Nail growth stimulating preparations

The subject of the invention is a nail polish constituting a krekardt for the treatment of nails.

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The nail plate that terminates and protects the nail is a calloused, hard, additional epidermal formation of the fingertip of the finger or toe, growing out of the pockets of the epidermis on the top of the finger or toe.

The material of the nail plate is mainly formed in the nail bed - a specialized tissue that occupies the lower part of the nail pocket from its proximal end to the lip. The area of ​​the nail matrix adheres distally to the nail bed, with which the longitudinally structured nail plate is firmly attached with its lower surface to the subcutaneous labrum. The dorsal area of ​​the epidermis located between the nail bed and fingertip is defined as the subcutaneous papillary labrum.

The surface of the nail plate is smooth and has a subtle pink color due to the skin's capillaries showing through. Only the half-moon-shaped area at the proximal end of the plate with a width of 1-5 mm - margin - is whitish.

The growth rate of the nail plate, i.e. its extension beyond the free edge, depends on the intensity of the formation of new nail cells in the nail matrix. The cellular material formed there differentiates into lamellar corneal structures, passively displaced. The nail continues to grow throughout life. Growth rate decreases with age. The average weekly increase in nail length in hands is 0.5 - 1.2 mm, and in addition to age and sex, this value may be affected by blood supply, nutrition and physiological load. Workers' nails should grow faster. Toenails, especially of the elderly, grow more slowly than toenails.

At a normal nail growth rate, a 35-year-old person needs about 6 months to grow a new fingernail, and toenails are renewed in about 12 months.

Nail growth and appearance can be negatively affected, in addition to the following factors leading to interruption of nail growth, numerous local or general disease processes, and the effects of poisons, drugs, chemicals and injuries.

Nail growth plays a decisive role in the treatment and in the necessary period of treatment of onychomycosis. Nail fungal infections are understood to mean nail bed infections caused by fungi that, as the disease progresses, extend to the entire nail, including the visible part of the nail plate.

In the case of distal subungual onychomycosis, which is the most commonly observed clinical type, pathogenic microorganisms dominate the nail, with first accessing the subungual callous layers. In the further course of infection, the lower layer of the nail plate is also attacked. In the later stages, discoloration and changes in the structure of the nail plate occur, as a result of which the appearance of the nails completely changes. Keratinophilic fungi, such as Trichophyton rubrum or T. mentagrophytes, change the nail plate in a very characteristic way. They lead to visible discolorations, which at an advanced stage accompany disorders of the layered structure of the nail plate and ultimately to the complete destruction of the protective cover. As a result of the developing infection, the subungual tissue remains of the epidermal papilla and the nail bed create an ideal habitat for subsequent microorganisms, which again contributes to additional changes in the chemical and physical properties of the lower side of the nail plate. After all, the nail plate separates from the nail bed, which causes patients great pain when moving. As a result of the action of fungi, people affected by the disease can lose the entire nail plate, so that only the excessively callous nail bed remains, so there is no protection against external influences. Due to the lack of a protective nail plate, deliberate movements are almost impossible.

The rate at which the infection spreads varies from case to case. It depends on the speed of development of microorganisms that penetrate from the free end of the nail to the nail matrix, as well as the speed of nail growth from the nail matrix to its free end.

Only a healthy nail is protected against the penetration of microorganisms from its free end, due to the speed of its growth. If nail growth slows down with

186 876 due to age or illness, germs can spread unhindered unless they counteract it.

Well-known nail fungal therapy currently involves topical treatment of diseased nails with anti-fungal nail polish, partly in combination with systemic anti-fungal agents. This method of treatment is inconvenient, because for the clinical cure of diseased nails, i.e. until the diseased nail surface has grown and new nail has grown, treatment must be carried out for a relatively long time. This leads to the fact that usually many months of patient treatment is often not completed, and therefore a positive result of therapy is not achieved. In addition, the often used combination local / systemic therapy is very expensive due to the prices of systemic antifungal agents.

It has now surprisingly been found that a formulation containing a vasodilator can accelerate the growth of nails when applied to nails, especially to diseased nails. These preparations are not only suitable as additional growth aid in the treatment of onychomycosis, but also can be used to treat nail growth disorders of various origins.

