WO2024187210A1

WO2024187210A1 - Combination drug for treating and reducing the relapse rate of vaginal mycosis

Info

Publication number: WO2024187210A1
Application number: PCT/AT2024/060094
Authority: WO
Inventors: Christian R. Noe; Marion Noe-Letschnig
Original assignee: Profem Gmbh
Priority date: 2023-03-15
Filing date: 2024-03-15
Publication date: 2024-09-19

Abstract

The invention relates to an oral antimycotic agent for use in the treatment of fungal infections, wherein the treatment comprises a topical adjunctive therapy with a dosage form to be applied topically. The invention furthermore relates to a dosage form to be applied topically for use in the treatment of fungal infections, for use in the treatment of vaginal side-effects of a systemic treatment of fungal infections and for use during the follow-up treatment for a fungal infection or to prevent a relapse thereof. The invention also relates to a kit comprising an oral antimycotic agent and a dosage form to be applied topically.

Description

Combination medicine for the treatment and reduction of relapse rates of vaginal mycoses

Chronic recurrent Candida vulvovaginitis (RWC) is a widespread disease that affects around 5% of women worldwide. Efficient medications have only recently been developed. There are two different therapeutic approaches. Firstly, there are preparations for oral use, according to a special treatment regimen, such as fluconazole, itraconazole or oteseconazole. These preparations have the advantage that - coming from the inside - they also reach deep fungal-infected layers and, if they remain in the body for a sufficiently long time, kill the fungi in the tissue. The active ingredient oteseconazole, approved in the USA in 2022, is an example of how relapses can be avoided through an extremely long residence time. The biological half-life of the pharmacologically highly active active ingredient is 138 days. Together with the very high dosage of oteseconazole, this results in a mean exposure duration of approximately 690 days.

A disadvantage of oral therapy is the increased risk of side effects. This results in severe limitations with regard to the use of oral antimycotics, particularly when used for longer periods, because this duration of treatment makes the drugs detrimental to the main target group, namely women of childbearing age. This is particularly true of oteseconazole with its proven reproductive toxic side effects. The disadvantage of using the most commonly used oral antimycotic, fluconazole, is primarily the high relapse rate in the treatment of RWC after discontinuation of therapy. Within six months of completing the six-month guideline therapy, 57% of patients experience a relapse.

There are three studies on the frequency of relapse after fluconazole treatment in which long-term observations were made: Martens et al. ( "Phase 3 study evaluating the safety and ef ficacy of oteseconazole in the treatment of recurrent vulvovaginal candidiasis and acute vulvovaginal candidiasis infections" American Journal of Obstetrics and Gynecology 227 . 6 ( 2022 ) : 880-el ), Donders et al. ( " Individualized decreasing-dose maintenance fluconazole regimen for recurrent vulvovaginal candidiasis (ReCiDiF trial) "American Journal of Obstetrics and Gynecology 199. 6 (2008): 613-el) and Sobel et al. ("Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis." New England Journal of Medicine 351. 9 (2004): 876-8 83).

Table : Relapse rate with oral antimycotic therapy

The study by Sobel in 2004 is the basis for the approval of fluconazole for the treatment of chronic recurrent vulvovaginal candidiasis in Europe and also for the established guideline therapy in many countries around the world. This study also clearly shows that the relapse rate is only delayed by six months with maintenance therapy, meaning that fluconazole has a suppressive effect primarily for the duration of treatment.

Donders' study used a dosing regimen in which decreasing doses were used over 12 months. The observation period was 18 months in total. The relapse rate shown in the table is based on the relapses during treatment (after dose reduction), which then repeatedly led to a dose increase.

It is noteworthy in the oteseconazole studies that the non-response rate in initial therapy with fluconazole is particularly high at 12.5%. The studies mentioned above do not include patients who do not respond to initial therapy in the analysis, so they are not included in the relapse rate as initially shown in the table. In the sense of recording an overall cure rate, this proportion should be recorded as a "primary relapse" in the statistical analysis and added to the analysis of the relapse rate; the actual relapse rate should therefore be increased by these non-responders (12.5%). increase .

Due to the disadvantages of the prior art, there is an acute need for improved treatment options for fungal infections, especially for RWC. A particularly great need is to reduce the relapse rates of existing therapies. It is an object of the invention to provide such treatment options.

The present invention therefore relates, in a first aspect, to an oral antimycotic for use in the treatment of fungal infections, wherein the treatment comprises a topical adjunct therapy with a topically applicable dosage form.

In a further aspect, the invention relates to a topically applicable dosage form for use in the treatment of fungal infections, wherein the treatment comprises, in addition to the topical treatment with the topically applicable dosage form, an oral treatment with an oral antimycotic agent.

In a further aspect, the invention relates to a topically applicable dosage form for use in the aftercare and/or relapse prophylaxis of a fungal infection, preferably a vaginal fungal infection, in particular RWC.

In a further aspect, the invention relates to a kit, preferably for the treatment of fungal infections, comprising an oral antimycotic and a dosage form for topical use.

In a further aspect, the invention relates to a method for treating fungal infections, comprising:

- administering an oral antifungal agent; and

- Use of a topical dosage form as adjunctive topical therapy.

Preferred embodiments of the individual aspects are described together below. All embodiments - such as the oral antimycotic, the dosage form for topical use, the fungal infection, or the treatment - are equally preferred for all aspects.

The tendency to relapse with existing therapies is rooted in a special host-guest relationship between the fungus and humans. In both humans and Candida, the arachidonic acid cascade is part of the native immune system, through which a disruption of the membrane integrity induces, among other things, the expression of inflammatory prostaglandins. In the case of a chronic infection, this leads to an interplay between infection and inflammation, so it is advisable to combat the infection and the inflammation simultaneously. Since oral antimycotics have no anti-inflammatory effect, the ongoing inflammation can induce a flare-up of the infection soon after the end of antimycotic therapy. The newly approved active ingredient oteseconazole has a particularly long half-life in the tissue. This prevents the infection from flaring up again for a much longer period than fluconazole. It is precisely this effect, however, that exacerbates the disadvantage of oral therapy mentioned above.

