularly limited. For example, ointments, creams,
Gels, pastas, semi-solids such as gels, lotions,
There are forms of external preparations that can be considered dermatologically, such as liquids such as emulsions, packs, lotions, rinses, and shampoos, patches containing water or containing no water, and solids of soaps. Further, it is not limited to any of aqueous, alcoholic, oily or neutral suspensions and liquids in a molten state, and semi-solids such as pastes and solids such as powders. In particular, for the treatment of skin disorders in patients suffering from atopic dermatitis of the head or intractable skin disorders,
External or external forms such as shampoos, gels, and rinses are extremely useful because conventional or known creams and ointments are difficult to use.

Therefore, the composite preparation can usually contain, in addition to the active ingredients (A) and (B), other optional components for forming various external preparations. As such other optional components, a medicinal component (A) and (B) a pharmaceutical preparation widely used external preparation base that can uniformly melt, mix and disperse the drug components can be used. Well, but not limited to, fats and oils such as olive oil and castor oil; waxes such as beeswax, lanolin and jojoba oil; hydrocarbons such as liquid paraffin, vaseline, ceresin, microcrystalline, wax, squalane; laurin Higher fatty acids such as acid, myristic acid, stearic acid and oleic acid; esters such as cetyl lactate, isopropyl myristate and octyl dodecyl myristate; higher alcohols such as cetyl alcohol, stearyl alcohol and lauryl alcohol; glycerin monostearate and mono Glycerin oleate, professional Nonionic surfactants such as lenglycol monostearate and polyoxyethylene cetyl alcohol ether; anionic surfactants such as sodium cetyl sulfate, sodium stearate and sodium N-acylglutamate; lower grades such as ethanol and isopropanol Alcohols; bases and the like that can be used conventionally or known dermatologically, such as purified water, distilled water, and water. Further, a small amount of a fragrance, a coloring agent, or the like may be added according to the purpose.

In the preparation of the external preparation of the present invention, it can be produced according to a conventional method known in pharmacy. In the preparation of the external preparation, the active ingredients (A) and (B) are preferably blended in such an amount as to give a preferable content in the above-mentioned preparation, and other optional components (base for external use)
Can be blended in an appropriate amount according to the external use form.

In the preparation of ointments, creams, lotions and the like as the external preparation of the present invention, for example, 1.6 to 5% by weight of the metronidazole compound (A) based on the total weight of the preparation And, based on the side effects and findings of pharmacological pharmacological effects, and also depending on the drug, 0.01 to 0.5% by weight of the antifungal agent in the amount based on the total weight of the formulation when included in the formulation, 0.001
0.1% by weight of corticosteroids, 0.01-0.5
% By weight of antibacterial agent or sulfa agent, 0.01 to 5% by weight
Antihistamine, 0.01 to 5% by weight of antiallergic agent, 0.005 to 0.5% by weight of antiinflammatory agent, 0.001
-0.1% by weight of antibiotic, and 0.01-5% by weight
One or more drug components selected from local anesthetics (B)
And 0 to 90% by weight of a hydrocarbon as a base, 0 to 90% by weight.
Wt% humectant, 0-90 wt% surfactant, 0-5
0 wt% thickener, 0-80 wt% distilled water, water such as purified water, 0-2 wt% preservative, 0-5 wt% buffer or pH adjuster, 0.5-20 Wt% higher fatty acids, 0
-50% by weight of lower alcohols and 0-30% by weight of higher alcohols can be blended, and further, trace amounts of fragrances, coloring agents and the like can be blended according to the purpose.

The proportions of these antifungal agents, corticosteroids, antibacterial agents or sulfa agents, antihistamines, antiallergic agents, antiinflammatory agents, antibiotics, and local anesthetics depend on the type of the drug, the type of treatment, and the purpose of treatment. It can be changed, and the ratio of the base is not limited to this, because it can be changed by an external preparation according to the purpose.

