WO2009071959A2

WO2009071959A2 - A composition in the form of a paint tincture or lacquer to treat fungal infections containing itraconazole and a process for the preparation thereof

Info

Publication number: WO2009071959A2
Application number: PCT/HU2008/000144
Authority: WO
Inventors: Tibor Past; Gyula MÓZSIK; Pál PERJÉSI; Leventéné SZABÓ
Original assignee: Pannonpharma Gyogyszergyarto Kft
Current assignee: Pannonpharma Gyogyszergyarto Kft
Priority date: 2007-12-04
Filing date: 2008-12-03
Publication date: 2009-06-11
Anticipated expiration: 2010-06-04
Also published as: WO2009071959A3

Abstract

The invention relates to lacquer and paint tincture compositions comprising the known antifungal active agent itraconazole, that can be directly applied topically to the affected horny surfaces, and the process for the preparation thereof.

Description

A composition in the form of a paint tincture or lacquer to treat fungal infections containing itraconazole and a process for the preparation thereof

The invention relates to compositions in the form of lacquer or paint tincture that can be directly applied topically to the affected keratinous surfaces, and which contain the well-known antifungal active agent itraconazole, and the process for the preparation thereof. Prior art

Nowadays - partly because of the wide-spread use of broad-spectrum antibiotics, and partly with the ever greater number of patients with immun deficiency - the frequency of fungal infections is on the increase. That is why it is now important even in otolaryngology to recognize the clinical appearance of and treat of fungal infections, for which properly formulated systemic and local compositions are necessary.

The itraconazole [IUPAC name: 4-[4-[4-[4-[2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l- ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]-piperazin-l-yl]phenyl]-2-(l-methylpropyl)-2,4-dihydro- l,2,4-triazol-3-one ] belongs to the recently introduced systemically applied group of azolic antifungal agents. The group also includes (in a broad sense) ketoconazole, and more strictly speaking, fluconazole or voriconazole. These have replaced agents, used earlier but causing numerous side-effects, e.g. 5-fluorcitozin or amphotericin-B. This group of agents exert their effect through inhibiting the ergosterol synthesis mediated by cytochrome P450 enzyme.

As a broad-spectrum antifungal principle, itraconazole is present in many drugs (e.g. Orungal, Itraconazole Sandoz), but - owing to its very poor solubility and its weak capacity for being absorbed - it is restricted to systemic use. So the available compositions are oral solutions, capsules, solutions to be injected intravenously.

An orally applicable, cyclodextrin-free solution containing itraconazole is described in the PCT- application No. WO05/023259. In document No. WOO 1/41765 a composition is described that has enhanced bioavailability and better solubility. The result was achieved through using a macromolecular aqueous solution.

In document No. WO01/47492 the possible formulation of antifungal agents which are practically insoluble in water, among them azole-type compounds (for example, itraconazole and saperconazole), is described, and formulation as a solid dispersion (together with acidic polymers) is suggested. In application No. EPl 103262 an antifungal solution containing itraconazole or saperconazole is described in which the active agent is present together with propylene-glycol in a solvent containing hydrochloric acid and alcohol.

In patent application No. WO 96/3001 1 an antifungal paint is described that contains several antifungal agents, among them itraconazole, in a solution of dimethyl-sulphoxide (DMSO), where C2-C4 aliphatic alcohol also my be present as a further component. In the compositions described the DMSO concentration is over 90%, while in the general disclosure it is mentioned that the DMSO concentration should always be at least 50%. Aliphatic alcohols, propylene-glycol or glycerol are applied as thinners.

In patent document No. WO 03/020250 a plaster to be used for the treatment of nail diseases is described that - among others - contains a penetration enhancing substance (which might be DMSO or several other alternatives) and an antifungal agent that is chosen from a larger group also including itraconazole.

Patent document No. WO 03/020248 gives details of a plaster for the treatment of nail diseases containing sertraconazole. DMSO as a possible penetration-enhancing substance is made use of here, too (besides numerous other alternatives).

In A. Ball et al.: "Corneal concentrations and preliminary toxicological evaluation of an itraconazole/dimethylsulphoxide ophthalmic ointment", J. of Veterinary Pharm. and Therap., Vol. 20, Issue

2, pp 100-104 an eye ointment containing micronized itraconazole and DMSO is disclosed which is indicated in the treatment of horses' eyes. It should be noted that the structure of the cornea is significantly different from that of skin.

In a publication found on the Internet [Compounded Medications for Podiatrists (http://www.healthwayrx.com/podiatry.htm] it is stated that, at present, Penlac is the only commercially available medicament for the topical treatment of nail fungi (the active agent being circlopirox). It is suggested that compositions containing other antifungal agents (e.g. itraconazole, ketoconazole and inflamation supressing ibuprofen) should be used in DMSO as solvent. The recommended concentration of the active principle is 1%, the maximum quantity of supplementary materials actually mentioned is 27%, so these compositions contain DMSO in a great proportion.

From the documents above it can be seen that, for the treatment of nail diseases, itraconazole is used in a DMSO solution, while it can also be gathered that, in liquid compositions, the DMSO concentration should be high, even above 50%.