The second known therapy concept for the treatment of RWC is a topical vaginal application which takes advantage of the interplay between infection and inflammation and uses a special formulation to deliver the antimycotic and an anti-inflammatory agent to the site of action at the same time. Such topical vaginal applications are described in WO 2007/131253 A2, WO 2019/096857 Al and WO 2019/096863 Al. Topical therapy delivers the active agents directly to the target organ, allowing significantly lower dosages. There is practically no systemic exposure to the medication. Since the inflammation is eliminated at the same time as the antimycotic treatment, relapses are much less common than with established fluconazole therapy. An additional positive effect of topical therapy is the moisturizing and protective effect of the cream base on the vaginal epithelium.

The present invention relates, inter alia, to combination medicinal products for the treatment and reduction of the relapse rate of chronic vulvovaginitis (RWC), in which the advantages of a topical therapy are combined with an oral therapy. These combination medicinal products consist of an oral antimycotic and a topically applied cream with mixed hydrophilic-hydrophobic properties and a mild antiseptic and anti-inflammatory effect. The invention particularly relates to combination medicinal products and their use for the treatment and reduction of the relapse rate in recurrent vulvovaginal candidiasis (RWC), in other fungal infections and in mixed infections, wherein an oral antimycotic is administered together with a mildly anti-inflammatory, antiseptic cream for vaginal application.

In a clinical study conducted as part of the invention, in which fluconazole was tested in combination with a drug-free but slightly antiseptic cream administered at the same time, it was surprisingly shown that the use of this cream in conjunction with oral therapy resulted in a significantly lower relapse rate of 39.2% after RWC treatment with fluconazole compared to the values for monotherapy (see example 3). In comparison to the study without topical treatment, the relapse rate improved from 65.4% (Sobel 2004, adjusted, with non-responders) to 39.2 percent.

This surprisingly clear therapeutic effect of taking an oral antimycotic at the same time as a slightly antiseptic and mildly anti-inflammatory topical cream is caused by the special properties of the cream, in which the individual components are specifically selected and combined based on their respective characteristics. This achieves the following additional effects, which complement the effect of the oral antimycotic: normalization of the vaginal environment and the vaginal epithelium through moistening, strengthening of the lipid membranes, inhibition of inflammation and protection against infection through an antimicrobial effect.

In a preferred embodiment, the composition of the cream is characterized in that it is preferably a mixed hydrophilic-hydrophobic cream and preferably not a hydrogel or a fatty ointment. Emulsions (oil in water or water in oil), preferably in the form of a cream, are particularly suitable for moistening the vaginal epithelium and at the same time protecting the lipophilic membrane components.

In a preferred embodiment, the dosage form to be applied topically is selected from the group consisting of creams, ointments, lotions, gels, pastes and suppositories. Creams are particularly suitable in connection with the invention. It is preferred if the topically applied dosage form is a cream for vaginal application.

In a preferred embodiment, the dosage form to be applied topically is an emulsion, preferably in the form of a cream.

The viscosity of the emulsions is largely determined by the water to oil ratio. In the same way that a very high water content in the emulsion has a negative effect, a very high fat content is also disadvantageous, since too high a fat content reduces adhesion to the mucous membrane. For this reason, it is particularly advantageous if the water to oil weight ratio in the emulsion preferably does not fall below the value of 2.0, in particular 2.2. This results in a particularly preferred window between 2.0 and 3, preferably 2.2 and 3, for the value of the water to oil weight ratio of the emulsions according to the invention. Such a cream, which is both hydrophilic and hydrophobic, gently moistens the vagina and thus, in contrast to orally applied medication, has a pain-relieving and inflammation-reducing effect on the vulva and vaginal mucosa, which is often very dry and vulnerable in RWC patients.

In a preferred embodiment, the dosage form for topical use is therefore an emulsion with an aqueous phase and an oil phase, the weight ratio of the water to the oil phase in this emulsion being at least 2.0, preferably at least 2.05, more preferably at least 2.1, more preferably at least 2.15, more preferably at least 2.2, more preferably at least 2.25, more preferably at least 2.3. It is also preferred if the weight ratio of the water to the oil phase in this emulsion is at most 3.0, preferably at most 2.9, more preferably at most 2.8, more preferably at most 2.7, more preferably at most 2.6, more preferably at most 2.55, more preferably at most 2.5. In particular, it is preferred if the weight ratio of the water to the oil phase in this emulsion is between 2.0 and 3.0, preferably between 2.05 and 2.9, more preferably between 2.1 and 2.8, more preferably between 2.15 and 2.7, more preferably between 2.2 and 2.6, more preferably between 2.25 and 2.55, more preferably between 2.3 and 2.5.

The influence of the water:oil weight ratio of Emulsions, in particular for vaginal use and in particular the effectiveness of NSAIDs, are described in WO 2019/096857 Al and WO 2019/096857 Al. The water:01 weight ratio is preferably calculated as described in WO 2019/096857 Al. Preferably, the mass of all components of the aqueous phase is added up and divided by the mass of all components of the oil phase.

Within the scope of the invention, it has been found to be particularly advantageous if the pH value of the dosage form to be applied topically, in particular emulsion, is in the range from 6.0 to 9.0, preferably 6.5 to 8.5, more preferably 7.0 to 8.0.

The person skilled in the art is familiar with the preparation of emulsions as described herein. In particular, the emulsions can be prepared as described in WO 2019/096857 A1 and WO 2019/096857 A1.