The external preparation of the present invention is not limited to pharmaceuticals.
Also includes quasi-drugs, cosmetics, etc. Further, the external preparation of the present invention is a metronidazole compound in the above-mentioned preparation,
Antifungals, corticosteroids, antibacterial or sulfa drugs, antihistamines, antiallergic drugs, antiinflammatory drugs, antibiotics, and other medicinal ingredients as needed, as long as they do not impair the effects of these drugs. May be included. Examples of these medicinal ingredients include known refreshing ingredients, vitamins, exfoliants, cortical depressants, antiseborrheics, anti-inflammatory agents, bactericides, antipruritics, and other drugs that can be used for skin diseases. Specific examples thereof include menthol, vitamins A and B, C, D, and E, salicylic acid, estradiol, glycyrrhizic acid, benzalkonium chloride, phenol, camphor and the like. Also, antiviral agents such as acyclovir, idoxuridine, ganciclovir, sanilvudine, zalcitabine, didanosine,
Zidovudine, vidarabine, nevirapine, foscarnet sodium hydrate, saquinavir mesylate, nelfinavir mesylate, lamivudine, ritonavir, indinavir sulfate and the like; narcotics and stimulants such as ethyl morphine hydrochloride, oxycodone hydrochloride, cocaine hydrochloride, pethidine hydrochloride,
Methamphetamine hydrochloride, dl-methylephedrine hydrochloride, morphine hydrochloride, fentanyl citrate, levallorphan tartrate and the like; antimetabolites such as actinomycin D, L-asparaginase, acegraton, ubenimex, uracil, etoposide, enocitabine, aclarubicin hydrochloride, idarubicin hydrochloride, Irinotecan hydrochloride, epirubicin hydrochloride, dounorubicin hydrochloride, doxorubicin hydrochloride, pirarubicin hydrochloride, fadrozole hydrochloride hydrate, bleomycin hydrochloride, procarbazine hydrochloride, mitoxantrone hydrochloride, carboplatin, carmofur, tamoxifen citrate, toremifene citrate, cyclophosphamide, cisplatin , Schizophyllan, cytarabine, cytarabine ocphosphate, dinostatin stimaramer,
Vinorelbine tartrate, sobuzoxane, thiotepa, tegafur, doxyfluridine, docetaxel hydrate, tretinoin, neocarzinostatin, nedaplatin, paclitaxel, bicalutamide, hydroxycarbamide, phosphestrol, busulfan, fluorouracil, flutamide, propylthiouracil, pentophytin, pentostatin Mer sodium, methyltestosterone, mepithiostane, G-mercaptopurine liposide, mercaptopurine, methotrexate, melphalan, streptococcal extract, pepromycin sulfate, vincristine sulfate, vinblastine sulfate, lentinan, and the like are also included.

In preparing the external preparation of the present invention, if necessary, antioxidants such as ascorbic acid, tocopherol, citric acid, dibutylhydroxytoluene and the like; preservatives such as dehydroacetic acid, salicylic acid, Methyl benzoate, propyl paraoxybenzoate,
Thymol and the like; humectants, for example, glycerin, lanolin, propylene glycol, 1,3-butylene glycol, urea, sodium hyaluronate; thickeners, for example, polyethylene glycol, xanthan gum, sodium carboxymethylcellulose, carboxypropylcellulose and the like Buffering agents and pH adjusters, for example, acids such as citric acid, lactic acid, hydrochloric acid, boric acid, sodium dihydrogen phosphate, sodium citrate, sodium hydroxide;
Alkalis such as potassium hydroxide and triethanolamine; lipid absorbents and the like; kaolin, bentonite and the like,
Known formulation components used in conventional external preparations can also be added.

The external preparation of the present invention as described above is extremely useful for treating atopic dermatitis and / or its related skin diseases, and for various skin diseases, for example, twice to three times a day. By applying it to the skin, the disease can be treated very well.

Such an external preparation of the present invention can be used for the treatment of atopic dermatitis and / or a skin disease related thereto.

[0063]

Next, the present invention will be described in detail with reference to examples and test examples, but the present invention is not limited to these examples and test examples.