The above selection of document also shows that, at the present state of technology, there is hardly an example of a topical composition that contains itraconazole and which is successful in practice, where this fact is due to the above-mentioned very poor solubility of itraconazole. At the same time ketoconazole, which was synthetized much earlier, is used in numerous topical formulations (anti-dandruff shampoo e.g. Nizoral, or cream).

In our experience the absorption of the active agent is significantly better in the case of the liquid compositions than in the described creamy compositions. In our opinion this can be explained by the fact that in the creamy compositions auxiliaries of relatively great molecular mass are applied which increases the apparent molecular mass of the active agent. We propose to explain our statement as follows (but we do not wish to absolutely attribute the efficacy of our invention to this reason).

In the clinical-pharmacological literature it is well known that the absorptive speed of orally taken substances that are absorbed through a passive diffusion mechanism depends partly on the chemical structure of the active agent and partly on its molecular mass. In the literature, the phrase "exclusion molecular mass" was coined, and this quantity is defined as between 0,8-2,2 kD depending on the molecular structure (the mass of the itraconazole molecule is about 0,7 kD). From the wide range of chemical structure-dependent exclusion masses and the relatively low values one can deduce that by the exclusion mass a so-called apparent mass is meant, which is made up of the active agent's molecular mass and that of the solvation envelope, which is primarily bonded to the active molecule more or less strongly, and which is made up of molecules of the solvent. In the ointments and creams the carriers (the solvents of the active agent) are usually a substances of much larger molecule [petrolatum (C₂₂H₄₆, C₂₃H₄₈), Makrogol-400 - Makrogol-4000, wool fat, beeswax, etc.] than the solvents having small molecular mass in a liquid composition (e.g. C₂-C₃ alcohols). As a result of this, the apparent molecular mass of the active ingredient is found to be theoretically much smaller in liquid compositions than in creams. This apparently smaller molecular mass in the liquids ensures a faster absorption and a more effective penetration depth than is found with creamy compositions of the same parameters.

It is also noted here that the usual oral dose of itraconazole is 200 mg per day, in case of a more serious infection or in the treatment of fungal infection of the limbs or nails the shock therapy is 3x200 mg per day.

Definition of the aim

Although the triazole antifungal compounds (fluconazole, itraconazole), which have spread since the 'eighties and whose efficacy surpasses that of the imidazole derivatives used earlier, have a diminished inhibiting effect on the liver's cytochrome P450 enzymatic system and so they can cause fewer side effects or interactions with other drugs, in the case of local fungal infections (e.g. on the feet or on the finger- or toenails) it would be even more advantageous to apply them locally, as there are several examples of this with ketoconazole (e.g. Nizoral mentioned above).

Itraconazole administered systemically might cause several side effects, for example, often vertigo, headaches, gastrointestinal side effects (vomiting, diarrhea), less frequently changes in the blood count, rhinitis, infections in the upper respiratory tract, sinusitis, disturbances in the liver function, and it may also interact with numerous drugs taken for a basic disease. It is obvious that with a topical composition that can be applied locally, and which can replace the systemic drugs, those side effects can be eliminated to a large extent. Therefore, the objective of the invention was to create a topically applicable antifungal composition containing itraconazole and having a local effect, and within this framework, the formulation of a paint tincture and a lacquer.

Recognition and solution of the problem There were several difficulties to overcome on the way towards the two compositions embodied in the invention (a paint ticture and a lacquer), the main problems arising from the poor solubility of itraconazole and, as a consequence of that, the inadequate penetration and bioavailability.

A solvent was to be found that is provably non-toxic, and which is capable of well penetrating into the skin and keratinous formulations while it was to be a good solvent for itraconazole. In the compositions involved in the invention, therefore, dimethylsulphoxide (DMSO) is used as a less-volatile solvent component, which meets the above requirements, i.e. it is a good solvent for itraconazole and can well penetrate into the skin and the keratinous formulations, and is capable of carrying the active agent into the body tissues. In addition, DMSO as a radical trap helps to improve the stability of itraconazole, which is a further advantage in its use. To realize the invention, besides DMSO, another suitable volatile solvent component and optionally further auxiliary materials had to be found and, in order to decrease the dissolution time, new methods to promote the dissolution of the active agent had to be looked for. In the case of the paint, among the auxiliary materials, water has an important role since without an adequate water content the treated surface (skin, nails) get desiccated and broken, thereby the open surface increases, which opens the way for the reinfection of the deeper layers. The rest of the auxiliary and vehicle materials will be dealt with in the detailed description of the invention and the claims.

In the case of the other composition according to the invention, i.e. the lacquer, an important function as well as a desired aim is the prevention of reinfection or repeated infection. That means that the infected surface must be isolated from the outer world, the flushing out of the active agent from the treated surface must be prevented (this could happen in the normal course of events during the daily cleansing activities).

An even more preferred solution is when the lacquer painted on the treatable surface participates in supplying the active agent (the molecules of the active agent migrate directly into the affected surface from the lacquer itself), through which an adequate and lasting local effect can be obtained. The latter, however, can only be attained if the lacquer composition is capable of releasing the active principle into the protectable area (e.g. fingernail) during a longer period of time in a sustained and reproducible way. To achieve that, several formulation problems had to be solved.

