MXPA06010187A - Cream-gel containing ivermectin - Google Patents

Abstract

The present invention relates to a pharmaceutical composition based on a compound of the avermectin family, in the form of a cream-gel comprising, in a physiologically acceptable medium, an oily phase dispersed in an aqueous phase by means of a non-surfactant polymeric emulsifier, said oily phase comprising oils having a melting point below 30°C and being free of solid fats having a melting point above 30°C. It also relates to the process for preparing same and to its use in the production of a pharmaceutical preparation intended for the treatment of dermatological conditions, in particular of rosacea.

Description

GEL-CREAM THAT CONTAINS IVERMECTINE DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition based on a compound of the avermectin family, in the form of a gel-cream, comprising, in a physiologically acceptable medium, an oily phase dispersed in an aqueous phase by a non-surfactant polymer emulsifier, and the oily phase comprises oils having a melting point of less than 30 ° C, and is free of solid fatty substances having a melting point above 30 ° C. It also relates to the preparation process, and its use in the manufacture of a pharmaceutical preparation intended for the treatment of dermatological conditions, in particular, of rosacea. Ivermectin is a mixture of two compounds that belong to the class of avermectins, 5-0-demethyl-22, 23-dihydroavermectin Ala and 5-0-demethyl-22, 23-dihydroavermectin A? B. They are also known under the name of 22, 23-dihydroavermectin Bla and 22, 23-dihydroavermectin B? B.

Ivermectin contains at least 80% of 22,23-dihydroaver ectin and less than 20% of 22,23-dihydroavermectin Bib. This active agent is part of the class of avermectins, a group of macrocyclic lactones produced REF .: 174756 by the bacterium Streptomyces avermi tilis (Reynolds JEF (Ed) (1993) Martindale, The extra, pharmacopoeia, 29th Edition. Press, London). Avermectins include, mainly, ivermectin, invermectin, averctin, abamectin, doramectin, eprino ectin, and selamectin. Ivermectin is, more particularly, an anthelmintic. It has already been described in humans, in the treatment of onchocerciasis by Onchocerca volvulus, of gastrointestinal strongyling (anguilulosis) (produced by Stromectol®), of human sarcoptic mange (Mein ing TL et al., N Engl J Med 1995 Jul 6; 333 (1): 26-30 The treatment of scabies wi th ivermectin) as well as in the treatment of diagnosed or suspected microfilaraemia in patients affected by lymphatic filariasis due to Wuchereria bañero f ti. Patent US 6,133,310 describes the use of topical ivermectin in the form of a lotion consisting of a mixture of ivermectin and water, and also refers to the possibility of a cream constituted, for its part, by the mixture of ivermectin and an excipient such as propylene glycol or sodium lauryl sulfate, but does not disclose any industrially acceptable pharmaceutical composition, that is, which exhibits a good cosmeticity and a sufficiently long shelf life (minimum 2 years).

