AT524378A1 - PREPARATION - Google Patents

Abstract

Aqueous composition comprising an aldehyde component, a surface tension reducer, a pH buffering system, with a volatile component.

Description

PREPARATION

The invention relates to a preparation for use in the treatment of

onychomycosis.

BACKGROUND OF THE INVENTION

According to estimates, around 8-10% of the European and American population can be diagnosed with a fungal infection of the toenails or fingernails (onychomycosis). The frequency of infection increases with the age of the group of people under consideration, and health and occupational exposure are also responsible for an increased infection rate. People who do intensive sports are also often affected by fungal nail infections. The infestation is caused by different species, the important groups being the dermatophytes of the genus Z/richophyton spp. (e.g. 7richophyton rubrum, T. mentagrophytes) and Epidermophyton floccosum, but yeasts (Candida species) can also be responsible for microbial infestation of the

Nail plate to be responsible.

Infection weakens and damages the nail plate, resulting in visual and structural changes. So become yellowish, white changes

of the nail observed, which can reach to the nail bed.

In most cases, the nail fungus infection is painless, so in many cases, after several unsuccessful attempts at treatment, the infection is accepted as chronic. However, the changed appearance of the toenails leads to personal restrictions for many people, e.g. in the choice of footwear, since the affected toes do not like to be shown visibly. There is also an increased risk of infection for people who have to work a lot with impermeable gloves (e.g. clean room staff, people in medical professions, etc.), as well as for people who do a high degree of sporting activities

engage in activities.

Treatment of nail fungus infestation depends on the severity of the infestation (intensity of the infection, number of nails affected) and can be carried out locally by applying appropriate active substances, by completely removing the nail or systemically

Appropriate active ingredients are administered, e.g. in oral form.

According to the state of the art, basic principles of local treatment methods can be found in

divided into different groups:

e Use of disinfectants from the group of oxidizing agents (peroxides or halogen-containing oxidizing agents, see WO 2010/125398 A2).

e* Use of fungicidally active substances: These include substances that have a high toxicity for fungi (bifonazole, clotrimazole, ciclopirox, amorolfine or metal pyrithione according to US 2009/0298805 A1 or formaldehyde according to FR 2 805 745 B1) and applied, for example, like a nail polish can become.

e Use of essential oils: lavender oil, tea tree oil (US 2006/0251593) and plant extracts are proposed in different preparation forms for the treatment of fungal nail infections.

e Laser treatments: Laser light is used to locally remove the affected areas. The affected areas are removed by increasing the temperature.

e Powdered preparations for local treatment.

e In situ release of nitrogen oxides: The local treatment of fungal infections by reacting nitrite salts with acids is proposed in WO 2011/155887 A1.

Other additives such as solvents, film formers, thickeners and swelling agents (permeation enhancers) are also used in the formulation of corresponding preparations. The swelling agents are substances containing mercaptan groups, which are able to soften the nail structure by swelling (US Pat. No. 6,123,690 and US Pat. No. 5,696,164).

The use of surface-active substances has also already been proposed according to the prior art for the formulation of antifungal preparations in WO 2010/014070 A2, the object disclosed there being the stabilization of the preparation containing lipid structures. Therefore, no specific

Requirements placed on the surfactants.

In systemic treatment, oral antimycotics such as griseofulvin, itraconazole, terbinafine (WO 2010/010470 A2) or fluconazole are administered over a longer period of time. These treatments require long periods of time because the antifungal drugs have to be stored in the nail structure, which can contain the infection. The health side effects of this long-term drug administration are considerable.

Effect of the proposed solutions, which have a variety of disadvantages.

Concepts for the local shift of the pH value show only little stability over time. The pH value is neutralized by the body's own abilities to buffer the pH value, perspiration and body cleansing, and the treatment activity is thus terminated. Similar problems arise with the topical application of oxidizing agents. After the decomposition/degradation of the oxidant, no antifungal activity remains in the affected areas. This is also the case with active principles,

which use the release of NO gases, is similarly the case.

