Classifications

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  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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  • A61K31/4164—1,3-Diazoles
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• Emulsions for the treatment of mucous membrane infections are provided.
• the invention relates to emulsions for the treatment of mucosal infections, in particular of inflammatory vaginal infections.
• WO 2007/131253 A2 relates to the use of an antifungal agent and an epithelial cell or endothelial cell adhesion inhibitor for the preparation of a combination drug for the topical treatment of candidiasis selected from vulvovaginal candidiasis, oropharyngeal candidiasis (oral thrush), diaper dermatitis (diaper sclerosis) and intertriginous dermatitis.
• WO 02/0768648 A2 relates to pharmaceutical compositions for topical use containing an antimycotic, e.g. Terbinafine, and a second active ingredient, e.g. Diclofenac or indomethacin.
• the compositions can be used for the prevention or treatment of fungal infections, especially by dermatophytes.
• US 5 686 089 A relates to topical pharmaceutical compositions containing an antimicrobial agent and a moisturizing component.
• the compositions may e.g. used in vaginal fungal infections.
• Mendling et al. (Mendling, Werner, et al., "Use of locally delivered dequalinium chloride in the treatment of vaginal infections: a review.” Archives of gynecology and obstetrics 293.3 (2016): 469-484) describes treatment options for vaginal infections with dequalinium chloride.
• the object of the present invention is to provide improved NSAID preparations which are particularly suitable for the treatment of mucous membrane infections and inflammations.
• Such emulsions should also be effective for persistent fungal infections, which occur especially in the vaginal area, as well as be microbiologically and chemically stable.
• the present invention relates to an emulsion, preferably in the form of an ointment or cream, comprising an aqueous phase and an oil phase (fatty phase) containing an NSAID, characterized in that (a) the NSAID is present in the aqueous phase in a concentration range which corresponds to one-half to one-tenth of the single-dose concentration customary for these active ingredients in other formulations, (b) the weight ratio of the aqueous phase to the oil phase in this emulsion is between 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 the range 7.0 to 8.0, preferably for the treatment of mucous membrane infections and mucosal inflammations, in particular for use in the topical treatment of mucosal infections and mucosal inflammation.
• the present invention relates to an emulsion, preferably in the form of an ointment or a cream, comprising an aqueous phase and an oil phase (fat phase) containing an antifungal and an NSAID, characterized in that (a) the NSAID in the aqueous phase in a concentration range corresponding to one half to one tenth of the single dose concentration customary for these active ingredients in other formulations, that (b) the weight ratio of the aqueous phase to the oil phase in this emulsion is between 2.0 to 2.7, and (c) that the pH of the emulsion is not below 6.5 and not above 8.5, preferably in the range 7.0 to 8.0, preferably for the treatment of dermal and vaginal fungal infections, in particular for use in the topical Treatment of vaginal fungal infections.
• the present invention provides improved preparations of the type described above.
• the preparations according to the invention in addition to the optimized pharmacokinetics by the attack directly at the site of infection, also show optimal pharmacodynamics.
• the preparations according to the invention enable a sufficient effectiveness of the NSAIDs when using low concentrations and thus low side effects.
• the combination preparations according to the invention thus not only a particularly good efficacy of the antimycotic is possible, but also the interaction with the NSAID significantly improved by a low concentration of NSAID nevertheless sufficient efficacy is ensured without the side effects (irritation, burning , etc.) to accept.
• the preferred NSAIDs used in the present invention are selected from the group consisting of diclofenac, bufexamac, ibuprofen, dexibuprofen, ketoprofen, flurbiprofen, piroxicam, meloxicam, lornoxicam, flufenamic acid, mefenamic acid, naproxen and indomethacin.
• concentration for topical therapy in which diclofenac is used is in the range of 1 to 2% (10 mg / or 20 mg / g).