The first task was to choose a film-forming substance that suitable adheres to the surface. Despite several trials, no satisfactory adhesion was achieved with the usual film-forming materials. In connection with the polyamide-base film-forming substances it was found surprisingly that they together with a colophony softener adhered better.

As with the paint so with the lacquer, dimethylsulphoxide (DMSO) is used as a less-volatile solvent for itraconazole and as a vehicle of penetration of it into the horny surfaces. The advantages of DMSO are that it is proven to be non-toxic, it is a good solvent for itraconazole and can satisfactorily penetrate into the skin and the horny plates. In the case of the lacquer, this latter is an important characteristic because the side of the solidified lacquer layer facing the horny plate changes into a porous matrix which helps the release of the active agent stored in the lacquer film and the penetration of it into the target areas enabling by it the desired supplement of the active agent. One of the problems with DMSO as used in the lacquer is that an increase in the DMSO concentration spoils the adhesive quality of the lacquer film. The cause of this is thought to possibly be that, under the quickly solidifying lacquer film, the DMSO - not being able to evaporate - forms a separate film and the layer of lacquer - floating on a liquid film - gets easily detached. This actually observed phenomenon must, if possible, be counteracted by carefully choosing the quality and amount of the other components, while the percentage of DMSO should be kept as low as possible.

It should be noted here that when a water/DMSO solution with 50 V/V % concentration is used, after ten minutes, erythema appears. Although, in the known plaster-type compositions, a lower DMSO concentration is found (if the ratio is calculated in relation to all components, but this practice is questionable when considering the effect produced, as the active agent and DMSO is not soluble in many of the components), but these compositions have a disadvantage as their composition, and consequently their manufacturing, is complicated. That was one of the reasons why it was thought to be necessary to develop a product (paint and lacquer) with good penetration and minimal DMSO concentration.

A solution had to be found for getting the active agent near to the skin or horny layer and the density of the composition had to be adjusted accordingly. The usual film-forming compositions are not suitable here. The inventors had to find some film-forming composition of a lower density than usual, because that is how it can be ensured that the active agent gets concentrated on the side of the treated surface, i.e. the concentration gradient points towards the treated skin or horny plate. It was observed by the inventors that the active agent, as the solvent (mixture) evaporates, begins to cristallize, so the density of the solidifying lacquer film (in this case ~ 1.008 g/cm³) is to be lower than that of the micro-cristalline active agent - it was found to be 1.34-1.37 g/cm³ - which forms by the evaporation of the more volatile solvent, because this ensures the increasing of the concentration of the micro-cristalline active agent on the side towards the treated surface, i.e. a density gradient pointing to the desired direction.

Another newly-found realization was that if a tenside-type auxiliary substance is used - belonging either to the ionic or non-ionic tenside family, for instance, Cremofor EL (BASF AG) - it also has a synergic effect improving the efficacy so the DMSO concentration can be further decreased in the paint compositions. The synergic effect of Cremofor EL and other substances of a similar structure is probably explainable by the fact that in other compositions (e.g. Paclitaxel), according to certain investigations, it has a cell-killing effect influencing the G-protein channels.

Detailed description of the invention

The first subject of the invention is an antifungal paint tincture composition comprising itraconazole or a pharmaceutically acceptable salt thereof as antifungal active agent, dimethylsulphoxide as less-volatile solvent component and one or more volatile solvent components, and optionally one or more auxiliary materials, where the amount of the dimethylsulphoxide is less than 50% V/V, preferably 10- 45 V/V %, more preferably 20-35 V/V %, most preferably about 30 V/V % in the composition.

The selection and preparation of the pharmaceutically acceptable itraconazole salts belongs to the general knowledge of a skilled person, but a few of these that can be advantageously used must be mentioned, for example, those that are formed with inorganic acids, such as methansulphonic acid, or with organic acids, for example, the double-base hydroxy or polyhydroxy acids, such as tartaric acid. The desirable concentration of itraconazole in the composition is about 0,4-4 mg/ml, prepferbly

0,5-2,0 mg/ml calculated for the total volume of the paint composition. For a skilled person it is obvious that it would be easy to put together a more dilute composition than this optimal concentration, but - because of the weak therapeutic effect - several daily administrations would be necessary (too low dosage), which is not to the purpose and inconvenient for the patient. With higher concentrations, there might arise problems of solubility, when the composition is put aside for a longer period, the principal agent might separate out, which is unacceptable in pharmacy.

The one or more volatile solvent components are chosen from among C2-C4 aliphatic alcohols, the ethers and mixed ethers formed from C2-C4 aliphatic alcohols, esters formed from C2-C4 aliphatic alcohols with aliphatic carboxylic acids, or from among any mixture of them. The aliphatic alcohols and aliphatic carboxylic acids may have straight or branced chain (e.g. isobutanol). As a mixed ether, t-butyl-methyl- ether is suitable, as alcohols ethanol, n-propanol and i-propanol may be used. The esters formed from C2- C4 aliphatic alcohols and aliphatic carboxylic acids are preferably derived from C2-C4 aliphatic carboxylic acids. As a volatile solvent component, it is advantageous to use C2-C4 aliphatic alcohol, preferably ethanol. This volatile component is used in an aqueous solution at least in 60 V/V %, preferably in 65-96 V/V %, more preferably 70 V/V %. This way, the component's concentration in the final composition is minimum 20 V/V %, preferably 30-80 V/V %, more preferably 50-70 V/V %.

