HU227194B1 - Pharmaceutical combinations for topical application - Google Patents

Abstract

A medicinal preparation contains a combination of several components to combat groups of pathogenic microorganisms already present jointly or likely to threaten health by concerted simultaneous action. Medicinal preparations of this kind have both human and veterinary action, in treating epidermal lesions, deficiencies, wounds and to prevent or avert infections of body-cavities. A preparation contains active ingredients that have poor water solubility at 20-100[deg]C (50 mg/l at room temp.), contain at least one fungicide, preferably of azolic or polyenic type; at least one antibacterial, preferably erythromycin-, azalide-, linkozamide-, polypeptide-type and at least a bacteriostatic sulphonamide. The components are present dispersed in pharmaceutically approved carriers when applied topically.

Description

The scope of the description is 22 pages (including 1 page figure)

HU 227 194 Β1

The present invention preferably relates to a pharmaceutical combination comprising a single composition against microbes pathogenic to humans and animals in co-occurring or threatening co-existence; a composition for human and veterinary topical use for the prevention and treatment of epithelial lesions, epidermis, epidermis, or bodily injuries, and which combines the active ingredient with an antifungal agent, an antibiotic agent and a sulfonamide. In a preferred and typical embodiment of the invention, the combination comprises as active ingredient a fungicide, an antibiotic and a bactericidal sulfonamide.

FIELD OF THE INVENTION The present invention relates to a combination of active ingredients having at least one active ingredient against several members of the fungal, bacterial and other microbial strains of the following groups:

Candida, Aspergillus, Fusarium and Chlamydia genus, as well as other aerobic bacteria: Gram-negative bacillus, Proteus, Pseudomonas, Enterobacter species, Escherichia coli, Klebsiella, Serratia marcescens, Citrobacter, Aeromonas; Gram-negative coccus such as Neisseria, Acinetobacter species; Gram-positive bacilli: as Corynebacterium species, Bacillus sphaericus, Gram-positive coccus as Streptococcus species; anaerobic bacteria: Gram-negative cococci such as Bacteroides, Fusobacterium; Gram-positive coccus such as Peptococcus, Peptostreptococcus species; Gram-positive bacilli such as Clostridium, Propionibacterium, Eubacterium species and mycobacterial species such as Mycobacterium ulcerans. The above microbes are opportunistically human and veterinary pathogens.

One of the basic ideas of the present invention is to capture the above spectrum in a single combination, preferably in a single formulation. To achieve this object of the invention, there are active ingredients in the medicament which are poorly soluble in water (<50 pg / ml at room temperature) at 20-100 ° C. Generally, three types of active ingredients are required: a fungicide, an antibiotic, and a sulfonamide; however, depending on the mechanism of action of the co-administered agents, two active ingredients may be sufficient to capture the desired microbial spectrum. Such variations are also contemplated as being part of the present invention.

The agent of the present invention is thus

(a) it contains a combination of three substances with low biological solubility (<50 pg / ml at room temperature), acceptable in human or veterinary medicine, at 20 to 100 ° C, which includes:

(i) at least one fungicide, preferably azole, and (ii) at least one antibacterial agent, preferably of the azalide, lincosamide, erythromycin derivative of polypeptide, and (iii) at least one poorly water-soluble bacteriostatic sulfonamide,

b) such that the active ingredients are dispersed in a carrier that is pharmaceutically acceptable at the site of therapeutic treatment;

c) and wherein the weight ratio of the active ingredients is i: ii: iii = 0.1-10: 0.1-10: 10-200-200, wherein the amount of carrier is about 80-99% by weight.

Preferably, the combination according to the invention is presented in a single formulation (formulation). However, it is also within the scope of the present invention to provide multiple active agents of various types, in a form ready for use in the combination of the invention. Without limiting the following, particular embodiments of the invention where the combination is contained in a single agent will be further illustrated.

Abbreviations and definitions used in this description:

MIC = minimum effective concentration. At this concentration of the active ingredient, the microbe does not grow under experimental conditions.

It is known that external ulcers (especially ulcerative ulcers) may be of different origins, but may have similar complications during treatment (VASA). 2000; 29: 62-70). Their healing is slow and difficult.

In the early treatment of external ulcers, light gauze dressings for open and exudative lesions are still used today. For ulcers covered with necrotic tissue, it has been recommended to change dressings impregnated with sterile saline 3-4 times daily. ("Advanced Medical Diagnostics and Therapy" Officina Nova 1990. 1160-1166). For burn injuries, the initial treatment is cooling the wound, replenishing the fluid, and then relieving the pain.

Burns are characterized by the fact that damaged and dead tissues remain in place and require special treatment. Traditionally, they triggered inflammation to trigger cell division (angiogenesis), which occurred after several days of waiting, while uncontrollably and significantly increased the risk of surface infection and pain. A thick, armor-like suture was formed on the surface (often 1 to 1.5 cm thick); if it was on the chest, surgical breathing had to be provided; often around the joints, immobility.

External ulcers are usually caused by circulatory disorders or mechanical influences. In many cases, multiple ulcers have damaged the collateral blood vessels, which are important for the healing of the ulcer.

Decubitus is a specific type of ulcer that results from poor blood supply and metabolism caused by prolonged pressure on the skin over the bony or cartilage base. The most frequently affected area is the skin covering the sacrum and hips, but the skin of the occipital area, the ear, the elbow, the heel and the ankle may also be decubitated. It is commonly seen in elderly, debilitated, lame and unconscious patients. The ulcer may be surface infected.

There are many methods used to treat decubitus. Initial lesions were treated topically with antibiotic-containing powders and a patch-like absorbent dressing (Gelfoamr®). Once clear, a hydrocolloid dressing such as DuoDerm® is applied. For the formation of decubitus, surgical wound cleaning, rinsing, 1% iodochloroxyquinolinum® [Vioform®] mixed with Lassar paste

In addition, a foam cushion was applied under the patient. Topical antiseptics are generally not recommended, but systemic, oral or parenteral antibiotic treatment for deep infections (Current Medical Diagnosis & Treatment, 1996 by Appleton & Flame, p. 146).

Symptoms of leg ulcer due to venous circulatory failure are irregular ulceration, often on the medial side of the leg, above the malleolus, accompanied by scarring of the lower leg, varicosity, hyperpigmentation, red, peeling areas and old ulcers. Ulceration is often preceded by red, itchy patches of stasis dermatitis.

Compression, along with cleaning the ulcer with saline solutions, has been recommended as a topical treatment; scissors were used to remove the yellow fibrinous scar, possibly with local anesthesia. Once clean, the ulcer was treated with metronidazole gel to inhibit the growth of Gram-negative bacteria and to reduce odor. The red, inflamed areas of the skin were lubricated with a medium to strong steroid ointment. The ulcer was then covered with occlusive hydroactive dressing (Duoderm® or Catinova®) or polyurethane foam (Allevyn®) followed by zinc boots which were changed weekly. Recent methods have been epidermal cell culture graft, laser, or Bioptron lamp irradiation.

Systemic antibiotics have also been recommended: oral dicloxacin11in ⁰ or ciprofloxacin (Current Medical Diagnosis & Treatment, 1996 by Appleton & Flame, p. 147).

Ointments have also been recommended for the treatment of burns and external ulcers (Hungarian Patent Nos. 184,410 and 195,618, WO98 / 44914) containing as active ingredient one or more sulfonamides, macrolide antibiotics, chloramphenicol or thiamphenicol, zinc oxide, chamomile oil, , and contained azulene. Specific examples of mixtures containing chloramphenicol, primicin sulphate, sulphonimidine, sulphamethoxazole as sulphonamide, as well as vaseline and wax, zinc oxide, chamomile oil and azulene have been reported. The product had the disadvantage of not being commercially available as a stable formulation of primicin sulfate and of very limited ability to prevent fungal infections due to the narrow fungicidal action of primicin or chloramphenicol. A further disadvantage was that the bacteriostatic agents used were not specific for ulcers, burns, etc. cases most frequently occurring in microorganisms; therefore, an excess of antibiotics had to be used even to achieve the correct bacteriostatic effect. However, the results presented by the pharmacy market for primicin-containing agents are encouraging. Part of the object of the present invention is to overcome the above drawbacks of this composition and to provide an agent which is more in line with the modern therapeutic requirements and which is closer to the therapeutic purpose. A further aim is to broaden the scope of application.

For the treatment of lumbar injuries, especially burns, ethanolic plant extract is available in spray form which allows for non-binding treatment (Irix®, Naksol®, 4,601,905 and 4,466,961). The disadvantage is that contacting open wounds with ethanol is temporarily painful; this limited the use of the substance manufactured by Human (Gödöllő).

Hungarian patent application HU 215 442 (WO 96/03135) has, by way of example, suggested suppositories for topical and prophylactic treatment of vaginal and genital infections and inflammations, namely a combination of four water-soluble active substances, namely chloramphenicol antibiotic, an antiprotozoal metronidazole together in polyethylene glycol as carrier. No in vitro or in vivo numerical biological experiments have been reported. Alternative or further recommended agents include, for example, erythromycin, oxytetracycline, and natamycin or nystatin, as well as antiviral agents and optionally borax, in any water-soluble form, without any indication of proportions and amounts. The use of this combination is questionable. In use, the water-soluble components are absorbed locally in the vaginal mucosa, requiring continuous replacement in the vagina, although high doses have been used to achieve a local effect. The active compounds are rapidly released into the serum at concentrations below the effective dose. This leads to the development of resistance of pathogenic microbes throughout the treated body. A further problem is the lack of stability: the suppository, preferably in polyethylene glycol, is rapidly degradable, meaning that it is an "ex tempore" product that must be prepared in a pharmacy for immediate use. Stable, long shelf life products are neither described nor practicable.

It is an object of the present invention to provide a topical agent for the treatment of ulcers and burns, which is effective against all microbes that endanger the wounds, is absorbed as much as necessary (i.e., does not burden the entire body), does not cause pain, leaves as little trace as possible (avoiding plastic surgery).