Locally, fungicidal substances such as bifonazole, clotrimazole, ciclopirox and amorolfine only have a limited effect. This is mainly due to two systematic causes: The substances are high-molecular substances and are insoluble in water. As a result, the preparations are systems with solubilizers or emulsions, which are difficult to penetrate into the branched and deep growth areas in affected nails. A much more critical disadvantage also lies in the

increasing resistance of fungi to known active ingredients.

Formulations that the sometimes extremely toxic solid substances such as lead or

Contain mercury salts are disadvantageous due to the high toxicity of the substances.

The use of varnish polymers to strengthen the nail structure has been described in the literature (DE 20 2013 009976 U1). If antimycotic substances are incorporated into the lacquer formulation, an antimycotic nail lacquer is produced (DE 20 2013 009 988 U1), the use of formaldehyde being in the manner claimed in DE 20 2013 009 988 U1

formulation is explicitly excluded.

Due to its high chemical reactivity, formaldehyde has a strong disinfecting effect and is still an important disinfectant in medical cleaning agents today. Chemical resistance of microorganisms to formaldehyde and other aldehydes or aldehyde-releasing substances is not to be expected due to the chemical reactivity and the biocompatibility or the occurrence in the metabolism. formaldehyde is coming

usually used as an aqueous solution (formalin) or in gaseous form.

Although the antimicrobial effect of formaldehyde is known, none have been found to date

optimal preparations for the treatment of nail fungus known. It is known from the state

Due to the ability of formaldehyde to enter into cross-linking reactions with the nail keratin, this substance was used to harden the nail structure in the case of brittle or mechanically weak nails. US Pat. No. 3,382,151 describes a combination of formaldehyde, garlic oil and surfactants as well as other vegetable oils as a formulation for hardening the nail structure. Coconut fatty acid ethanolamides are proposed for emulsifying the otherwise insoluble oil components. The task of stronger penetration of the nail substance is achieved by the addition of surfactants, and an aseptic and antifungal effect, which is known to be caused by formaldehyde, was also mentioned as a side effect. However, the components mentioned in US Pat. No. 3,382,151 reduce the necessary access of the active ingredients to the affected areas in the event of repeated exposure

application in a disadvantageous way.

AT 516 544 B1 describes a preparation for local treatment, which is an aqueous solution containing an aldehyde component, a surfactant and a water-miscible solvent. The special composition ensures deep penetration into the nail and a particularly good effect against nail fungus

achieved.

The preparations customary according to the state of the art leave residues on and in the affected nail area which, in the case of a subsequent repeated application, impair the effect of the newly applied active ingredients in the course of an application for treatment

hamper adversely from nail fungus.

BRIEF DESCRIPTION OF THE INVENTION

The object is therefore to provide a preparation which is suitable for the local treatment of nail fungus and is easy to handle and which can be incorporated into the affected

nail structure occurs.

This object is achieved by an aqueous composition comprising e an aldehyde component, e a substance that reduces the surface tension,

e a pH buffer system, with a volatile component.

Composition value after evaporation of the volatile component between 7 and 9.

The present invention uses the antimicrobial effect of aldehydes or aldehyde-releasing compounds to combat fungal infestation of the toenails or fingernails. By adding a substance that reduces the surface tension, the penetration depth of an aldehyde-containing aqueous solution into the damaged nail areas is increased to such an extent that the undesired nails can be completely eliminated

fungal attack succeeds.

In the context of the invention, the term aldehyde component includes substances which themselves contain aldehyde groups (such as formaldehyde, -—propionic acid dialdehyde, succinic acid dialdehyde, glutaraldehyde, glyoxal, methylglyoxal) but also chemical compounds which are able to split off aldehydes. These include, for example, acetals such as dimethylformal, 2,5-dimethoxy-tetrahydrofuran, 1,1,3,3-tetraethoxy-propane,

hemiacetals and aminals.

