EA041079B1 - EMULSION FOR TOPICAL TREATMENT OF SKIN AND MUCOSA INFECTIONS - Google Patents

Description

The invention relates to emulsions for the local treatment of infections of the skin and mucous membranes, in particular urogenital infections.

Man lives in symbiosis with a gigantic number of microorganisms that mainly colonize his intestines and skin surface as commensals. The collection of these microorganisms is called the human microbiome. The microbiome of the female vagina, which is dominated by lactic acid bacteria, has a special composition. Under normal physiological conditions, these bacteria create a slightly acidic environment in the vagina, which has a protective effect against bacterial infections. However, vaginal infections often occur for various reasons, caused on the one hand by the almost ubiquitous fungi of the Candida species, which easily pass from commensals to pathogens, and on the other hand by bacteria such as Gardnerella vaginalis, Mobiluncus or Prevotella spp. and streptococci or staphylococci or, for example, typical intestinal microbes such as Enterobacter, E. coli and/or, for example, Klebsiella pneumoniae, which can easily enter the vagina during infection due to spread due to the proximity of the orifices of the body. Initially, this leads to an asymptomatic disruption of colonization. If certain thresholds of foreign microorganisms are exceeded and infection-supporting factors are added, then a virulent infection eventually occurs. If left untreated, the infection can become chronic, usually with biofilm formation. Even asymptomatic disorders of colonization are increasingly recognized as a risk factor for infertility, miscarriage and preterm birth, as well as cystitis and some forms of incontinence.

US 2007/292355 A1 relates to anti-infective foam compositions containing an anti-infective and keratolytic agent. The compositions are used in the treatment of fungal, bacterial or viral infections.

AT 11910 U1 refers to a composition containing chlorhexidine, a bisphosphonate, a non-steroidal anti-inflammatory drug (NSAID) and an immunomodulator (tetracycline) for the treatment or prevention of, among other things, infections or inflammation of the oral cavity, mucous membrane or skin.

DE 102008034944 A1 relates to honey-based microemulsions which, together with other active substances, including NSAIDs, can be administered to the body by topical application to the skin or orally, nasally or transdermally.

WO 2011/060083 A1 relates to methods for preventing or treating otitis externa with compositions containing antibiotics, antifungals, antiparasitics, antiviral actives, NSAIDs, analgesics, anesthetics and/or steroids.

WO 02/078648 A2 relates to topical pharmaceutical compositions containing an antifungal agent, eg terbinafine, and an additional drug, eg diclofenac or indomethacin.

The present invention relates to drugs for the local treatment of bacterial dysbioses and manifestations of infectious diseases, including mixed infections with fungal and other microorganisms. Accordingly, the present invention relates to an emulsion for the topical treatment of skin and mucosal infections, in particular urogenital infections, in particular for use in the topical treatment of urogenital bacterial infections, which is characterized in that an antimicrobial active and an anti-adhesive active, preferably an NSAID, are used in combination.

Impaired bacterial colonization of the vagina and even symptomatic vaginal infections are common. The transition from asymptomatic, not yet inflammatory colonization disorder to symptomatic disease is more accurately defined by the terms vaginosis and vaginitis. The terms aerobic vaginosis/vaginitis and anaerobic vaginosis/vaginitis (synonym: bacterial vaginosis) are more precise definitions of pathogens. A problem common to all vaginal infections, regardless of the pathogen, is the formation of so-called biofilms. The surfaces of the mucous membrane of the affected organs (vagina, urethra, bladder, penis) are covered with these biofilms. In these biofilms, microorganisms are surrounded by a layer of mucous substances. The individual microbial components of the biofilm perform different tasks in the cellular system and also exchange resistance mechanisms. The microbes most commonly found in bacterial dysvaginosis are prominent biofilm formers. This makes therapeutic access in the case of overt infection much more difficult, and as a result, chronicity or frequent relapses develop during the course of the infection. Recent studies confirm that re-infection is often caused by a partner. Therefore, partner treatment is always prescribed. In men, reservoirs of infection are most commonly found in the folds of the foreskin and/or the first third of the urethra.

Bacterial dysbioses and infections can be effectively treated with a drug combination consisting of an antimicrobial drug with an anti-adhesive active. When adhesion is inhibited, the biofilm breaks down and detaches from the host epithelium. This simultaneously releases all the microbes contained in it and makes them again available for direct antimicrobial treatment. A class of anti-adhesion actives that are particularly useful consists of non-steroidal anti-inflammatory drugs (NSAIDs). In addition to the anti-adhesion effect, they have

- 1 041079 anti-inflammatory effect and immediate suppression of pain, which is an additional special advantage in terms of vaginal infections, which are often associated with pain. Since chronic infections are also accompanied by chronic inflammation, the anti-inflammatory effect is also of particular importance, especially in the case of chronic infections. The presence of NSAIDs in the described concentrations and conditions in the emulsion in the described composition and in the described proportions is decisive for the destruction of the biofilm. NSAIDs that are particularly suitable for the present invention are diclofenac, bufexamac, ibuprofen, dexibuprofen, flurbiprofen, ketoprofen, piroxicam, meloxicam, lornoxicam, flufenamic acid, mefenamic acid, indomethacin or naproxen.

The standard concentration at which diclofenac is topically applied to the skin is in the range of 1 to 2% (10 or 20 mg/g). In the context of the present invention, diclofenac is preferably used in an amount of 0.1 to 0.5% (1-5 mg/g cream), preferably 0.2 to 0.4%. The usual concentration at which ibuprofen is used for topical application is 5% (50 mg/g cream/gel). In the context of the invention, ibuprofen is used in a preferred amount of 0.5 to 2.5% (5-25 mg/g cream), preferably 1 to 2%. Additional examples of preferred NSAIDs and their preferred amounts (Concentration in accordance with the invention) can be found in table. A.