The most common complication of wounds is infection of the wound surface, which can lead to endotoxic shock or even sepsis. Damaged skin is no longer able to function as a barrier, thus gradually invading pathogenic microbes. Gram-negative, Gram-positive bacteria and fungi can also be found. More than a thousand pathogens have been isolated during the clinical treatment of burns, causing minor or major complications. In external ulcers, more than 170 strains of pathogens have been isolated, most of which overlap the pathogens spectrum of burn injuries, although the proportion of anaerobic bacteria is higher (1984; 1999).

Therefore, we first clarified what microbes are to be dealt with. According to our literature, the microbes listed below have so far been isolated from burns (mainly large burns affecting more than 50 percent of the body surface; publications 1998-2000). Only Candida and Mucor species were isolated from external ulcers (1988). Of these, the bacterial and fungal types that are the most common or represent a large group of opportunistically pathogenic microbes are shown below (1998, 1992; 1973; 1997).

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mushrooms: Candida tropicalis Aspergillus flavus Candida parapsilosis Aspergillus fumigatus Candida albicans Aspergillus terreus Torulopsis (Cand.) Glabrata Aspergillus niger Fusarium oxysporum Mucor spp. Trichosporon Bejelii Rhizopus spp. Penicillium spp. Other microbes: Chlamydia trachomatis bacteria: Aerobic bacteria: Anaerobic bacteria: Gram-negative bacilli Gram-negative cocci: Proteus mirabilis Bacteroides fragilis Proteus vulgaris Bacteroides onus Pseudomonas aeruginosa Bacteroides spp. Enterobacter aerogenes Fusobacterium mortiferum Enterobacter faecalis Fusobacterium mucleatum Enterobacter cloacae Escherichia coli Gram-positive cocci: Klebsiella pneumoniae Peptococcus magnus Klebsiella oxytoca Peptococcus assaccharoliticus Serratia marcescens Peptostreptococcus anaerobius Citrobacter spp. Peptostreptococcus micros Aeromonas spp. Gram-negative cocci: Gram-positive bacilli: Clostridium welchii Neisseria meningitidis Clostridium perfingens Neisseria spp. Clostridium spp. Acinetobacter anitratus Propionibacterium acnes Gram-positive bacilli: Eubacterium lentum Mycobacterium ulcerans Gram-positive cocci: Corynebacterium spp. Group D Streptococcus Bacillus sphaericus Staphylococcus aureus

Streptococcus pyogenes Streptococcus faecalis Streptococcus spp.

The present invention also relates to the treatment of body cavities, including the renal and vaginal cavities, and areas that are affected by bacterial and fungal diseases (infections) transmitted sexually in humans and other mammals. For example, in addition to what is listed above:

Neisseria gonorrhea 45

Trepponema pallidum Haemophylus ducreyi Chlamydia trachomatis.

In view of the above, we have assessed the extent to which the drugs so far recommended or used have covered the above 50 spectra to meet other requirements. We have not found an antibiotic that is effective enough on its own against Gram-positive, Gram-negative bacteria and fungi, while penetrating the wound and causing no pain. The silver sulfadiazine, 55 widely used in burns, unfortunately does not provide adequate protection against certain strains of Pseudomonas and can cause fever, leukopenia, and retard peeling. Mafenide is effective against Pseudomonas, but its application is painful and delays the healing of burns. Povidone-iodine affects both Gram-negative, Gram-positive bacteria and fungi, but it hardly penetrates the stomach, its application is painful and it dries the wound quite well. Amphotericin B is a broad-spectrum antifungal agent that is used systemically and locally in mycosis with burns. However, its potent cytotoxic effect causes significant side effects; Skin irritation is common during topical application (1991). Nystatin is a very good anti-Candida agent in burns and other infections, but has only a weak effect on Aspergillus and Mucor species (1982). It has also been suggested to use dicloxacycline and clindamycin for advanced infections of streptomycin, fradiomycin sulphate, kanamycin, chloramphenicol, tetracyclin (JP 54 140712) and advanced ulcers. All of these have a spectrum of action that does not fully cover the microflora of ulcers. Ointments containing bacitracin and neomycin have also been used, but bacitracin has no activity against Gram-negative bacteria and resistance to neomycin is common (1990). It is also known that certain azalides (azithromycin, clarithromycin and others)

It is also saline against certain streptococci and Chlamydia pneumoniae against Chlamydia trachomatis. Azithromycin and darithrornycin were administered orally for the treatment of uncomplicated skin infections caused by Streptococcal pharyngitis (Current Medical Diagnosis & Treatment, 1996 by Appleton & Flame, page 1336).

We found it crucial to have a lasting and effective defense against the fungi present. Some fungi, including some of the Candida genus, are otherwise part of a healthy human and veterinary microflora. Candida albicans can be harvested from the oral cavity, stool and vagina of most healthy individuals. Opportunusan, however, has a decisive and damaging effect on the healing and peeling of pathogens - and especially ulcers and burns.

At the same time, we aimed to ensure that the topical application of potent antibacterial agents would not pose a threat to the organism in terms of resistance, i.e., to avoid absorption of these substances.

It is another objective of the product to be well applicable in the veterinary field. In particular, the effective treatment of burns and ulcers in livestock, domestic and farmed animals is economically significant in terms of both animal health and the quality of the products (meat, skin, wool). This again requires an agent that is not absorbed during treatment and does not induce human resistance in veterinary and even slaughter animals.

One aspect of the present invention is a combination of antimicrobial agents having an efficacy spectrum as close as possible to the aforementioned pathogens, thus minimizing the risk of infection during healing while being insoluble in water; it does not reduce the effect of other antibiotics - which are injected into the body in conventional form to treat other conditions; it is homogenizable in the selected carriers and is sufficiently stable (shelf life of at least 2 years). This can conveniently be used in a known, anhydrous, oily suspension, emulsion or solution, in ointment, which promotes healing of the lesions with little or no scarring, as disclosed in U.S. Patent No. 213,469; WO98 / 44914.

The combination and composition described in the introduction to the present invention, which are the subject of the present invention, meet the above requirements.

Thus, the present invention relates, on the one hand, to a synergistic, multi-component drug. It is essential that it contains poorly water soluble components (<50 pg / ml at room temperature) as active ingredient at 20-100 ° C. Thus, the active ingredients are limited locally to the region of application, even though open wounds are still present at the beginning of the treatment.

One of the components is a fungicide of the human or veterinary pharmaceutically acceptable antifungal type, preferably azole or polyene, selected from those of the present invention which are effective for Candida, Aspergillus and / or

Human and veterinarian opportunistic pathogenic fungal strains of the Fusarium family. It is particularly preferred that the agent contains as active ingredient one or more fungicides active against several members of opportunistic pathogenic strains of the following fungi: Candida tropicalis, Candida parapsilosis, Candida albicans, Torulopsis (Cand.) Glabrata, Fusarium oxisporum, Trishosporon Bejelii, Aspergillus flavus, Aspergillus Aspergillus terreus, Aspergillus niger, Mucor spp., Rhizopus spp., Penicilium spp. and / or Chlamydia trachomatis.

Said "azoles" are structurally different but similar in their antifungal activity and have a broad spectrum to meet our expectations. They are insoluble in water and also act well on Candida and Aspergillus species (1986; 1984). Preferred are miconazole, itraconazole, econazole, ketoconazole, and / or fluconazole. We particularly recommend the use of miconazole, since the risk of cross-resistance is minimized.

The second essential component of the combination according to the invention is a water-insoluble antibacterial agent comprising one or more antibacterial agents which are preferably active against several members of the following opportunistically pathogenic bacterial strains:

aerobic bacteria: Gram-negative bacilli, Proteus, Pseudomonas, Enterobacter species, Escherichia coli, Klebsiella, Serratia marcescens, Citrobacter, Aeromonas; Gram-negative coccus such as Neisseria, Acinetobacter species; Gram-positive bacilli: as Corynebacterium species, Bacillus sphaericus, Gram-positive coccus as Streptococcus species; anaerobic bacteria: Gram-negative cococci such as Bacteroides, Fusobacterium; Gram-positive coccus such as Peptococcus, Peptostreptococcus species; Gram-positive bacilli such as Clostridium, Propionibacterium, Eubacterium species and mycobacterial species such as Mycobacterium ulcerans, Neisseria gonorrhea, Trepponema pallidum, Haemophylus ducreyi and / or other bacterial microbes such as Chlamydiae, especially Chlamydia.

We have found that macrolide, azalide, lincosamide, polypeptide type antibiotics are suitable.

Preferred macrolides are erythromycin derivatives, roxythromycin and derivatives thereof. Of the azalides, azithromycin, clarithromycin, clyncomycin and others are preferred. Azithromycin is considered particularly advantageous because it is effective against most anaerobic species (1995), does not cause cross-resistance, and is already very low dose effective and synergistic based on MlC values (see Examples 1/1 and I / 2).

Among the polypeptide antibiotics, thyrothricin, magainin, cecropin are particularly suitable. Many of the polypeptide antibiotics have not only antibacterial (Gram-positive and Gram-negative), but also antifungal activity. According to the present invention, several polypeptide antibiotics still under development will be useful in the agents of the present invention.

The above fungicides and antibiotics are generally commercially available in the form of their water-soluble salts to provide a sufficiently effective serum level. However, according to the invention, the compounds are water insoluble,

Hydrophobic forms of Β1 are used. This ensures that, at the site of treatment, the active ingredient is not absorbed from the vehicle into the systemic circulation unchanged; remains in place at a concentration that provides a lasting microbicidal effect in the treatment area.

A further active ingredient of the present invention is a bacteriostatic sulfonamide. Sulfadimidine and / or sulfamethoxazole in water insoluble forms are preferred.

It is a further fundamental discovery of the present invention that in the presence of the bacteriostatic and fungistatic agents we deem necessary, synergism between the active ingredients occurs between the members of the groups: the combinations together have an effect beyond the expected additive result.

This synergism is shown as a fungicide for miconazole, as an antibiotic for azithromycin, as sulfonamide for sulfametoxazole, as a test organism for common ointment, one of the most common pathogenic microbes in ulcers, Staphylococcus aureus (see Example I.2). Compared to the MICs (mg / ml) of ointments in which only one or two of the 3 active ingredients were present (in any combination), it was found that ointments containing the lowest MICs of the tested Staphylococcus aureus ATCC 6538 measured .