• Diclofenac is used according to the invention in a concentration of 0.1% to 0.5% (1-5 mg per g of cream), preferably from 0.2% to 0.35%.
• ibuprofen is used in a preferred amount of 0.5 to 2.5% (5 to 25 mg per g cream), preferably 1 to 2%.
• NSAIDs preferred NSAIDs and their preferred amounts
• NSAIDs particularly preferred within the scope of the invention are the following NSAIDs:
• the invention relates to medicament combinations which are particularly suitable for vaginal administration, and to their production and use.
• a special composition and a special one are found Production process as particularly advantageous.
• the observation of specific parameters leads to a particularly good therapeutic effect in the treatment of vaginal vaginal infections.
• the present compound relates only to the group of non-steroidal anti-inflammatory drugs (NSAIDs), because drugs of this group also have an analgesic and anti-inflammatory effect in addition to the antiadhesive effect which prevents the attachment.
• NSAIDs non-steroidal anti-inflammatory drugs
• Both effects, especially the anti-inflammatory effect, are especially welcome in relapsing forms of candidal mycosis because they are associated with chronic inflammation and severe pain.
• Preferred NSAIDs are diclofenac, ibuprofen, dexibuprofen ketoprofen, flubiprofen, maleficain, naproxen, lornoxicam and indomethacin.
• Preferred antimycotics are nystatin, ciclopirox or ciclopiroxolamine, or antifungals from the group of azoles (imidazoles, triazoles, tetrazoles) such as clotrimazole, fluconazole, miconazole, itraconazole, tioconazole, voriconazole, bifonazole, econazole, isoconazole, fenticonazole, sertaconazole, ketoconazole, posaconazole, Quileconazole, otesconazole (VT-1161), from Ibrexafungerp (SCY-078).
• the ratio of the proportions of the antimycotic and the NSAID is of particular importance in order to obtain an optimal effect.
• the antifungal may be in the usual
• Dosages are used (clotrimazole 1-10%, ketoconazole 1-5%, preferably 2%, nystatin 100,000 IU / ml or g). Since the NSAID exerts its effect in the same way on the pathogen in the vagina and the vaginal epithelium, on the one hand the topical application of the drug, in which it is indeed applied directly at the site of action, clearly superior to a systemic application, on the other hand, therefore, the NSAID in far lower doses are used than in the usual systemic applications as analgesics.
• a therapeutic effect is achieved as low as one-tenth, preferably one-fifth, of an active substance concentration which is used in conventional dermal formulations of NSAID (in the case of diclofenac 200 to 500 mg / 100 g of ointment).
• the low drug concentration is also particularly advantageous because the systemic uptake of the NSAID is negligible and there is no risk of systemic side effects.
• topical application to mucous membranes can easily lead to overdose of the NSAID (for example, a cream containing diclofenac: from 0.5% is painful and rapid)
• NSAID-containing creams (1-2% diclofenac, 5% ibuprofen) on mucous membranes are warned against the application on the market (eg instructions for use Voltaren Emulgel, Ibutop-Gel) because irritation of the mucous membranes occurs counteracts anti-inflammatory effect. Therefore, according to the invention, the NSAID should not be used in any amount greater than 50% of the usual lowest formulation for dermal applications. At this concentration irritations may already occur.
• the active ingredient concentration of the NSAID to be used preferably moves in a relatively small amount therapeutic window of 10 - 60, preferably 20-40% of the usual value for topical formulations.
• a particularly preferred emulsion according to the present invention contains diclofenac as NSAID, wherein diclofenac is contained in a concentration range of 0.2-0.4% by weight of the emulsion. Even more preferred is when diclofenac is present in a concentration range of 0.2-0.35 weight percent of the emulsion. Most preferred is a concentration range of 0.25-0.35 weight percent. Higher levels of lower alcohols, such as ethanol or isopropanol, (> 10%) increase the irritant effect and therefore counteract the pain and inflammation-reducing effects.
