Antifungal compositions with a high release rate of the drug as an elastic liquid dressing

0001The present invention relates to novel formulations of the known antifungal azole derivatives, which have a depot effect despite film formation and a higher bioavailability of the active ingredients and thereby enable short-term therapy.

0002Preparations of antifungal derivatives have already been known for the treatment of mycoses in humans, especially the mycoses of the skin. With these preparations, 21 d therapy time was required for a complete renovation.

0003In order to shorten the duration of therapy, a certain depot effect and a higher bioavailability of the active ingredients are required, especially to eliminate the germs or to achieve a mycological remediation. The known formulations are only suitable for this to a limited extent because only a small proportion of the liquid volume at the site of the infection is detached from the available active substance. If you want to reduce the duration of therapy, e.g. to 1 d, with a single application without further increasing the active ingredient concentration, you have to ensure that the active ingredient is optimally bioavailable.

0004From FR-A No. 2275194, Example G, a composition is known which contains a vinylpyrrolidone / vinyl acetate copolymer and an antifungal azole derivative.

0005Isopropyl myristate and 2-octyldodecanol or a spreading agent and a solubilizer are known in connection with the copolymers mentioned above from FR-A No. 1589917, Examples I to 111.

0006In these two documents, however, there is no indication that the compositions in question would enable a satisfactory effect to be achieved by a single application.

0007It has now been found that such formulations of antifungal agents which contain 2 to 10% by weight of spreading agent from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl stearate, caprylic / capric acid esters of saturated fatty alcohols of chain length C.₁₂ to C₁₈, Waxy fatty acid esters such as artificial duckbone ovary fat, silicone oils, isopropyl myristate / isopropyl palmitate / isopropyl stearate mixture, coconut fatty acid isopropyl ester, 1 to 8% by weight solubilizer and as a film-forming agent a fast-drying polyvinylpyrrolidone, a terpolymer vinyl acetate 30% and 40% vinyl acetate from 30% vinyl acetate and 30% vinyl acetate from 30% vinyl acetate 30% a vinyl pyrrolidone vinyl acetate copolymer which is soluble in both water and organic solvents, and also contain the usual formulation auxiliaries, enable an optimal release of the active ingredient and thus a therapy duration reduced to one day by reaching high concentrations of the active ingredient. This effect is achieved in that the effectiveness of the active ingredients contained in the formulations is increased by spreading oils and solubilizers and adhering film-forming agents, and the active ingredient release can thereby be increased up to ten times.

0008The elastic liquid plaster formulations according to the invention represent a new application principle for the dermal treatment of mycoses which, in addition to being very effective, also protects the environment from infection by closing the infection site. The formulations according to the invention are particularly well suited for the treatment of nail mycoses.

0009The formulations according to the invention can be both solutions and sprays.

0010Active ingredients that can be formulated in this way are all antifungal azole derivatives, especially imidazole and triazole derivatives. They are present in the agents according to the invention in amounts of 0.05 to 1, preferably 0.1 to 1% by weight.

0011For example, the compounds of the following formulas may be mentioned:<chemistry id="chem0001" num="0001"><img file="EP0055397B1_D0001.tif" /></chemistry>Clotrimazole<chemistry id="chem0002" num="0002"><img file="EP0055397B1_D0002.tif" /></chemistry>Trifonazole<chemistry id="chem0003" num="0003"><img file="EP0055397B1_D0003.tif" /></chemistry>Lombazole

0012Numerous other antimycotically active azole dirvates are known from DE-OS No. 2430039. They can also serve as active ingredients in the agents according to the invention.

0013Spreading agents are understood to be oily liquids which are particularly well distributed on the skin [R. Keymer,_"Pharm. Ind. ", 32 (1970), 577-581].

0014Suitable solubilizers for the agents according to the invention are above all: benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerin, di- and tripropylene glycol, waxes etc., and other additives used in cosmetics.

0015Macromolecular compounds which can dissolve or swell both in water and in organic solvents and which form a type of film after drying are suitable as film formers. Such film images are polyvinyl pyrrolidone or vinyl pyrrolidone / vinyl acetate copolymers with different vinyl acetate contents. A terpolymer of 30% by weight vinyl pyrrolidone, 40% by weight vinyl acetate and 30% by weight vinyl propionate is also suitable.

0016Water and all water-miscible solvents are suitable as solvents. Examples include alkanols, such as ethanol and isopropyl alcohol, propylene glycol, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.

0017One or more solvents can be used in the preparation of the formulations according to the invention.