It has been found to be particularly advantageous to have a combination of active ingredients with a pronounced synergism in which the three active ingredients are present in a weight ratio of azithromycimmiconazole: sulfamethoxazole = 0.5-1.5: 0.5-1.5: 90-190, preferably about 1: 1: 140 containing by weight. For ointment, the corresponding preferred composition is, for example, azithromycin 0.02%, miconazole 0.02%, sulfamethoxazole 2.8%, zinc oxide 3-4%, petroleum jelly 20%, azulene 0.12 t%, preferably in the form of aetheroleum camomillae and / or aetheroleum millefolii.

In the agents of the present invention, the active ingredients are contained in a carrier. The role of the carrier is to ensure a uniform distribution and to ensure that the active ingredients are localized at the desired site until they are effective.

As carriers, substances which are pharmaceutically acceptable at the site of treatment can be used, that is, they do not damage open wounds or body cavities or its mucous membranes.

According to the present invention, the active compounds are in the form of a uniformly distributed suspension in the form of a suspension, emulsion or solution.

The amount of carrier in the composition is from about 80% to about 99% by weight and depends on the form and formulation of the particular agent. Preferably, the composition in the form of an ointment is 85-95% by weight of the carrier, 90% to 98% of the carrier in the case of a spray oily composition and about 95-99% by weight of the carrier in the case of a foam composition.

The agents may preferably be in the form of an ointment or spray. Preferably, the carrier may be at least one pharmaceutically acceptable, water-immiscible vegetable or mineral oil, fat, and / or wax at the site of treatment. Thus, for example, petroleum jelly, lanalkol, cetyl stearate and / or beeswax can be used. The active ingredients and excipients used are soluble in the vehicle or form a suspension, emulsion, in such a way as to ensure an even distribution, without undesirable absorption into the subcutaneous layers or into the systemic circulation. Spray formulations generally contain a siloxane-type solvent, such as hexamethyldisiloxane.

Preferably, the medicament of the present invention is in a single formulation, preferably in a formulation and formulation suitable for the selected ointment, foam or spray form. However, it is feasible to dispense and apply the agent separately in multiple packs, but it is necessary to ensure that the proportions remain as prescribed. Thus, the invention also encompasses embodiments which are prepared and / or formulated so that, for example, the agent of the invention containing the antibacterial or antifungal agent can be administered simultaneously or sequentially from a separate tube or vessel according to a precise protocol.

This solution is advantageous, for example, at an advanced stage of healing, when it is no longer necessary to continuously provide antimicrobial treatment to complete the healing process, while the constant presence of other components is required.

A preferred formulation of the agent of the invention for treating both external wounds and body cavities is the foam formulation. The agent is marketed in a liquid state in a properly fitted vial, which ensures that an appropriate amount of agent can be delivered to the surface of the region to be treated, if necessary with propellant. Once applied to the area to be treated, the agent solidifies in the form of a foam and then collapses to form an even protective layer that ensures the presence of the active ingredients around the wound. This form, as carrier, again comprises a foam-solidifying substance which, at the site of application, meets the pharmaceutical criteria and dissolves and / or suspends, emulsifies the substances present in both liquid and foamed form.

The carrier material for foam formulations is preferably polysiloxane and / or oligosiloxanes and optionally air, nitrogen, inert gas as propellant.

SUMMARY OF THE INVENTION The present invention relates to a combination, preferably in the form of a single composition, for the prevention and treatment of skin lesions, external ulcers, burns, radiation necrosis, wounds (hereinafter referred to as "wounds"),

(a) containing: as an active substance

Slightly soluble in water (<50 pg / ml at room temperature) at 20-100 ° C, acceptable in human or veterinary medicine

HU 227 194 Β1

(i) an antifungal agent, preferably of the azole or polyene type; and (ii) an antibacterial agent, preferably an erythromycin derivative, an azalide, lincosamide, a polypeptide type antibiotic, and (iii) a poorly soluble bacteriostatic sulfonamide; preferably azulene or gua-azulene, v) an exfoliating agent, preferably a water-insoluble zinc salt such as zinc oxide,

(b) the active ingredients are in a dispersed form in a pharmaceutically acceptable carrier at the site of treatment, and

c) wherein the weight ratio of the above active ingredients is i: ii: iii: iv: v = O, 1-10: 0.1-10: 10-200: 10-100: 10-250, with a carrier ratio of about 80-99 %.

These products are mainly used to treat surface burns, ulcers (leg ulcers, decubitus) and to repair epithelium. We have found it particularly advantageous (in terms of both maximum protection of cross resistance and rapid wound healing) of the following composition: azithromycin 0.01-1.51%, preferably 0.02%, miconazole 0.01-1.5%, preferably 0.02% by weight, sulfamethoxazole 1-19% by weight, preferably 2.8% by weight, zinc oxide 3-4% by weight, azulene 0.05-0.20% by weight, preferably 0.12% by weight, preferably aetheroleum camomillae and / or aetheroleum in mycelium form, and optionally the carrier is petroleum jelly, lanalkol, cetyl stearate, paraffin and / or beeswax.

The use of azulene and zinc oxide in ointment for the treatment of skin wounds has been previously recommended (WO98 / 44914). The advantageous presence of these agents is also possible with the synergistic active compound combination of the present invention, without the need for the synergistic effect of the active compounds (see Examples 1/1 and I / 2) to be denied.

A further subtype of the agent of the invention is a combination, preferably in a single composition, for treating the cavities of the human or animal body, the vagina, the rectum or their epithelial cells, the epithelium,

(a) containing: as an active substance

Slightly soluble in water (<50 pg / ml at room temperature) at 20-100 ° C, acceptable in human or veterinary medicine

i) an antifungal agent which is preferably of the azole or polyene type and ii) an antibacterial agent, preferably erythromycin, azalide, lincosamide, polypeptide type antibiotic and iii) a poorly soluble bacteriostatic sulfonamide, iv) an agent promoting local circulation of body fluids and blood, preferably azulene or guaiazulene,

v) an epithelializing agent, preferably a water-insoluble zinc salt such as zinc oxide,

(b) the active ingredients are in a dispersed form in a pharmaceutically acceptable carrier at the site of treatment, and

c) wherein the weight ratio of the above active ingredients is i: ii: iii: iv: v = 0.1 to 10: 0.1 to 10: 10 to 200: 10 to 100: 10 to 250, with a carrier ratio of about 80 to 99 %. A particularly preferred composition for this embodiment is a synergistic composition comprising: azithromycin, erythromycin derivative or clindamycin 0.01-1.5% by weight, preferably 0.02% by weight, miconazole 0.01-1.5% by weight , preferably 0.02%, sulfamethoxazole 1-19%, preferably 2.8%, zinc oxide 3-4%, azulene and gua-azulene 0.05-0.20%, preferably 0.12% , preferably in the form of aetheroleum camomillae and / or aetheroleum millefolyl, and optionally the carrier is petroleum jelly, lanalkol, cetyl stearate, paraffin wax and / or beeswax.

They may advantageously be in the form of tablets, dragees, suppositories, foams, oily suspensions, solutions or emulsions for spray application, provided that they are all in ready-to-use dosage forms and packaged formulations and may contain appropriate excipients. Preferably, the suppository suppository may contain as adjuvant adeps solidus 50 and / or triglycerides.

The agent of the present invention may optionally contain a pharmaceutically acceptable coloring agent, a perfume, or an essential oil as an additional ingredient. This may be necessary for pediatric use, although the products do not smell or look anyway. Further additives may be stabilizers or buffers, such as adipic acid, malic acid, oleic acid, succinic acid, tartaric acid, boric acid, lactic acid and the like.

The present invention also provides methods of treating co-occurring or co-occurring pathogenic microorganisms for human and veterinary use, for the prevention and treatment of lesions of the epithelial, epithelial, epidermis, or cavities, wherein the combination comprises at least one active ingredient. optionally active against several members of human and veterinary pathogenic fungal strains and bacterial strains: Candida, Aspergillus, Fusarium fungal strains, and also aerobic bacteria: Gram-negative bacilli, Proteus, Pseudomonas, Chlamydia and / or Enterobacter species, Escherichia coli, Escherichia coli, Aeromonas; Gram-negative coccus such as Neisseria, Acinetobacter species; Gram-positive bacilli: as Corynebacterium species, Bacillus sphaericus, Gram-positive coccus as Streptococcus species; anaerobic bacteria: Gram-negative cococci such as Bacteroides Fusobacterium; Gram-positive coccus such as Peptococcus, Peptostreptococcus species; Gram-positive bacilli such as Clostridium, Propionibacterium, Eubacterium species and mycobacterial species such as Mycobacterium ulcerans, other microbes of Chlamydia species, such as Chlamydia trachomatis.

Treatments using a combination of at least one active agent against multiple members of the opportunistically pathogenic microbes, Candida tropicalis, are particularly effective.

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Candida parapsilosis, Candida albicans, Torulopsis (Cand.) Glabrata, Fusarium oxisporum, Trishosporon endelii, Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, Mucor spp., Rhizopus spp. and / or Penicilium spp., or a combination comprising at least one active ingredient that is active against several members of the following opportunistically pathogenic microbes: Aerobic bacteria: Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Enterobacter aerugenes, Enterobacter faecalis, Enterobacter cloacae, Escherich Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Citrobacter spp., Aeromonas spp., Gram-negative cocci: Neisseria meningitidis, Neisseria spp., Acinetobacter anitratus, Gram-positive bacilli:, Corynebacterium spp., Bacillus spp. Group D Streptococcus, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis, Streptococcus spp., Anaerobic bacteria: Gram-negative cocci: Bacteroides fragilis, Bacteroides auxus, Bacteroides spp., Fusobacterium mortiferum, Fusobacterium mortiferum , Peptostreptococcus anaerobius, Peptos treptococcus micros, Gram-positive bacilli: Clostridium welchii, Clostridium perfingens, Clostridium spp., Propionibacterium acnes, Eubacterium lentum and other microbes of Chlamydia species, such as Chlamydia trachomatis.