In a preferred embodiment, the composition of the cream is further characterized in that a solubilizer with antiseptic effect is preferably used for its production. Among the compounds available for this purpose, the group of higher-value alcohols stands out, which directly contribute to the antiseptic effect of the cream according to the invention. The preferred solubilizer for the production of creams according to the invention is propylene glycol in a concentration range of 5-20%.

Relapses in RWC are triggered either by reinfection or by activation of existing colonies. In any case, there is strong growth of the yeast fungi before the onset of symptoms. Conventional, purely antiseptic preparations (e.g. octenidine or povidone-iodine-containing agents) are, however, often very problematic in clinical use since, in the case of severe pre-existing inflammation, they worsen the clinical picture due to their additional highly irritating properties. They are therefore not preferred for drug combinations according to the invention. Since antiseptics are usually used in low concentrations to increase the antimicrobial stability of semi-solid dosage forms, they could in principle also protect the patient from a new infection. Many commonly used antiseptics are quaternary ammonium compounds. Their mechanism of action is based on the disruption of the integrity of the lipid double membrane of the microorganisms. Since human cells are also surrounded by a lipid double membrane, the arachidonic acid cascade can in principle also be triggered in the patient's vaginal epithelium, which would lead to inflammation and pain. Since the group of antiseptic alcohols does not have such an effect on membranes, these compounds are preferred as components in a cream according to the invention for preventing reinfections. This applies in particular to phenoxyethanol, which is particularly preferred in a concentration of 1-4% both because of its slightly antibacterial effect and because it increases the microbiological stability of the cream. Since the addition of a mild antiseptic to the cream inhibits germ growth, the relapse rate after antimycotic therapy is significantly reduced. This finding is also supported by the fact that bacterial colonization is known to increase the frequency of relapses of fungal infections.

In connection with the invention, it is preferred if the dosage form to be applied topically is non-irritating. The person skilled in the art is familiar with how to determine whether a topical composition is irritating. In particular, the irritant effect can be determined using a scoring system, preferably a visual analogue scale.

The irritant effect of the dosage form can alternatively be determined using the Drai ze eye irritation test, preferably according to OECD test guideline TG 405 of October 9, 2017. The dosage form to be applied topically preferably has a score of no more than 3, preferably no more than 2, in particular no more than 1 in all categories of the Drai ze eye irritation test. "Non-irritating" is therefore understood here to mean preferably a score of no more than 3, preferably no more than 2, in particular no more than 1 in all categories of the Drai ze eye irritation test.

In a preferred embodiment, the dosage form for topically applied has an antiseptic, anti-inflammatory and/or analgesic effect. In particular, it is preferred if the dosage form for topically applied has an antiseptic effect, in particular an antibacterial effect. It is also particularly preferred if the dosage form for topically applied has an anti-inflammatory effect. In a preferred embodiment, the dosage form for topical use contains an antiseptic. The antiseptic is preferably an antiseptic alcohol, preferably phenoxyethanol and/or a polyhydric alcohol. Among the polyhydric alcohols, glycols are particularly preferred, preferably selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol and/or hexylene glycol; in particular propylene glycol.

In a preferred embodiment, the concentration of antiseptic alcohols in the dosage form for topical use is not more than 20% by weight, preferably not more than 19% by weight, more preferably not more than 18% by weight, more preferably not more than 17% by weight, more preferably not more than 16% by weight, more preferably not more than 15% by weight. Preferably, however, the concentration is at least 1% by weight, preferably at least 2% by weight, more preferably at least 3% by weight, more preferably at least 4% by weight, more preferably at least 5% by weight. In particular, it is preferred if the concentration is from 1 to 20% by weight, preferably from 2 to 18% by weight, more preferably from 3 to 16% by weight, more preferably from 4 to 14% by weight, more preferably from 5 to 12% by weight, more preferably from 5.5 to 10% by weight, more preferably from 6 to 8% by weight, more preferably from 7% by weight.

It has been found to be particularly advantageous if the dosage form for topical use contains a polyhydric alcohol, preferably a glycol, preferably selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol and/or hexylene glycol, in particular propylene glycol in a concentration of 1 to 20% by weight, preferably 2 to 18% by weight, more preferably 3 to 16% by weight, more preferably 4 to 14% by weight, more preferably 5 to 12% by weight, more preferably 5.5 to 10% by weight, more preferably 6 to 8% by weight, more preferably 7% by weight.

It is also particularly advantageous if the dosage form for topical application contains phenoxyethanol, preferably in a concentration of 0.1 to 4% by weight, preferably 0.2 to 3% by weight, more preferably 0.3 to 2.5% by weight, more preferably 0.5 to 2% by weight, more preferably 0.7 to 1.5% by weight, more preferably 0.8 to 1.2% by weight, more preferably 1% by weight. It is particularly preferred if the dosage form for topical application

- a polyhydric alcohol, preferably a glycol, preferably selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol and/or hexylene glycol; in particular propylene glycol; and

- contains phenoxyethanol. In this case, it is preferred if the components mentioned are present in the concentrations given above. It is particularly preferred if the dosage form for topical use contains propylene glycol in a concentration of 5 to 20% by weight, preferably 7% by weight, and phenoxyethanol in a concentration of 1 to 4% by weight, preferably 1% by weight.

Formulations which have proven to be particularly suitable for the purposes of the invention are described in Example 1. Preferably, the dosage form for topical use has a composition according to formulation A, B, C, D, E, F or G of Example 1. Formulation C is particularly preferred. Formulation D is also particularly preferred.

As already mentioned above, it is preferred if the dosage form for topical use does not contain certain substances, in particular irritating substances. It is preferred that the dosage form for topical use is essentially free of quaternary ammonium compounds. It is also preferred that the dosage form for topical use is essentially free of povidone-iodine. It is also preferred that the dosage form for topical use is essentially free of polyhexanide, octenidine, chlorhexidine and/or dequalinium chloride. Such compounds can attack cell membranes and can therefore have an irritating effect under certain circumstances.