Thus, the invention relates to nail polish, which is a preparation for the treatment of nails, containing at least one active substance, a film-forming substance and, optionally, auxiliary substances, and the feature of this preparation is that as the active substance it contains a vasodilator with the general formula I

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2 wherein R and R are independently hydrogen, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, phenyl-C 1 -C 8 -alkyl, naphthyl-C 1 -C 4 -alkyl or C 3 -C 8 -cycloalkyl, or R¹ and R² together with the nitrogen atom, they form a aziridinyl, azetinyl, pyrrolidinyl, piperidinyl, hexahydroazepinyl, heptamethylimino group, octamethylimino group, morpholinyl or 4-C 1 -C 4 alkylpiperazinyl heterocyclyl, wherein the carbon atoms in this heterocyclyl are optionally substituted with C 1 -C 6 alkyl groups R³ is hydrogen, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, phenylC 1 -C 8 -alkyl, naphthyl-C 1 -C 8 -alkyl, benzyl, phenyl, naphthyl, C 1 -C 8 -cycloalkyl or C 1 -C 6 -alkyl mono- or polysubstituted halogen, and Ai a2 and a3 independently represent hydrogen or acetyl, or dihydralazine, diisopropylamine, diazoxide, nifedipine, nicardipine, verapamil, diltiazem, nizoldipine, nitrendipine, nivaldipine, isradypine, felodipine, galipodine, . diperdipine, fiuspirylene, prymoside, phytopharon, nicerogoline, cyclandelate, quinapril, lisinopril, benzazepril, captopril, ramipril, fosinopril, digazapril, trandolapril, pentoxifiline, 2-pentoxypyrin-2-di-salt, torb , 6-diamino-4-piperidinopyridine, and 2,6-diamino-4-butoxyi, 3,5-triazine -oxide or mixtures thereof, and optionally contains a topically acting antifungal agent.

Nail polish as a vasodilating compound preferably contains 6-amino-4-piperidine-1,2-dihydro-1-hydroxy-2-iminopyrimidine.

The nail polish preferably contains a compound having a vasodilatory effect in an amount of 0.1-10% by weight, preferably 2-5% by weight.

The nail polish as a topical antifungal agent preferably contains hydroxypyridone, such as cyclopirox, pirocotone or rylpyrox, a morpholine derivative such as amorphine, azole, such as bifonazole, clotrimazole, econazole, miconazole, oxiconazole, croconazole, fethconazole isoconazole or an allyl compound such as terbinafine or naphthifine, or griseofulvin, tolcyclate, tolnaftate or butenafine.

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The varnish according to the invention, in addition to the active substance dissolved in a solvent or in a mixture of solvents, contains one or more film-forming substances which, after the preparation has dried, form a water-insoluble layer on the nails.

As film-forming substances, e.g. cellulose nitrate-based substances or physiologically acceptable polymers usually used in cosmetics, preferably in the form of a mixture with cellulose nitrate, are used. Such polymers include, for example polyvinyl acetate and partially saponified polyvinyl acetate, copolymers of vinyl acetate and acrylic acid or crotonic acid or maleic acid monoalkyl ester, ternary copolymers of vinyl acetate, crotonic acid and vinyl neodecanoate or vinyl acetate, crotonic acid and vinyl propionate, and vinyl ester copolymer monoalkyl maleic acid, especially maleic acid monobutyl ester, copolymers of fatty acid vinyl ester and acrylic acid or methacrylic acid, copolymers of N-vinylpyrrolidone, methacrylic acid and methacrylic acid alkyl ester, copolymers of acrylic acid and methacrylic acid or alkyl ester of acrylic acid or methacrylic acid alkyl ester, especially quaternary ammonium copolymers or polymers, copolymers or mixtures containing ethyl acrylate, methyl methacrylate or trimethylammonioethyl methacrylate chloride, or polyvinylacetals and polyvinyl butyrals, alkyl-substituted poly-N-vinylpyrrolidones, alkyl esters of olefin copolymers and maleic anhydride, and rosin reaction products with acrylic acid. Alkyl groups in esters are usually short chain groups and usually contain no more than 4 carbon atoms.