In a particularly preferred embodiment, the aldehyde component is glutaraldehyde.

For the purposes of the invention, the term surface tension reducing substance includes substances which reduce the surface tension of the composition compared to this composition without the surface tension reducing substance. Examples of substances that reduce surface tension are, in particular, surfactants, but additives to solvents can also be used to reduce surface tension. Examples of suitable surfactants are the alkyl sulfates, alkyl sulfonates and alkyl ether sulfates or, for example, the alkyl phosphonates and alkyl phosphates.

The chemical group of the tenside should be selected in such a way that the function of the tenside is not deactivated by reaction with the aldehyde component. In a preferred form, the surfactant is selected from the group consisting of quaternary ammonium salts

and preferably itself a substance active as a biocide.

Surfactants from the group of quaternary ammonium salts, for example didecyldimethylammonium chloride or benzyl-C12-C15-alkyldimethylammonium chloride, are particularly preferred.

which also have an antimicrobial effect themselves.

Due to the reduced surface tension of the aqueous composition modified with surfactants, the treatment solution can penetrate sufficiently deeply into the very fine

Penetrate growth channels in the affected nail areas. Due to the high penetration depth

Depot effect difficult.

Basically, a pH buffer system is a mixture of substances whose pH value (concentration of oxonium ions) changes much less when an acid or a base is added than would be the case in an unbuffered system. Buffer solutions contain a mixture of a weak acid and its conjugate or corresponding base (or the respective salt) or a weak base and its conjugate or

corresponding acid.

The pH buffer system used in the composition according to the invention is a buffer which adjusts the pH to a maximum of pH 6. This makes the composition storage-stable. The composition therefore has a pH of

maximum 6 on.

One of the constituents of the buffering system, a non-aqueous component, is a volatile component. The pH rises to 7-9 by evaporation of the volatile component of the buffer system, preferably an acid of the buffer system. The volatile component is therefore preferably an acid. In practice, this evaporation occurs, for example, following the local application of the composition to the affected nail. The increase in the pH value at the application site means that the local pH value is shifted in the direction of the optimal pH value for the application. In the case of glutardaldehyde, it is known from the literature that an optimum effect of the antimicrobial effect is observed at a pH value of 7.5 - 8.5.

In principle, there are different systems for providing a pH buffer system with a volatile component, the pH value being between 7 and 9 after evaporation of the volatile component. First of all, the pH buffer system is to be understood in such a way that the pH value of the entire composition is in the ideal stabilizing range for the

composition, preferably the pH of the composition is at most 6.

After evaporation of the volatile component of the pH buffer system, the pH begins to rise and reaches a maximum of 7 to 9. A buffer system with these properties is possible for the person skilled in the art with knowledge of pKa values and the Henderson-Hasselbalch

Equation easy to determine.

7717

acetate included.

However, buffer systems with other moderately strong acids and their corresponding moderately strong bases and mixtures thereof are also possible. For example, the acid can also be formic acid, acetic acid, propionic acid and the base

corresponding salts of these acids or mixtures thereof can be used.

In one embodiment variant, there is also a volatile, water-miscible

Solvent provided.

The volatility of the solvent supports and improves the reaching of all affected areas, as there are high concentrations of on-site, inside the MNagel

Disinfectants can be generated.

Examples of solvents are acetone, but also alcohols and polyethylene glycols, it being important to ensure that any acetal/hemiacetal compound formed can decompose reversibly to form the aldehyde components and the inventive effect of the preparation is therefore not lost. The volatile solvent or solvent mixture can also lower the surface tension. A possible reaction of the solvent with the aldehyde components is only permissible if the reaction is reversible and the aldehyde component can be released again by reverse reaction during use, so that the effect according to the invention occurs. In a preferred embodiment, alcohols are used, which are also used as

Biocides are used, e.g. 1-propanol, 2-propanol or ethanol.