Furthermore, it is preferred that the dosage form for topical application is essentially free of ethylene glycol. Ethylene glycol can have a slightly toxic effect and is therefore also not preferred as an ingredient.

Furthermore, it is preferred if the dosage form to be applied topically is essentially free of primary Ci to C3 alcohols, in particular free of methanol, ethanol, propanol and isopropanol. Such alcohols are typically volatile and can have a drying effect.

In a preferred embodiment, the dosage form for topical use contains an anti-inflammatory active ingredient. Non-steroidal anti-inflammatory drugs (NSAIDs) are particularly preferred as anti-inflammatory active ingredients. Topical compositions containing NSAIDs are disclosed in WO 2007/131253 A2, WO 2019/096857 A1 and WO 2019/096863 A1. The NSAIDs and in particular the NSAID concentrations disclosed therein are also preferred in connection with the present invention. In particular, the NSAIDs are preferably used in concentrations that are below the usual concentrations for these active ingredients. The usual concentration in which diclofenac is used in medications approved for topical therapy is in the range of 1 to 2% (10 mg/g or 20 mg/g). According to the invention, diclofenac is preferably used in a concentration of 0.1% to 0.5% (1 - 5 mg per g), preferably 0.2% to 0.35%. The usual concentration of ibuprofen used in medications approved for topical therapy is 5% (50 mg/g cream/gel). According to the invention, ibuprofen is preferably used in an amount of 0.5 to 2.5% (5 - 25 mg per g), preferably 1 to 2%. This allows the anti-inflammatory effect of the NSAIDs to be used on the one hand. On the other hand, the low concentrations ensure that the topical therapy does not have an irritating effect.

The following NSAIDs are particularly preferred in connection with the invention:

- diclofenac, preferably in a concentration of 0.1 to 0.5% by weight;

- indomethacin, preferably in a concentration of 0.1 to 0.4% by weight;

- Naproxen, preferably in a concentration of 1 to 5% by weight;

- Ibuprofen, preferably in a concentration of 0.5 to 2.5% by weight;

- Dexibuprofen, preferably in a concentration of 0.25 to 1.25% by weight;

- ketoprofen, preferably in a concentration of 0.25 to 1.25% by weight;

- Mef enamic acid, preferably in a concentration of 0.5 up to 4 wt.%;

- Lornixocam, preferably in a concentration of 0.02 to 0.04% by weight.

It is particularly preferred if the dosage form for topical use contains diclofenac, preferably where the concentration of diclofenac is not more than 0.5% by weight, preferably not more than 0.4% by weight, more preferably not more than 0.3% by weight. In particular, it is preferred if the concentration of diclofenac is from 0.1 to 0.5% by weight, preferably from 0.2 to 0.4% by weight, more preferably 0.3% by weight.

A further object of the invention relates to a slight increase in the anti-inflammatory, pain-relieving effect of the cream according to the invention in order to compensate for the lack of this effect in oral antimycotics. This can be achieved by adding an anti-inflammatory natural product suitable for vaginal application, such as CBD oil, St. John's wort oil or tea tree extract. The dosage form for topically applied therefore preferably contains an anti-inflammatory natural product, preferably selected from St. John's wort oil, tea tree extract and/or CBD, in particular CBD oil.

Another object of the invention is the use of combination drugs according to the invention consisting of an oral antibiotic and a cream according to this invention for the treatment of RWC and other fungal infections as well as mixed vaginal infections. Any approved antimycotic is suitable as an antimycotic. Antimycotics from the "azole" class, such as itraconazole, oteseconazole and preferably fluconazole, are preferred.

In connection with all aspects of the invention, it is preferred if the oral antimycotic is a conazole, preferably fluconazole, ketoconazole, itraconazole, posaconazole, oteseconazole and/or voriconazole, in particular fluconazole. It is also preferred if the oral antimycotic is ibrexafungerp. It is particularly preferred if the oral antimycotic is fluconazole in a single dose of 100 to 200 mg, preferably 150 mg.

In connection with all aspects of the invention, it is further preferred if the fungal infection is a vaginal fungal infection is . Preferably, the fungal infection is a chronic fungal infection, preferably a chronic vaginal fungal infection. It is particularly preferred if the fungal infection is a vaginal infection caused by Candida albicans . In particular, it is preferred if the fungal infection is a candidal mycosis, preferably a vulvovaginal candidiasis, in particular a chronic recurrent candidal vulvovaginitis (RWC). It is also preferred if the fungal infection is a mixed infection, in particular a mixed vaginal infection.

The specialist is familiar with treatment regimens for oral antimycotics. The oral antimycotics can preferably be used according to the respective approved treatment regimens. It is particularly preferred if fluconazole is administered as an oral antimycotic in a dose of 100 to 200 mg, in particular 150 mg, at least once a week.

With regard to the dosage form to be applied topically, it is advantageous if a higher application frequency is selected during the induction period or for the treatment of an acute attack of the fungal infection. After such an induction period, the treatment frequency can optionally also be reduced, particularly when used for follow-up treatment and/or relapse prevention.

In a preferred embodiment, particularly in the treatment of an acute attack, the dosage form to be applied topically is therefore applied at least three times a week, preferably at least once a day, preferably at least twice a day. It has been shown that such frequent application of the topical treatment can lead to particularly good results, particularly in the induction period or for the treatment of an acute attack. This treatment is preferably carried out for a period of at least 4 days, preferably at least 6 days, in particular at least 9 days. In particular, it is preferred if this treatment is carried out for a period of between 4 and 18 days, preferably between 6 and 14 days, more preferably between 8 and 12 days, in particular 10 days.