As it has been mentioned, the volatile component is added in an aqueous solution. The water that gets into the composition this way is considered as an auxiliary material but such as has a noteworthy role because it hydrates the surface treated (skin, fingernail), it prevents desiccation and breakage. The desired ratio of the volatile component and water can be adjusted by adding these components to the composition separately, for example, water and absolute ethanol is added during the preparation of the composition.

The dissolution process in the paint composition can be promoted by using ionic or non-ionic tensides, or even a mixture of such tensides, for example, Cremofor EL. The concentration of these components in the final composition is about 0.001-5 % by mass, or preferably 0.005-1 % by mass, more preferably 0.1 % by mass.

The first subject of the invention includes a process for the preparation of an antifungal paint tincture composition, which comprises mixing itraconazole or its pharmaceutically acceptable salt as the antifungal active agent, dimethylsulphoxide as less volatile solvent component, and one or more volatile solvents, and optionally one or more additional auxiliary materials, obtaining a solution, in which the amount of dimethylsulphoxide is less than 50 V/V %, preferably 10-45 V/V %, more preferably 20-35 V/V %, and most preferably 30 V/V %. The dissolution of the active agent is promoted by methods a) to c) below, applied only one or more in combination: a) heating and/or mechanical stirring; b) irradiation by ultrasound; c) irradiation by microwaves.

If the concentration of the active agent is relatively low in the solution, for example less than 1 mg/ml, preferably less than 0.6 mg/ml, and the solution contains small amount of water, for example less than 5 or 10 V/V %, method a) mentioned above, i.e. heating and/or mechanical stirring, may be enough. The dissolution process can be carried out at the boiling point of the volatile solvent as a maximum, or at 30-80⁰C, or preferably at 5O⁰C, accompanied by mechanical stirring. With the increase of the water content, itraconazole's solubility decreases strikingly, so much so that with a water content above 5-10% the dissolution process cannot be accomplished within a reasonable period of time using method a).

If the concentration of the active agent in the solution is relatively low, for example less than 1 mg/ml, preferably less than 0.6 mg/ml, while the solution contains more water, for example more than 5-10

V/V %, instead of or together with method a), the next one, method b) - irradiation by ultrasound - can be taken use of. The preferable frequency range is 28.5-100 kHz, preferably 37 kHz, with an energy density of

0.1-2.0 W/ml, preferably 0.14 W/ml. The length of time for the irradiation is dependent on several parameters, for example, composition or energy density, but by suitable adjustment of the parameters, a preferred irradiation time of 5 to 30 minutes, more preferably 10 minutes can be achieved. If the concentration of the active agent is relatively high, for example higher than 1 mg/mi, preferably 0.6 mg/ml, and the water content is more than 5-10 V/V %, method c) can be successfully used, i.e. the irradiation by microwave. The whole spectrum of microwaves (300 MHz-300 GHz) can be used, but the wavelength range of 0.12-36.8 cm is preferable, the range between 12-24 cm is more preferred, with a preferred energy density of 0.5-8.0 W/ml, more preferably 4.5 W/ml. It is advisable to use the irradiation divided in portions to avoid warming up owing to the energy absorbing property of the water and other solvents, so, for example the scheme below might be used: irradiation of 0.6-10 minutes, preferably 2 minutes; 10-60 sec, preferably 20 sec pulse mode; at a starting temperature of maximum 85, preferably

5O⁰C. The other subject of the invention is an antifungal lacquer composition that contains itraconazole or its pharmaceutically acceptable salt as active agent; a film-forming agent which can be selected from the group of nitrated cellulose or a cellulose derivative (e.g. nitrocellulose, acetyl cellulose, or a mixture thereof, or in a form whose consistency is modified by camphor), polyvinyl alcohol, polyvinyl acetate, polyamide and a mixture of them; dimethylsulphoxide as a less- volatile solvent component, where the amount of DMSO is less than

50 WV %, preferably 1-20 V/V %, more preferably 5-15 V/V %, and most preferably 10 V/V %; a volatile solvent component, optionally, as an auxiliary material, a softener, preferably a resin, optionally, as an auxiliary material, a less volatile solvent in which itraconazole has a poor solubility, preferably ethyl-lactate or glycol-acetate, and optionally, one or more additionaly usual auxiliary materials.

In the lacquer composition according to the invention, itraconazole is present preferably as 1-15 %o by mass, more preferably 2-10 %o by mass, most preferably 2-4 %o by mass, as compared to the dry mass of the film-forming component. As usual one or more film-forming components, nitrated cellulose or a cellulose derivative, polyvinyl alcohol, polyvinyl acetate, or a polyamide (e.g. Degalan LP), or a suitable mixture of thereof is used. The concentration of the film-forming component in the composition is 100-750 ml/mg, preferably 150-500 mg/ml, more preferably 200-250 mg/ml.