• medicaments according to the present invention require the safe retention of the active ingredient, especially the NSAID component at the site of action, in order to achieve the desired therapeutic effect. Therefore, in the drug, the ratio of the oil phase containing the antimycotic to the water phase in which the NSAID is located is in a relatively narrow range. Solutions, emulsions or gels with high water and / or alcohol content are to be excluded as dosage forms according to the present invention, because an uncontrolled loss due to vaginal discharge is to be expected.
• Semi-solid emulsions oil in water or water in oil
• the viscosity of the emulsions is strongly determined by the water to oil ratio.
• the ratio of water to oil is of particular importance. With a higher proportion of fatty components, the development of effectiveness is hindered. On the other hand, it comes with a lower fat content to a stronger irritant effect.
• the water: oil ratio should not exceed the value of 2.7.
• the active agent is washed out too quickly with the vaginal secretions, whereby there is insufficient time to unfold the adhesion-promoting effect on the outer layer of the vaginal epithelium to which the fungus adheres.
• the excessively high water: oil ratio very quickly washed out active ingredient may at best cause as a side effect also a irritating effect.
• the water: oil weight ratio in the emulsion should not fall below the value of 2.0.
• a window results between 2.0 and 2.7, preferably between 2.1 and 2.6, even more preferably between 2.2 and 2.55.
• the NSAIDs according to the invention be in salt form (or ionic form), both during incorporation and during use. Therefore, their incorporation into the formulation is important.
• the NSAID is typically incorporated into the aqueous phase prior to the preparation of the emulsion by the method of the invention.
• the solid salt of the NSAID can be incorporated in finely crystalline or micronized form, or as a hydrogel in the (largely) finished emulsion.
• NSAIDs are weak acids with a pKa 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 the weakly acidic environment partly in free form and are thus extracted into the oil phase, which can lead to a reduced effect or loss of activity.
• the emulsion according to the invention is suitable for vaginal administration.
• compositions which have a high content of mucous membrane damaging substances such as ethanol or isopropanol. It is therefore preferred that the emulsion according to the invention does not contain more than 10% by weight, in particular not more than 5% by weight, of ethanol. It is also preferred that the emulsion according to the invention does not contain more than 15% by weight, in particular not more than 7.5% by weight, of isopropanol.
• the combination of a lipophilic antimycotic, the structural type of clotrimazole, with the weak acids of the NSAIDs also results in the combination being stable only in a relatively narrow pH window.
• clotrimazole becomes unstable, whereas with NSAIDs a decrease in chemical stability in the alkaline medium can occur (in the case of diclofenac from pH 8.00 - 8.5).
• the chemical stability is in turn from the Water: oil ratio and influenced by the proportion of alcoholic substances.
• combination medications of azoles and the acidic NSAIDs unfavorable stability requirements arise from the direct reactivity of the active ingredients.
• the pH of an emulsion influences the basic physiological compatibility. Therefore, relatively narrow limits are also set with regard to the pH of the formulation.
• the (aqueous phase of the emulsion) has a pH in the range of 6.5 to 8.5, preferably 7-8.
• the preservative commonly used in comparable emulsions containing only clotrimazole is not always sufficiently effective.
• the semi-solid antifungal drugs according to the present invention are therefore preferably protected with such preservatives and antiseptics against microbial attack, which are effective in the pH range of the emulsion.
• the content of the antiseptic is expediently kept low in order not to impair the normal vaginal flora.
• the biofilms that are formed by the growth of the fungi often contain not only fungi but also other pathogenic microorganisms.
• Preferred antiseptics are quaternary ammonium salts, such as benzalkonium chloride, and dequalinium chloride, as well as phenoxyethanol.
• Preferred concentrations are at least 0.2 weight percent for benzalkonium chloride, at least 0.2 weight percent for dequalinium chloride, and at least 2 weight percent for phenoxyethanol.