Example 1 External Cream Formulation: (a) Active ingredient metronidazole 2 g clotrimazole 0.1 g clobetasol propionate 0.005 g (b) oil phase glycol monostearate 10 g setanol 7 g liquid paraffin 9 g white petrolatum 3. 5 g (C) Aqueous phase Propylene glycol 6.5 g Sodium lauryl sulfate 1 g Purified water Amount that totals 100 g Production method: (b) Oil phase, (c) Aqueous phase at about 85 ° C.
(C) The aqueous phase is added to (b) the oil phase, and the active ingredient is added with stirring (a). Thereafter, the mixture is cooled to a temperature of about 25 ° C. with continuous stirring. Collect the resulting cream in a suitable container.

Example 2: Cream for external use (a) Active ingredient metronidazole 2 g lidocaine 0.05 g prednisolone valerate 0.005 g (b) oil phase glycol monostearate 10 g setanol 7 g liquid paraffin 9 g white petrolatum 3.5 g (C ) Aqueous phase Propylene glycol 6.5 g Sodium lauryl sulfate 1 g Purified water Amount that totals 100 g Production method: (b) oil phase and (c) aqueous phase each at about 85 ° C
(C) The aqueous phase is added to (b) the oil phase, and the active ingredient is added with stirring (a). Thereafter, the mixture is cooled to a temperature of about 25 ° C. with continuous stirring. Collect the resulting cream in a suitable container.

Example 3 External Cream Formulation: (a) Active ingredient metronidazole 2 g chloramphenicol 0.001 g hydrocortisone acetate 0.001 g (b) oil phase glycol monostearate 10 g setanol 7 g liquid paraffin 9 g white petrolatum 3. 5 g (C) Aqueous phase Propylene glycol 6.5 g Sodium lauryl sulfate 1 g Purified water Amount that totals 100 g Production method: (b) Oil phase, (c) Aqueous phase at about 85 ° C.
(C) The aqueous phase is added to (b) the oil phase, and the active ingredient is added with stirring (a). Thereafter, the mixture is cooled to a temperature of about 25 ° C. with continuous stirring. Collect the resulting cream in a suitable container.

Example 4: Cream Base Formulation: (a) Active ingredient metronidazole 2.5 g ketoconazole 0.1 g (b) oil phase 5 g stearate 5 g stearyl alcohol 5 g liquid paraffin 5 g isopropyl myristate 1 g span 60 1 g thymol 0.2 g (C) Aqueous phase Tween 60 0.5 g Propylene glycol 5 g Triethanolamine 0.4 g Distilled water Amount to make the total amount 100 g Production method: (b) Oil phase, (c) Aqueous phase at about 85 ° C.
(C) The aqueous phase is added to (b) the oil phase, and the active ingredient is added with stirring (a). Thereafter, the mixture is cooled to a temperature of about 25 ° C. with continuous stirring. Collect the resulting cream in a suitable container.

Example 5: Cream for external use Formulation: (a) Active ingredient metronidazole 3 g pipemidic acid trihydrate 0.1 g prednisolone 0.001 g (b) Oil phase glycol monostearate 5 g polyoxyethylene (23) cetyl ether 2 g Cetanol 6 g White petrolatum 5 g Liquid paraffin 5 g Tri (caprylic caproic acid) glyceryl 5 g Octyldodecyl myristate 3 g Propyl parahydroxybenzoate 0.1 g (C) Aqueous phase Propylene glycol 7 g Methyl paraoxybenzoate 0.1 g Distilled water A total of 100 g Production method: (b) oil phase and (c) aqueous phase each at about 85 ° C
(C) The aqueous phase is added to (b) the oil phase, and the active ingredient is added with stirring (a). Thereafter, the mixture is cooled to a temperature of about 25 ° C. with continuous stirring. Collect the resulting cream in a suitable container.