Table A

Examples of standard and preferred concentrations in accordance with the present invention

Active substance Single dose Maximum daily dose Example Single dose Maximum daily dose Example Concentration according to the invention Feather orally / intravenously locally Diclofenac sodium 25-75 mg ISO- 225 mg Voltaren 50 mg tablets 75 mg ampoules 40-80 mg 240 mg Voltadol analgesic gel 0.2-05 wt.% 1%, 10 mg/g 2% 20 mg/g Indomethacin 25-75 mg 50-150 mg Indocid 25 mg-75 mg 20-40 mg 40-80 mg Indomet Gel 1%, 10 mg/g 0.1-0.4 wt.% Naproxen 250-500 mg 1000 mg Naproxen FT 250/500 mg, Naproxen suspension 50 mg/ml 0.5-2.5 wt.% ibuprofen 200-800 mg 2400 mg ibuprofen FT 200/400/800 mg 100-250 mg 1000 mg Ibutrop cream/gel 5%, 5 g/100 g 0.5-2.5 wt.%

The following NSAIDs are particularly preferred within the scope of the present invention.

NSAIDs Preferred Concentration (wt%) Preferred individual dose (mg) diclofenac 0.1-0.5 (preferably 0.2-0.4) 4-8 mg Indomethacin 0.1-0.4 2-8 mg Naproxen 1-5 20-100 mg ibuprofen 0.5-2.5 10-50 mg Dexibuprofen 0.25-1.25 5-25 mg Ketoprofen 0.25-1.25 5-25 mg Mefenamic acid 0.5-4 10-40 mg Lornoxicam 0.02-0.04 0.4-0.8 mg

The concentration limit according to the table above applies to application to open wounds (possibly in the case of skin fungal infections) and to mucous membranes. For use on less inflamed skin, the maximum concentration of NSAIDs up to the standard amount when applied topically is possible.

In a preferred embodiment, the emulsion is available in the form of an ointment or cream. Preferably it is an aqueous-oil phase emulsion containing an antimicrobial active and an NSAID, characterized in that (a) the NSAID in the aqueous phase is in a concentration range that corresponds to 1/2-1/10 of the standard concentration used for these actives. substances in approved skin formulations;

(b) the weight ratio of the aqueous phase to the oil phase in this emulsion is from 2.0 to 2.7; and (c) the pH of the emulsion is not less than 6.5 and not more than 8.5, preferably in

- 2 041079 range from 7.0 to 8.0, preferably for the treatment of infectious diseases of the genitourinary system, in particular for use in the local treatment of vaginal infections and cystitis in women, as well as for local treatment of a partner (for the glans penis, the initial third of the urethra ).

In particular, the preparations according to the invention show not only optimized pharmacokinetics when applied directly to the site of infection, but also optimal pharmacodynamics. This not only provides a particularly good efficacy of the antimicrobial active, but also significantly improves the interaction with NSAIDs, providing sufficient efficacy at low concentrations of NSAIDs without the side effects (irritation, burning, etc.) that may develop. In practice, this means that combinations of antimicrobials and NSAIDs that were not previously used for these side effect reasons can be made available to patients with the teachings of the present invention and successful therapy can now be provided to these patients. However, according to the invention, it has been shown that the concentration of NSAIDs in the aqueous phase is of decisive importance for the optimal pharmacodynamic effect. The availability of the administered NSAID is achieved through the interaction of the preparation process, the water/oil ratio and the pH value, which ensures the predominant presence of the NSAID in the form of its salt.

Semi-solid emulsions (oil in water or water in oil), preferably in the form of a cream, are particularly well suited for effective and concentrated application of active substances to biofilm surfaces. The viscosity of emulsions is largely determined by the ratio of water to oil. Surprisingly, it has been found that the ratio of water to oil is of particular importance in the preparation of an emulsion. A large proportion of fatty components hinders the development of efficiency. On the contrary, a lower proportion of fat leads to a stronger irritant effect.

It is known that the search for a dosage form for topical use in the vagina is hampered by the fact that the drug can easily leak out during application, which makes reliable dosing difficult. In view of the relatively narrow therapeutic window, the medicaments according to the present invention assume that the active substance, especially the NSAID component, remains securely at the site of action in order to achieve the desired therapeutic effect. For this reason, the ratio of the oil phase containing the antifungal agent to the aqueous phase containing the NSAID in the drug is in a relatively narrow range. Thus, if the viscosity is further reduced to a greater extent by increasing the proportion of the aqueous phase, an uncontrolled loss due to leakage from the vagina can be expected. Liquid emulsions or gels with high water content or low viscosity should be excluded as dosage forms for vaginal use according to the present invention.

Since chronic vaginal infections are at the same time associated with chronic inflammation of the vaginal epithelium, in such cases a cure can only be achieved if it is ensured that the NSAID remains in the vagina.

To achieve optimal therapeutic effect, the ratio of water to oil should not exceed 2.7. Above this level, the active substance is washed out too quickly with vaginal secretion, which means that there is not enough time to provide an anti-adhesive effect on the outer layer of the vaginal epithelium to which the pathogen adheres. An active substance that is washed out very quickly when the water to oil ratio is too high may further cause an irritant effect as a side effect.

Just as in the case of too much water in the emulsion, which has a negative effect, too much fat should be avoided. In view of the low concentration at which NSAIDs are used, in order to achieve a therapeutic effect, it is especially important that the release of the active substance at the site of action is rapid and not protracted. Slow release, for example, from the oil phase does not guarantee the achievement of the required therapeutic concentration at the site of action. For this reason, the weight ratio of water to oil in the emulsion should not fall below 2.0. Therefore, the weight ratio of water to oil of the emulsions according to the invention also ranges between 2.0 and 2.7, preferably between 2.1 and 2.6, even more preferably between 2.2 and 2.55.

It is important that the NSAIDs be in the salt form (or ionic form) according to the invention both at the time of administration and at the time of use. Therefore, their inclusion in the composition is important. When the NSAID is included in its free form, or when it is included as a salt in the oil phase, the therapeutic effect is significantly impaired. While the antifungal agent is preferably introduced into and present in the oil phase, the method of the invention generally comprises introducing the NSAID into the aqueous phase prior to making the emulsion. Alternatively, the solid NSAID salt may be included in the finished (mostly) emulsion in finely divided crystalline or micronized form, or as a hydrogel.