• the bacterial microorganisms found in the vaginal biofilms are typical intestinal bacteria such as Enterobacter, E. coli and / or Klebsiella pneumoniae as well as anaerobes such as Gardnerella vaginalis and Prevotella spp. a special role. These are probably also covered by the claimed antiseptics, but it is expedient, in proven cases of such an infection, instead of the antiseptic or in addition to use an anti-anaerobic antibiotic. Therefore, the addition of an antibiotic which acts against anaerobic bacteria, another object of the invention.
• Preferred antibiotics are phosphomycin, clindamycin, metronidazole, nitrofurantoin, nitrofurazone, nitrofurantoin, nifuratel, nifuroxacin, nitroxoline, trimethoprim, sulfadiazine and cotrimoxazole.
• Mucosal surfaces provide ideal conditions for the formation of biofilms, which are particularly resistant to therapy.
• the vaginal microbiome carries through the Influencing the moist, physiologically acidic milieu of the vagina is crucial to the effectiveness of topically applied drug forms, since the availability of the drugs is pH-dependent. These conditions are one of the contributing factors that currently marketed topical antimycotics have only a very limited success in the treatment of chronic vulvovaginitis, especially in the presence of mixed infections with bacteria.
• the composition of the drug combinations according to the invention is particularly suitable in the combinations described for the treatment of even complex chronic vaginal inflammation.
• emulsions according to this invention are also very suitable for the treatment of mycoses, in particular candidal mycoses, but also infections with Malassezia.
• the emulsions according to the invention are preferably used in the treatment of dermal and vaginal fungal infections, in particular for use in the topical treatment of vaginal fungal infections.
• the emulsions according to the invention can be used for the treatment of infectious diseases, in particular vaginal infections by Candida albicans or mixed vaginal infections by Candida albicans and bacteria, such as Enterobacter, E. coli, Klebsiella pneumoniae, Gardnerella vaginalis, Prevotella spp.
• a particular embodiment of the present invention is for use in the treatment of bacterial vaginosis.
• Another particular embodiment of the present invention is useful in the treatment of dermal and mucosal fungal and mixed infections, preferably candidal mycosis, in particular vulvovaginal candidiasis, oropharyngeal candidiasis, diaper rash, anal eczema, intertriginous dermatitis, and malasseziamycosis (pityriasis versicolor ).
• candidal mycosis in particular vulvovaginal candidiasis, oropharyngeal candidiasis, diaper rash, anal eczema, intertriginous dermatitis, and malasseziamycosis (pityriasis versicolor ).
• emulsions are the subject of the present invention, which contain no antifungal or antimicrobial agent. Because of their reliable release of the NSAID, which results from the specific composition, these are very well suited to be used in the after-treatment of mucosal infections, in particular of vaginal inflammations. Such semi-solid emulsions are also very well suited to treat chronic inflammation of other causes, especially inflammation of the mucous membranes and adjacent tissues. Examples of this arise in the after-treatment of chronic cystitis, in atrophic vaginitis or in inflammation of the anal mucosa.
• the emulsions according to the invention are therefore used in particular for use in the treatment of mucosal inflammations and mucosal infections, in particular of vaginal infections and vaginal inflammations, in particular chronic inflammations and infections.
• Figure 1 Clinical Phase II study. Pain diaries of patients with recurrent vulvovaginal candidiasis (RWC) containing emulsions containing different diclofenac Na concentrations (CP1: 0.2% by weight, CP2: 0.3% by weight, CP3: 0.4% by weight) or with a control composition
• the pain intensity was recorded on a pain scale of 0 to 10 by the patients at the time of recording, and the graph shows the mean of the treatment groups during the course of the treatment Pain intensity is given, however, the healing curve flattens off as soon as the daily dose is halved (starting on day 4).
• CP 2 shows an optimal healing process, and on the second day the pain level has dropped to 50% of the initial value.