In a further preferred embodiment, in particular when used for follow-up treatment and/or relapse prevention, the topically applied dosage form is administered between once a week and once a day, preferably between twice a week and applied three times a week. It has been shown that a somewhat lower application frequency can be advantageous, particularly in follow-up treatment and/or relapse prevention, as very good results are achieved and compliance problems are reduced at the same time. This treatment, in particular follow-up treatment and/or relapse prevention, is preferably carried out for a period of at least 2 weeks, preferably at least 1 month, in particular at least 2 months. It is particularly preferred if this treatment is carried out for a period of between 2 weeks and 18 months, preferably between 1 month and 12 months, in particular between 3 months and 6 months. Such a long duration of topical treatment or topical concomitant therapy is particularly effective in reducing the relapse rate.

A combination drug according to the invention necessarily contains two different drug forms. The treatment of RWC usually follows a fixed therapy plan. In order to ensure reliable administration of the two components, the packaging is of particular importance. Another object of this invention is therefore a packaging of the combination drug that is adapted to the therapy cycle. For this purpose, the cream is packed in a tube, the capacity of which corresponds to one therapy cycle, with a precisely coordinated number of tablets or capsules.

The use of a cream according to the invention is not limited to use in a mixed topical-oral drug combination, but also includes combinations in which the antimycotic agent suitable for oral use is administered parenterally or topically.

The use of a cream according to the invention is not limited to the use in combination with an oral antimycotic, but also includes the use of a cream according to the invention as a protective and at the same time mitigating protection against vaginal infections, in particular for the aftercare and relapse prophylaxis of a RWC infection.

All percentages (%) herein refer to weight percentages (wt.%) unless otherwise indicated.

The present invention particularly relates to the following preferred embodiments. Embodiment Al. An oral antifungal agent for use in the treatment of fungal infections, wherein the treatment comprises topical adjunct therapy with a topically applied dosage form.

Embodiment A2. Oral antimycotic for use according to the preceding embodiment, wherein the dosage form to be applied topically is selected from the group consisting of creams, ointments, lotions, gels, pastes and suppositories; in particular wherein the dosage form to be applied topically is a cream.

Embodiment A3. Oral antimycotic for use according to any one of the preceding embodiments, wherein the dosage form to be applied topically is an emulsion, preferably in the form of a cream.

Embodiment A4. An oral antifungal agent for use according to any preceding embodiment, wherein the topically applied dosage form is a cream for vaginal application.

Embodiment A5. Oral antimycotic for use according to any one of the preceding embodiments, wherein the dosage form to be applied topically is an emulsion with an aqueous phase and an oil phase, wherein the weight ratio of the water to the oil phase in this emulsion is at least 2.0, preferably at least 2.05, more preferably at least 2.1, more preferably at least 2.15, more preferably at least 2.2, more preferably at least 2.25, more preferably at least 2.3.

Embodiment A6. Oral antimycotic for use according to any one of the preceding embodiments, wherein the dosage form to be applied topically is an emulsion with an aqueous phase and an oil phase, wherein the weight ratio of the water to the oil phase in this emulsion is at most 3.0, preferably at most 2.9, more preferably at most 2.8, more preferably at most 2.7, more preferably at most 2.6, more preferably at most 2.55, more preferably at most 2.5.

Embodiment A7. Oral antimycotic for use according to any one of the preceding embodiments, wherein the dosage form for topical use is an emulsion with an aqueous phase and an oil phase, wherein the weight ratio of the water to the oil phase in this emulsion is between 2.0 and 3.0, preferably between 2.05 and 2.9, more preferably between 2.1 and 2.8, more preferably between 2.15 and 2.7, more preferably between 2.2 and 2.6, more preferably between 2.25 and 2.55, more preferably between 2.3 and 2.5.

Embodiment A8. Oral antimycotic for use according to one of the preceding embodiments, wherein the dosage form to be applied topically, in particular emulsion, has a pH in the range of 6.0 to 9.0, preferably 6.5 to 8.5, more preferably 7.0 to 8.0.

Embodiment A9. Oral antimycotic for use according to one of the preceding embodiments, wherein the dosage form for topical use has a score of at most 3, preferably at most 2, in particular at most 1 in all categories of the Draize eye irritation test, preferably determined according to OECD test guideline TG 405 of October 9, 2017.

Embodiment A10. Oral antimycotic for use according to any of the preceding embodiments, wherein the topically applied dosage form has an antiseptic, anti-inflammatory and/or analgesic effect.

Embodiment All. Oral antimycotic for use according to one of the preceding embodiments, wherein the dosage form for topically application has an antiseptic effect, in particular an antibacterial effect.

Embodiment A12. Oral antimycotic for use according to any of the preceding embodiments, wherein the topically applicable dosage form has an anti-inflammatory effect.

Embodiment A13. An oral antimycotic for use according to any one of the preceding embodiments, wherein the topically applicable dosage form contains an antiseptic.

Embodiment A14. An oral antifungal agent for use according to any one of the preceding embodiments, wherein the antiseptic is an antiseptic alcohol, preferably phenoxyethanol and/or a polyhydric alcohol.

Embodiment A15. Oral antimycotic for use according to any one of the preceding embodiments, wherein the polyhydric alcohol is a glycol, preferably selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol and/or hexylene glycol; in particular propylene glycol. Embodiment A1 6. Oral antimycotic for use according to one of the preceding embodiments, wherein the concentration of antiseptic alcohols in the dosage form for topical use is not more than 20% by weight, preferably not more than 19% by weight, more preferably not more than 18% by weight, more preferably not more than 17% by weight, more preferably not more than 16% by weight, more preferably not more than 15% by weight.