The volatile component is selected preferably from the group of C2-C4 aliphatic alcohols, ethers or mixed ethers derived from C2-C4 aliphatic alcohols, esters formed from C2-C4 aliphatic alcohols with aliphatic carboxylic acids, or any mixtures of them, more preferably ethanol, t-butyl-methyl-ether, ethyl acetate, propyl acetate or butyl acetate, or any mixture of them. The final concentration of this component in the composition is min. 50 V/V %, preferably 70-95 V/V %, more preferably 90 V/V %. As a volatile solvent component, ethyl acetate is used preferably, which may contain 0.1-30 % by mass of propyl and/or butyl acetate. The proportion of ethyl acetate to DMSO may vary preferably between 9.5:0.5 and 8:2 (V/V), more preferably 9: 1 (V/V).

To improve adhesion, a softener, for example a resin, can be used as an auxiliary material; the amount of this softener is 1-20 % by mass of the dry matter of the film- forming component, preferably 2- 15 % by mass, more preferably about 10 %. Preferably colophony is applied as softener (primarily in case of polyamide-type film-forming substances, but in case of nitrocellulose the softener might be Eudragit, camphore, or a mixture of them).

It should be emphasized here that when using a colophony as softener with a polyamide-base film- forming substance, an unexpected and excellent adhesion was achieved. In order to dissolve the film-forming and auxiliary materials, another, less-volatile solvent - preferably ethyl lactate or glycol acetate - might also be necessary, which, however, is not a good solvent for itraconazole, and whose proportion depending on the material and amount of the film-former and softener could be between 0.5 to 5%. This component is basically used for setting the viscosity but these materials can advantageously influence the properties of the film (flexibility, adhesion). The second subject of the invention includes a process for the preparation of an antifungal lacquer composition comprising the following steps: dissolving itraconazole or its pharmaceutically acceptable salt as antifungal active agent and a film- forming substance which is selected preferably from the group of nitrated cellulose or a cellulose derivative, polyvinyl alcohol, polyvinyl acetate, polyamide or a mixture of them, optionally a softener, preferably a resin, as well as optionally one or more auxiliary materials in a mixture comprising

- dimethylsulphoxide as a less volatile solvent, where the amount of it is less than 50 V/V %, preferably 1-20 V/V %, more preferably 5-15 %, most preferably 10 V/V %;

- volatile solvent components preferably selected from the group of C2-C4 aliphatic alcohols, ethers or mixed ethers formed with C2-C4 aliphatic alcohols, esters formed from C2-C4 aliphatic alcohols with aliphatic carboxylic acids, or a mixture of them, more preferably ethanol, terc-butyl-methyl-ether, ethyl acetate or butyl acetate or an optional mixture of them; most preferably ethyl acetate or a mixture of ethyl acetate, butyl acetate, isobutyl acetate; and necessary, if desired, the viscosity is set by one or more solvents, preferably by a solvent in which itraconazole has a poor solubility and which is less volatile, preferably by ethyl lactate or glycolic acetate. The quality and proportion of the volatile and less-volatile solvents are selected in such a way that when 60 % by mass of the volatile solvents have evaporated, the remaining solvents may form an over- saturated solution of itraconazole. Furthermore, the amount and proportion of the film-forming and solvent components should be selected keeping in mind that, when at least 60 % by mass of the drying lacquer has evaporated, the density of the remainder should be lower than that of the solid active agent. The itraconazole salt contained in the antifungal paint and lacquer composition is one formed with an inorganic acid, e.g. methanesulphonic acid and an organic acid, more preferably with an organic double- base hydroxy or polyhydroxy acid. The use of a tartaric salt may be advantageous.

A further subject of the invention is the use of the antifungal paint and a lacquer composition of the invention for the treatment of fungal infections on the horny plates on limbs. The combined application of the paint and lacquer compositions of the invention was found especially efficacious, as they supplemented each other's effects. It was recognized that the treatment is more effective (especially that of toe- and fingernails) if the possibility of over-infection was blocked. Infection of the nails starts either from the open nail-ends or the nail-bed. The paint is effective on the skinny surface at the nail-ends and the nail-bed. On those same surfaces the lacquer will not adhere, but it will cover the surface of the nail, preventing over-infection, while, at the same time, it counteracts the washing-off of the active agent during the normal daily cleansing activities.

Subsequently, the lacquer will for a long time ensure a supply of the active agent (a retarded effect), whose molecules have wandered out of the horny layer or have become inactive (see: microbiological dissolution studies), so the treatment has to be repeated less frequently.

The one or more further auxiliary materials mentioned above might be a scent, a colouring agent, a viscosity modifier, an adhesion enhancer. The lacquer composition could be made more aesthetic by using (as auxiliary material) an organic dye (not of pigment type), such organic dyes as could be antifungal themselves thus enhancing the efficacy of itraconazole.

Figures

That the active agent gets released from the solid lacquer is verified by the following photos documenting the results of the microbiological experiments.

Fig: 1 - Solid lacquer without active agent [Candida albicans, culture medium: Moller-Hinton agar (Oxoid), T = 30 ⁰C; t = 24 hours].

Fig. 2 - 50 μl (50 μg itraconazole) solid lacquer desiccated onto filter paper disc [Candida albicans, culture medium: Moller-Hinton agar (Oxoid), T = 30 ^CC; t = 24 hours].

Fig. 3 - 50 and 100 μl (50 and 100 μg itraconazole) desiccated onto filter paper disc [Candida albicans, culture medium: Moller-Hinton agar (Oxoid), T = 30 °C, t = 24 hours].