The dermatological affections are frequently linked to an increase in skin sensitivity, particularly in the case of rosacea, which is an inflammatory dermatosis that mainly affects the central part of the face and is characterized, among other features, by the formation of the skin. face, flushing, facial flushing. This type of pathology requires, in particular, the use of galenic formulations that allow it to spread easily, and give the user a pleasant feeling and well-being. There is, therefore, a need to have a topical pharmaceutical composition containing at least one compound of the avermectin family and, more particularly ivermectin, which is perfectly adapted to the pathology, and specifically to the sensitized skins, which it is industrially acceptable, that is, that it presents a formulation that is physically stable (without phase separation), and also chemically (without modification of the stability of the active ingredient) and that optimizes the penetration of ivermectin into the skin. In this way, the Applicant has developed an ivermectin-based composition in the form of a gel-cream that perfectly meets these expectations, comprising an oily phase dispersed in an aqueous phase, by a non-surfactant polymer emulsifier, this oily phase comprises oils that have a melting point lower than 30 ° C and are free of solid fatty substances that have a melting point higher than 30 ° C. This gel-cream formulation, is a non-greasy, moisturizing, very well tolerated emulsion with an emulsifier, a non-surfactant polymer. This formulation also combines the advantages of a gel (ease of application, rapid release of the active agent, feeling of freshness with application) with those of a cream (well-being of the skin, neither dryness nor redhibitory tightness for a sensitive skin) and is particularly suited to the treatment of rosacea. Classical emulsions, such as those described in the prior art, are quasi-homogeneous unstable systems of two immiscible liquids, in which one of them is dispersed in the other, in the form of fine droplets (micelles). This dispersion is stabilized thanks to the action of surfactant emulsifying agents that modify the structure and the force ratio at the interface level, and therefore, increase the stability of the dispersion, decreasing the surface tension energy. The surfactant emulsifiers are amphiphilic compounds that have a hydrophobic part that has affinity with the oil, and a hydrophilic part that has affinity with water and thus creates a link between the two phases. Therefore, ionic or non-ionic emulsifiers stabilize oil / water emulsions by adsorbing at the interface and forming lamellar layers of liquid crystals. The emulsifying power of nonionic surfactants is closely linked to the polarity of the molecule. This polarity is defined by the HLB (Hydrophilic / Lipophilic Balance). In general, conventional emulsions are stabilized by a mixture of surfactants whose HLB can be quite different, but whose proportion in the mixture corresponds to the HLB required by the fat phase to be emulsified. This type of surfactant emulsifier is often used in a concentration comprised between 3 and 7%. Non-surfactant polymer emulsifiers, such as the cross-linked acrylate / C?-3o alkyl acrylate polymers allow the preparation of quasi-homogeneous systems (oily phase dispersed in an aqueous phase) called polymer emulsions. The polymeric emulsification is obtained by spherical stabilization: the globules of the dispersed phase (oil) are surrounded by a hydrophilic polymer that is anchored in these, thanks to a grafted hydrophobic chain. The crystalline phase is absent and this type of emulsifier does not affect the surface tension, contrary to surfactant emulsifiers. These non-surfactant polymer emulsifiers are hydrophilic compounds, which are not characterized by an HLB value and do not form micelles. That is why polymer emulsions are also called "emulsifier-free systems". These emulsifiers are effective from the 0.1% concentration. In addition, the use, in the oily phase, of the composition of liquid oils with a melting point of less than 30 ° C makes it possible to obtain a gel-cream that is fluid, light and of a non-greasy texture for its application, and facilitates the preparation of the gel. cream, which can also be done at room temperature. Therefore, due to its composition, this gel-cream simultaneously guarantees the stability and harmlessness of the composition. It offers an easier application than that of a classic emulsion due to its gelled structure and its "quick-break" effect and leaves a pleasant feeling of freshness. The nguick-break effect ", characterized in that the emulsion" breaks "immediately and releases the aqueous and oily phases, is due to the sensitivity of the homopolymers and copolymers of acrylic acid to the electrolytes During the application on the skin of an emulsion Containing this type of polymeric emulsifier, the polymers come in contact with the salts present on it.This quick-break effect "favors a more rapid release of the phase containing the active ingredient.

Therefore, the Applicant has discovered surprisingly, that the gel-cream composition according to the invention also allows a better release of the active principle and a better penetration of this into the skin, with respect to the classical emulsions. The object of the invention is therefore a pharmaceutical composition based on a compound of the avermectin family in the form of a gel-cream comprising, in a physiologically acceptable medium, an oily phase dispersed in an aqueous phase, by an emulsifier. polymeric non-surfactant, and this oily phase comprises oils with a melting point below 30 ° C, and is free of solid fatty substances having a melting point higher than 30 ° C.

The compounds of the avermectin family are chosen from ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin, and, preferably, ivermectin. Therefore, the invention also aims at a pharmaceutical composition based on ivermectin in the form of a gel-cream comprising, in a physiologically acceptable medium, an oily phase dispersed in an aqueous phase by a non-surfactant polymer emulsifier, and the Oily phase comprises oils with a melting point lower than 30 ° C and free from solid fats having a melting point higher than 30 ° C.