Embodiment A17. Oral antimycotic for use according to one of the preceding embodiments, wherein the concentration of antiseptic alcohols in the dosage form for topical use is at least 1% by weight, preferably at least

2 wt.%, more preferably at least 3 wt.%, more preferably at least 4 wt.%, more preferably at least 5 wt.%.

Embodiment A18. Oral antimycotic for use according to any one of the preceding embodiments, wherein the concentration of antiseptic alcohols in the dosage form for topical use is from 1 to 20% by weight, preferably from 2 to 18% by weight, more preferably from 3 to 16% by weight, more preferably from 4 to 14% by weight, more preferably from 5 to 12% by weight, more preferably from 5.5 to 10% by weight, more preferably from 6 to 8% by weight, more preferably from 7% by weight.

Embodiment A19. Oral antimycotic for use according to one of the preceding embodiments, wherein the dosage form for topical use contains a polyhydric alcohol, preferably a glycol, preferably selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol and/or hexylene glycol, in particular propylene glycol in a concentration of 1 to 20% by weight, preferably 2 to 18% by weight, more preferably

3 to 16 wt.%, more preferably from 4 to 14 wt.%, more preferably from 5 to 12 wt.%, more preferably from 5.5 to 10 wt.%, more preferably from 6 to 8 wt.%, more preferably from 7 wt.%.

Embodiment A20. Oral antimycotic for use according to any one of the preceding embodiments, wherein the dosage form for topical use contains phenoxyethanol, preferably in a concentration of 0.1 to 4% by weight, preferably 0.2 to 3% by weight, more preferably 0.3 to 2.5% by weight, more preferably 0.5 to 2% by weight, more preferably 0.7 to 1.5% by weight, more preferably 0.8 to 1.2% by weight, more preferably 1% by weight. Embodiment A21. Oral antimycotic for use according to any one of the preceding embodiments, wherein the topically applied dosage form contains phenoxyethanol in a concentration of 1 to 4 wt.%.

Embodiment A22. Oral antimycotic for use according to any one of the preceding embodiments, wherein the topically applied dosage form

- contains phenoxyethanol; preferably wherein the polyhydric alcohol and the phenoxyethanol are each present in a concentration as defined in one of the preceding embodiments.

Embodiment A23. Oral antimycotic for use according to any one of the preceding embodiments, wherein the dosage form for topical use contains propylene glycol in a concentration of 5 to 20% by weight, preferably 7% by weight, and phenoxyethanol in a concentration of 1 to 4% by weight, preferably 1% by weight.

Embodiment A24. An oral antifungal for use according to any preceding embodiment, wherein the topically applied dosage form comprises a composition according to Formulation A, B, C, D, E, F or G of Example 1.

Embodiment A25. An oral antifungal for use according to any preceding embodiment, wherein the topically applied dosage form comprises a composition according to Formulation C of Example 1.

Embodiment A26. An oral antifungal for use according to any preceding embodiment, wherein the topically applied dosage form comprises a composition according to Formulation D of Example 1.

Embodiment A27. An oral antimycotic for use according to any preceding embodiment, wherein the topically applied dosage form is substantially free of quaternary ammonium compounds. Embodiment A28. An oral antimycotic for use according to any preceding embodiment, wherein the topically applied dosage form is substantially free of povidone-iodine.

Embodiment A29. An oral antifungal agent for use according to any preceding embodiment, wherein the topically applied dosage form is substantially free of polyhexanide, octenidine, chloexidine and/or dequalinium chloride.

Embodiment A30. An oral antimycotic for use according to any preceding embodiment, wherein the topically applied dosage form is substantially free of ethylene glycol.

Embodiment A31. Oral antimycotic for use according to one of the preceding embodiments, wherein the dosage form for topical use is substantially free of primary Ci to C3 alcohols, in particular free of methanol, ethanol, propanol and isopropanol.

Embodiment A32. Oral antimycotic for use according to any one of the preceding embodiments, wherein the topically applicable dosage form contains an anti-inflammatory active ingredient.

Embodiment A33. An oral antifungal agent for use according to any preceding embodiment, wherein the topically administered dosage form comprises a non-steroidal anti-inflammatory drug (NSAID).

Embodiment A34. An oral antimycotic for use according to any one of the preceding embodiments, wherein the NSAID is diclofenac, preferably in a concentration of 0.1 to 0.5% by weight; indomethacin, preferably in a concentration of 0.1 to 0.4% by weight; naproxen, preferably in a concentration of 1 to 5% by weight; ibuprofen, preferably in a concentration of 0.5 to 2.5% by weight; dexibuprofen, preferably in a concentration of 0.25 to 1.25% by weight; ketoprofen, preferably in a concentration of 0.25 to 1.25% by weight; mefenamic acid, preferably in a concentration of 0.5 to 4% by weight; or lornixocam, preferably in a concentration of 0.02 to 0.04% by weight.

Embodiment A35. Oral antimycotic for use according to any of the preceding embodiments, wherein the NSAID is diclofenac and wherein the concentration of diclofenac is not more than 0.5 wt.%, preferably not more than 0.4 wt.%, more preferably not more than 0.3 wt.%.

Embodiment A36. An oral antifungal for use according to any preceding embodiment, wherein the NSAID is diclofenac and wherein the concentration of diclofenac is from 0.1 to 0.5 wt.%, preferably from 0.2 to 0.4 wt.%, more preferably 0.3 wt.%.

Embodiment A37. Oral antimycotic for use according to one of the preceding embodiments, wherein the dosage form for topical use contains an anti-inflammatory natural product, preferably selected from St. John's wort oil, tea tree extract and/or CBD, in particular CBD oil.

Embodiment A38. Oral antimycotic for use according to any one of the preceding embodiments, wherein the oral antimycotic is a conazole, preferably fluconazole, ketoconazole, itraconazole, posaconazole, oteseconazole and/or voriconazole, in particular fluconazole.