Figs 1-3 demonstrate the inhibiting effect of the lacquer film that contains the active agent. In the photos (taken after 24 hours) it can be clearly seen that while the lacquer itself has no inhibiting effect (Fig

1), that containing 50 and 100 μg itraconazole (Figs 2 and 3) shows the inhibition zones caused by the active agent streaming out of the lacquer (inhibition of growth). Within the inhibition zones, the concentration of the active agent exceeds that of MIC. Further experiments (not documented by photos) showed that the release of the active agent could still be measured even after 10 to 14 days, (in the experiment, the lacquer film was removed from the fungal bed after every 24 hours, then it was rinsed with water and replaced onto a fresh culture of Candida albicans, and the inhibiting effect was visually checked after 24 hours), all in all, it is enough to apply the lacquer only once a week. It makes things much easier for the patients.

It can be seen clearly that while the inactive components themselves show no inhibiting effect (Fig.

1), it can be seen that the active agent (50 mg) streaming out of the lacquer (Fig. 2) creates a clear inhibition zone (inhibition of growth). The concentration of the active agent within the inhibition zones exceeds the value of MIC. In Fig. 3, the same effect can be seen at two different active agent concentrations (50 and 100 μg itraconazole).

The invention is further detailed by the following non-limiting examples. The claimed scope is defined by the set of claims.

Example 1 A paint tincture containing itraconazole A magnetic stirring rod is placed in a hermetically sealed weighing bottle of 150 ml. Into the vessel, 50 mg itraconazole and 50 ml dimethylsulphoxide (DMSO) are measured. The vessel is placed on a heatable magnetic stirring plate. The temperature of the latter is set to between 30 and 40 ⁰C, while the speed of stirring is chosen between 80 and 100 rpm. After stirring for 30 minutes, 49 ml abs. ethanol is added into the vessel. When the active agent has dissolved - keeping up the stirring and the heating - very slowly (by drops) 21 ml distilled water is added to the solution; all the time, care should be taken that no local water concentration emerges, which could cause precipitation. The volume of the solution is topped up to 97 ml with a mixture (proportion of volume 30:70) of DMSO and ethanol of 70 V/V% (diluted with water), then the solution is homogenized. Stirring and heating is terminated. The composition of the solvent is analyzed (HPLC, Karl-Fischer). Based on the result of the analysis, the desired proportion of the solvents is - if necessary - adjusted by adding the component that is present in a lower concentration, finally, the volume is brought up to 100 ml by adding a mixture of DMSO and (water diluted) ethanol of 70 V/V%, the proportion of the two components being 30:70.

Lastly, the finished paint is packaged; containers of arbitrary volume, e.g. 30-ml bottles having polypropylene or high-pressure polyethylene seal, or a 10-ml bottle having a built-in brush in the cap, manufactured from dark glass for liquid medicaments, filled to 82.5±2.5 V/V %, can be used.

Example 2

A paint tincture containing itraconazole with Cremophore EL emulsifϊer The procedure is the same as in Example 1, but, before adding the 21 ml distilled water, 100 mg

Cremophore EL emulsifier is dissolved in the water, and this solution is then added into the vessel.

Example 3

Production of a paint tincture containing itraconazole in a microwave reactor Into a glass-stoppered 150-ml vessel, 150 mg itraconazole and 30 ml DMSO are measured. The vessel is eqipped with liquid seal and pneumatic mixing is arranged. As a mixing gas, an inert gas (He, N?, Ar) saturated with DMSO at 4O⁰C is used. The vessel is placed in the irradiation zone and the pneumatic mixing is started. Irradiation frequency is set at 2437.2±24,8 MHz, the energy of the irradiation zone is set at 4.5 W/ml with the help of the volume of the ballast water. Irradiation is done in 3x20-secυnd intervals with a 100-second cooling period inserted between each irradiation. The mixing gas then is saturated at 40⁰C with a mixture of DMSO and ethanol of 96% by mass, the proportion of the two components in the mixture being 30:70 V/V. The pneumatic mixing is then continued with this gas. 70 ml ethanol of 96 % by mass is added to the solution in the vessel, which now has some precipitation. The irradiation is continued in 20-second periods with 100-second cooling stops till the active agent is completely dissolved (further 3-4 irradiation periods). Should the temperature of the mixture go above 55°C, the cooling periods could be lengthened (e.g. to 200 seconds). The dissolution completed, the pneumatic mixing is terminated, the solution is left to cool down to room temperature (about 2O⁰C), the volume is then topped up to 100 ml with a mixture of DMSO and ethanol of 96 % by mass (the two components' proportion being 30:70 V/V). Lastly, the finished paint is packaged; containers of arbitrary volume, e.g. 30-ml bottles having polypropylene or high-pressure polyethylene seal, or a 10-ml bottle having a built-in brush in the cap, manufactured from dark glass for liquid medicaments, filled to 82.5±2.5 V/V %, can be used.