Rapid release is provided if the active substance is present in the aqueous phase of the emulsion, which suggests the presence of NSAIDs in the form of a salt. Most NSAIDs are weak acids with a pKa value of 4-5 (diclofenac 4.15; ibuprofen 4.91; mefenamic acid 4.2; indomethacin 4.5; naproxen 4.2). Accordingly, they are already present in a slightly acidic environment, partly in

- 3 041079 free form, and thus are extracted into the oil phase, which can lead to a decrease in effect or loss of effect. Since the proportion of active ingredient in the NSAID present as free acid increases in the oil phase as the pH decreases, a pH value of at least 6 is suitable for producing therapeutic effects in drugs at active ingredient concentrations according to invention. In the case of NSAIDs, however, there may be a decrease in chemical stability in an alkaline environment (in the case of diclofenac from pH 8.00-8.5). It should also be noted that the pH value of the emulsion affects the fundamental physiological compatibility. For this reason, relatively narrow limits are also set on the pH value of the composition. According to the invention (the aqueous phase of the emulsion) has a pH value in the range from 6.5 to 8.5, preferably 7-8.

Within the scope of the invention, antibiotics or antiseptics are preferably used as antimicrobial agents.

Among the bacterial microorganisms found in vaginal biofilms are typical intestinal microbes such as Enterobacter, E. coli, Klebsiella pneumoniae and Enterococci, but also ureaplasmas and mycoplasmas, as well as Gardnerella vaginalis, Prevotella spp. and Mobiluncus play a special role. Preferred antibiotics within the scope of the present invention, which are also particularly suitable for the treatment of these organisms, are fosfomycin, clindamycin, metronidazole, nitrofurantoin, nitrofurazone, nifuratel, nifuroxacin, nitroxoline, trimethoprim, sulfadiazine and cotrimoxazole.

Antiseptics can act on both non-bacterial microorganisms, such as Trichomonas, and bacteria. At higher concentrations, antiseptics have an antibacterial effect and are suitable, alone or together with an antibiotic, for combination with the anti-adhesive active of the invention. The antimicrobial effect of antiseptics is mainly based on the violation of the integrity of the plasma membrane. Because of the fundamentally identical structure of endothelial cell membranes, these active substances have an inherent potential to induce inflammation. Since this potential is inhibited by NSAIDs, the combination preparations of the invention with antiseptics provide a particular therapeutic advantage.

Preferred antiseptics are quaternary ammonium salts such as benzalkonium chloride and dequalinium chloride, as well as phenoxyethanol. Preferred concentrations are at least 0.2% by weight for benzalkonium chloride, at least 0.2% by weight for dequalinium chloride, and at least 2% by weight for phenoxyethanol. In the context of the present invention, the terms antimicrobial active, antibacterial active, antibiotics, antiseptics, etc. substances are to be understood as being considered as such active substances in conventional pharmaceutical use. Substances considered to be such active substances can be taken, for example, from the Rote Liste (Red Data Book) (Rote Liste Service GmbH (editor and publisher), Rote Liste 2014 - Arzneimittelverzeichnis fur Deutschland (Red Data Book 2014) - Drug Compendium for Germany) (including EC approvals and certain medical devices), 2047 pages, ISBN 978-3-939192-80-0), the contents of which are included in this application. Benzyl alcohol, ethanol or propanol are not antibacterial active substances in the context of the invention.

In the combinations described, the drug combination composition according to the invention is particularly suitable for the treatment of even complex chronic inflammations of the vagina.

In special cases, it is advisable to add an odorous substance to the emulsion. Thus, the addition of a terpene to the emulsion, preferably farnesol, which additionally has a biofilm inhibitory effect, is a preferred subject of the invention.

The emulsions according to the invention are suitable for use on mucous membranes, in particular in urogenital infections. Unsuitable for vaginal use, for example, compositions that have a high content of substances that damage the mucous membrane, such as ethanol or isopropanol. Therefore, the emulsion according to the invention preferably contains no more than 10% ethanol. Also preferably, the emulsion of the invention contains no more than 20% isopropanol. Since keratinized layers do not occur in mucous membranes, for example in the urogenital region, a keratolytic effect is undesirable. For this reason, strongly acidic keratinolytic salicylic acid is not an NSAID according to the invention.

The emulsions of the present invention are also suitable for the treatment of diseases of the mucosa of the male genitourinary system, the penis and the urethra.

Cystitis is widespread. It is usually caused by a bacterial infection. The bladder is difficult to access for local treatment. However, since a woman's urethra is at the anterior entrance to the vagina, the most common route of infection is from the vagina to the urethra. In addition, in urological and gynecological practice, symptoms are often observed that can be attributed to isolated inflammation of the urethra. Thus, the vagina becomes the main reservoir of germs in urethritis and cystitis. Even though the treatment of acute cystitis with antibiotics can be supported by oral administration of anti-adhesive plant extracts that adhere to the bladder wall, nevertheless, the restoration of the vaginal flora, which is also usually

- 4 041079 affects the infection, is the main prerequisite for a long-term cure. This can be achieved with drugs according to the invention. For this reason, according to the present invention, the drugs are therapeutic agents effective against cystitis, either alone or in combination with bladder-only drugs.

In addition to purely bacterial infections, mixed infections with fungal infections (mainly Candida yeast) are common. WO 2007/131253 A2 claims drug combinations for the topical treatment of fungal infections, the particular effect of which is based on the fact that, in addition to the antifungal active, another active is added which prevents fungal adhesion to the epithelium. Some of the mixed infections mentioned can be treated with the combinations claimed in WO 2007/131253 A2. However, in severe cases of mixed infections, it is advisable or necessary not to be limited to the treatment of a fungal infection, but to supplement the drug with an antibacterial active substance in a triple combination.