Embodiment A39. An oral antifungal for use according to any preceding embodiment, wherein the oral antifungal is ibrexafungerp.

Embodiment A40. An oral antifungal agent for use according to any preceding embodiment, wherein the oral antifungal agent is fluconazole in a single dose of 100 to 200 mg, preferably 150 mg.

Embodiment A41. An oral antifungal agent for use according to any preceding embodiment, wherein the fungal infection is a vaginal fungal infection.

Embodiment A42. An oral antifungal agent for use according to any preceding embodiment, wherein the fungal infection is a chronic fungal infection, preferably a chronic vaginal fungal infection.

Embodiment A43. An oral antifungal agent for use according to any preceding embodiment, wherein the fungal infection is a vaginal infection caused by Candida albicans.

Embodiment A44. Oral antimycotic for use according to one of the preceding embodiments, wherein the fungal infection is a mixed infection, in particular a mixed vaginal infection.

Embodiment A45. Oral antimycotic for use according to one of the preceding embodiments, wherein the fungal infection is a candidomycosis, in particular a vulvovaginal candidiasis.

Embodiment A46. An oral antimycotic for use according to any preceding embodiment, wherein the fungal infection is chronic recurrent Candida vulvovaginitis (RWC).

Embodiment A47. Oral antimycotic for use according to one of the preceding embodiments, preferably for use in the treatment of an acute attack of the fungal infection and/or in an induction period of treatment, wherein the dosage form for topical use is applied at least three times a week, preferably at least once a day, preferably at least twice a day, preferably wherein the application is carried out for a period of between 4 and 18 days, preferably between 6 and 14 days, more preferably between 8 and 12 days, in particular 10 days.

Embodiment A48. Oral antimycotic for use according to one of the preceding embodiments, preferably for use in the follow-up treatment and/or relapse prophylaxis of the fungal infection, wherein the topically applicable dosage form is applied between once a week and once a day, preferably between twice a week and three times a week, preferably wherein the application is carried out for a period of between 2 weeks and 18 months, preferably between 1 month and 12 months, in particular between 3 months and 6 months.

Embodiment A49. A topically applied dosage form for use in the treatment of fungal infections, wherein the treatment comprises, in addition to topical treatment with the topically applied dosage form, oral treatment with an oral antimycotic.

Embodiment A50. Topically applied dosage form for use in the aftercare and/or relapse prevention of a fungal infection, preferably a vaginal fungal infection, especially RWC .

Embodiment A51. A topically applicable dosage form for use according to any one of the preceding embodiments, wherein the topically applicable dosage form is as defined in any one of the preceding embodiments.

Embodiment A52. A topically applied dosage form for use according to any one of the preceding embodiments, wherein the oral antifungal agent is as defined in any one of the preceding embodiments.

Embodiment A53. A topically applicable dosage form for use according to any one of the preceding embodiments, wherein the fungal infection is as defined in any one of the preceding embodiments.

Embodiment A54. A kit, preferably for the treatment of fungal infections, comprising an oral antimycotic and a dosage form for topical application.

Embodiment A55. Kit according to the preceding embodiment, wherein the dosage form to be applied topically is as defined in any of the preceding embodiments.

Embodiment A56. A kit according to any preceding embodiment, wherein the oral antimycotic is as defined in any preceding embodiment.

Embodiment A57. Kit according to any one of the preceding embodiments, wherein the fungal infection is as defined in any one of the preceding embodiments.

Embodiment A58. A method for treating fungal infections comprising:

- administering an oral antifungal agent; and

- Use of a topical dosage form as adjunctive topical therapy.

Embodiment A59. Method according to the preceding embodiment, wherein the dosage form to be applied topically is as defined in any of the preceding embodiments.

Embodiment A60. The method of any preceding embodiment, wherein the oral antifungal agent is as defined in any preceding embodiment. Embodiment A61. Method according to any one of the preceding embodiments, wherein the fungal infection is as defined in any one of the preceding embodiments.

Further preferred embodiments are listed below as embodiments Bl to B12.

Embodiment Bl. Combination medicinal product consisting of an oral antimycotic and a topical cream with mild anti-inflammatory and antiseptic action.

Embodiment B2. The use of a combination medicinal product according to embodiment B1 for the treatment of RWC and other fungal infections, as well as mixed infections.

Embodiment B3. Combination medicinal product according to embodiment Bl and B2, characterized in that the oral antimycotic is a conazole, preferably fluconazole

Embodiment B4. Combination medicinal product according to embodiments Bl and B2, characterized in that the cream is a mixed hydrophilic-hydrophobic emulsion with a water to oil, preferably in a weight ratio in the range between 2 - 3.

Embodiment B5. Cream according to embodiment B4, characterized in that it contains a solubilizer with antiseptic effect, preferably a higher-value alcohol, particularly preferably propylene glycol in a concentration of 5 - 20%.

Embodiment B6. A cream according to embodiments B4 and B5, characterized in that it contains an antiseptic suitable for medical or cosmetic use, which is not a quaternary ammonium compound and which is preferably an antiseptic alcohol, with phenoxyethanol in a concentration of 1-4% being particularly preferred.

Embodiment B7. A cream according to embodiments Bl and B4, characterized in that it contains an anti-inflammatory natural product suitable for vaginal application, such as St. John's wort oil, tea tree extract or CBD oil, to strengthen the anti-inflammatory effect.

Embodiment B8. A packaging adapted to the therapy cycle of the combination medicinal product according to embodiments Bl and B2, in which the cream is in a tube, the capacity of which corresponds to one therapy cycle, with a precisely agreed number of tablets or capsules are packed together.

Embodiment B9. The use of a cream according to embodiment B2, wherein the antimycotic agent suitable for oral use is administered parenterally or topically.