As physiologically acceptable solvents there may be mentioned substances commonly used in cosmetics, such as hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones and esters, in particular acetic acid esters and monohydric alcohols such as ethyl acetate and butyl acetate, optionally in combination with aromatic hydrocarbons , such as toluene, and / or with alcohols such as ethanol or isopropanol.

It is known that the solvent system is important for drying time, spreadability and other important properties of the varnish or varnish film. The solvent system is preferably an optimal mixture of low-boiling liquids (solvents with boiling point up to 100 ° C) and medium-boiling liquids (solvents with boiling point up to 150 ° C), possibly with a low proportion of high-boiling liquids (solvents boiling up to 200 ° C) ).

The varnishes of the invention may further contain additives for use in cosmetics, such as plasticizers based on phthalates, glycerine triacetate or camphor, dyes or colored pigments, pearlescent agents, sedimentation retarders, sufonamide resins, silicates, fragrances, crosslinkers such as dioctyl sulfosuccinate sodium, lanolin derivatives, sunscreen agents such as 2-hydroxy-4-methoxybenzophenone, substances with antibacterial activity and substances with keratolytic and / or keratoplastic effect, such as ammonium sulfite, thioglycolic acid esters and salts, urea, allantoin, enzymes and salicylic acid.

Dyed or pigmented nail polishes have, for example, the advantage that the formulation according to the invention can be adapted to the aesthetic preferences of patients, and changes in the appearance of the nails are invisible to third parties.

Nail polishes are prepared in such a way that the water-insoluble film-forming substance in dissolved form is mixed with the active substance or substances, and optionally the preparation is subjected to further processing.

The content of the topical antifungal agent in the nail polish depends on the structure of the antifungal agent used, its ability to release from the varnish layer, penetration into the nail and antifungal properties.

The varnish according to the invention, in the form of a solvent-containing formulation, contains a topical antifungal agent usually in an amount of 0.5-20, preferably 2-15 wt. The lowest content of antifungal agent in medicinal nail varnishes used in the therapeutic treatment of mycoses is 4% by weight; nail polishes used in prophylaxis contain less than 4% by weight and at least 1% by weight antifungal agent.

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The nail polish preferably contains a topical antifungal agent in an amount of 0.5-20% by weight, preferably 2-5% by weight.

A compound of formula I is preferred, wherein R¹ and R² together with the nitrogen atom form a heterocyclyl piperidinyl, R³ is hydrogen, and A1 a2 and A³ independently represent hydrogen or acetyl.

Particularly preferred is the compound of formula I in which R1 and R2 together with the nitrogen form a piperidinyl heterocyclic and R3, A¹, a2 and a3 are hydrogen.

Compounds such as dihydralazine, diisopropylamine or diazoxide are also preferred.

Also preferred are calcium antagonist compounds, such as nifedipine, nicardipine, verapamil, diltiazem, nizoldipine, nitrendipine, nivalaldipine, isradipine, felodipine, nimodipine, galopamil, fendiline, flunarizine, amlodipine, cyclosperpinine, diperidinol.

Angiotensin converting enzyme inhibitors, such as quinapril, lisinopril, benzazepril, captopril, ramipril, fosinopril, digitazapril or trandolapril are preferred.

Methylxanthine compounds such as pentoxifylline, propentophylline or torbafilin are also preferred.

In addition, hair growth promoting compounds, such as 2,4-diamino-6-alkoxy-3-sulfoxypyrimidine hydroxide internal salts with 1-6 carbon atoms in the alkoxy group, described in EP 0 427 625, or the internal salt of 2.4 hydroxide are preferred diamino-6-butoxy-3-sulfooxy-pyrimidine; pyridine 1-oxide derivatives described in WO 92 21317, or 2,6-diamino-4-piperidine-pyridine; 2,6-diamino-1,3,5-triazine derivatives as described in WO 91 19701, or 2,6-diamino-4-butoxy-1,3,5-triazine 1-oxide.

Compounds of formula I are prepared as described in US 3461461.