In a preferred embodiment, it is provided that the volatile, water-miscible solvent is an alcohol. Alcohols can achieve an increase in local concentration when using an aldehyde component with a higher boiling point, e.g. glutaraldehyde. In this case, too, suitable alcohols are selected, for example, from

Group consisting of 1-propanol, 2-propanol, ethanol or mixtures thereof.

For the purposes of the invention, the term “volatile” (be it as a volatile component of the pH buffer system or as a volatile solvent) becomes more volatile in accordance with Directive 2004/42/EC of the European Parliament and Council of April 21, 2004 on limiting emissions Organic compounds understood that the volatile component of the pH buffer system or the volatile solvent is an organic compound that has an initial boiling point of maximum 250 ° C at a

standard pressure of 1013 mbar. The vapor pressure is preferably this

Clapeyron equation).

The specific composition of the preparation is preferably as follows:

e 0.1 to 30% by weight, preferably 0.5-15% by weight, particularly preferably between 1-5% by weight, of aldehyde component,

e 0.05 to 10% by weight, preferably 0.05-5% by weight, preferably between 0.1 and 3% by weight, of a substance that reduces surface tension,

e 5 to 80% by weight, preferably 10 to 45% by weight, of volatile solvent,

oe 0.05--1% wt.%, preferably 0.1-0.5 wt.% pH buffer system,

e 0 to 5% by weight other substances,

e Balance to 100% by weight water.

The individual values refer to the entire composition.

The amount of surface tension reducing agent is preferably between 0.05 and 10% by weight. When the surface tension reducing agent is a surfactant, the proportion is preferably 0.05 to 5% by weight, more preferably 0.1 to 3% by weight.

In a preferred embodiment, the pH buffer system is an acetic acid/acetate buffer with 0.02-0.4% by weight acetic acid and 0.03-0.6% by weight acetate salt,

preferably sodium acetate.

Colorants, dyes or fragrances are particularly suitable as "other substances". However, these must be compatible with the function of the aldehyde component and the surface tension reducing component. In a particularly preferred form, natural or nature-identical fragrances such as citronellal, peppermint oil or lavender oil are used, which also have an antimicrobial effect

(ideally 0.1 to 5% by weight).

In one aspect, the invention relates to a preparation of the type mentioned above

Drug.

In particular, the invention relates to a preparation of the aforementioned type for treatment

of onychomycosis (nail fungus).

It is preferably a topical treatment of nails (fingernail, toenail). Topical treatment can be done by applying the preparation to a

nail happen.

The invention is based on the knowledge of the combination of up to 4 different ones

Active substance groups for the treatment of nail fungus:

1]. The antimicrobial effect of aldehyde components, e.g. glutaraldehyde, methylglyoxal, etc. serves as the primary mechanism.

2. A substance that reduces surface tension (usually a tenside component) is used to ensure good wetting of the nail and lower surface tension, which is compatible with aldehydes.

3. A volatile solvent, e.g. isopropanol (which ideally also has an antimicrobial effect) supports the transport of the aldehyde component to the desired location.

4. A pH buffer system, which shifts the pH value in the nail to the range of 8 - 9 through evaporation, improves the optimal effect of the aldehyde component, while increased stability is achieved during storage due to the lower pH value, e.g. pH 5 to 6

becomes.

In addition, fragrances can also be used which themselves have an antimicrobial effect and thus, in addition to developing a fresh smell, also by themselves

germicidal effect support the antifungal function.

By lowering the surface tension, the treatment solution penetrates very deeply into the dry nail, resulting in a very thorough treatment. The preparation is then allowed to dry. The alcohol component initially has a germicidal effect, after rapid evaporation an increased concentration of antimicrobial aldehyde, surfactant and fragrance remains. In addition, the slow evaporation of the volatile organic acid from the buffer leads to a gradual increase in the pH value, and thus to the formation of the optimal effect of the aldehyde component, which can be e.g. glutaraldehyde.