Example 6: Ointment for external use Formulation: (a) Active ingredient metronidazole 2 g crotamiton 1 g fluocinolone acetonide 0.001 g (b) Oil phase White petrolatum 45 g Cetanol 20 g Polyoxyethylene hydrogenated castor oil 5 g Tween 80 2 g Fluid Paraffin 5 g Propyl parahydroxybenzoate 0.1 g (C) Aqueous phase Methyl paraoxybenzoate 0.1 g Distilled water Amount to make the total amount 100 g Production method: (b) oil phase and (c) aqueous phase at about 85 ° C.
(C) The aqueous phase is added to (b) the oil phase, and the active ingredient is added with stirring (a). Thereafter, the mixture is cooled to a temperature of about 25 ° C. with continuous stirring. Collect the resulting ointment in a suitable container.

Example 7: Ointment for external use Formulation: (a) metronidazole 2 g diphenhydramine hydrochloride 0.2 g lidocaine 0.1 g (b) oil phase stearyl alcohol 7 g cetanol 3 g white petrolatum 30 g glycol monostearate 10 g span 80 5 g Liquid paraffin 5 g (C) Aqueous phase Propylene glycol 5 g Tween 80 1 g Distilled water Amount that totals 100 g Production method: (b) oil phase, (c) aqueous phase at about 85 ° C.
(B) Add the oil phase to the (C) water phase and add the active ingredient (a) with stirring. Thereafter, the mixture is cooled to a temperature of about 25 ° C. with continuous stirring. Collect the resulting ointment in a suitable container.

Example 8: Ointment for external use Formulation: (a) Active ingredient metronidazole 2 g Gentamicin sulfate 0.005 g (b) Oil phase Glycostearate 15 g Monooxystearate polyoxyethylene glycol 3 g Polyoxyethylene setostearyl ether 2 g Cetanol 5 g Beeswax 5 g White petrolatum 20 g (C) Aqueous phase Distilled water Amount that totals 100 g Production method: (b) Oil phase, (c) Aqueous phase at about 85 ° C.
(B) Add the oil phase to the (C) water phase and add the active ingredient (a) with stirring. Thereafter, the mixture is cooled to a temperature of about 25 ° C. with continuous stirring. Collect the resulting ointment in a suitable container.

Example 9: Lotion Formulation: (a) Active ingredient metronidazole 2 g betamethasone valerate 0.005 g bifonazole 0.05 g (b) oil phase stearic acid 2 g cetanol 1.5 g petrolatum 4 g squalane 5 g tri (caprylic acid / caprin acid) Acid) glycerin 2 g Sorbitan monooleate 2 g Polyethylene glycol 5 g (C) Aqueous phase Dipropylene glycol 5 g Triethanolamine 0.7 g Purified water 60 g (d) Aqueous phase isopropanol 10 g Purified water Amount to be 100 g in total Production method: (b) ) The oil phase and (c) the aqueous phase are each at about 70 ° C.
(B) Add the oil phase to the (C) water phase and add the active ingredient (a) with stirring. Then, after cooling to a temperature of about 40 ° C. with continuous stirring, (d) adding an aqueous phase and cooling to a temperature of about 25 ° C. with stirring. The resulting lotion is collected in a suitable airtight container.

Example 10: Patch Formulation: (a) Active ingredient metronidazole 3 g crotamiton 1 g prednisolone 0.05 g (b) base D-sorbitol (70%) 30 g purified water 9 g kaolin 13 g titanium oxide 1 g (C) base Gelatin 1g Purified water 4g (d) Base Sodium metaphosphate 0.1g Purified water 1g (e) Base Sodium polyacrylate 5g Starch acrylate 300 1g Propylene glycol 5g Castor oil 1g Magnesium alumina hydroxide 0.25g Monooleic acid Sorbitan 0.5 g polyoxyethylene sorbitan monooleate 0.5 g (f) base D-sorbitol (70%) 14 g dibutylhydroxytoluene 0.2 g (g) base methacrylic acid / n-butyl acrylate copolymer 3 g ( h) Base D-sorbitol (70%) 4.9 g Tartaric acid 1.5 g Production method: (b) The base was adjusted to a temperature of about 40 ° C., and (d) the base was adjusted to a temperature of about 60 ° C. while stirring. Then, while adding (c) the base and stirring, the (g) base is added. To this, a well-mixed mixture of (a) the active ingredient and (e) the base is added, (f) the base is added, and (h) the base is added little by little with stirring. 14 g of the resulting plaster was weighed and uniformly applied to a 10 cm × 14 cm nonwoven fabric to obtain a patch.