• Changes in the production process and in the percentage composition of an oil-water mixture according to base formulation A showed surprising changes in the clinical efficacy apart from the usual dose-response relationships.
• the significantly improved or possibly even reduced efficacy can be derived from a particularly rapid onset of action (local analgesia) or a delay in the onset of action or the intensification of pre-existing pain.
• Changes in the preservatives are associated with changes in pH.
• the preparation of the examples given is carried out according to general procedure 1.
• the adjustment of the pH to achieve the optimum effect of the respective preservative is carried out by adding suitable buffer solutions, by which the respective amount of purified water has been replaced.
• the pH value has a significant influence on the locally bioavailable amount of active ingredient via the shift in the proportion of free active ingredient compared to the proportion present as salt. Depending on the pKa values of the non-steroidal anti-inflammatory drugs used, this results in a pH optimum of the combination preparations according to the invention according to the present invention.
• Example 3 Influence of the weight ratio aqueous phase / oil
• the individual portions of the water and the oil phase are summed up as shown in the table. Since emulsifiers, e.g. Sorbitan monostearate and polysorbate 60, at the interfaces between the two phases, they are neither the water nor the oil phase attributable.
• emulsifiers e.g. Sorbitan monostearate and polysorbate 60
• the weight ratio of the water to the oil phase could be calculated without involving the substances dissolved in the phases (clotrimazole, diclofenac-Na, benzyl alcohol, cetylstearyl alcohol).
• Tab. 3 only water and Attributable to propylene glycol of the water phase, and cetyl palmitate, 2-octyldodecanol and cetystearyl alcohol of the oil phase.
• the water-oil ratios 2.7, 3.1, 2.4, 2.4, 2.0, 1.7 given in Table 3 would, according to this calculation, be 2.9, 3.4, 2.6 , 2,6, 2,1, 1,8.
• the range of 2.0 to 2.7 according to the invention would correspond to a range of 2.1 to 2.9 in this calculation.
• Diclofenac Na was prepared and tested for clinical efficacy.
• sorbitan monostearate, polysorbate 60, cetyl palmitate, 2-octyldodecanol and cetostearyl alcohol are melted at a temperature of 70-75 ° C.
• Clotrimazole and then benzyl alcohol are added to the clear melt with stirring at a temperature of 60 ° C. to 70 ° C.
• diclofenac sodium is dissolved in purified water with heating.
• the aqueous solution is added with stirring to the oil phase and homogenized. With slow cooling with further homogenization of the resulting w / o emulsion, a phase reversal takes place in which a hydrophilic, homogeneous cream is formed.
• sorbitan monostearate, polysorbate 60, cetyl palmitate, 2-octyldodecanol and cetostearyl alcohol are melted at a temperature of 70-75 ° C.
• diclofenac sodium is dissolved in purified water with heating.
• the aqueous solution is added at a temperature of 60 ° C - 70 ° C with stirring to the oil phase and homogenized.
• the incorporation of the NSAID may be accomplished by stirring in a hydrogel dissolved NSAID or by stirring the (micronized) NSAID as a solid during the emulsion preparation instead of dissolving in water.
• Example 9 Preparation of base formulation A by incorporation of the NSAID into the oil phase
• Creams containing various concentrations of diclofenac Na were prepared according to Basic Formulation A according to General Preparation Procedure 2 and tested for their clinical effectiveness. Purified water was changed to diclofenac Na, the content of the lipid components, the O / W emulsifier polysorbate 60 and the preservative benzyl alcohol were identical in the formulations.
• sorbitan monostearate, polysorbate 60, cetyl palmitate, 2-octyldodecanol and cetostearyl alcohol are melted.
• Benzyl alcohol is added to the clear melt with stirring (lipid phase).
• Purified water is boiled and 70% of the required mass is added to the lipid phase with stirring according to the recipe (phase inversion and formation of an O / W preemulsion).