Example 4

Production of a paint tincture containing itraconazole using ultrasound extracting reactor

Into a glass-stoppered 100-ml measuring flask, 200 mg itraconazole and 30 ml DMSO are measured. The flask is placed in an ultrasound extracting reactor. The temperature of the sample is adjusted to 40±l°C. The extraction process is carried out at a frequency of 37 kHz, at an energy density of 0.14 W/ml for 5 minutes. Then, adding 70 ml ethanol of 90 V/V% to the content of the flask, the extraction is continued till the active agent is totally dissolved (about 5 min). When the solid matter has been dissolved, the irradiation is stopped, and the content of the flask is allowed to cool to room temperature (about 2O⁰C). The final volume of 100 ml is achieved by adding to the solution a mixture of DMSO and ethanol of 90 V/V%, the proportions of the two components being 30:70 V/V. Lastly, the finished paint is packaged; containers of arbitrary volume, e.g. 30-ml bottles having polypropylene or high-pressure polyethylene seal, or a 10-ml bottle having a built-in brush in the cap, manufactured from dark glass for liquid medicaments, filled to 82.5±2.5 V/V %, can be used.

Example 5 The procedure is the same as in Example 3 and 4, the only difference being that instead of ethanol, an aqueous solution of n-propanol is used.

Example 6

The procedure is the same as in Example 3 and 4, the only difference being that instead of ethanol, an aqueous solution of i-propanol is used.

Example 7

The procedure is the same as in Example 3 and 4, the only difference being that instead of ethanol, a mixture of n-propanol, i-propanol, ethanol is used.

Example 8

Production of a lacquer containing itraconazole

Into a glass-stoppered 30-ml measuring flask, 20 mg itraconazole, 18 ml ethyl acetate, and 2 ml DMSO are measured. The active agent is dissolved assisted by magnetic stirring (80-120 rpm) at room temperature. Keeping up the magnetic stirring, 500 mg colophony (Fluka AG) is added to the solution and the stirring is continued till the softener has been totally dissolved. After full dissolution, as a film-forming agent, 4.50 g Degalan LP 62/03 (Degussa special product, Haffner GmbH & Co. Holding KG, Asperg, DE) is added in small portions; care should be taken to prevent the solid, swelling film-forming substance does not stick to the bottom. Should sticking to the bottom be observed, the dosing must be stopped and can only be continued after the material stuck to the bottom has been loosened. After all the film-forming additive has been poured in, the stirring should be kept up for another 30 minutes and after it terminated.

In the final package, disposable sandpaper (PP 150-PP 250) strips (min. 30) are added, these may be used to make the finger- or toenail surface rougher in order to promote the adhesion of the lacquer. If the cap of the bottle carries no brush, a special, applicator stick with a perforated end, made of polypropylene or high-pressure polyethylene or glass, is also added to the packing unit.

Advantages

Besides decreasing the well-known, numerous systemic side-effects of the active agent, when this composition is applied, a further significant biological advantage can be the exposure to a lower dosage (during a systemic treatment cycle, the patient is exposed to an average of 8 g of the active agent in a short time, whereas, in the case of a six-month long local treatment the total exposure to the active agent will not exceed approx. Ig). On the other hand, because of the high price of the active agent (about $6500-7000 per kg), the composition is more economical than the systemic drugs.

A further advantage is that - during the treatment - resistance can be noticed much sooner than with a systemic treatment and, in case of need, the treatment can be changed sooner.

Claims

1. An antifungal paint tincture composition comprising itraconazole or a pharmaceutically acceptable salt thereof as antifungal active agent, dimethylsulphoxide as less-volatile solvent component and one or more volatile solvent components, and optionally one or more auxiliary materials, where the amount of the dimethylsulphoxide is less than 50% V/V, preferably 10-45V/V %, more preferably 20-35 V/V %, most preferably about 30 WV % in the composition.

2. The antifungal paint tincture composition according to claim 1, where the concentration of itraconazole is 0.4-4 mg/ml, preferably 0.5-2.0 mg/ml in the composition.

3. The antifungal paint tincture composition according to claim 1 or 2, where the one or more volatile component is selected from the group of C2-C4 aliphatic alcohols, preferably ethanol, n-propanol, i- propanol, ethers and mixed ethers formed from C2-C4 aliphatic alcohols, esters formed from C2-C4 aliphatic alcohols with aliphatic carboxylic acids; and any mixtures and solutions thereof, preferably aqueous solutions.

4. The antifungal paint tincture composition according to any of claims 1 to 3, which comprises as an effect enhancer auxiliary material an ionic or non-ionic tenside or a mixture of such tensides, preferably Cremofor EL.

5. A process for the preparation of an antifungal paint tincture composition, characterized by mixing itraconazole or a - pharmaceutically acceptable salt thereof as antifungal active agent, dimethylsulphoxide as less volatile solvent component and one or more volatile components, and optionally one or more auxiliary materials, where the amount of the dimethylsulphoxide is less than 50 V/V %, preferably 10-45 V/V %, more preferably 20-35 V/V %, most preferably about 30 V/V % in the composition, and the dissolution of the active agent is enhanced by the use of one or more methods of a)-c) as follows: a) heating and/or mechanical stirring, b) irradiation by ultrasound, c) irradiation by microwaves.

6. The process according to claim 5, characterized by enhancing the dissolution of the active agent in the carrier in method a) at a temperature of 30-80 ⁰C, preferably 50 ⁰C, preferably assisted by mechanical stirring.