For the treatment, the combination according to the invention is applied topically at the site of injury at the effective dose corresponding to the injury, preferably in a single composition which

(a) contain the following: as active substance

Slightly soluble in water (<50 pg / ml at room temperature) at 20-100 ° C, acceptable in human or veterinary medicine

(i) an antifungal agent, preferably an azole, a polyene fungicide, and (ii) an antibacterial agent, preferably an erythromycin derivative, an azalide, lincosamide, a polypeptide antibiotic, and (iii) a poorly soluble bacteriostatic sulfonamide,

b) and wherein the active ingredients are in the form of a pharmaceutically acceptable carrier at the site of treatment,

c) and wherein the weight ratio of the active ingredients is i: ii: iii = 0.1-10: 0.1-10: 10-200-200 and the carrier is present in an amount of about 80-99% by weight.

Especially effective methods have been found to employ a synergistic drug comprising at least one of the following as an antifungal agent: an azole, preferably miconazole, itraconazole, econazole, ketoconazole, fluconazole, at least one of the following: azithromycin, roxythromycin, roxythromycin, , thyrotricin, magainin, cecropine, erythromycin and contains sulfamethoxazole as the sulfonamide.

Methods of using synergistic compositions containing azithromycin: miconazole: sulfamethoxazole in a weight ratio of 0.5-1.5: 0.5-1.5: 90-190, preferably about 1: 1: 140 by weight, are highly recommended.

The present invention relates to a method of treating the above-mentioned subtypes of the invention for the prevention and restoration of live skin wounds, external ulcers (e.g., leg ulcer, decubitus, etc.), burns, radiation necrosis, topical wound infection, and such a combination is used

(a) containing: as an active substance

Slightly soluble in water (<50 pg / ml at room temperature) at 20-100 ° C, acceptable in human or veterinary medicine

(i) an antifungal agent, preferably of the azole or polyene type; and (ii) an antibacterial agent, preferably an erythromycin derivative, an azalide, lincosamide, a polypeptide type antibiotic, and (iii) a bacteriostatic sulfonamide, (iv) guaiazulén,

v) an epithelializing agent, preferably a water-insoluble zinc salt such as zinc oxide,

(b) the active ingredients are in a dispersed form in a pharmaceutically acceptable carrier at the site of treatment, and

c) wherein the weight ratio of the above active ingredients is i: ii: iii: iv: v = 0.1 to 10: 0.1 to 10: 10 to 200: 10 to 100: 10 to 250, with a carrier ratio of about 80 to 991% . Preferred is a treatment using a synergistic drug comprising: azithromycin 0.01-1.5% by weight, preferably 0.02% by weight, miconazole 0.01-1.5% by weight, preferably 0.02% by weight, sulfamethoxazole 1-19% by weight, preferably 2.8% by weight, zinc oxide by 3-4% by weight, gua-azulene and azulene 0.05-0.2% by weight preferably 0.12% by weight, and optionally as carrier materials are vaseline, lanalkol, cetyl stearate, paraffin wax and / or beeswax. Guaiazulene and azulene may also be used in the form of aetheroleum chamomillae and / or aetheroleum millefolii.

The present invention further relates to a method of treatment of the above, for treating human or animal body cavities, vagina, rectum or their epithelial cells, mucous membranes, microorganisms responsible for opportunistic pathogens in these areas, and for the treatment of sexually transmitted diseases in humans and other mammals. and / or curing by topical application of a combination or composition comprising:

(a) the active substance is poorly soluble in water (<50 pg / ml at room temperature) at 20 to 100 ° C and is acceptable in human or veterinary medicine

(i) a fungicide of the azole or polyene type, and (ii) an antibacterial agent, preferably of the erythromycin, azalide, lincosamide, polypeptide type and (iii) a poorly soluble bacteriostatic sulfonamide,

EN 227 194 Β1 arc) active substance which promotes the circulation of body fluids and blood, preferably azulene or guaiaculene,

v) furthermore, an epithelializing agent, preferably a water-insoluble zinc salt such as zinc oxide,

(b) the active ingredients are in a dispersed form in a pharmaceutically acceptable carrier at the site of treatment,

c) and wherein the weight ratio of the above active ingredients is i: ii: iii: iv: v = O, 1-10: 0.1-10: 10-200: 10-100: 10-250, wherein the carrier is present in an amount of about 80-991. %.

The carriers used for the methods of treatment include at least one pharmaceutically acceptable, water-immiscible vegetable or mineral oil, fat, and / or wax, preferably vaseline, lanalkol, cetyl stearate and / or beeswax. In each of these, the active ingredients are suspended, emulsified or dissolved in the carrier.

The topical treatment is preferably carried out with ointments, effervescent tablets, sprays or foam formulations containing common carriers. The spray and foam formulation used may further comprise a polysiloxane and / or oligosiloxane carrier and optionally a propellant for applying the composition to the surface to be treated.

For treatment, the agents should be applied in the following dosage forms: when applying ointment, spray or foam, it is necessary to apply a coating of 10-15 mg / cm ² on the surface. In the case of an ointment, especially if a gauze dressing is used, the dose may be increased to 20-90 mg / cm ² . Usually one or two treatments a day are sufficient. Exceptionally, multiple treatments may be given at the beginning of the treatment and on large, open, strongly exuding wounds.

Specifically, the treatments of the present invention may be performed as follows:

For fresh, not very sensitive wounds, the product (ointment, spray, foam, etc.) can be applied directly. For sensitive and severely painful cases, it is advisable to use a spray or foam or to apply the ointment to a gauze plate and apply it to the wound. The bandage is changed every 12 or 24 hours. The wounds from the rim to the center of the wound and from the inside to the outside are visibly peeled, healing without the formation of var.

Multiple day, even week burns, or very slow healing, "armor-like" suture wounds are treated as follows. The agent is applied to the entire surface to be treated. In this case, the spray, foam or gauze application is again applied, preferably with a 12 or 24 hour dressing change. Depending on the thickness of the penis, the agent can relieve pain in as little as 10-30 minutes, then penetrates the hard toe to soften and elasticate. Avara is detached in more pieces in later dressing replacements, but under the var, the sputum begins to heal and further heals from below.

In practice, the treatment of the cavities should be carried out in such a way that the cavity of the injured mucosa provides a uniform dose of the above-mentioned 10-15 mg / cm ² dose. This can be accomplished reliably by providing a cone of suitable size. One or two treatments a day are recommended, or a new treatment may be necessary if the product is wiped or washed.

The use of a foam material requires a dispensing head on which the flow rate can be adjusted (preferably at the factory).

One or two tablets per day may be placed in the cavity for treatment, preferably effervescent tablets. The tablet disintegrates in about 2 to 10 minutes and exerts its effect on the damaged or intact mucosa by healing or preventing the ulcer. The tablet or suppository preferably has a size of 2-4 g.

The advantages of using the composition of the invention are summarized below, but are not exhaustive:

When treating wounds and ulcers, strong local blood circulation starts immediately, with local analgesic and antiseptic effects. Var and stew are not formed. Larger burns do not require surgery to remove the var. Smooth surface, leather cover of the same quality and elasticity as the original. The drug is easy to use, does not require prior disinfection, dead tissue is detached. It is also suitable for sunburn, freeing up local contractures, speeding up surface circulation, and treating scarring.

The active ingredients ensure that the formation of tissue and epithelium is coordinated in such a way that the skin base develops when adhered to the wound base, so that there is no scar on the wound line leading to a smooth skin surface. The painless healing process also means that there will be no contractures, joints and muscles can move freely throughout the process.

In grade I burns, pain disappears in a few minutes, even on a large burned surface; II. Degrees of burns relieve pain in 15-20 minutes, depending on the extent.

The burned skin does not have to be peeled off; in the case of blisters, just drain the liquid and then apply the agent without removing the burned tissue.

The skin surface I and II. degree of burn practically heals, III. In case of degree of burn, the result is aesthetically acceptable.

The advantage of the agents according to the invention in the case of "pressure points" (decubitus) (where the tissues are necrotized and infected with the circulation and pain enhancement practically eliminated) is as stated above. At the pressure points, the wounds on the back heal, even though the patient is lying on it.

It is also effective in treating bites - of course it does not replace the necessary vaccinations (for example against rabies). Prevents infections, relieves pain, and provides rapid tissue regeneration.

In the cavities or at the edges of the cavities without infection, they can be used similarly to heal wounds.

In Cure and Prevention of Sexually Transmitted Diseases, Obstetrics and Gynecology9

In the presence of Β1, it is useful in the treatment of the following diseases: genital herpes, condyloma acuminatum (after laser treatment), episiotomy, secondary wound healing after episiotomy, vulva injuries, etc. 5

The combination may also be used for veterinary treatment. Includes regular treatment of livestock, wildlife and pet animals. Economically important animals include cattle, horses, pigs, dogs, cats, monkeys, laboratory laboratory animals, deer, wool and fur animals such as sheep, foxes and the like. The wound closes in a short time, followed by the recovery of the animal. In most cases, the animals' hair is completely regenerated.

In particular, the composition is useful in the treatment of wounds occurring in the veterinary field of the following diseases: abscess, abscessus interdigitalis, fistulas, ulcers, callus pyoderma, combustion, congelation, decubitus, dehyscalated wounds, various types of dermatitis such as D. interdigitalis, D. scroti, D. podo, D. allergica, various types of eczema, excoriation, filum suppuration, furunculosis, hot spot, cheloids, lick granuloma, mastitis, armor (turtle), perianal fistula, perianal necrosis, dermatitis pustula, pyoderma, skinfold pyoderma, plantar ulcer, 25 plantar erosion, vulnus contusum, vulnus punctum, etc.

The invention is further illustrated by the following examples, which are not intended to be limiting.

I. Biological Examples

The MIC value is the minimum concentration of test substance in the medium at which the test organism of choice cannot reproduce under the test conditions. By reducing the concentration of the test substance below the inhibitory concentration, reproduction begins. 35

Test media:

For Bacteria: Soya bouillon, which normally contained trypsin-digested casein, soy peptone, glucose, sodium chloride, potassium hydrogen phosphate and distilled water.

For mushrooms: Sabouraud broth containing glucose, trypsin digested casein and water.

The assay was performed in a germ-free environment.

An approximate concentration series of the samples in nutrient broth was prepared for MIC determination. The dissolution was carried out in a 60 ° C water bath. Composition of the concentration series:

- 100 μΙ of solutions of motherq at different concentrations

- constant volume broth (9.8 ml).