Example 11 Patch (Plaster) Formulation: (a) Active ingredient metronidazole 3 g Indomethacin 1 g (b) Base liquid paraffin 7 g Isopropyl myristate 3 g Polybutene 15 g 1,3 pentadiene copolymer resin 26 g (C) base Agent Polyoxyethylene sorbitan monostearate 1.5 g Zinc oxide 3 g Titanium oxide 2 g Dibutylhydroxytoluene 0.2 g Crotamiton 1 g (d) Kaolin 6 g (e) Natural rubber latex (as solid) 15 g Synthetic rubber SBR (as solid) 17 g (f) Glycerin 0.25 g Purified water 1 g Sodium polyacrylate 0.05 g Production method: (b) Adjust the base mixed and melted at a temperature of about 110 ° C. to a temperature of about 90 ° C .; Add the active ingredient, temperature of about 70 ℃ , And a mixture of the base (c) and the base (d) is added thereto. While stirring, the base is added, and the base is added at a temperature of about 70 ° C. The resulting plaster is spread on a non-woven fabric or a woven fabric at a rate of 100 g / m ² and cut into a size of 10 cm × 14 cm.

Example 12: Gel Formulation: (a) Active ingredient metronidazole 3 g Diphenhydramine hydrochloride 0.5 g betamethasone 0.01 g (b) Oil phase Polyoxyethylene oleyl alcohol ether 1 g (c) Water phase Polyethylene glycol 1500 6 g Polyoxy Ethylene glycol 400 2 g Disodium EDTA 0.2 g (d) Aqueous phase Dipropylene glycol 8 g (e) Aqueous phase potassium hydroxide 0.1 g (f) Aqueous phase Carboxyvinyl polymer 0.5 g Methyl cellulose 0.2 g Purified water 100 g in total Production method: (f) After the aqueous phase is uniformly dissolved, (c) the aqueous phase is added, (a) the active ingredient is added, heated, dissolved and dispersed. Then, (d) an aqueous phase and (b) an oil phase are added to form about 6
Heated and melted to a temperature of 0 ° C. is added. While stirring, the aqueous phase is neutralized by adding (e) and cooled to a temperature of about 25 ° C. The resulting gel is collected in a suitable container.

Test Example 1: Clinical Test Example An external preparation of the present invention was applied to an actual patient with atopic dermatitis, and its therapeutic effect was examined. As an external preparation of the present invention,
The cream for external use prepared in Example 1 was used. An external cream (metronidazole single agent) prepared in the same manner as in Example 1 except that only metronidazole was used as an active ingredient was used as a reference test example. The target patients are as follows. Reference test patient A: A female subject of age 40 who suffers from atopic dermatitis Test subject B: Female test subject of age 38 who suffers from atopic dermatitis C: Patient who suffers from atopic dermatitis 55 year old woman

Test method: As a reference test example, topical metronidazole topical cream was applied twice a day to the face of atopic skin inflammation to subject patient A for 4 consecutive weeks, and the state of the inflammation was observed. Was observed. As a test example of the present invention, for the subjects B and C, the cream for external use produced in Example 1 was continuously applied to the face of atopic dermatitis twice a day for 3 to 4 times a day.
It was applied over a week and its inflammatory status was observed.

Skin irritations such as rash and eczema at the start of treatment,
The subsequent healing status over time was scored at 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks to evaluate the therapeutic effect. After 4 weeks, the presence or absence of pruritus on the skin surface and the skin condition were evaluated. Table 1 shows the results.

The evaluation scores in Table 1 are as follows. <Skin condition> 5: Skin irritations such as rash and eczema are severe, and even pain is suffering. 4: Skin irritations such as rash and eczema are severe, but there is no evaluation of about 5. 3: Skin irritations such as rash and eczema can be confirmed.
Not so much. 2: Skin irritations such as rash and eczema can be slightly confirmed, but are not so different from normal skin. 1: Normal skin condition without skin irritations such as rash and eczema. <Skin pruritus> 3: Severe pruritus, unconsciously scratching skin. 2: A state in which there is a slight pruritic feeling, but the skin can be kept from scratching. 1: No pruritus is felt.