The antifungal active is preferably a drug from the group of nystatin, ciclopirox or ciclopiroxolamine or a drug from the group of azoles (imidazoles, triazoles, tetrazoles) such as clotrimazole, fluconazole, miconazole, itraconazole, tioconazole, voriconazole, bifonazole, econazole, isoconazole, fenticonazole, sertaconazole , ketoconazole, posaconazole, quilseconazole, oteseconazole (VT-1161), or ibrexafungerp (SCY-078).

Medicines in accordance with the present invention have been developed mainly for the treatment of vaginosis and cystitis. Therefore, the invention relates to the use of the emulsions according to the invention in the topical treatment of infectious diseases, in particular in the topical treatment of urogenital infections. Preferably, the infectious disease is a microbial (especially bacterial) urogenital infection, especially a microbial (especially bacterial) urogenital infection in women. In a particularly preferred embodiment, the infectious disease is a mixed vaginal infection caused by Candida albicans and bacteria such as Enterobacter, E. coli, Klebsiella pneumoniae, Gardnerella vaginalis, or Prevotella spp. In another preferred embodiment, the infectious disease is asymptomatic or symptomatic bacterial vaginosis or asymptomatic or symptomatic dysbiosis of the glans penis and/or urethra in men.

Both acne and genetic hair loss are linked to the male sex hormone testosterone. In fact, the contribution of this hormone to the pathogenetic process lies primarily in the activation of the sebaceous glands in the skin and hair follicles. The accumulated sebum is subsequently an ideal substrate for bacterial infection, especially with propionibacteria or Candida and Malassezia fungi. While Malassezia is mainly associated with pityriasis versicolor, propionibacteria are the main cause of acne. Both types of bacteria are involved in hair loss. The large amount of sebum that accumulates in hair follicles is an ideal substrate for biofilm formation. In principle, the same criteria apply to this biofilm as to biofilms that form in the vagina. In this case also, the biofilm must first be destroyed and its adhesion to the epithelium must be removed so that the anti-infective agent can subsequently exert its effect. Thus, according to the present invention, the emulsions are also very well suited for the treatment of skin diseases, especially pityriasis versicolor, acne and hair loss. Because skin infections can affect a much larger and much less defined area than vaginal infections, specific emulsions may be preferred in these cases. In particular, shampoos are suitable for treating hair loss, while anti-acne creams, sticks or solutions are suitable for treating acne.

Hereinafter the invention will be explained in more detail with the help of the following examples, to which, however, it is not limited.

Examples

Preparation of base composition A, general preparation instructions 1.

The components sorbitan monostearate, polysorbate 60, cetyl palmitate, 2-octyldodecanol and cetostearyl alcohol are melted at a temperature of 70-75°C. Clindamycin (and possibly clotrimazole) and then phenoxyethanol are added to the clear melt with stirring at 60-70°C. At the same time, diclofenac sodium is dissolved in purified water by heating. The aqueous solution is added to the oil phase with stirring and homogenized. Upon slow cooling with further homogenization of the resulting water-in-oil emulsion, a phase inversion occurs, which leads to a hydrophilic homogeneous cream.

- 5 041079

Table 1

emulsion components Clindamycin 2.00 2.00 Diclofenac sodium 0.20 0.30 Sorbitan monostearate 2.00 2.00 Polysorbate 60 1.50 1.50 Cetyl palmitate 3.00 3.00 2-octyldecanol 13.50 13.50 Cetostearyl alcohol 10.00 10.00 P enoxyethanol 1.00 1.00 Purified water Eur. Pharm. 66.80 66.70 100.0 100.0

Emulsions containing phenoxyethanol as an antibacterial agent.

Table

F1 - phenoxyethanol as an antibacterial agent

The composition of the emulsion Wt% clotrimazole 1 Diclofenac sodium 0.4 Sorbitan monostearate 2 Polysorbate 60 1.5 Cetyl palmitate 3 2-octyldodecanol 13.5 Cetylstearyl alcohol 10 P enoxyethanol 4 Purified water, Heb. Pharm. 64.6 Total 100

Case example: 24-year-old female patient (EH), almost constant complaints due to fungal infections for 3 years, sexual intercourse is hardly possible for many years. For 1 week, complaints about the exacerbation of the condition. Burning and itching in the vagina.

Gynecological examination (Gyn.E.): vulvar and vaginal mucosa massively reddened, creamy greenish vaginal contents all over; native smear of secretions: masses of leukocytes adhering to epithelial cells and masses of fungal hyphae, mixed flora, few lactobacilli, dirty background - lytic cells, intermediate flora.

Therapy: F1 for 2 weeks, 0-0-1 Hb applied vaginally, then F1 if needed.

Examination after 3 years: no complaints since the last therapy;

Gynecological examination: the mucous membrane is not irritated, normal vaginal microflora, lactobacilli.

Example: emulsions containing dequalinium chloride.

F2 - Dequalinium chloride as an antibacter

Real agent table

The composition of the emulsion Wt% clotrimazole 1 Diclofenac sodium oh, s Sorbitan monostearate 2 Polysorbate 60 1.5 Cetyl palmitate 3 2-octyldodecanol 13.5 Cetylstearyl alcohol 10 Phenoxyethanol 1 Dequalinium chloride 0.4 Purified water, Heb. Pharm. 67.3 Total 100

Case example: 40-year-old female patient (AKS), almost monthly complaints due to fungal infections for many years, in each case from 1 week to 10 days, intercourse is hardly possible for many years. Within 1 week additional liquid discharge from the vagina with an unpleasant odor. Burning and itching in the vagina.

Gynecological examination: the mucosa is very reddened, the discharge is insignificant, slightly greenish; native smear of secretions: abundant biofilm plaques on thick fungal hyphae, leukocytes +++, practically no lactobacilli, intermediate flora.

Therapy: F2 for 1 week, 0-0-1 Hb applied vaginally.

Evaluation after 2 years: no symptoms for 2 years, only occasionally very minor fungal infection, treated with residual F2.