The invention can also be applied to any active selected from the family of avermectins and, in particular, avermectin, abamectin, doramectin, eprinomectin and selamectin, and mixtures thereof. By physiologically acceptable means, means compatible with the skin, mucous membranes, lips, nails, scalp and / or hair. The term "oils with a melting point lower than 30 ° C" means oils in the liquid state at room temperature. The expression "solid fatty substances" means, in particular, waxes, fatty acids and fatty alcohols having a melting point above 30 ° C, and which are present in the solid state at room temperature. By "free from solid fatty substances" according to the invention is meant a composition comprising less than 1% of solid fats, preferably less than 0.1%, and even more preferably less than 0.05% of solid fats . The composition according to the invention is described as a stable emulsion because it has good physical and chemical stability over time, even at a temperature above room temperature (for example 45-55 ° C), as the examples show. which are described later. The composition according to the invention is, advantageously, a gel-cream comprising: a) an oily phase comprising oils with a melting point lower than 30 ° C, and free of solid fatty substances having a higher melting point at 30 ° C, b) a non-surfactant polymeric emulsifier, c) at least one compound from the avermectin family, d) a solvent and / or propenetrant active agent, e) and water. The composition according to the invention is preferably a gel-cream comprising: a) an oily phase comprising oils with a melting point lower than 30 ° C, and free of solid fatty substances having a melting point higher than 30 ° C, b) a non-surfactant polymeric emulsifier, c) ivermectin, d) a solvent and / or active propenetrant, e) and water. Therefore, the oily phase comprises liquid oils, among which may be mentioned, for example, vegetable, mineral, animal or synthetic oils, silicone oils, Guerbet alcohols and their mixtures; A non-polar mineral oil (high surface tension) of paraffin oil type will preferably be used. As an example of mineral oil, there may be mentioned, for example, Primol 352, Marcol 82 and Marcol 152 sold by the company Esso. As vegetable oil, we can mention the sweet almond oil, palm oil, soybean oil, sesame oil, sunflower oil, an ester, such as cetearyl isononanoate, as the product sold under the name of Cetiol SN by the Cognis France company, the adipate of diisopropyl, as the product sold under the name of Ceraphyl 230 by the ISF company, isopropyl palmitate as the product sold under the name of Crodamol IPP by the company Croda, the caprylic / capric triglyceride such as Miglyol 812 sold by the company Huls / Lambert Riviere. As the silicone oil, there may be mentioned a dimethicone as the product sold under the name of Dow Corning 200 fluid, a cyclomethicone as the product sold under the name Dow Corning 244 fluid by Dow Corning, or the product sold under the name Mirasil CM5 by the company SACI-CFPA. The amount of the oily phase present in the composition is in an amount ranging in general from 4 to 60% and preferably from 5 to 20%, and more precisely from 8 to 12% by weight with respect to the total weight of the composition. the composition. By non-surfactant polymer emulsifier according to the invention is meant an emulsifier system comprising at least one copolymer consisting of a majority fraction of monoolefinically unsaturated C3-C6 carboxylic acid monomer or its anhydride and a minor fraction of ester monomer of fatty chain of acrylic acid. The emulsifying copolymers of the invention are described in the patent application EP-A-0268164 and are obtained according to the preparation methods described in that same document. The acrylate / C?-C3o alkyl acrylate copolymer such as the products sold under the names Pemulen TR 1 and Pemulen TR 2 or the product sold under the name Carbopol 1342 and Carbopol 1382 by the company GOODRICH or its products are more particularly used. mixtures Preferably, the composition according to the invention comprises a non-surfactant polymer emulsifier selected from Pemulen TRl and Pemulen TR2. The amount of surfactant emulsifiers present in the composition according to the invention is generally between 0.25% and 2%, preferably 0.25 to 1%, and more preferably 0.3 to 0.6% by weight, based on weight total of the composition. The composition according to the invention contains from 0.001 to 10% of ivermectin by weight, with respect to the total weight of the composition. Preferably, the composition comprises 0.01 to 5% by weight, based on the total weight of the composition, and more preferably 0.01 to 1% by weight, based on the total weight of the composition. As an example of a solvent and / or a propenetrating agent for the active agent of ivermectin, preference will be given to propylene glycol, alcohols of the ethanol, isopropanol, butanol, benzyl alcohol, N-methyl-2-pyrrolidone or DMSO, polysorbate 80 , phenoxyethanol and their mixtures.