[0080]

[Table 1]

As described above, four weeks later, patients A, B, and C
The skin condition was the same as that of a healthy person, but patients B and C who applied the topical cream of Example 1 which is the combined preparation of the present invention, from patients A which applied the topical metronidazole alone. However, the pruritus disappeared as soon as possible, and the improvement of the skin was also quick. In addition, in the patient C, since the symptom of atopic dermatitis could not be confirmed at the third week, the application was terminated at the second week at the request of the patient. In addition, as a result of clinical tests, pigmentation such as liver spots, sparrow eggs, etc., and scars observed in the skin condition of patients who had used adrenal hormones such as steroids, the topical agent according to the present invention was used. By this, it was confirmed that patients B and C decreased or disappeared more than patient A. In addition, there was no pharmaceutical irritation at the time of application. In addition, even after the administration was stopped, no rebound or the like as seen in the topical steroid preparation was observed.

Test Example 2: Clinical Test Example An external preparation of the present invention was applied to an actual patient with atopic dermatitis, and its therapeutic effect was examined. As an external preparation of the present invention,
The cream for external use prepared in Example 3 was used. An external cream (metronidazole single agent) prepared in the same manner as in Example 3 except that only metronidazole was used as the active ingredient was used in the reference test example.

Test Method: As a reference test example, a topical cream (metronidazole monotherapy) was applied twice a day to the left arm of the subject patient A of Test Example 1 suffering from atopic dermatitis for 4 consecutive weeks. Then, the state of the inflammation was observed. As a test example of the present invention, the topical cream prepared in Example 3 twice a day was applied to the right arm of a subject patient A suffering from atopic skin inflammation twice a day.
It was applied for 4 consecutive weeks, and the state of inflammation was observed.

Skin irritations such as rash and eczema at the start of treatment,
The subsequent healing status over time was scored at 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks to evaluate the therapeutic effect. After 4 weeks, the presence or absence of pruritus on the skin surface and the skin condition were evaluated. Table 2 shows the results. The evaluation scores in Table 2 are the same as in Table 1.

[0085]

[Table 2]

As described above, in the same patient A, the skin condition of the left and right arms improved after 4 weeks in the same symptom of the same patient A, but the combination preparation of the present invention was obtained from the left arm to which the external preparation of metronidazole alone was applied. The right arm to which the topical cream of Example 3 was applied had no pruritus earlier and improved the skin earlier. In addition, as a result of clinical trials, pigmentation such as liver spots, sparrow eggs, etc. observed in the skin condition of patients who had used corticosteroids such as steroids, scars, etc., showed that the external preparation according to the present invention was used. As a result, it was confirmed that the skin condition became closer to that of a healthy person. Thereafter, when the topical cream used for the right arm was applied to the left arm, the skin condition improved to the same as the right arm. In addition, there was no pharmaceutical irritation at the time of application. In addition, even after the administration was stopped, no rebound or the like as seen in the topical steroid preparation was observed.

Test Example 3: Clinical Test Example The topical preparations prepared in the examples were applied to patients suffering from actual eczema / rash, seborrheic dermatitis and the like, and the therapeutic effects thereof were examined. The following patients were applied as target patients. Target patient D: A woman of age 60 who suffers from makeup rash Target patient E: A man of age 34 who suffers from seborrheic dermatitis Target patient F: A 33 year old who suffers from axillary odor Male Target patient G: 45-year-old male suffering from insect bites Target patient H: Male 57-year-old suffering from ringworm Target patient 1: 30-year-old suffering acne Female Target patient J: Age 2 with suppurative dermatitis on the head
8 year old man