Gynecological examination: the mucous membrane is not irritated, lactobacilli.

- 6 041079

Table

F3 - Dequalinium chloride as an antibacterial agent

The composition of the emulsion Wt% clotrimazole 1.00 Diclofenac sodium 0.30 Sorbitan monostearate 2.00 Polysorbate 60 1.50 Cetyl palmitate 3.00 2-octyldodecanol 13.50 Cetylstearyl alcohol 10.00 propylene glycol 7.00 Dequalinium chloride 0.40 Purified water, Heb. Pharm. 61.40 Total 100.00

Example: 31-year-old female patient (FJ), almost monthly premenstrual complaints for about 3 years, in each case for about 1 week to 10 days, due to recurrent fungal infections. Within 1 week additional liquid discharge from the vagina with an unpleasant odor. Burning and itching in the vagina.

Gynecological examination: the mucous membrane is slightly reddened, the discharge is liquid, with an unpleasant odor; native smear of secretions: bacterial vaginosis (RG III), additional fungal hyphae, abundant leukocytes.

Therapy: F3 for 1 week, 0-0-1 Hb, vaginally.

Examination after 4 months: subjectively, there are no more complaints since the therapy. Gynecological examination: the mucous membrane is not irritated; native smear of secretions: normal vaginal flora (RGI).

Example: emulsions containing clindamycin.

Table

F4

The composition of the emulsion Wt% Clindamycin 2 Diclofenac sodium o,h Sorbitan monostearate 2 Polysorbate 60 1.5 Cetyl palmitate 3 2-octyldodecanol 13.5 Cetostearyl alcohol 10 propylene glycol 7 P enoxyethanol 1 Purified water, Heb. Pharm. 59.70 Total 100

Case example: female patient, 31 years old (EC), bacterial vaginosis resistant to therapy for several months, discharge with an unpleasant odor, especially in the postmenstrual period; as a result of microbial smear, many Gardnerella and Prevotella appear.

Gynecological examination: the mucosa is very reddened, the vaginal secretion is liquid and has an unpleasant odor; native smear of secretions: many key cells, leukocytes +++, bacterial vaginosis (RGIII).

Therapy: F4 for 1 week, 0-0-1 vaginally, then Hylaktiv Vagilact.

Examination after 2 years: after the above therapy without complaints, once a very mild fungal infection; gynecological examination: mucous membrane without irritation, normal flora from lactobacilli (RGI).

Example: emulsions containing fosfomycin trometamol.

Table

F5

The composition of the emulsion Wt% Fosfomycin trometamol 2 Diclofenac sodium 0.4 Sorbitan monostearate 2 Polysorbate 60 1.5 Cetyl palmitate 3 2-octyldodecanol 13.5 Cetylstearyl alcohol 10 propylene glycol 7 P enoxyethanol 1 Purified water, Heb. Pharm. 66.6 Total 100

Case example: female patient 69 years old (ET), recurrent urinary tract infection in

- 7 041079 for about 2 years, repeatedly received treatment with cyproxin. Within 2 weeks, the urge to urinate and burning in the vagina increased; gynecological examination: pain from pressure over the bladder; atrophic mucosa, bleeding on contact, atrophic cervix, soldered, opened with Cervix brush urogenital probe; discharge: characteristic of atrophy, aerobic mixed flora (RGIII), abundant leukocytes.

Therapy: F5 for 1 week, 0-0-1 Hb was applied vaginally, additionally Ovestin.

Control examination after 2 weeks: subjectively, there are no more complaints from the moment of therapy.

Gynecological examination: mucous membrane without atrophy, no pain from pressure over the bladder and urethra; native smear of discharge: onset of normal vaginal flora (RGI), no leukocytes.

Table

F6

The composition of the emulsion Wt% Fosfomycin trometamol 2 clotrimazole 1 Diclofenac sodium 0.3 Sorbitan monostearate 2 Polysorbate 60 1.5 Cetyl palmitate 3 2-octyldodecanol 13.5 Cetylstearyl alcohol 10 propylene glycol 7 P enoxyethanol 1 Purified water, Heb. Pharm. 58.7 Total 100

Case study: 36-year-old female patient (CS), 2 years ago first UTI after holiday in Thailand with gross hematuria and prolonged burning sensation, within 2 months again pain in the lower abdomen and UTI (again after holiday in Thailand), recurring burning sensation , especially after urination, the urge to urinate became more frequent for 2 weeks, after antibiotic treatment (1 week) there is no improvement in bladder problems, but now itching and burning in the vagina are additionally felt.

Gynecological examination: pressure pain over the bladder; the vaginal mucosa is rather unchanged, pronounced cervicitis with bloody erosion around the cervix about 1 cm in size; native smear of secretions: bacterial vaginosis, masses of leukocytes covered with bacteria, single lactobacilli, hyphae ++; microbiological smear culture: masses of E. coli.

Therapy: F6 for 10 days, 0-0-1 vaginally, additional 2 sachets of monural with an interval of 3 days.

Examination after 4 weeks: subjectively, there are no more complaints since the therapy.

Gynecological examination: mucous membrane without irritation, no pain from pressure over the bladder and urethra; native smear of discharge: normal vaginal flora (RGI), no leukocytes.

Table

F7

The composition of the emulsion Wt% Fosfomycin trometamol 2 Diclofenac sodium oh, s Sorbitan monostearate 2 Polysorbate 60 1.5 Cetyl palmitate 3 2-octyldodecanol 13.5 Cetylstearyl alcohol 10 propylene glycol 7 P enoxyethanol 1 Purified water, Heb. Pharm. 59.7 Total 100

Example: influence of the mass ratio of the aqueous phase/oil on the clinical efficacy of NSAIDs.

Surprisingly, changes in viscosity clearly affect clinical performance even with a small range of variation. These examples were prepared in accordance with the general instructions for preparation 1 by changing the content of oil components and water content.