Three to three replicates of each of the series were inoculated with 10 μΙ of the prepared inoculum. The test samples were dissolved in a solvent. As a negative control, medium without test organism was used. Positive control: medium + 100 μΙ inoculum and optionally solvent.

1/1. example

MICs of active substances in 9 different microbial strains.

The following substances were tested: azithromycin, darithromycin, erythromycin, miconazole, primicin sulphate.

test organisms:

Bacteria: Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, Streptococcus pyogenes. Fungi: Aspergillus flavus, Fusarium oxysporum, Candida albicans, Candida parapsilosus.

Media: Soya bouillon, Sabouraud broth.

Solvents: methanol a. r. and primicin sulphate in a mixture of butanol: ethanol: water = 1: 1: 2. Negative control: medium without test organism. Positive control: medium and 10 μΙ inoculum.

After preparation of the strains, preparation of the inoculum and incubation, the ICC values were determined as above. The results of the measurements are summarized in Table I.

Table I

MIC values (pg / ml)

Active substance »microbe 1 azithromycin clarithromycin miconazole primycin Escherichia coli 6.0 95 500 < 100 < Staphylococcus aureus 2.0 0.2 3.0 0.2 Pseudomonas aeruginosa 65 80 500 < 100 < Serratia marcescens 8.0 100 500 < 100 < Streptococcus pyogenes 3.0 1.0 0.5 0.5 Aspergillus flavus 500 < 100 < 2.0 100 < Fusarium oxysporum 500 < 100 < 8.0 < 100 < Candida albicans 500 < 100 < 0.5 18 Candida parapsilosis 500 100 < 0.2 5.0

Azithromycin stops all of the bacteria tested. Prymycin also has an acceptable effect on Candisos, Escherichia coli. Coconut dusts on all 60 da type fungi, but not all bacteria tested10

HU 227 194 Β1 riumra. Miconazole inhibits all fungi and cocci tested.

// 2nd example

Determination of MlC value of ointments containing various active substances in Staphylococcus aureus strain.

Nine ointments were used with the following markings: AMS, 0, A, M, S, AM, AS, Msm AMS-P20, 28-alk (the meaning of the markings is shown in Table I of the final result) and Staphylococcus aureus strain ATCC 6538 as test organism. purchased from DSMZ (Deutsche Sammlungen von Mikroorganismen und Zellkulturen GmbH). The composition of the ointments is the same as in Fig. 11/1. Example 1B, the active ingredients are listed in the table. The ointment samples were dissolved in 1-butanol puriss. The maximum soluble concentration was 10 mg / ml ointment. Positive control: medium + 100 μΙ inoculum + 100 μΙ 1% 1-butanol. The MIC value is the ointment concentration at which no growth was observed in the respective solutions. The results of the measurements are shown in Annex II. are summarized in Table.

//. spreadsheet

Ointment sign agent MIC (mg / ml) AMS Azithromycin + micona- Zole + sulfamethoxazole 2.0 0 - > 10.0 THE azithromycin 4.0 M miconazole > 10.0 S sulfamethoxazole > 10.0 AM Azithromycin + micona- Zole 3.0 DIG Azithromycin + sulfame- toxazole 3.0 MS miconazole + sulfame- toxazole > 10.0 AMS-P20, 28 ALK azithromycin + miconazole + sulfamethoxazole, dissolved in paraffin 2.0

The results show synergism in the microbes examined. The addition of both miconazole and sulfamethoxazole increased the effect of azithromycin. The lowest MIC was determined in the presence of the 3 active compounds. The carrier did not reduce the effect.

The next 1 / 3-1 / 10. general method used in examples:

Cylinder Method (Agar Diffusion Method): The method involves applying the antibiotic by diffusion through a vertical cylinder to the solid layer in the Petri dish to such an extent that the growth of the microorganism in the medium in a circular area or in a "zone" around the antibiotic cylinder inhibited.

Test media

Bacteria: - Müller-Hinton agar containing beef broth; 4 g of solid, 17.5 g of acid casein hydrolyzate, 1.5 g of starch, 17 g of agar, 1000 ml of distilled water; - Tripticase-Soy agar containing 15 g of pancreatic digested casein, 5 g of papaic digested soy, 5 g of sodium chloride, 15 g of agar in 1000 ml of distilled water.

Fungi: - Sabouraud dextrose agar containing 40 g dextrose, 10 g peptone, 15 g agar, 1000 ml distilled water; - Tripticase-Soy-agar

The media are inoculated with 0.12-2 ml of culture medium diluted in physiological saline so that the number of cells is 10 ^{4 to} 10 ⁶ / ml on the agar layer.

The assay was performed in plastic Petri dishes (20 x 100 mm), agar layer 4 mm. Each sample is assayed in 3 replicate inoculated Petri dishes. Test organisms Staphylococcus

aureus ATCC 6354 Streptococcus pyogenes ATCC 19615 Escherichia coli ATCC 8739 Klebsiella pneumoniae CIP 106976 Clostridium perfringens ATCC 9081 Serratia marcescens ATCC 43424 Proteus mirabilis ATCC 12453 Candida albicans ATCC 10231 Aspergillus niger ATCC 16404

1/3. example

Ointment inhibitory effect on various test organisms (antimicrobial capacity or activity).

Specimens tested: The active compounds tested in the ointment are as described in Figs. azithromycin, sulfamethoxazole, miconazole, azithromycin + sulfamethoxazole, azithromycin + miconazole, sulfamethoxazole + miconazole. Ointments without antimicrobial components are used as blank.

The ointment samples were placed in a 7.5 mm diameter cylinder and incubated for 24 hours for bacteria and 48 hours for fungi.

The results are shown in Table III. is shown in Table.

///. Inhibition zone (mm)

Active substance -> microbe 4 b * Sulf Azita Mico Mico & Azita Azita + Sulf Mico & Sulf Azita + + mico Sulf Staphylococcus aureus 0 0 14.68 0 12.79 14,73 0 12.64 Streptococcus pyogenes 0 0 22.51 0 21.27 23.59 0 20.0

HU 227 194 Β1

III. Table (continued)

Active substance -> microbe 1 b * Sulf Azita Mico Mico & Azita Azita + Sulf Mico & Sulf Azita + + mico Sulf Proteus mirabilis 0 10.18 2.72 0 0 7.3 5.75 7.3 Escherichia coli 0 9.81 11.41 0 9.25 10.88 9.35 10.64 Klebsiella pneumoniae 0 10.46 10.27 0 5.65 12.95 7.73 10.56 Serratia marcescens 0 7.05 8.25 0 5.03 8.83 2.65 6.80 Clostridium perfringens 3.34 3.30 16.22 4.97 14.24 18.94 3.88 13.84 Candida albicans 0 0 0 10.01 9.94 0 8.94 10.02 Aspergillus niger 0 0 0 9.65 8.4 0 8.4 8.69

azith: azithromycin; sulf: sulfamethoxazole, mico: miconazole

The combination of azithromycin, sulfamethoxazole and miconazole makes the ointment effective against all bacterial and fungal strains tested. Klebsiella pn., Serratia m. and Clostridium perf. synergism between azithromycin and sulfamethoxazole, mutually enhancing the effect of each other. Gram-positive Clostridium perf. bacteria are sensitive to other components of the ointment, probably essential oils (Chamomillae and Achillea oils).

1/4. example

Antimicrobial activity of vaginal tablets

The tablets are described in Figs. Prepared according to example. The antimicrobial capacity of the tablets is 1/3. However, the tablets are placed on the surface of the agar layer and not on the cylinder. Samples were incubated as above. The results are shown in Table IV. is shown in Table.

ARC. spreadsheet

test organisms Inhibition zone mm Staphylococcus aureus 14.8 Streptococcus pyogenes 20.2 Serratia marcescens 27.87 Clostridium perfringens 11.14 Candida albicans 19.13 Aspergillus fumigatus 22.21

The results show that the tablet is active in vitro against aerobic, anaerobic bacteria and fungi.

1/5. example

Antimicrobial Effect of Spray Formulations prepared according to example. The microbiological tests in parallel with the ointment and spray formulations are described in Table 1/3. using the cylinder method as described in Example 1b. The sample is sprayed into a syringe and the sample is immediately placed in the cylinder. The results are shown in Table V.

Table V Inhibition zone (mm)

test organisms Spray Ointment Staphylococcus aureus 18.13 11.83 Streptococcus pyogenes 31.38 23.25 Serratia marcescens 12.64 4.75 Clostridium perfringens 16.63 3.07 Aspergillus fumigatus 11.3 4.08

The above has a good effect on both formulations. The inhibition zone of the spray samples is larger than that of the ointment, probably due to the hexamethyldisiloxane carrier, which promotes diffusion of the active ingredients.

1/7. example

Anti-microbial effect of ointment

The ointment is prepared according to FIG. prepared in accordance with example 1, in which azithromycin is replaced by darithrornycine and the 1/3. as described in Example 1.

Samples tested: The following active compounds are tested in the ointment as described in Example 1 to 5: clarithromycin, sulfamethoxazole, miconazole, clarithromycin + sulfamethoxazole, clarithromycin + miconazole, clarithromycin + sulfamethoxazole + miconazole. Ointments without antimicrobial components are used as blank. The results are shown in Table VII. is shown in Table.

VII. spreadsheet

Active substance -> microbe 1 Sulf Clarion Mico Clarion + Sulf Clarion + mico Clarion + mico + Sulf Staphylococcus aureus 0 17.51 0 17.48 18.24 14.02 Streptococcus pyogenes 5.4 2.1 0 4.85 2.41 5.25

HU 227 194 Β1

VII. Table (continued)

Active substance -> microbe 1 Sulf Clarion Mico Clarion + Sulf Clarion + mico Clarion + mico + Sulf Clostridium perfringens 0 18.83 2.69 19.49 19.56 13.74 Candida albicans 0 0 8.44 0 12.48 12.12

clarit: clarithromycin; sulf: sulfamethoxazole, mico: miconazole

Consequently, the ointment has a high antibacterial and antifungal capacity. A clear synergistic effect was found between clarithromycin and miconazole.