7. The process according to claim 5 or 6, characterized by enhancing the dissolution of the active agent in the carrier in method b) by ultrasound irradiation on frequency of 28.5-100 kHz, preferably 37 kHz, preferably at an energy density of 0.1-2.0 W/ml, more preferably 0.14 W/ml.

8. The procedure as according to claim 5, characterized by enhancing the dissolution of the active agent in the carrier in method c) by microwave irradiation at a wavelength of 0.12-36.8, preferably 12,24 cm, preferably at an energy density of 0.5-8.0 W/ml, more preferably 4.5 W/ml, and preferably using reflex- klystron or magnetron for the irradiation.

9. Process according to any of claims 5 to 8, characterized by using method a) when the concentration of itraconazole in the solution is lower than 0.6 mg/ml, and the carrier contains maximum 4 V/V % of water; using method b) when the concentration of itraconazole in the solution is lower than 0.6 mg/ml, and the carrier contains more than 4 V/V % of water; using method c) when the concentration of itraconazole in the solution is higher than 0.6 mg/ml, and the carrier contains more than 4 V/V % of water.

10. An antifungal lacquer composition comprising itraconazole or a pharmaceutically acceptable salt thereof as antifungal active agent, a film-forming substance, which can be selected from the group of nitrated cellulose or cellulose derivative, polyvinyl alcohol, polyvinyl acetate, polyamide and a mixture of them; dimethylsulphoxide as a less volatile solvent component, where the amount of the dimethylsulphoxide is less than 50% V/V, preferably 1-20 V/V %, more preferably 5-15 V/V %, most preferably about 10 V/V % in the composition; a volatile solvent component; optionally a softener, preferably a resin as an auxiliary material, optionally a less-volatile solvent in which itraconazole has a poor solubility, preferably ethyl lactate or glycolic acetate, and optionally one or more usual auxiliary materials.

11. The lacquer composition as according to claim 10, where the itraconazole content in relation to the dry matter of the film-former is 1-15 mass %o, preferably 2-10 mass %o, more preferably 2-4 mass %>.

12. The lacquer composition according to claim 10 or 11, where the volatile solvent component is selected from the group of C2-C4 aliphatic alcohols, ethers and mixed ethers formed from C2-C4 aliphatic alcohols, esters formed from C-2-C4 aliphatic alcohols with aliphatic carboxylic acids, or any mixtures of them, more preferably ethanol, t-butyl-methyl-ether, ethyl acetate or butyl acetate, or any mixtures of them.

13. The lacquer composition according to any of the claims 10 to 12, where the amount of the film- forming substance is 100-750 mg/ml, preferably 150-500 mg/ml, most preferably 200-250 mg/ml.

14. The lacquer composition according to any of claims 10 to 13, which comprises as adhesion promoting auxiliary softener a resin, preferably colophony, the amount of which in proportion to the dry matter of the film- former is 2-15 % by mass, preferably about 10 % by mass, and the film-forming substance is a polyamide, e.g. Degalan LP.

15. A process for the preparation of an antifungal lacquer composition, characterized by comprising the following steps: dissolving itraconazole or a pharmaceutically acceptable salt thereof, applied as an antifungal active agent, and a film-forming substances, preferably selected from the group of nitrated cellulose or a cellulose derivative, polyvinyl alcohol, polyvinyl acetate, polyamide and a mixture of them, and optionally a softener, preferably a resin, and optionally one or more auxiliary materials in a mixture comprising the followings: dimethylsulphoxide as a less-volatile solvent, where the amount of the dimethylsulphoxide is less than 50 V/V %, preferably 1-20 V/V %, more preferably 5-15 V/V %, most preferably 10 V/V % in the final composition. volatile solvent component selected from the group of C2-C4 aliphatic alcohols, ethers and mixed ethers formed from C2-C4 aliphatic alcohols, esters formed from C2-C4 aliphatic alcohols with aliphatic carboxylic acids, or an optional mixture of them, more preferably ethanol, t-butyl-methyl-ether, ethyl acetate or butyl acetate, or any mixture of them; most preferably ethyl acetate, butyl acetate, isobutyl acetate, or a mixture of them, if desired, adjusting the viscosity by one or more solvents, preferably by a less volatile solvent in which itraconazole has a poor solubility, preferably ethyl lactate or glycolic acetate.

16 The process according to claim 15, characterized by choosing the amount and the proportion of the volatile and less-volatile solvent components and the optional auxiliary materials in a way that when 60 % of the solvents is evaporated, the solution of itraconazole is over-saturated in the remaing solvents.

17. The process according to claim 15 or 16, characterized by choosing the amount of the fϊlm- forming and solvent components and the amount of the optional other materials in a way that the density of the drying lacquer is lower than the density of the solid active agent.

18. The antifungal paint tincture composition according to claims 1 to 4, or the antifungal lacquer composition according to claims 10 to 14, where the itraconazole salt is formed either with an inorganic acid, preferably with methane sulphonic acid, or with an organic acid, preferably with an organic double- base hydroxy or polyhydroxy acid.

19. The use of the antifungal paint tincture composition according to claims 1 to 4 and/or the lacquer composition according to claims 10 to 14 in the treatment of fungal infections of the horny plates on the limbs.