An increase in water content and therefore a decrease in viscosity leads to local irritation and a decrease in clinical efficacy due to increased release and increased wetting of the mucous membranes.

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table 2

Effect of Aqueous Phase/Oil Mass Ratio on Clinical Performance

Phase Fat component/viscosity reduced Main compositions Fat component/viscosity increased clotrimazole (oil) 1.0 1.0 1.0 1.0 1.0 1.0 Diclofenac sodium (water) 0.3 0.3 0.3 oh, s 0.3 0.3 Sorbitan monostearate (-) 2.0 2.0 2.0 2.0 2.0 2.0 Polysorbate 60 (-) 1.5 1.5 1.5 1.5 1.5 1.5 Cetyl palmitate (oil) h, o h, o h, o h, o h, o h, o 2-octyldodecanol (oil) 13.5 13.5 13.5 13.5 13.5 14.5 Cetylstearyl alcohol (oil) 7.5 5 10 10 14 16 Benzyl alcohol (oil) 1.0 1.0 1.0 1.0 1.0 Phenoxyethanol (oil) 1.0 propylene glycol (water) 7 Water (water) 70.2 72.7 67.75 60.7 63.7 60.7 Total 100 100 100 100 100 100 Clinical Efficiency Irritation Irritation Corresponds Corresponds reduced reduced Total water phase 70.5 73.0 68.0 68.0 64.0 61.0 Total oil phase 26 23.5 28.5 28.5 32.5 35.5 Water phase/Oil phase 2.7 3.1 2.4 2.4 2.0 1.7

To calculate the weight ratio of the aqueous phase to the oil phase, the individual proportions of the aqueous and oil phases are summarized as shown in Table 1. 2. Since emulsifiers, such as sorbitan monostearate and polysorbate 60, are located at the interfaces between the two phases, they do not belong to either the water or oil phase.

If we calculate the ratio of the aqueous phase to the oil phase of the concentrated emulsion (i.e. the intermediate product of components A, B, J, C, E, G, H and half of the K) of example 2 of WO 02/0768648 A2, a ratio of 3.1 ( oil phase: terbinafine, butylhydroxytoluene, benzyl alcohol, isopropyl myristate, total 11.52 g/100 g; aqueous phase: diclofenac sodium and water, total 35.94 g/100 g; ratio 3.1). Thus, such an emulsion has a water to oil ratio outside the scope of the invention and is therefore not suitable in the context of the present invention.

Alternatively, the weight ratio of the aqueous phase to the oil phase can be calculated without taking into account the substances dissolved in the phases (clotrimazole, sodium diclofenac, benzyl alcohol, cetylstearyl alcohol). With this method of calculation, only water and propylene glycol will be assigned to the aqueous phase in table. 3, and cetyl palmitate, 2-octyldodecanol and cetylstearyl alcohol to the oil phase. Water-oil ratio 2.7; 3.1; 2.4; 2.4; 2.0; 1.7, given in table. 3 will correspond to the values 2.9; 3.4; 2.6; 2.6; 2.1; 1.8 according to this calculation method. The range according to the invention from 2.0 to 2.7 will correspond to the range from 2.1 to 2.9 according to this method of calculation.

However, in the context of the present invention, the calculation of the mass ratio of the aqueous phase to the oil phase should be performed as shown in table. 3, i.e. taking into account the substances dissolved in the phases.

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Table 3

Additional Examples of the Effect of Aqueous Phase/Oil Mass Ratio on Clinical Performance

Oil component/viscosity reduced Main compositions Oil component/viscosity increased clotrimazole oil 1.00 1.00 1 1 1 1.00 1.00 Diclofenac sodium water 0.30 0.30 0.25 0.3 0.4 0.30 0.30 Sorbitan monostearate 2.00 2.00 2 2 2 2.00 2.00 Polysorbate 60 1.50 1.50 1.5 1.5 1.5 1.50 1.50 Cetyl palmitate oil 3.00 3.00 3 3 3 3.00 3.00 2-octyldodecanol oil 13.50 13.50 13.5 13.5 13.5 13.50 14.50 Cetylstearyl alcohol oil 7.50 5.00 10 10 10 14.00 16.00 benzyl alcohol oil 1.00 1.00 1 1.00 1.00 P enoxyethanol oil 1 4 propylene glycol water 7 Purified water, Heb. Pharm. water 70.20 72.70 67.75 60.7 64.6 63.70 60.70 Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Clinical Efficiency Irritation Irritation Corresponds Corresponds Corresponds reduced reduced Water phase/ oil phase 2.7 3.1 2.4 2.4 2.1 2.0 1.7 Water phase 70.50 73.00 68.00 68.00 65.00 64.00 61.00 Oil phase 26.00 23.50 28.50 28.50 31.50 32.50 35.50

Example: influence of pH value on the clinical efficacy of NSAIDs.

Using emulsions with clotrimazole and NSAIDs, the effect of pH on the clinical efficacy of NSAIDs was investigated. Emulsions with different concentrations of diclofenac sodium were prepared and studied for their clinical efficacy.

Table 4

The dependence of clinical efficacy on the concentration of NSAIDs

Concentration, wt.% Concentration, wt.% Concentration, wt.% Concentration, wt.% clotrimazole 1 1 1 1 Diclofenac sodium OD 0.25 0.5 0.75 Sorbitan monostearate 2 2 2 2 Polysorbate 60 1.5 1.5 1.5 1.5 Cetyl palmitate 3 3 3 3 2-octyldodecanol 13.5 13.5 13.5 13.5 Cetylstearyl alcohol 10 10 10 10 benzyl alcohol 1 1 1 1 Purified water, Heb. Pharm. 67.9 67.75 67.5 67.25 Total 100 100 100 100 pH 7.6 7.8 8.1 8.1 Clinical Efficiency Slightly lowered Compliant Meets requirements, causes slight irritation Causes mucosal irritation

The combined use of clotrimazole and NSAIDs alters both microbiological and chemical stability [Ref. Pharmacopoeia] compared to a comparable formulation of clotrimazole due to pH shifts in the emulsion system.