1/7. example

Comparative antimicrobial examination of suppository and ointment

The cone is shown in Fig. 11/7. prepared according to example.

The microbiological examination is described in Fig. 1/3. using the cylinder method as described in Example 1b. The suppository samples and tissue samples were compared in the same Petri dish. The suppositories were cut into pieces 4 mm long and 7 mm in diameter into the cavity of the agar layer.

At an incubation temperature of 37 ° C, the suppository melts and the active ingredients are diffused into the agar layer. The 25 results are from Vili. is shown in Table.

1/9. example

Antimicrobial efficacy of ointment

The ointment is prepared according to FIG. and 11/12 is prepared using the polyene antifungal naphthytin instead of miconazole. The antibacterial and antifungal capacity of the formulations is shown in I / 3. The cylinder was tested according to the cylinder method described in Example 1-1.

Test organisms: Staphylococcus aureus Streptococcus pyogenes Clostridium perfringens Candida albicans Aspergillus fumigatus

The results show that the ointment also has good antimicrobial activity against bacteria and fungi.

II. preparations

Vili. Inhibition zone (mm)

test organisms Cone Ointment Staphylococcus aureus 18.26 10.67 Streptococcus pyogenes 31.91 21.31 Clostridium perfringens 20.61 16.63 Candida albicans 6.86 7.47 Aspergillus fumigatus 23.72 4.08

It follows from the above that both formulations are effective inhibitors of aerobic and anaerobic bacteria and fungi. Larger inhibition zones for suppositories are a consequence of carriers and result in the preparation of a liquid at 37 ° C which facilitates diffusion of the active ingredients.

1/8. example

Antimicrobial efficacy of ointment

The ointment is prepared according to FIG. and 11/12 is prepared in accordance with Examples 1 to 5, using a polyene-type antifungal nystatin instead of miconazole. The antibacterial and antifungal capacity of the formulations is shown in I / 3. The cylinder was tested according to the cylinder method described in Example 1-1.

Test organisms: Staphylococcus aureus Streptococcus pyogenes Clostridium perfringens Candida albicans Aspergillus fumigatus

The results show that the ointment also has good antimicrobial activity against bacteria and fungi.

11/1. example. Ointment Composition:

t% 9 azithromycin 0,020 0.1 miconazole 0,020 0.1 sulfamethoxazole 2.80 14.0 ZnO 3.75 18.75 Cetyl Stearate 1.25 6.25 Lanalcol 3.37 16.85 Cera alba 3.11 15.55 Vaseline ophth 20.90 104.5 Aetheroleum chamomillae 0.56 2.80 Aetheroleum millefolii 0.56 2.80 Vaselinum album ad 500

The above composition is the MIC value of the microbial culture (1/1 and

I / second tests) at a concentration of 10 ² -fold. Can be used as an ointment.

General way of making ointments:

The zinc oxide and sulfonamide are weighed and thoroughly homogenized in a mortar, and the powder mixture is transferred to a vessel sealed with a stirrer. In another vessel, the alcoholic cetylstearylicum, lanalcolum, cera alba, vaseline, paraffin components are weighed and the mixture is melted. The melt is added to the powder mixture under continuous stirring and cooling with ice water. We'll make it

A solution of azithromycin, miconazole in absolute ethanol, to which aetheroleum chamomillae and aetheroleum millefoliil are added. The resulting blue solution is mixed with the cooled ointment. The ointment is stirred until the previously white ointment is uniformly blue. The desired amount of paraffin is then uniformly mixed. A blue ointment for direct use is obtained. Stable under normal conditions at room temperature in a sealed tube for at least 2 years.

II / second Example Composition:

t% 9 clarithromycin 0,040 0.2 miconazole 0,020 0.2 sulfamethoxazole 2.80 14.0 ZnO 3.75 18.75 Cetyl Stearate 1.25 6.25 Lanalcol 3.37 16.85 Cera alba 3.11 15.55 Vaseline ophth. 20.90 104.5 Aetheroleum chamomillae 0.56 2.80 Aetheroleum millefolii 0.56 2.80 Vaselinum album ad +500

Preparation: See section 11/1. example

11/3. Example Ointment Composition:

t% g azithromycin 0.02 0.1 miconazole 0.02 0.1 sulfamethoxazole 2.80 14.0 ZnO 3.75 18.75 Cetyl Stearate 1.25 6.25 Lanalcol 3.37 16.85 Cera alba 3.11 15.55 Vaseline ophth. 20.90 104.5 Aetheroleum chamomillae 0.56 2.80 Aetheroleum millefolii 0.56 2.80 Vaselinum album 216.92 Paraffinum liquidum 101.38

Preparation: See section 11/1. example

11/4. Example Vaginal Tablet Composition:

1 tablet mg 1 production lot g azithromycin 0.35 1.05 miconazole 0.35 1.05 sulfamethoxazole 47.60 142.80 Lactose 914.00 2742.0 Viapur® 102 (Merck) 220.00 660.0 adipic acid 110.00 330.0 Sodium hydrogen carbo- sodium 88.00 264.0 Magnesium stearate 16.00 48.0 Aerosil 3.70 11.1 Altogether 1400 4200

First we prepare the following mixture:

a) Miconazole and azulene are mixed with portions of sulfamethoxazole and the other components in a mortar. 300 g of lactose are added with stirring and then sieved through a 0.630 mm sieve.

b) Aerosil is mixed with 100 g of lactose and sieved through a 0.630 mm sieve.

c) Sodium bicarbonate and adipic acid are pulverized and mixed and sieved through a 0.200 mm sieve.

d) Sieve the magnesium stearate through a 0.200 mm sieve.

Mixtures a), b) and c) are homogenized. Finally, the magnesium stearate is added and homogenized. Tablets are prepared in the usual manner.

11/5. Example Vaginal Tablet Composition:

t% azithromycin 0.02 miconazole 0.02 sulfamethoxazole 2.80 Stearin 0.5 Aerosil 2000 0.25 TWIN 20 0.12 Magnesium stearate 1.2 Sodium bicarbonate 6.47 adipic acid 8.39 corn starch 10.6 Lactose 69.73

Preparation: The above materials are made into tablets in the usual manner. It breaks down in the vagina within 10 minutes.

HU 227 194 Β1 /// 6. Example Rectal Cone Composition:

t% g azithromycin 0.02 0.06 miconazole 0.02 0.06 sulfamethoxazole 2.8 8.4 Adeps solidus ad 300

Preparation: 100 of 300 mg of suppositories each are prepared in the usual manner from the above materials.

11/7. Example Vaginal Cone Composition:

t% g azithromycin 0.02 0.06 miconazole 0.02 0.06 sulfamethoxazole 2.8 8.4 Butyrum cacao ad 300

Preparation: From the above materials, 100 suppositories of 300 mg each are prepared in the usual manner.

11/8. example Rectal or vaginal suppository Composition:

t% g azithromycin 0.02 0.2 miconazole 0,020 0.2 sulfamethoxazole 2.80 14.0 Aetheroleum chamomillae 0.56 2.80 Aetheroleum millefolii 0.56 2.80 Witepsol® (Hüls) ad 500

Preparation: See page 11/9. example

11/9. Example Spray Composition:

g azithromycin 0.1 miconazole 0.1 sulfamethoxazole 14.0 ZnO 18.75 Cetyl Stearate 6.25 Lanalcol 16.85 Cera alba 15.55 Vaselinum album ophth. 104.4 Vaselinum album 318.3 Aetheroleum chamomillae 2.80

g Aetheroleum millefolii 2.80 DM 0.65 hexamethyldisiloxane 500.00

Preparation: From suitable materials according to 11/1. Preparing the ointment according to example. The resulting material was dissolved cold (10-15 ° C) in DM 0.65 hexamethyldisiloxane (Wacker-Chemie GmbH) with caution as the operation was flammable. The product is filled into vials, given that the specific volume is high, so that the vials can be approximately half filled. The product is a sprayable substance which, when applied by means of an air pump, forms a uniform oily layer when applied to the surface to be treated.

11/10. Example Foam Composition:

t% 11/1. example ointment 48 DM 0.65 hexamethyldisiloxane 2 DM 100 polydimethylsiloxane 50

Production: A11 / 1. As an example, the materials used therein are formulated in an ointment. The resulting material was dissolved cold (10-15 ° C) in DM 0.65 hexamethyldisiloxane, and DM 100 polydimethylsiloxane (Wacker-Chemie GmbH) was added to the resulting suspension. A sprayable suspension is obtained which is dispensed into vials with an inert propellant. Filling ratio: 75% propellant, 25% slurry. When applied to the surface to be treated, it forms a foam which, when crushed, forms a uniform, well-sealed layer that covers the surface for 24 hours.

///. Clinical treatments

111/1. Example 2 Treatment of burn wounds

CJ 30 year old male patient with right lower limb II. degree of burn on a surface of about 900 cm ² because the paint thinner solvent spilled on his pants and then inflamed. In accident surgery, it was brushed with Merbromin® (active ingredient mercurochrom). After 1 week, a thick stump was formed, he had severe pain and a plastic surgery was planned. Regular treatment of this wound, covered with a stomach about 4-8 mmm thick, was started according to Fig. 11/1. blue ointment prepared according to example 1, one treatment a day. On the first day, the stink was an inflamed, highly exuding, odorous surface. The pain disappeared during the first day. From day 6, the formation of new skin around the wound became apparent. By day 8, the discharge area was reduced to two strips of about 1 cm * 4 to 6 cm. On day 9 there was no open wound. At that time, the patient drove a 460 km drive, without pain and fatigue, driving his own car. The wound eventually healed without a scar.

HU 227 194 Β1 //// 2. EXAMPLE 1 Preliminary Human Clinical Results Treatments were performed on an outpatient prescription

II / 6th example. The ointment was applied topically initially at least once a day or twice or more as needed in the case of severe discharge. Wounds without mucus were not or were no longer covered with gauze.

K. Cs. 4 year old boy, approx

2x3 cm III. degree of burn wound. The patient was treated with the composition and the wound was completely healed within 11 days.

F. A. A 31-year-old male, diagnosed with varicosity two years ago, has now developed dermatosclerosis with four ulcers (one 2.5x1 cm) in the middle of the sclerotic area. The composition was treated and the ulcer was closed and the wounds healed after 7 weeks.