The composition of the invention contains from 0.1% to 20% and, preferably, from 1% to 10% of a solvent and / or propenetrating agent for the active agent of ivermectin. The composition of the invention also contains water in an amount ranging from 30 to 95%, and preferably from 60 to 80% by weight, based on the total weight of the composition. The water used in the composition according to the invention will preferably be purified water. The composition according to the invention can also comprise a carbomer in an amount ranging from 0 to 2%. Among the carbomers, Carbopol 981, Carbopol ETD 2020, Carbopol 980 or Carbopol Ultrez 10 NF sold by the company BF Goodrich can be cited as non-limiting examples. The composition according to the invention may also comprise co-emulsifiers to decrease the size of the oily globules of the emulsion formed by the polymeric emulsifier. Mention may be made of nonionic surfactants such as Eumulgin B2 (ceteareth 20) or Tween 80 (polysorbate 80), or even sorbitan esters (including Span 20) or fatty alcohol ethers (including Eumulgin B2) or poloxamer 124 Preferably, the gel-cream based on a compound of the avermectin family according to the invention comprises: 5 to 20% of oily phase, 0.25 to 1% of non-surfactant polymer emulsifier, 0 to 2% of carbomer , 0 to 5% of co-emulsifier, 0.01 to 5% of at least one avermectin, 0.1 to 20% of solvents and / or propenetrating agents, 60 to 80% of water. Preferably, the gel-cream based on ivermectin according to the invention comprises: 5 to 20% of oily phase, 0.25 to 1% of non-surfactant polymer emulsifier, 0 to 2% of carbomer, 0 to 5% of co-polymer. emulsifier, 0.01 to 5% ivermectin 0.1 to 20% solvents and / or propenetrating agents, 60 to 80% water. More preferably, the ivermectin-based cream gel according to the invention comprises: 8 to 15% oil phase, 0.25 to 1% non-surfactant polymer emulsifier, 0 to 2% carbomer, 1 to 5% co-oil. -emulsifier, 0.01 to 5% ivermectin, 4 to 20% solvents and / or propenetrating agents, 60 to 80% water. The composition according to the invention may also contain, additives normally used in the cosmetic or pharmaceutical field, such as: - wetting agents such as glycerin or sorbitol; - gelling agents; - calming agents, such as allantoin and talc; - preservatives, such as esters of parahydroxybenzoic acid; - moisture regulating agents; - pH regulating agents, such as citric acid and sodium hydroxide; - osmotic pressure modifying agents; - UV-A and UV-B filters; - and antioxidants, such as α-tocopherol, butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT), vitamin E, propylgalate or citric acid. Of course, the skilled man will know how to adapt the choice of the additives or the possible compounds that will be added to these compositions, and also the process in such a way that the advantageous properties intrinsically related to the present invention are not altered or substantially altered for the planned addition. These additives may be present in the composition from 0.001 to 20% by weight, with respect to the total weight of the composition. The gel-cream according to the invention will preferably have a viscosity corresponding to a flow threshold ranging from 15 to 60 Pascal (Pa.), In particular from 20 to 50 Pa, measured using a Haake rheometer of type VT500. The composition according to the invention can be prepared according to a "hot" (60-70 ° C) or "cold" (room temperature) mode, depending on the nature of the additives used. in particular, the process for preparing the gel-cream according to the invention is carried out at room temperature (called "cold") and comprises successively the following steps; a) the constituents of the fatty phase are mixed until it is homogeneous; b) the constituents of the aqueous phase are dissolved in water until a complete homogeneity is achieved; c) the non-surfactant polymer emulsifier and the optional carbomer are dispersed in the aqueous phase obtained in b) until a homogeneous gel is obtained; d) The fat phase is incorporated under moderate mechanical agitation to the homogeneous gel obtained in c) to form an emulsion; e) The constituents of the active phase are mixed; Ivermectin is solubilized in this mixture; then this phase is incorporated into the emulsion obtained in d) under moderate mechanical agitation; f) the neutralizing agent is incorporated at the end of step e) or during one of the preceding steps, under moderate mechanical agitation, to obtain a defined pH. Preferably, this pH will be between 6.0 and 6.5. The verification of the natural pH of the mixture and the optional correction with a solution of a neutralizing agent, as well as the incorporation of the possible additives may be carried out according to their chemical nature, during one of the stages of the preparation process described above. The term "moderate mechanical agitation" used during the preparation process according to the invention, a mechanical agitation comprised between 500 to 1200 rpm measured with a Rayneri-type agitator, and, more preferably, between 600 and 1000 rpm. Another object of the invention is the use of the composition according to the invention for the manufacture of a pharmaceutical preparation intended to treat dermatological conditions. "Dermatological conditions" are understood, more particularly, rosacea, acne vulgaris, seborrheic dermatitis, perioral dermatitis, acneiform eruptions, transient acantholytic dermatitis, and acne miliaris necrotica. The composition according to the invention is adapted, in particular, to the treatment of rosacea. Below, by way of illustration and without any limiting character, various formulations of gel-cream type comprising ivermectin according to the invention will be given. The quantities are given in% by weight, unless otherwise mentioned.