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Table 5

Options with different preservatives

Compound wt% wt% wt% wt% wt% clotrimazole 1 1 1 1 1 Diclofenac sodium 0.4 0.3 0.3 0.25 0.25 Sorbitan monostearate 2 2 2 2 2 Polysorbate 60 1.5 1.5 1.5 1.5 1.5 Cetyl palmitate 3 3 3 3 3 2-octyldodecanol 13.5 13.5 13.5 13.5 13.5 Cetylstearyl alcohol 10 10 10 10 10 Sorbic acid 0.2 bhfsrny pacivor (>.2201 0.0X74 Purified water, Evr.Pharm. 64.6 60.7 62.7 67.4299 68.4626 Total 100 100 100 100 100 pH 7.9 7.6 7.9 7.5 5.6 Clinical Efficiency Corresponds Corresponds Corresponds Corresponds reduced Microbiological stability Corresponds Corresponds Corresponds Corresponds Corresponds

Example: antifungal shampoo for hair loss.

Table

F8

The composition of the emulsion Wt% Ketoconazole 2 Diclofenac sodium 0.3 Ammonium lauryl sulfate 15.00 Lauramide 4.00 Sodium chloride 1.00 Farnesol 1 Disodium EDGA 0.2 Methylparaben 0.08 Propylparaben 0.05 Purified water, Heb. Pharm. 76.37 100

Structural formula of ibrexafungerp (SCY-078)

Structural formula of oteseconazole (VT-1161)

Accordingly, the invention relates to the following preferred embodiments.

1. An emulsion for the topical treatment of skin infections and mucosal infections, in particular urogenital infections, where an antimicrobial active and an anti-adhesive active, preferably an NSAID, are used in combination.

2. An emulsion according to Embodiment 1 which further contains an antifungal active.

3. An emulsion according to embodiment 1 or 2, preferably in the form of an ointment or cream with an aqueous phase and an oily phase, containing an antimicrobial active and an NSAID, where (a) the NSAID in the aqueous phase is in the concentration range that corresponds to 1/2- 1/10 of the standard concentration used for these active substances in approved dermal formulations;

- 11 041079 (b) the mass ratio of the aqueous phase to the oil phase in this emulsion is between the values of 2.0 and 2.7;

(c) the pH value of the emulsion is not less than 6.5 and not more than 8.5, preferably in the range from 7.0 to 8, preferably for the treatment of urogenital infections, in particular for use in the topical treatment of vaginal infections and cystitis in women , as well as for local treatment of a partner (head of the penis, the initial third of the urethra).

4. An emulsion according to embodiment 1 or 2, preferably in the form of a cream, cream, shampoo, solution or stick, with an aqueous phase and an oily phase, containing an antimicrobial active and an NSAID, where (a) the NSAID in the aqueous phase is in the range concentration, which in the case of skin application corresponds at most to the standard concentration, and in the case of application to mucous membranes corresponds to 1/2-1/10 of the standard concentration for these active substances; and (b) the pH value of the emulsion is not less than 5.5 and not more than 8.5, preferably for the topical treatment of skin infections, in particular for use in the topical treatment of acne, hair loss, pityriasis versicolor and atopic dermatitis.

5. An emulsion according to any one of embodiments 1-4, wherein the NSAID is diclofenac, bufexamac, ibuprofen, dexibuprofen, flurbiprofen, ketoprofen, piroxicam, meloxicam, lornoxicam, flufenamic acid, mefenamic acid, indomethacin, or naproxen.

6. The emulsion of any one of embodiments 1-5, wherein the antimicrobial active is an antibiotic.

7. An emulsion according to embodiment 6 wherein the antibiotic is fosfomycin, clindamycin, metronidazole, nitrofurantoin, nitrofurazon, nifuratel, nifuroxacin, nitroxoline, trimethoprim, sulfadiazine, or cotrimoxazole.

8. The emulsion of any one of embodiments 1-7, wherein the antimicrobial active is an antiseptic.

9. An emulsion according to embodiment 8, wherein the antiseptic is selected from the group consisting of benzalkonium chloride, preferably at a concentration of at least 0.2% by weight; dequalinium chloride, preferably at a concentration of at least 0.2% by weight; and phenoxyethanol, preferably at a concentration of at least 2% by weight.

10. An emulsion according to any one of embodiments 2-9 wherein the antifungal active is nystatin, ciclopirox or ciclopiroxolamine or an azole antifungal agent, preferably clotrimazole, fluconazole, miconazole, itraconazole, thioconazole, voriconazole, bifonazole, econazole, isoconazole, fenticonazole, sertaconazole, ketoconazole, posaconazole, quilseconazole, oteseconazole (VT-1161) or ibrexafungerp (SCY-078).

11. An emulsion according to one of embodiments 1-10, wherein the NSAID is diclofenac and is contained in a concentration range of 0.2-0.4% by weight of the emulsion.

12. An emulsion according to any one of embodiments 1-11, additionally containing an odorous substance, preferably a terpene, in particular farnesol.

13. An emulsion according to any one of embodiments 1-12 for use in the topical treatment of infectious diseases, in particular for use in the topical treatment of skin and urogenital infections.

14. An emulsion for use according to Embodiment 13, wherein the infectious disease is a mucosal infection, in particular a urogenital infection.

15. An emulsion for use according to embodiment 13 or 14, wherein the infectious disease is a microbial urogenital infection, in particular a microbial urogenital infection in women.

16. An emulsion for use according to embodiment 15, wherein the microbial urogenital infection is a bacterial urogenital infection.

17. An emulsion for use according to any one of embodiments 13-16, wherein the infectious disease is a mixed vaginal infection caused by Candida albicans and bacteria such as Enterobacter, E. coli, Klebsiella pneumoniae, Gardnerella vaginalis, or Prevotella spp.

18. An emulsion for use according to any one of embodiments 13-17, wherein the infectious disease is asymptomatic or symptomatic bacterial vaginosis or asymptomatic or symptomatic dysbiosis of the glans penis and/or urethra in men.