Subject K: Herpes dermatitis on the neck (water blister)
A 25-year-old man who suffers from sickness Subject Patient L: A 24-year-old man who suffers from suppuration due to eczema due to a rash on the upper arm Subject Patient M: Age 45 who suffers from candidiasis between fingers
Aged woman Subject Patient N: Age 63 with dry eczema on back
Old man Subject Patient O: Age 6 with swelling and eczema on shoulder
3-year-old man Target patient P: Age 3 who suffers from early herpes on the forehead
3 year old male Subject Q: Age 23 with dry eczema on lower limbs
Old woman

Test Method: For the subject patients D, E and F, the topical cream prepared in Example 3 was applied twice a day for 4 consecutive weeks, and the effect was observed. The topical ointment prepared in Example 6 was applied to the subject patient G twice a day until the symptoms improved, and the effect was observed. For the target patient H, the topical cream prepared in Example 4 was applied twice a day for 4 consecutive weeks, and the effect was observed. For the subject patient I, the topical cream prepared in Example 2 was applied twice a day until the symptoms improved, and the effect was observed. For the subject patient J, the gel prepared in Example 12 was used 2 times a day.
It was applied until the symptoms improved up to three times, and the effect was observed.

For the subject patient K, the topical cream prepared in Example 5 was applied 2-3 times a day until the symptoms improved,
The effect was observed. The topical ointment prepared in Example 8 was applied to the subject patient L twice a day until the symptoms improved, and the effect was observed. To the subject patient M, the lotion prepared in Example 9 was applied 2-3 times a day until the symptoms improved, and the effect was observed. For the subject patient N, the patch prepared in Example 10 was continuously used once or twice a day 3
It was applied for a week and its effect was observed. Target patient O
To the plaster prepared in Example 11 1 day
２2 consecutive applications over 3 weeks and the effect was observed. The cream prepared in Example 1 was applied to the target patient P 2 to 4 times a day until the symptoms improved, and the effect was observed. For the target patient Q, the topical ointment prepared in Example 7 was applied 2-3 times a day until the symptoms improved,
The effect was observed.

Skin irritations such as rash and eczema at the start of treatment,
The subsequent healing status over time was scored at 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks to evaluate the therapeutic effect. After 4 weeks, the presence or absence of pruritus on the skin surface and the skin condition were evaluated. The results are shown in Table 3.

The evaluation scores in Table 3 are as follows. <Skin condition> 5: Skin irritation is so severe that it is incomparable to healthy human skin. 4: Skin irritation is not as good as rating 5. 3: Skin inflammation can be confirmed, but not as high as evaluation 4. 2: Skin irritation can be slightly confirmed, but not so much as normal skin. 1: Normal skin condition that is almost the same as that of a healthy person. <Irritative state> 3: A state of intense itching and unconsciously scratching the skin. 2: A state in which there is a slight pruritus, but the skin can be kept from scratching. 1: No pruritus is felt. <State of smell or pain> 3: Smells unpleasant. There is pain to gin. 2: Smell to some extent. Pain that you will not notice unless you touch it. 1: No smell at all. No pain at all.

[0093]

[Table 3]

As described above, the topical cream of the present invention is effective in treating various dermatitis in 3 to 7 days after the start of application, and improves the skin irritability, and after 3 to 4 weeks, it improves the normal skin. It has not changed. Patient D had been using the steroid for a long period of about 6 months, and his skin had become keloid-like due to its side effects, but his dermatitis had subsided. For patient H, the disease in ringworm was about 40
The skin has not improved completely after 4 weeks due to the long period of time, but the skin condition has improved several times. In addition, there was no pharmaceutical irritation at the time of application. Further, even after the administration was stopped, no rebound such as side effects as observed in the topical steroid preparation was observed.

Although not shown here, when the topical cream of Example 1 of the present invention is used, light insects such as mosquitoes, light rashes, and inflammation such as weeding are reduced by about 3%.
Itching and swelling disappeared in about 0 to 60 minutes, and in the early case of acne and the like, its presence disappeared the next day. It is also known that light injuries such as abrasions can be completely cured in a shorter time than using other disinfectants, for example, commercially available mercurochrome.