As antifungal agents constituting hydroxypyridones, for example: 1-hydroxy-4-methyl-6-n-hexyl-6-isohexylpyridone, 1-hydroxy-4-methyl-6-n-heptyl-pyridone or 1-hydroxy-4-methyl-6-n-hexyl-6-isoheptyl- 2-pyridone, 1-hydroxy-4-methyl-6-octylpyridone or 1-hydroxy-4-methyl-6-isooctyl-2-pyridone, especially 1-hydroxy-4-methyl-6- (2,4,4 -trimethylpentyl) -2-pyridone, 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone, 1-hydroxy-4-methyl-6- &lt;cyclohexylmethyl-2-pyridone or 1-hydroxy-4-methyl -6 cyclo-heksyloetylo-2-pyridone, wherein the cyclohexyl group may be substituted with methyl, 1-hydroxy-4-methyl-6- (2-bicyclic [2.2.1] heptyl) -2-pyridone, 1-hydroxy-3,4-dimethyl-6-benzyl-2 pyridone or 1-hydroxy-3,4-dimethyl-6-dimethylbenzyl-2-pyridone and 1-hydroxy-4-methyl-6- (P-phenylethyl) -2-pyridone.

The varnish according to the invention, as an additional aid for accelerating growth, significantly reduces the time of treatment in the case of onychomycosis therapy, which, in addition to optimizing the cost of therapy, significantly improves patient compliance. In the light of previous bad experiences during therapy, resulting from insufficient discipline of patients due to the lack of quickly visible effects of treatment, this is extremely important.

Compared to hydrophilic systems, the advantage of the water-insoluble varnish layer created after the varnish has dried is that it is not removed from the surface of the nails during washing, bathing or showering, so it does not need to be reapplied. In addition, this layer prevents contact with water from leaching of the active substance that has already penetrated the nail.

Treatment of the early stage of distal subungual onychomycosis using the varnish according to the invention is also possible without additional specific antifungal therapy.

The use of the varnish according to the invention is not limited solely to the therapy or additional support of the treatment of onychomycosis. The varnish according to the invention can also be used to treat nail growth disorders caused by various other causes.

The content of active substance in the varnish according to the invention depends on the structure of the individual active substances, and therefore on their release from the varnish layer and their penetration in the nail.

The varnish according to the invention, in the form of a solvent-containing formulation, contains the active substance in an amount of 0.1-10, preferably 2-5 weight percent

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Nail polishes usually contain an antifungal agent in an amount of 2-80, preferably 1060, especially 20-40% by weight, based on the amount of non-volatile components, i.e. the total amount of film-forming substances, a vasodilator, possibly pigments, plasticizers and other non-volatile additives as well as a topical antifungal agent.

A nail polish preparation can be used in the manufacture of a medicament for the treatment of nail growth disorders.

The invention is illustrated by the following examples.

Example 1

A preparation was prepared with the following composition:

6-Amino-4-piperidine-1,2-dihydro-1-hydroxy-2-iminopyrimidine 2.5%

Ethyl acrylate / methyl methacrylate / trimethylammonioethyl methacrylate chloride in a 1: 2: 0.2 molar ratio (see Uberzogene Arzneiformen, authors Bauer, Lehmann, Osterwald and Rothgang, pp. 239-242, Wiss.

Verlagsgesellschaft mbH, Stuttgart, 1988;

EUDRAGIT®RL 100) 7.0%

Ethanol 96% 75.0%

Ethyl acetate 10.5%

Butyl acetate 5.0%

Quantitative data are given in percent by weight.

Nail polish was prepared by dissolving various ingredients in a solvent.

The effect of the preparation according to the invention has been demonstrated in permeation tests carried out on cow horn plates and in treatment trials on test subjects. Permeation tests have determined the release of the active substance from a particular preparation and the subsequent permeation through the keratin material can be examined.

A reference preparation by dissolution was also prepared

6-amino-4-piperidine-1,2-dihydro-1-hydroxy-2-iminopyrimidine 21.5% in 96% ethanol 97.5%

A) Cow's horn penetration test

The active substance permeation measurements were carried out using the four-time infrared transmission spectroscopy ATR method (see Th. M. Bayerl et al; J. Invest Dermatol. 105: 291-295, 1995):

100 [mu] l of the tested preparation (preparation according to the invention or comparative preparation) was applied to the upper surface of cow horn plates 0.5 mm thick. Cow horn plates were attached with the bottom surface to the top surface of the silicon crystal. After penetration of the active substance through the cow's horn plate, the FTIR spectrum depended on the concentration of the active substance, so based on comparative measurements of the tested preparation applied directly to the measuring crystal, it was possible to quantify the amount of penetrating active substance depending on the time.