M. J. A 66-year-old diabetic hypertensive female was diagnosed with varicosity with a severely 3x4 cm ulcer in the lower left limb. The composition was treated and the ulcer was closed and the wound healed after 9 weeks (see photos in Figures 1A and 1B).

D. J. A 50-year-old woman, diagnosed with thrombophlebitis for 25 years, was treated with an ulcer in the lower right limb, just above the ankle on the inside. When the product was used, the ulcer was closed and the wound healed after 4 weeks.

Μ. K. A 68-year-old male, diagnosed with varicosity, had a persistent 3x6 cm ulcer on his lower left leg 2 months ago. When treated with the composition, the ulcer was closed and the wound healed after 11 weeks (see photos in Figures 1C and 1D).

S. 0. A 77-year-old woman, diagnosed with varicosity, developed a 1x1 cm deep ulcer in the lower left leg above the ankle. When treated with the product, the ulcer was closed and the wound healed after 10 weeks.

111/3. Example IV Veterinary treatments

The following describes the treatment of different animal species through one or two specific examples in each group. All cases were performed at the Budapest Veterinary Clinic. Wounds and injuries are described in Section II / 6. was treated with ointment prepared according to example. Improvements have been noted by veterinarians.

a) Horse, 3 year old Hungarian half-breed mare, body weight: 350 kg.

Case Study 11/04/2002 Burn and tear in the leg. Treatment: Topically twice a day without patch. April 20, 2002 wound healing.

(b) Guinea pig, 2 years old female, body weight: 50 g.

Case description: March 3, 2002. Dog bite. Treatment: Topically once a day. March 24, 2002 wound closed, healed.

(c) Tortoise, male 13 years old, body weight: 500 g. Case description: March 3, 2002. dog bite, broken armor, damaged soft tissue. Treatment: Wound topically twice daily. 12.04.2002 wound closure, definite improvement.

d) Dog, 13 year old female medium poodle. Weight: 7 kg. Case description: 23.01.2001. burns. Treatment: Topically twice daily. 2002nd

02.02.02 healed.

e) Dog, 3 year old female white West Highland Terrier.

Weight: 10 kg. Case Study 25/01/2001 Scarring wound, 1st degree burn. Treatment: Topically once daily. 11/04/2001 Wound healing, full recovery.

111/4. EXAMPLE 1 Treatment of Sexually Transmitted Diseases in Humans

Female patients are treated according to II / 8. Example 3 tablets in the following three groups: bacterial vaginosis (15 cases), vulvovaginal candidiasis (21 cases) and Trichomonas vaginitis (6 cases). Each patient is of fertile age and more or less infected with all three microbes. The three groups are named according to the dominant vaginal infection based on the following observations: anamnesis, physical examination, vaginal fluid pH, potassium hydroxide test, microscopic examination of smear from vaginal secretions. Treatment: After the evening bath, 1 tablet is inserted into the vagina for three consecutive days. Before and after treatment, the pH of the vagina is determined. The results of 42 patients treated for 3 months were plotted against the mean pH as shown in Tables IX, X and XI below. are summarized in tables.

IX. spreadsheet

Bacterial vaginosis (15 cases)

Vaginal pH Subjective complaints KOH test Treatment before 5.5 stinging odor. positive Treatment after 4.5 normal flow negative improvement no changed depraved Result 11 4 -

Table X.

Vulvovaginal candidiasis (21 cases)

Vaginal pH Subjective complaints In native cytology, fungal threads Treatment before 4.8 cottage cheese positive Treatment after 4.5 normal flow negative improvement no changed depraved Result 18 3 -

HU 227 194 Β1

XI. spreadsheet

Trichomonas vaginitis (6 cases)

Vaginal pH Subjective complaints KOH test Treatment before 5.0 pungent saqú foamy stream. positive Treatment after 4.5 normal flow negative improvement unchanged depraved Result 5 1 -

It will be understood by those skilled in the art that most treatments will be in combination with internal drug therapy. For trichomonal vaginitis, treatment was supplemented with oral Kiion therapy and sexual partner treatment.

Summarizing the results, it can be concluded that the use of the tablet alone or (in practice, in most cases) in combination is a promising alternative for the treatment of all three clinical cases.

111/5. Example 3 Obstetric and gynecological application of ointment

In II / 6. The ointment of Example 1 is used in the treatment of various wounds as described in Example XII. 80 patients with the diseases listed in Table II.

XII. spreadsheet

herpes genital Condyloma acu- minatum (lézerte- Rapid after) Episio Tom Secondary wound healing vulva on hámsérü- lese 5 15 35 4 21

Treatment: Apply ointment on both sides of the gauze and place it on the wound or on the wound surface. The gauze leaf is changed once or twice a day. The wounds usually close within 2-3 weeks. Full healing occurs within 4-16 weeks.

Claims (32)