• Approximately 30% of the pre-emulsion is removed from the kettle and dispersed therein, clotrimazole and diclofenac sodium.
• the medicated preemulsion is added to the pellet to the drug-free preemulsion and filled with purified water (remaining 30%) to the final mass.
• the cream is stirred until it reaches room temperature and finally added twice over the three-roll mill for homogenization (pH 6.99).
• sorbitan monostearate, polysorbate 60, cetyl palmitate, 2-octyldodecanol and Cetostearyl alcohol are melted.
• Benzyl alcohol is added to the clear melt with stirring (lipid phase).
• Purified water is boiled and 70% of the required mass is added to the lipid phase with stirring according to the recipe (phase inversion and formation of an O / W preemulsion).
• About 30% of the preemulsion is taken out of the kettle and dispersed therein clotrimazole.
• the medicated preemulsion is added to the pellet to the drug-free preemulsion and filled with purified water (remaining 30%) to the final mass.
• the cream is stirred with the addition of micronized diclofenac sodium in several portions until it reaches room temperature and finally passed through the three-roll mill for homogenization twice.
• Emulsion CP1 0.2% by weight of diclofenac Na
• Emulsion CP2 0.3% by weight of diclofenac Na
• Emulsion CP3 0.4% by weight of diclofenac Na
• Emulsion 2 containing 0.3% by weight of diclofenac Na, proved to be particularly advantageous.
• a complete clinical cure (complete symptom-free examination by the attending physician) was achieved in all patients in this group. In the control group, only one cure was achieved in 40% of the patients.
• the invention relates to the following preferred embodiments:
• An emulsion comprising an aqueous phase and an oil phase containing an NSAID, characterized in that (a) the NSAID is present in the aqueous phase in a concentration range which is one half to one tenth of the concentration customary for these active ingredients ( b) the weight ratio of the water phase to the oil phase in this emulsion is between 2.0 and 2.7 and that (c) the pH of the emulsion is not lower than 6.5 and not higher than 8.5, preferably in the range 7.0 to 8.0.
• aqueous phase-oil phase emulsion containing an antimycotic and an NSAID characterized in that (a) the aqueous phase NSAID is present in a concentration range which is one-half to one tenth of the concentration commonly used for these agents in that (b) the weight ratio of the water phase to the oil phase in this emulsion is between 2.0 and 2.7 and that (c) the pH of the emulsion is not lower than 6.5 and not higher than 8.5 preferably in the range 7.0 to 8.0.
• An emulsion according to embodiment 1 or 2 characterized in that the weight ratio of the water to the oil phase in this emulsion is between 2.1 and 2.6, preferably between 2.2 and 2.55.
• azoles preferably clotrimazole, fluconazole, miconazole, itraconazole, tioconazole, voriconazole, bifonazole, econazole, isoconazole, fenticonazole, sertaconazole, ketoconazo
• NSAID diclofenac preferably in a concentration of 0.2 to 0.5 weight percent, ibuprofen, preferably in a concentration of 0.5 to 2.5 weight percent, bufexamac, Dexibuprofen, flurbiprofen, ketoprofen, piroxicam, meloxicam, lornoxicam, flufenamic acid, mefenamic acid, indomethacin, preferably in a concentration of 0.1 to 0.4 weight percent, or naproxen, preferably in a concentration of 0.5 to 2.5 weight percent ,
• Phenoxyethanol or propylene glycol or a combination of these two is.
• Emulsion according to any of embodiments 1 to 20 for use in the treatment of chronic urogenital tract infections Emulsion according to any of embodiments 1 to 21 for use in the treatment of chronic vaginal fungal infections.
• Emulsion according to embodiments 1 to 25 for use in the treatment of dermal or mucosal fungal infections preferably candidiasis, in particular vulvovaginal candidiasis, oropharyngeal candidiasis, diaper rash, anal eczema, intertriginous dermatitis, and malasseziamycoses.

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