Tests have shown that the varnish formulation according to the invention has more than ten times the permeation rate of the active substance through the keratin material compared to the permeation rate for the comparative formulation. This is surprising because it could not be predicted that the active substance from the solid, water-insoluble layer formed after the varnish has dried is biologically more accessible than the same substance from the ethanol solution.

B) Performance tests

The properties of the varnish formulation according to the invention in terms of promoting nail growth were tested on two persons. For direct comparison, finger and uncoated fingernails, in each case a different hand or foot, were used. In order to distinguish or exclude misinterpretation of the results, caused by the possible faster growth of the nails of the working hand due to better blood supply to the nails, one test person was coated with the test finger nails of the hand more frequently used for work, and the other the finger nails of the hand less used for work. Thus, the test substance was treated with the nails of the right working hand and the left

186 876 feet, while the test substance was applied to a second person in a way that is a mirror reflection of the method used in the first person.

To determine the growth rate, the length of all nails was determined using a caliper, with the starting point of measurement being the top of the collar, since this point is always at a fixed place. The nail edge was chosen as the second measuring point.

Results: (Increased length of treated nails compared to untreated nails. Treatment time 4 weeks, once daily)

Hand nails treated working hand + 45.3% treated non-working hand + 18.6%

Toenails treated left foot + 27.6% treated right foot + 23.9%

In addition to measuring the increase in nail length, the nail surface growth was additionally determined using a transparent film.

Results: (Increased surface area of ​​treated nails compared to untreated nails. Treatment time 4 weeks, once daily)

Hand nails treated working hand + -53.3% treated non-working hand + -45.7%

Toenails treated left foot + 110.8% treated right foot + 177.5%

Example 3 A preparation was prepared with the following composition:

6-Amino-4-piperidine-1,2-dihydro-1-hydroxy-2-iminopyrimidine 2.0% 4- [3- [p- (1,1-dimethylpropyl) phenyl] -2-methylpropyl] -2 hydrochloride , 6-dimethyl morpholine 5.00%

EUDRAGIT® RL 100 10.0%

Ethanol 96% 73.0%

Ethyl acetate

Example 4

A preparation was prepared with the following composition: 4-Amino-4-piperidine-1,2-dihydro-1-hydroxy-2-iminopyrimidine 2.5%

-Hydroxy-4-methyl-6-cyclohexyl-2-pyridone 8.0%

50% Solution of methyl vinyl ether copolymer and maleic acid monobutyl ester in isopropanol 35.0%

Ethanol 96% 44.5%

Ethyl acetate 10.0%

Example 5

A preparation was prepared with the following composition:

5 - [(3,4-dimethoxyphenyl) methyl-amino] -2- (3,4-dimethoxyphenyl) -2-isopropyl valeritrile (verapamil hydrochloride) 2.0%

- [2,4-Dichloro-β- (2,4-dichlorobenzyloxy) phenethyl] -imidazole (miconazole) 2.0%

Polyvinyl butyral 3.8%

Cellulose nitrate 3.1%

Dibutyl phthalate 0.6%

Ethyl acetate iU, G%

Ethanol 96% 78.5%

Example 6

A preparation was prepared with the following composition:

Angiotensin converting enzyme inhibitor in combination with an allylic antifungal agent

(2S, 3aS, 6aS) -1-N - [(S) -1-ethoxycarbonyl-3-phenylpropyl] alanyl] octahydrocyclopenta [b] pyrrole-2-carboxylic acid (ramipril) 2.0%

186 876 (E) -N- (6,6-Dimethyl-2-heptene-4-yl) -N-methyl-1-naphthylmethylamine (terbinafine) 0.5%

Methacrylic acid / ethyl acrylate 1: 1 copolymer 6.5%

Ethanol 96% 71.0%

Ethyl acetate 20.0%

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