[0096]

As described above, a metronidazole compound, an antifungal agent, a corticosteroid agent, an antibacterial agent or a sulfa agent, an antihistamine agent, an antiallergic agent, an antiinflammatory agent,
The external preparation of the present invention comprising a complex containing, as an active ingredient, one or more drug components of an antibiotic and a local anesthetic showed excellent therapeutic effects without side effects.

External preparations currently on the market containing antifungal agents, corticosteroids, antibiotics and the like have some therapeutic effects, but may exhibit side effects. The metronidazole-based conjugate of the present invention has not only a remarkable therapeutic effect, but also side effects, due to the interaction of these conjugates in a trace amount of other drugs in a smaller amount than those on the market. could not. Therefore, a metronidazole external preparation is an extremely useful external preparation for the treatment of skin diseases in place of a steroid external preparation, but a complex agent based on a metronidazole compound of the present invention is a more useful external preparation and its medical The dermatological contributions are enormous and currently seem to be of most value in treating dermatological disorders.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-6-227989 (JP, A) JP-A-10-7584 (JP, A) JP-A-6-234616 (JP, A) 505617 (JP, A) Transplantation, Vol. 31, No. 5, p. 326-329 (1981) Allergy Clin. Im munol. , P. 637-644 (October 1999) Clinical Pharmacy, Vol. 9, p. 94-101 (1990) Crit. Care. Med. , Vol. 12, No. 6, p. 483-455 (1984) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/00-31/4164 A61P 17/00-17/04 CA (STN) REGISTRY (STN)

Claims (13)

(57) [Claims] (A) Formula (I): (Wherein, R ¹ and R ² are each independently a linear or branched alkyl group or alkyl alcohol group, and include a hydroxyl group, a benzyl group, a phenyl group, a cycloalkyl group, an ether group, and / or A nitroimidazole derivative or a pharmacologically acceptable salt thereof represented by the formula: (B) an antifungal agent, a corticosteroid agent, an antibacterial agent or a sulfa agent, an antihistamine agent, an antiallergy An external preparation for treating atopic dermatitis, comprising a composite preparation containing, as an active ingredient, at least one drug component selected from a drug, an anti-inflammatory agent, an antibiotic, and a local anesthetic. 2. The compound represented by formula (I) is 2- (2
The external preparation according to claim 1, which is -methyl-5-nitroimidazol-1-yl) ethanol. 3. The external preparation according to claim 1, wherein the drug component (B) is an antifungal agent and a corticosteroid agent. 4. The preparation according to claim 1, wherein the content of the nitroimidazole derivative or the pharmaceutically acceptable salt (A) thereof is 0.1 to 0.1% in the preparation.
The external preparation according to any one of claims 1 to 3, which is 20% by weight. 5. The method according to claim 5, wherein the content of the antifungal agent is 0.0005 in the preparation.
The external preparation according to any one of claims 1 to 4, wherein the amount is from 2 to 2% by weight. 6. The external preparation according to claim 1, wherein the content of the corticosteroid is 0.0001 to 1% by weight in the preparation. 7. The external preparation according to any one of claims 1 to 6, wherein the content of the antibacterial agent or the sulfa agent is 0.001 to 5% by weight in the preparation. 8. The preparation according to claim 8, wherein the content of the antihistamine is 0.0% in the preparation.
The external preparation according to any one of claims 1 to 7, wherein the amount is from 01 to 10% by weight. 9. The composition according to claim 9, wherein the content of the antiallergic agent is 0.0
The external preparation according to any one of claims 1 to 8, wherein the amount is from 01 to 10% by weight. 10. The anti-inflammatory agent content in the preparation is 0.001.
The external preparation according to any one of claims 1 to 9, wherein the amount is from 5 to 5% by weight. 11. The antibiotic content is 0.000 in the preparation.
The external preparation according to any one of claims 1 to 10, which is 1 to 5% by weight. 12. The method according to claim 12, wherein the content of the local anesthetic is 0.00
The external preparation according to any one of claims 1 to 11, which is 1 to 5% by weight. 13. The external preparation according to any one of claims 1 to 12, wherein the pH of the preparation is in the range of 3.0 to 9.0.