The effect is based on several principles: e Fast supporting effect through the alcohol component e Lowering of the surface tension through the tenside resulting in deep penetration e Increase in the effective concentration of tenside (cationic disinfectant) and the aldehyde component (e.g. glutaraldehyde) through evaporation of the alcohol e Evaporation of the active ingredients ( Alcohol and aldehyde) also leads to the gas phase effect

e Reaction with nail structure leads to depot formation

e Due to the evaporation of the acid from the buffer, the pH value begins to rise slowly towards the slightly alkaline optimum effect of the aldehyde components (e.g. pH 7.5 - 8.5 for glutaraldehyde)

e No resistance formation possible

e No formation of polymer/lacquer layers (cf. Loceryl)

e Other aldehydes (possibly glyoxal, methylglyoxal) are also suitable.

application example

An example of an embodiment of the formulation according to the invention is given below

shown:

Compound Function Wt% Glutaraldehyde! aldehyde component 1.14 fatty alcohol sulfate? | surface tension 0.11

disparaging substance

2-propanol? Volatile Solvent 5.01 Sodium Acetate* Buffer Component I 0.08 Acetic Acid” Buffer Component II (Volatile) 0.06 Water 93.60

total 100.00

added as a 25% by weight aqueous solution, proportion of this solution 4.57% by weight added as a pure substance added as a pure substance added as a pure substance

added as a 96% by weight aqueous solution, proportion of this solution 0.06% by weight

A composition according to the invention contains the antimicrobial agents glutaraldehyde and 2-propanol. The buffer system consists of acetic acid and sodium acetate. 1 to 2 drops of the product are applied to the nail affected by the nail fungus and then allowed to air dry. As the acetic acid evaporates, the pH value of the solution shifts to the optimum range for the glutaraldehyde.

The formula has been used on several people with toenail fungus. In doing so, the

Treatment carried out three times during the first week, then during the following

Monthly 2 to 3 times per week and then 1 - 2 times per month continued. Already after

Within a few weeks of treatment, subjects showed regrowth of the

healthy nail in the treated areas.

Claims (13)

EXPECTATIONS 1. Aqueous composition, comprising e an aldehyde component, e a substance reducing the surface tension, e a pH buffer system, with a volatile component. 2. Composition according to claim 1, characterized in that the pH after Evaporation of the volatile component is between 7 and 9. 3. Composition according to claim 1 or claim 2, characterized in that the aldehyde component is a compound selected from the group formaldehyde, glyoxal, propionic acid dialdehyde, succinic acid dialdehyde, glutaraldehyde, methylglyoxal or a mixture thereof, or an acetal, hemiacetal or aminal of one of the above mentioned aldehydes. 4. Composition according to one of Claims 1 to 3, characterized in that the substance which reduces the surface tension is a surfactant which is preferably selected from the group consisting of the alkyl sulfates, alkyl sulfonates, alkyl ether sulfates, alkyl phosphonates, alkyl phosphates or quaternary ammonium salts. 5. Composition according to any one of claims 1 to 4, characterized by a pH Value of maximum pH 6. 6. Composition according to any one of claims 1 to 5, characterized in that the buffer system comprises acetic acid/acetate. 7. Composition according to any one of claims 1 to 6, additionally characterized by a volatile, water-miscible solvent. 8. Composition according to claim 7, characterized in that the solvent is an alcohol, preferably selected from the group 1-propanol, 2-propanol, ethanol or mixtures thereof. 9. Composition according to any one of claims 7 or 8, characterized by e 0.1 to 30% by weight, preferably 0.5-15% by weight, particularly preferably between 1-5% by weight, of aldehyde component, e 0.05 to 10% by weight, preferably 0.05 - 5% by weight, preferably between 0.1 and 3% by weight surface tension reducing substance, 10. Preparation according to one of claims 1 to 9 as a medicament. 11. Preparation according to any one of claims 1 to 9 for use in treatment of onychomycosis. 12. Preparation for use according to claim 11, characterized in that the Treatment includes topical treatment of nails. 13. Preparation for use according to claim 12, characterized in that the topical treatment comprising multiple applications of the preparation.