0018The following auxiliaries can be used in the tests to determine an optimal formulation: glycerol, paraffin viscous, paraffin viscous, triethanolamine, collagen, allantoin, novantisol acid, perfume oils. The following are also suitable:

0019<ul id="ul0001" list-style="none"><li>a) Substances that can stabilize a suspension, for example, colloidal silica, montmorillonite and others</li><li>b) surfactants (contains emulsifiers and wetting agents), for example:<ul id="ul0002" list-style="none"><li>1. anionic, such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester / monoethanolamine salt;</li><li>2nd cationic such as cetyltrimethylammonium chloride;</li><li>3rd ampholytic, such as di-Na-N-lauryl-ßiminodipropionat or lecithin;</li><li>4th non-ionogenic, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, cetyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether.</li></ul></li><li>c) Stabilizers to prevent the chemical degradation that occurs with some active ingredients, such as antioxidants, for example tocopherols, butylated hydroxyanisole.</li><li>d) Acidic aqueous solutions can be stabilized by the addition of preservatives customary in cosmetics, for example p-hydroxybenzoic acid esters.</li></ul>

0020Effectiveness test of the agents according to the invention on trichophyton-infected guinea pigs.

0021We used trichophyton-infected Pirbrightwhite guinea pigs with an average weight of 600 g as a test model for comparative effectiveness testing of the agents according to the invention. The animals were shaved on the back with an electric hair clipper so that approx.¹/ 10 mm long stumps remained.

0022Trichophyton mentagrophytes was infected by gently rubbing in a spore suspension of the pathogen germinated in Sabouraud nutrient solution for 24 hours on an approx. 2 x 2 cm area of ​​the sheared back of the animals. 0.5 ml of germ suspension, 1-3 x 10⁵ contained infectious fungal particles.

0023With this mode of infection, the first symptoms of dermatophytosis appear as reddening and scaling of the skin 2-3 d postinfectionem. In untreated animals, dermatophytosis is maximal at around 14 d post infection: extensive hair loss and bloody integument defects within an inflammatory, scaly peripheral zone.

0024The formulations to be tested were applied once, on the second day post infection, locally to the reddened infection site of the animals. In each case 0.5 ml of the formulations = 5 mg of active ingredient^* applied. The course of the infection was evaluated daily until the twentieth day post infection.

0025The results are given in the examples. (+ = weak effect, ++ = effect, +++ = good effect, ++++ = very good effect.)

0026In the examples below, recipes for agents according to the invention are given. The individual components are mixed together at room temperature and thereby dissolve.

0027If instead of the formulations according to the invention those are used which contain water-insoluble polymers, for example methacrylates, instead of the polymers mentioned, the mycosis is aggravated.

0028If such formulations are used which, in addition to the active ingredient, only contain the polymers mentioned, but contain no spreading agents or solubilizers, only a weak effect is achieved.

Example 1:

0029<tables id="tabl0001" num="0001"><img file="EP0055397B1_D0004.tif" /></tables>Effect in the guinea pig test +++ = good effect

Example 2:

0030<tables id="tabl0002" num="0002"><img file="EP0055397B1_D0005.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 3:

0031<tables id="tabl0003" num="0003"><img file="EP0055397B1_D0006.tif" /></tables><tables id="tabl0004" num="0004"><img file="EP0055397B1_D0007.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 4:

0032<tables id="tabl0005" num="0005"><img file="EP0055397B1_D0008.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 5:

0033<tables id="tabl0006" num="0006"><img file="EP0055397B1_D0009.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 6:

0034<tables id="tabl0007" num="0007"><img file="EP0055397B1_D0010.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 7:

0035<tables id="tabl0008" num="0008"><img file="EP0055397B1_D0011.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 8:

0036<tables id="tabl0009" num="0009"><img file="EP0055397B1_D0012.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 9:

0037<tables id="tabl0010" num="0010"><img file="EP0055397B1_D0013.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

0038<tables id="tabl0011" num="0011"><img file="EP0055397B1_D0014.tif" /></tables>Effect in the guinea pig test +++ = good effect

Example 11:

0039<tables id="tabl0012" num="0012"><img file="EP0055397B1_D0015.tif" /></tables><tables id="tabl0013" num="0013"><img file="EP0055397B1_D0016.tif" /></tables><tables id="tabl0014" num="0014"><img file="EP0055397B1_D0017.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 13:

0040<tables id="tabl0015" num="0015"><img file="EP0055397B1_D0018.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Example 14:

0041<tables id="tabl0016" num="0016"><img file="EP0055397B1_D0019.tif" /></tables>Effect in the guinea pig test ++++ = very good effect

Sprays

0042The active ingredient solutions prepared according to Examples 1 to 14 can also be processed into sprays. For this purpose, 60-90% active ingredient solution is mixed with 20-40% of the usual blowing agents, e.g. N₂, N₂O, CO₂, Propane, butane, halogenated hydrocarbons etc.