Use of active substances and carriers suitable for human and veterinary use in the manufacture of a pharmaceutical combination, preferably in a single composition, for the prevention and control of infections of pathogenic microorganisms, which coexist or threaten to coexist, in epithelial, epithelial, (a) it contains only poorly soluble (or <50 pg / ml at room temperature) water-soluble active substance (s) at 20-100 ° C: (i) at least one fungicidal agent, preferably of the azole type; and (ii) at least one antibacterial agent, preferably of the azalide, lincosamide, polypeptide, or erythromycin derivative; and (iii) at least one poorly water-soluble bacteriostatic sulfonamide, b) and wherein the active ingredients are in the form of a dispersion in a pharmaceutically acceptable anhydrous carrier at the site of treatment c) and wherein the weight ratio of said active ingredients is i: ii: iii = 0.1 to 10: 0.1 to 10: 10 to 200, wherein the ratio of carrier is about 80 to 99% by weight. Use according to claim 1 for the preparation of a composition comprising an antifungal agent effective to a plurality of members of the human or veterinary pathogenic fungal strains of the Candida, Aspergillus and / or Fusarium family. 3. Use according to any one of claims 1 to 3, for the preparation of a composition comprising an agent active against pathogenic strains of the following fungi: Candida tropicalis, Candida parapsilosis, Candida albicans, Torulopsis (Cand.) glabrata, Fusarium oxisporum, Trishosporon B2B, Aspergillus flavus, Aspergillus , Mucor spp., Rhizopus spp. and / or Penicilium spp. Use according to claim 3, for the preparation of a composition comprising at least one of the following antifungal agents: miconazole, itraconazole, econazole, ketoconazole, fluconazole. 5. Use according to any one of claims 1 to 3 for the preparation of a composition comprising an antibacterial agent, preferably active on several members of the following opportunistically pathogenic bacterial strains: aerobic bacteria: Gram-negative bacilli such as Proteus, Pseudomonas, Enterobacter species, Escherichia coli, Klebsiella, Serratia marcescens, Citrobacter, Aeromonas; Gram-negative coccus such as Neisseria, Acinetobacter species; Gram-positive bacilli as Corynebacterium species, Bacillus sphaericus, Gram-positive cocci as Streptococcus species; anaerobic bacteria: Gram-negative cococci such as Bacteroides, Fusobacterium; Gram-positive coccus such as Peptococcus, Peptostreptococcus species; Gram-positive bacilli such as Clostridium, Propionibacterium, Eubacterium species and Mycobacterium species such as Mycobacterium ulcerans and / or Chlamydia-like microbes such as Chlamydia trachomatis. 6. Use according to any one of claims 1 to 6 for the manufacture of a composition comprising as antibiotic at least one of azithromycin, roxythromycin, clarytromycin, clyndamycin, clyncomycin, thyrotricin, magainin, cecropine and sulfamethoxazole as sulfonamide. 7. Use according to any one of claims 1 to 4 for the preparation of a synergistic composition comprising the active ingredient miconazole, azithromycin and sulfamethoxazole in a weight ratio of 0.1-1: 0.1-1: 10-35, preferably 0.1: 0.1: 14. HU 227 194 Β1 8. Use according to any one of claims 1 to 6, wherein the carrier is at least one water-immiscible vegetable or mineral oil, fat, and / or wax, preferably petroleum jelly, lanalkol, cetyl stearate and / or beeswax, and all active ingredients are suspensions, emulsions or in the form of a solution. 9. The use according to any one of claims 1 to 6 for the manufacture of a combination and composition for the treatment of human or veterinary epithelial, epileptic, epistaxial skin, for the prevention and treatment of live skin wounds, external ulcers, burns, radiation necrosis, wound infections, (a) containing as active ingredient poorly soluble in water (<50 pg / ml at room temperature), 20-100 ° C, acceptable for human or veterinary use i) an antifungal agent which is preferably poorly water soluble and ii) at least one antibacterial agent, preferably an azalide, lincosamide, polypeptide, erythromycin derivative antibiotic, and iii) a poorly soluble bacteriostatic sulfonamide, iv) an agent promoting local circulation of blood and body fluids, preferably azulene or guaiazulene, v) an epithelializing agent, preferably a water-insoluble zinc salt such as zinc oxide, (b) the active compounds are in a dispersed form in a pharmaceutically acceptable anhydrous carrier at the site of treatment, and c) wherein the weight ratio of the above active ingredients is i: ii: iii: iv: v = 0.1-10: 0.1-10: 10-200: 10-100: 10-250, wherein the ratio of carrier is about 80-99 which composition optionally contains, as an additional ingredient, a pharmaceutically acceptable coloring agent, perfume, essential oil, in the form of ointments, foams, or sprays, in the form and dosage form suitable for administration, and as a carrier for the foam or spray formulations; and / or oligosiloxane, and optionally a propellant for applying the composition to the surface to be treated. Use according to claim 9 for the preparation of a synergistic composition comprising: azithromycin 0.01-1.5%, preferably 0.02%, miconazole 0.01-1.5%, preferably 0.02% sulfamethazole 1-19%, preferably 2.8%, zinc oxide 3-4%, azulene and gua-azulene 0.05-0.20%, preferably 0.12%, preferably aetheroleum chamomillae and / or in the form of aetheroleum millefolyl, optionally with a carrier such as petroleum jelly, lanalkol, cetyl stearate, paraffin and / or beeswax. Use of the active ingredients listed in claim 9 or 10 for the manufacture of a composition or combination for the treatment of human or veterinary skin with prophylaxis of puncture lesions, external ulcers, burns, radiation necrosis, wounds (hereinafter referred to as "wounds"). and healing, and restoring the epithelium, while preventing or curing co-infection with groups of pathogenic microorganisms that are co-occurring or threatening to coexist, using a combination of at least one active ingredient of opportunistic human and veterinary pathogenic fungal strains and bacteria. Candida, Aspergillus and / or Fusarium fungi, and also aerobic bacteria: Gram-negative bacilli such as Proteus, Pseudomonas, Enterobacter species, Escherichia coli, Klebsiella, Serratia marcescens, C. itrobacter, Aeromonas; Gram-negative coccus such as Neisseria, Acinetobacter species; Gram-positive bacilli: as Corynebacterium species, Bacillus sphaericus, Gram-positive coccus as Streptococcus species; anaerobic bacteria: Gram-negative cococci such as Bacteroides, Fusobacterium; Gram-positive coccus such as Peptococcus, Peptostreptococcus species; Gram-positive bacilli such as Clostridium, Clostridium, Propionibacterium, Eubacterium species and Micobacterium species such as Mycobacterium ulcerans and Chlamydia-like microbes such as Chlamydia trachomatis. Use according to claim 11, in combination with at least one active agent active against several members of the opportunistically pathogenic microbes: Candida tropicalis, Candida parapsilosis, Candida albicans, Torulopsis (Cand.) Glabrata, Fusarium oxysporum, Trishosporon Bejelii, Aspergillus flavus, Aspergillus fumigatus, Aspergillis terreus, Aspergillus niger, Mucor spp., Rhizopus spp. and / or Penicilium spp. Use according to claim 11, in combination with at least one active agent active against several members of the opportunistically pathogenic microbes: Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Enterobacter aerogenes, Enterobacter faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella , Serratia marcescens, Citrobacter spp., Aeromonas spp., Neisseria meningitidis, Acinetobacter anitratus, Corynebacterium spp., Bacillus sphaericus, D - Streptococcus, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis, Str. ., Fusobacterium mortiferum, Fusobacterium mucleatum, Peptococcus magnus, Peptococcus assaccharoliticus, Peptostreptococcus anaerobius, Peptostreptococcus micros, Clostridium welchii, Clostridium perfingens, Clostridium spp., Propionibacteria, Propionibacteria amydia trachomatis. Use according to claim 11 in a synergistic combination, preferably in a single composition, which is (a) contain the following: as active substance Slightly soluble in water (<50 pg / ml at room temperature) at 20-100 ° C, acceptable in human or veterinary medicine (i) an antifungal agent, preferably azole and Ii1 ii) at least one antibacterial agent, preferably erythromycin, azalide, lincosamide or erythromycin derivative type, and iii) at least one poorly water-soluble bacteriostatic sulfonamide, b) and wherein said active ingredients are in the form of a dispersion in a pharmaceutically acceptable anhydrous carrier at the site of treatment; c) and wherein the weight ratio of the active ingredients is i: ii: iii = 0.1-10: 0.1-10: 10-200-200, wherein the ratio of carrier is about 80-99% by weight. 15. A 11-14. Use according to any one of claims 1 to 3, in combination with at least one of the following azole antifungal agents: miconazole, itraconazole, econazole, ketoconazole and fluconazole, and at least one of azithromycin, roxythromycin, clarytromycin, clyncomycin, thyrotricin, magnesium, . 16. Use according to any one of claims 1 to 4, with a synergistic composition comprising the active ingredient miconazole, azithromycin and sulfamethoxazole in a weight ratio of 0.1-1: 0.1-1: 10-35, preferably 0.1: 0.1: 14. 17. 11-16. Use according to any one of claims 1 to 4, with a composition or combination which is (a) contain the following: as active substance Slightly soluble in water (<50 pg / ml at room temperature) at 20-100 ° C, acceptable in human or veterinary medicine (i) an antifungal agent which is preferably a water-insoluble azole; and (ii) at least one antibacterial agent, preferably an azalide, lincosamide, polypeptide, or erythromycin derivative; and (iii) a poorly soluble bacteriostatic sulfonamide; an excipient, preferably azulene or guaiaculene, v) an epithelializing agent, preferably a water-insoluble zinc salt such as zinc oxide, b) wherein the active compounds are in a dispersed form in a pharmaceutically acceptable anhydrous carrier at the site of treatment, and c) wherein the weight ratio of the above active ingredients is i: ii: iii: iv: v = 0.1-10: 0.1-10: 10-200: 10-100: 10-250, wherein the ratio of carrier is about 80-99 %. 18. 11-17. Use according to any one of claims 1 to 3, with a synergistic composition having the active ingredient: azithromycin 0.01-1.5%, preferably 0.02%, miconazole 0.01-1.5%, preferably 0.02%, sulfamethoxazole 1 -191%, preferably 2.81%, zinc oxide 3-41%, azulene and gua-azulene 0.05-0.20% by weight, preferably 0.12% by weight, preferably in the form of aetheroleum camomillae and / or aetheroleum millefoliil and as carrier Vaseline, lanalkol, cetyl stearate, paraffin wax and / or beeswax. The use of claim 18, wherein the composition is in the form of an ointment or spray. 20. A 11-19. Use according to any one of claims 1 to 6 for the preparation of a veterinary treatment composition. 21. The use of active substances and carriers suitable for human and veterinary use in the manufacture of a pharmaceutical composition, preferably in a single composition, against micro-organisms pathogenic to humans and animals, co-occurring or threatening to co-exist, human and veterinary, body cavities, vagina, rectum and their epithelial cells. , treating mucous membranes, healing lesions, restoring epithelial tissue, (a) it contains only poorly soluble (or <50 pg / ml at room temperature) water-soluble active substance (s) at 20-100 ° C: (i) at least one azole fungicide and (ii) at least one antibacterial agent which is preferably azalide, lincosamide, polypeptide and (iii) at least one bacteriostatic sulfonamide, (iv) a local blood and body fluid promoting agent such as azulene or guailinazulene, v) an exfoliating agent, preferably a water-insoluble zinc salt such as zinc oxide, b) and wherein the active ingredients are in the form of a dispersion in a pharmaceutically acceptable anhydrous carrier at the site of treatment c) and wherein the weight ratio of said active ingredients is i: ii: iii: iv: v = 0.1-10: 0.1-10: 10-200: 10-100: 10-250, wherein the ratio of carrier is about 80-991. %. Use according to claim 21, wherein the at least one active ingredient is active against a plurality of members of the group of microbes pathogenic to humans and animals: Candida tropicalis, Candida parapsilosis, Candida albicans, Torulopsis (Cand.) Glabrata, Fusarium oxisporum, Trishosporon Bejelii, Aspergillus flavus, Aspergillus fumigatus, Aspergillis terreus, Aspergillus niger, Mucor spp., Rhizopus spp. and / or Penicilium spp. 23. A 21-22. The use according to any one of claims 1 to 5, wherein at least one active ingredient is active against several members of the opportunistically pathogenic microbes: Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Enterobacter aerogenes, Enterobacter faecalis, Enterobacter doacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca. , Aeromonas spp., Neisseria meningitidis, Acinetobacter anitratus, Corynebacterium spp., Bacillus sphaericus, Group D Streptococcus, Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis, Streptococcus spp., Bacteroides fragilis, Bacteroides fragilis, , Peptococcus magnus, Peptococcus assaccharoliticus, Peptostreptococcus anaerobius, Peptostreptococcus micros, Clostridium welchii, Clostridium perfingens, Clostridium spp., Propionibacterium acnes, Eubacterium lentum, Chlamydia species such as Chlamydia too. 24. A 21-23. Use according to any one of claims 1 to 3, wherein the at least one active ingredient is a vagina GB 227 194 opportun1 and opportunistic pathogens of the rectal cavities and several members of the following microbes in the field of sexually transmitted diseases of humans and other mammals: such as Neisseria Gonorrhea, Neisseria gonorrhea, Trepponema pallidum, Haemophylus duc. 25. A 21-24. The use according to any one of claims 1 to 3, wherein the fungicide comprises at least one azole from the group miconazole, itraconazole, econazole, ketoconazole, fluconazole, at least one of azithromycin, roxythromycin, clarithromycin, clyncomycin, thyrotricin, magainin, cecropropin, as an antibiotic. 26. A 21-25. Use according to any one of claims 1 to 4 for the preparation of a synergistic composition comprising the active ingredient miconazole, azithromycin and sulfamethoxazole in a weight ratio of 0.1-1: 0.1-1: 10-35, preferably 0.1: 0.1: 14. 27. A 21-25. Use according to any one of claims 1 to 4, wherein the carrier is at least one water-immiscible vegetable or mineral oil, fat, and / or wax, such as petroleum jelly, lanalkol, cetyl stearate and / or beeswax, and all active ingredients in suspension, emulsion or solution. is present. 28. A 21-25. Use according to any one of claims 1 to 19, for the preparation of a synergistic composition comprising: azithromycin 0.01-1.5%, preferably 0.02%, miconazole 0.01-1.5%, preferably 0.021%, sulfamethazole 1-191 %, preferably 2.81%, zinc oxide 3-4%, gua-azulene and azulene 0.05-0.20%, preferably 0.12%, preferably in the form of aetheroleum chamomillae and / or aetheroleum millefoliil. Use according to claim 28 for the manufacture of a suppository composition comprising as adjuvant adeps solidus 50 and / or triglyceride, and optionally as a further adjuvant a pharmaceutically acceptable colorant, perfume, essential oil. 30. A 21-29. Use according to any one of claims 1 to 4, in a preparation and formulation suitable for administration in the form of an ointment, foam or spray, containing a polysiloxane and / or oligosiloxane as carrier for the spray or foam and optionally propellant for applying the composition to the surface to be treated. . 31. A 21-30. The use according to any one of claims 1 to 6 for the preparation of a composition for treating body cavities, which is in a formulation and formulation for administration in the form of tablets, dragees, suppositories, foams, oily suspensions, sprays and optionally further adjuvants. 32. A 21-31. Use according to claims 1 to 4 for the manufacture of a veterinary composition.