Embodiment BI O. An invention according to embodiment B9, characterized in that the antimycotic agent is applied topically and is oteseconazole or ibrexafungerp.

Embodiment Bl l. The use of a cream according to embodiments B2 and B4. as a protective and at the same time mitigating protection against microbial vaginal infections, preferably for follow-up treatment after a RWC infection.

The present invention is illustrated by the following examples , to which it is of course not limited .

Example 1: Examples of topical dosage forms investigated

Seven different emulsions were prepared, essentially as described in WO 2019/ 096857 Al and WO 2019/ 096857 Al. The composition of the emulsions is shown in the following table:

The microbiological stability and clinical tolerability of all formulations were tested. The microbiological stability of all formulations A to G was assessed as satisfactory. The clinical tolerability of formulations A and C-G was assessed as good; formulation B was slightly irritating and thus less favorable, but still applicable for the purposes of the invention.

Example 2: Therapy trial with formulation variants

Therapy trials were carried out with different formulation variants from Example 1. Formulation Example C performed particularly well.

As an example, a therapy trial that was carried out using formulation variant F is described below:

JS: Patient after childbirth, breastfeeding period, postpartum amenorrhea. No improvement after local treatment with Dalacin cream. Subjective complaints: severe soreness, burning, slight itching. Gynecological examination findings: mucous membrane very red, atrophic, secretion: RG ITT, mixed bacterial flora, no hyphae. D: postpartum vaginitis, mixed infection with postpartum atrophy of the vaginal mucosa.

Use twice daily for three weeks, plus Linoladiol. Check-up after three weeks. Sub . Significant improvement, but still a slight sore feeling. Secretion status: S: significantly reduced bacterial concentration, significantly improved mucous membrane appearance. Further therapy: Continue formulation F once daily, continue Linoladiol twice a week, Gynophilus capsules . Example 3: Study - Comparison of relapse rates of a combination treatment according to the invention (including non-responders)

The efficacy of topical treatment with a cream according to formulation C from example 3 as adjunctive therapy to standard oral therapy comprising fluconazole 150 mg was investigated in a clinical study.

Treatment regimen: Fluconazole 150 mg orally plus cream according to formulation C.

Induction therapy over 10 days with cream application twice daily for 6 days, once daily for 4 days and fluconazole 150 mg on days 1, 4 and 7, followed by maintenance therapy with cream twice weekly and 1 tablet of fluconazole 150 mg once weekly for 24 weeks.

In the clinical study, a relapse rate of 35.8% or 39.2% including non-responders was found. This is a significant reduction in the relapse rate compared to purely oral therapy with fluconazole. A comparison of the relapse rate found with previous clinical studies on monotherapy with oral fluconazole is shown in the following table:

The concomitant topical therapy with the cream according to formulation C of example 3 thus led to a very significant reduction in the relapse rate compared to monotherapy with fluconazole.

Claims

Claims:

1 . An oral antifungal agent for use in the treatment of fungal infections, where the treatment includes adjunctive topical therapy with a topically applied dosage form .

2. Oral antimycotic for use according to claim 1, wherein the dosage form to be applied topically is an emulsion, preferably in the form of a cream, preferably for vaginal application.

3. Oral antimycotic for use according to one of the preceding claims, wherein the dosage form for topical use has an antiseptic, anti-inflammatory and/or analgesic effect.

4. Oral antimycotic for use according to one of the preceding claims, wherein the dosage form for topical use contains an antiseptic, preferably an antiseptic alcohol, preferably phenoxyethanol and/or a polyhydric alcohol.

5 . Oral antimycotic for use according to one of the preceding claims, wherein the topically applied dosage form

- contains phenoxyethanol.

6. Oral antimycotic for use according to one of the preceding claims, wherein the concentration of antiseptic alcohols in the dosage form for topical use is from 1 to 20% by weight.

1. Oral antimycotic for use according to one of the preceding claims, wherein the dosage form for topical use contains propylene glycol in a concentration of 5 to 20% by weight, preferably 7% by weight, and phenoxyethanol in a concentration of 1 to 4% by weight, preferably 1% by weight.

8. Oral antimycotic for use according to any one of the preceding claims, wherein the topically applied dosage form is non-irritating, preferably wherein the topically applied dosage form has a score of at most 2 in all categories of the Draize eye irritation test, preferably determined according to OECD test guideline TG 405 of 9 October 2017.

9. An oral antifungal agent for use according to any one of the preceding claims, wherein the topically applied dosage form contains an anti-inflammatory active ingredient.

10. Oral antimycotic for use according to the preceding claim, wherein the anti-inflammatory active ingredient is a non-steroidal anti-inflammatory drug (NSAID) or an anti-inflammatory natural product, in particular selected from St. John's wort oil, tea tree extract and/or CBD.

11. Oral antimycotic for use according to one of the preceding claims, wherein the oral antimycotic is a conazole, preferably fluconazole, ketoconazole, itraconazole, posaconazole, 0-teseconazole and/or voriconazole, in particular fluconazole; or ibrexafungerp.

12. Oral antimycotic for use according to any one of the preceding claims, wherein the fungal infection is a vaginal fungal infection, preferably a chronic recurrent Candida vulvovaginitis (RWC).

13. A topically applied dosage form, preferably as defined in any one of claims 1 to 12, for use in the treatment of fungal infections, wherein the treatment comprises, in addition to the topical treatment with the topically applied dosage form, an oral treatment with an oral antimycotic agent.

14. A dosage form for topically use, preferably as defined in any one of claims 1 to 12, for use in the aftercare and/or relapse prophylaxis of a fungal infection, preferably a vaginal fungal infection, in particular RWC.

15. Kit comprising an oral antimycotic and a dosage form for topical use, preferably as defined in any one of claims 1 to 12.