EXAMPLES Example 1 Ivermectin 1.0 Mineral oil 10.00 Tocopherol 0.20 Propylparaben 0.10 Disodium edetate 0.10 Glycerol 5.00 Allantoin 0.20 Acrylate / acrylate crosslinked polymer 0.30 C 0-3 alkyl (Pemulen TRl) Carbomer 0.15 Polysorbate 80 4.00 Propylene glycol 4.00 Phenoxyethanol 1.00 Sodium hydroxide cs pH 6.30 Purified water cs 100 This gel-cream can be prepared according to the preparation procedure carried out at room temperature (cold) comprising the following steps: a) the mineral oil, tocopherol, and propylparaben are mixed until complete homogeneity is achieved; b) glycerol, allantoin, sodium edetate dissolve in water until complete homogeneity is achieved; c) the crosslinked polymer of acrylate / C 1 or 3 alkyl acrylate and the carbomer are dispersed in the aqueous phase previously obtained in step b) until obtaining a homogeneous gel; d) The fat phase obtained in stage a) is incorporated under moderate mechanical agitation (Rayneri: 1000 rpm) to the homogeneous gel obtained in step e); e) polysorbate 80, propylene glycol and phenoxyethanol are mixed; the ivermectin is solubilized in this mixture; then, this phase is incorporated into the emulsion obtained in stage d) under moderate mechanical agitation (Rayneri: approximately 600 rpm); The neutralizer is incorporated under moderate mechanical agitation (Rayneri: approximately 600 rpm) to obtain pH 6.30.