19. An emulsion for use according to any one of embodiments 13-18, wherein the infectious disease is a chronic infectious disease.

20. The emulsion of any one of embodiments 1-12 for use in the treatment of acne.

21. An emulsion according to Embodiment 20 available as a stick or solution for acne treatment.

22. An emulsion according to any one of embodiments 1-12 for use in the treatment of skin fungal infections, preferably candidiasis and malasseziosis.

23. Emulsion, preferably shampoos, according to any of Embodiments 1-12 for

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Claims (28)

use in the treatment of hair loss. 24. A method for preparing an emulsion according to any one of embodiments 1-12, wherein the NSAID is introduced through the aqueous phase in the preparation of the emulsion. 25. The method of preparing an emulsion according to any one of embodiments 1-12, wherein the NSAID is administered as a finely crystalline or micronized salt to an antifungal-containing emulsion. CLAIM 1. An emulsion for topical treatment of skin and mucosal infections, wherein an antimicrobial active selected from an antibiotic and an antiseptic and a non-steroidal anti-inflammatory agent (NSAID) are used in combination, wherein (a) the NSAID is diclofenac at a concentration of 0.1 to 0.5 wt.%, indomethacin in a concentration of 0.1 to 0.4 wt.%, naproxen in a concentration of 1 to 5 wt.%, ibuprofen in a concentration of 0.5 to 2.5 wt.%, dexibuprofen in concentrations from 0.25 to 1.25 wt.%, ketoprofen in a concentration of 0.25 to 1.25 wt.%, mefenamic acid in a concentration of 0.5 to 4 wt.% or lornoxicam in a concentration of 0.02 to 0.04 wt.%, where the NSAID is present in the form of a salt; (b) the weight ratio of the aqueous phase to the oil phase in this emulsion is from 2.0 to 2.7, taking into account the substances dissolved in the phases; and (c) the pH value of the emulsion is not less than 6.5 and not more than 8.5. 2. The emulsion according to claim 1, intended for the local treatment of urogenital infectious diseases. 3. An emulsion according to claim 1 or 2, wherein the pH of the emulsion is in the range of 7.0 to 8.0. 4. An emulsion according to any one of claims 1 to 3, which additionally contains an antifungal active. 5. An emulsion according to any one of claims 1 to 4 in the form of an ointment or cream, shampoo, solution or stick for the topical treatment of skin infections. 6. An emulsion according to any one of claims 1 to 5, wherein the antimicrobial active is an antibiotic. 7. The emulsion of claim 6 wherein the antibiotic is fosfomycin, clindamycin, metronidazole, nitrofurantoin, nitrofurazon, nifuratel, nifuroxacin, nitroxoline, trimethoprim, sulfadiazine, or cotrimoxazole. 8. An emulsion according to any one of claims 1 to 7, wherein the antimicrobial active is an antiseptic. 9. Emulsion according to claim 8, where the antiseptic is selected from the group consisting of benzalkonium chloride, preferably at a concentration of at least 0.2 wt.%; dequalinium chloride, preferably at a concentration of at least 0.2% by weight; and phenoxyethanol, preferably at a concentration of at least 2% by weight. 10. An emulsion according to any one of claims 4 to 9, wherein the antifungal active is nystatin, ciclopirox or ciclopiroxolamine, or an antifungal agent from the azole group, preferably clotrimazole, fluconazole, miconazole, itraconazole, thioconazole, voriconazole, bifonazole, econazole, isoconazole, fenticonazole, sertaconazole, ketoconazole, posaconazole, quilseconazole, oteseconazole (VT-1161) or ibrexafungerp (SCY-078). 11. An emulsion according to any one of claims 1 to 10, wherein the NSAID is diclofenac and is contained in a concentration range of 0.2-0.4% by weight of the emulsion. 12. An emulsion according to any one of claims 1 to 11, additionally containing an odorous substance, preferably a terpene, in particular farnesol. 13. Use of the emulsion according to any one of claims 1 to 12 in the topical treatment of infectious diseases such as skin and urogenital infections. 14. Use according to claim 13, wherein the infectious disease is a mucosal infection, such as a urogenital infection. 15. Use according to claim 13 or 14, wherein the infectious disease is a microbial urogenital infection, such as a microbial urogenital infection in women. 16. Use according to claim 15, wherein the microbial urogenital infection is a bacterial urogenital infection. 17. Use according to any one of claims 13-16, wherein the infectious disease is a mixed vaginal infection caused by Candida albicans and bacteria such as Enterobacter, E. coli, Klebsiella pneumoniae, Gardnerella vaginalis or Prevotella spp. 18. Use according to claim 16 or 17, wherein the infectious disease is asymptomatic or symptomatic bacterial vaginosis or asymptomatic or symptomatic dysbiosis of the glans penis and/or urethra in men. 19. Use according to any one of claims 13-18, wherein the infectious disease is a chronic infectious disease. - 13 041079 20. Application according to any of pi. 13-19, where the infectious disease is a fungal infection of the skin, preferably candidiasis or malassezia. 21. Use according to claim 13, wherein the infectious disease is acne. 22. Use according to claim 21, wherein the emulsion is in the form of an acne stick. 23. Use of an emulsion according to any one of claims 1 to 12 in the local treatment of cystitis in women and for the local treatment of a partner (glans penis, initial third of the urethra). 24. Use of an emulsion according to any one of claims 1 to 12 in the treatment of hair loss. 25. Use according to claim 24, wherein the emulsion is in the form of a hair shampoo. 26. Use of an emulsion according to any one of claims 1 to 12 in the topical treatment of atopic dermatitis. 27. A method for preparing an emulsion according to any one of claims 1 to 26, wherein the NSAID is introduced into the aqueous phase during the preparation of the emulsion. 28. A method for preparing an emulsion according to any one of claims 4 to 24, wherein the NSAID is introduced as a finely crystalline or micronized salt into an emulsion containing an antifungal agent. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 -