The invention relates to a pharmaceutical composition suitable for the topical treatment of nail mycosis and a process for preparing the composition. Nail mycosis (αnychomycosis) is a very frequent disease the treatment of which is very diffi¬ cult. This disease is medicated by systemic treatment, by the oral addition of antimycotics , in this case, how¬ ever, a highly increased therapeutical dose should be administered into the organism, as a consequence of which the organism suffers injuries by strong side-effects. According to another method the topical treatment is carried out by using paintings and ointments. The dis¬ advantage of these paintings and ointments is that they do not remain long-lasting on the nail surface, this treatment requires therefore the use of occlusive bandage, which hinders the patient in using his treated limb. A further disadvantage of the known topical treatment is that it is only rarely successful. The most radical method of treatment of nail mycosis is the ablation (surgical removal) of the nail which is, however, on one hand a very painful intervention, on the other hand, the patient. is unable to. work for a long time.

So there is a need of a much simpler therapy of nail mycosis, which has less side effects to the organism.

Aim of the invention is to prepare a com¬ position enabling the topical treatment of nail mycosis.

The composition according to the invention assures a lαng- -lastiπg active ingredient concentration, it cannot be washed with water and can be used very easily and the patient is not hindered in working during the therapy.

It has been found that the above aim can be achieved by a composition comprising a pharmaceutically effective amount of a topical antimycotic, preferably that of imidazole structure and optionally of an antiseptic, pre¬ ferably salicylic- acid or a salt or ester thereof dissolved if necessary in an organic solvent, preferably in a lower alcohol or in the ester thereof formed with lower carbo- xylic acid, a coat forming agent preferably colloidion and optionally a lower polyvalent alcohol.

The basis of the invention is the recognition that antimycotics, especially compounds of imidazole struc¬ ture usable for topical treatment remain effective for a long time, if they are admixed to coat forming agents - if necessary with suitable additives and in solvents, resp. - and applied onto the surface to be treated in the form of nail polish.

On the basis of the above recognition a composi¬ tion for treating nail mycosis is prepared according to the invention in a way that a topical antimycotic active ingre¬ dient, preferably an antimycotic of imidazole structure and optionally an antiseptic compound, preferably salicylic acid or the salt or estεr thereof is formed into nail polish by dissolving them if necessary in an organic solvent,

« preferably in lower alcohol or in the ester thereof formed with a lower carboxylic acid, and by mixing them with a coat forming agent, preferably with collodion as well as optionally with a lower polyvalent alcohol. As topical antimycotic active ingredient prefer¬ ably l-(2.-chlorophenyl-c£ ₃ oC-diphenylbeπzyl)-imidazole or 1- -(2,4-dichlαro-f 2,4-dichlorobenzylαxy/-phenetyl)imidazole is used. In addition to the above-mentioned compound of imidazole structure, however, compounds of antimycotic activity known per se can also be used, but owing to the wide spectrum as well as the long duration of effect the mentioned compounds proved to be the most preferable con¬ cerning the invention.

In addition to the compound of antimycotic activity an antiseptic compound could optionally be used for preparing the composition in order to prolong the effect of the antimycotics. Salicylic acid or a salt of ester thereof are preferably used utilizing the keratαly- tic activity of these compounds. As carrier of the composition a coat forming agent, preferably collodion, i.e. an about 4 % solution of nitrocellulose in ether-alcohol micture of 3 : 1 ratio of volume is used. After the solvent is evaporated this material forms a long-lasting waterproof coating on the surface to be treated and assures at the same time that the active ingredient remains stable and -acts with suitable intensity .

It has been found, however, that the thus- formed lacquer coat can further be improved, namely its elasticity can be increased (its cracking can be prevented) and the effectivity of the active ingredient therein can be enhanced if a lower polyvalent alcohol, preferably propyleπe glycol is added to the composition as further carrier.

The amount of the ingredients of the compo¬ sition is determined by the circumstances of the prepa¬ ration and storage of said nail polish as well as cir¬ cumstances of use. Preferably, the composition contains besides 1 part by weight of antimycotic 2-5 parts by weight of antiseptic, and an organic solvent, if needed, in an amount up to 40 parts by weight, preferably 5-35 parts by weight, 15-35 parts by weight of a coat forming agent and, if needed, 3-15 parts by weight of a lower poly¬ valent alcohol.

The composition is prepared by the simple mixing of the components. The active ingredients are ad¬ mixed to the other ingredients of the composition in themselves or if they are hardly soluble in the carriers, then dissolved in an organic solvent, preferably In a lower alcohol or ester, e.g. absolute ethyl alcohol or ethyl acetate.

The composition obtained by the mixing of the active ingredients and carriers can effectively be used for treating nail mycosis caused by a wide variety of

fungus strains. The composition can be used especially against infections caused by Trychophyton species but it is also effective against Candida albicans, Scopula- riopsis brevtcaulis and other fungus strains.

The composition can be used in the human and veterinary therapy, as well. In latter case it may be used for treating oπychomycosis of meat-eating animals. It is particularly useful for treating dogs and cats but it can be applied to any other meat-eating animals, too.

The treatment is very simple and easy, the composition is applied onto the nail and the thusformed lacquer coat is renewed from time to time. Depending on the seriousness of the infection the nail mycosis can be alleviated by a regular treatment for 1 to 6 month. Furthe one month treatment is advisable after the alleviation of the symptoms in order to prevent the renewed infection.

Advantage of the invention is that the compo¬ sition of the invention enables the treatment of nail mycosis involving no painful intervention or deleterious side effects to the organism. The application of the com¬ position is simple and makes the treatment of nail myco¬ sis much easier.

The invention is described more detailed in the following Examples. In the Examples "part" means part y weight. Example 1

A composition is prepared against nail mycosis

with the following composition:

0.4 part of l-/2-chlorophenyl-cl,o(.-diphenyl- benzyl/-imidazole antimycotics, 1.0 part of salicylic acid antiseptic, 8.0 part of absolute alcohol solvent,

2.0 part of propyleπglycol carrier additive, 8.6 part of collodion carrier. The two active ingredients are dissolved in alcohol and the alcoholic solution is mixed with the mixture of propyleπglycol and collodion. The lacquer thus-obtained is ready for use. Example 2

A composition is prepared against nail mycosis containing the following compounds: 0.4 part of 1-/2, 4-dichlαro-(i-(2, 4-dichloro- beπzyloxy)-pheπethyϊ)-Imidazole antimycotic, 1.0 part of salicylic acid antiseptic, 4.0 part of ethylacεtate solvent, 4.0 part of propylene glycol carrier additive,

10.6 part of collodion carrier. The composition Is prepared from the active ingredients and the other components according to Example 1.

The stability and biological activity of the composition of the invention have been examined in vitro, v/hile their therapeutical usability has been tested in vivo. The details of the examination are described as

follows .

The stability of compositions according to Examples 1 and 2 as well as those having similar com¬ position but containing no salicylic acid have been exa- mined in vitro. The tests were carried out according to the prescriptions of the Orszagos Gydgyszereszeti Inte- zet (Hungarian Pharmaceutical Institute). The test com¬ positions have been kept on room temperature for six months and they have been examined from time to time for strange organic materials and decomposition^products .

From the compositions containing the active ingr.edieπt according to Example 1 a sample was taken corresponding to 500 /ug. of antimycotic, from which a thin layer chromatogram was made in contrast to the pure active ingredient with a 4:6 ratio of volume chloroform- methaπol mixture; the chromatogram was made visible with the glacial acetic acidic-aqueous solution of potassium iodide. No imidazole decomposition product was detected even after six months. For examining carbiπol decomposition products a thin layer chromatogram was made from samples similar as described before, developed this time with saturated diisopropvlether. The chromatogram was evaluated in ultra¬ violet light. No decomposition product could be detected either, even after six months.

From the compositions containing the active ingredient according to Example 2 a sample was taken

corresponding to 200 /ug. of antimycotics. A thin layer chromatogram was developed with a 6:3:1 ratio of volume n-hexaπe-chloroform-methanαl mixture and evaluated as described before in iodine vapour atmosphere. It was found that the composition contained no strange organic materials iπdetectable amount even after a storage for six months.

The biological effectivity of the compositions were examined according to the disc method specified in 6th Eddition of Pharmacαpea Hungarica for the biological evaluation of antibiotics, by using self-prepared test discs. The samples of the composition according to Examples 1 and 2, prepared by chain dilution according to the pre¬ scription were applied to the culture of test fungus strains inoculated into culture medium and the extinction ring was examined by different concentrations. The exa¬ minations were carried out on Candida alblcans, Scopula- riopsis brevicaulis as well as on Trlchophyton rubrum and Menthagrophytes strains, respectively. The compositions according to Examples 1 and 2 proved to be the most effective against the Trlchophyton strains, they showed an intensive activity against the Candida alblcans strain and showed a good result against the Scopulariopsis bre¬ vicaulis strains, too. This result is very interesting considering the Trlchophyton strains are fast always present among the pathogens of nail mycosis, without their killing the nail mycosis cannot be alleviated.

Q -

The therapeutical examination was carried out on groups of 58 voluntary patients. The patient suffering from nail mycosis have been instructed to treat their nails with the composition of Example 1 keeping the lacquer coat constantly. The patients have been examined after 28 weeks, then after further 6 weeks and the results were evaluated using the following scale:

A. the position before treatment (100 % mycosis) B: uncertain decrease (recovery in a ^' degree less than 25 %) C: the infected surface decreased by 25-50 % D: the infected surface decreased by 50-75 % E: the infected surface decreased in a degree greater than 75 % F: the nail is clinically free from symptoms. The following Table shows the percentage ratio of the patients having reached the different recovery levels at the end of the examination period.

Extent After a treatment After a treatment of recovery for 28 weeks for 34 weeks

B 10.4 % 8.6 0

C 11.5 % 7.5 %

D 20.5 % 32.5 %

E 30.6 % 9.4 %

F 27.0 % 42.0 %

Though the examinations were not carried out under clinical conditions (neither the identification of the pathogenic fungus strains nor the control of the exact keeping of the treating instructions were examined) the results show that the composition of the invention can effectively be used for the medical treatment of nail mycosis .