Example 2: Ivermectin 1.0 Mineral oil 10.00 Tocopherol 0.20 Disodium edetate 0.10 Glycerol 5.00 Acrylate / acrylate crosslinked polymer of 0.30 C? O-3o alkyl (Pemulen TRl) Carbomer 0.15 Polisorbate 80 4.00 Propylene glycol 4.00 Phenoxyethanol 1.00 Triethanolamine cs pH 6.00 Purified water cs 100 Example 3: Ivermectin 0.50 Capric / Caprylic Triglycerides 10.00 Tocopherol 0.20 Disodium edetate 0.10 Sorbitol 5.00 Zinc acetate 0.50 Acrylate / acrylate crosslinked polymer 0.30 C? 0-3 alkyl (Pemulen TRl) Carbomer 0.15 N-methylpyrrolidone 5.00 Phenoxyethanol 1.00 Sodium hydroxide cs pH 6.00 Purified water cs 100 Example Ivermectin 1.00 Mineral oil 10.00 Sorbitan Laurate 1.00 Tocopherol 0.20 Propyl paraben 0.10 Disodium disodium 0.10 Glycerol 5.00 Allantoin 0.20 Acrylate / acrylate crosslinked polymer 0.30 C 0-3 alkyl (Pemulen TRl) Carbomer 0.15 Polysorbate 80 3.00 Poloxamer 124 1.00 Propylene glycol 4.00 Phenoxyethanol 1.00 cs pH 6 Sodium hydroxide 6.00 Purified water cs 100 Example 5: Ivermectin 1.00 Mineral oil 10.00 Sorbitan laurel 1.00 Tocopherol 0.20 Propyl paraben 0.10 Disodium disodium 0.10 Glycerol 5.00 Allantoin 0.20 Acrylate / acrylate crosslinked polymer 0.30 C ?o-3o alkyl (Pemulen TRl) Carbomer 0.15 Polysorbate 80 4.00 Propylene glycol 4.00 Benzyl alcohol 3.00 cs pH 6.3 Sodium hydroxide 6.00 Purified water cs 100 Example 6: Ivermectin 0.03 Mineral oil 10.00 Sorbitan Laurato 1.00 Tocopherol 0.20 Propil paraben 0.10 Disodium edetado 0.10 Glicerol 5.00 Allantoin 0.20 C10-30 alkyl acrylate / acrylate crosslinked polymer 0.30 (Pemulen TRl) Carbomer 0.15 Polysorbate 80 4.00 Propylene glycol 4.00 Benzyl alcohol 3.00 Poly (methyl methacrylate) 2.00 cs pH 6.3 Sodium hydroxide 6.00 Purified water cs 100 Example 7: Ivermectin 0.03 Mineral oil 5.00 Sweet almond oil 5.00 Sorbitan Laurate 1.00 Tocopherol 0.20 Propil paraben 0.10 Edetado disódico 0.10 Glicerol 5.00 Allantoin 0.20 Cryo-3o alkyl acrylate / acrylate crosslinked polymer (Pemulen TRl) Carbomer 0.15 Polysorbate 80 4.00 Propylene glycol 4.00 Benzyl alcohol 3.00 cs pH 6.3 Sodium hydroxide 6.00 Purified water cs 100 Example 8: Eprinomectin 1.00 Mineral oil 10.00 Tocopherol 0.20 Propyl paraben 0.10 Disodium disodium 0.10 Glycerol 5.00 Allantoin 0.20 Acrylate / acrylate crosslinked polymer 0.30 C10-30 alkyl (Pemulen TRl) Carbomer 0.15 Polysorbate 80 4.00 Propylene glycol 4.00 Phenoxyethanol 1.00 cs pH Sodium hydroxide 6.30 Purified water cs 100 These compositions are intended to be applied daily on clean and dry skin. Patients affected by rosacea notice a relief from the first applications and after 10 days of treatment there is an improvement in the redness of rosacea.

Example 9: Chemical and physical stability of the formulations a) PB and chemical stability The pH variation of the formulations is measured at 4, 8, 10 and 12 weeks, at room temperature (25 ° C) and at 45 ° C. 60% RH = 60% relative humidity 75% RH = 75% relative humidity Therefore, these results show a stability of the described formulations against the pH that does not vary with time, either at room temperature or at 45 ° C . Chemical stability is a dosage of the active in HPLC at room temperature and 45 ° C, after 4, 8 and 12 weeks.

The results show that the active is stable in the composition and does not degrade with time, whatever the temperature at which the product is stored. b) Physical stability The physical stability of the formulations is measured by a macroscopic and microscopic observation of the formulation at room temperature, at 4 ° C and at 45-55 ° C after 4, 8, 10, 12 and 16 weeks. At room temperature, macroscopic observation allows to guarantee the physical integrity of the products and microscopic observation allows to verify that there is no recrystallization of the solubilized active and there is no significant evolution of the size of the globules of the emulsion. At 4 ° C, microscopic observation verifies the non-recrystallization of the solubilized active. At 45-55 ° C, the macroscopic observation verifies the integrity of the finished product. The formulations described have been tested in examples 1 and 2. No recrystallization of the product or phenomenon of phase separation has been observed. { gap} over time, either at room temperature, at 4 ° C or at 45-55 ° C.

Therefore, the formulations as described in the examples are chemically and physically stable.

Example 10: Measurement of the viscosity of the formulations A Haake rheometer of type VT500 is used with an SVDIN measuring device. The rheograms were performed at 25 ° C and at the shear rate of 4 s-1 (y), and the shear stress was measured. The flow threshold (tO expressed in Pascals) is defined as the force required (minimum shear stress) to overcome the van der Waals-type cohesion forces and to cause the flow The flow threshold is assimilated to the value found in the Shear rate of 4 s ~ A These measurements are made in TO, after 4, 8 and 12 weeks *: Use of a Haake VT 550 rheometer that induces a slight increase in the characteristic values of the viscosity. The results obtained do not show a significant variation of the flow threshold; therefore, the viscosity of the composition according to the invention is stable over time.

Example 11: Release-Penetration A study has been carried out with the objective of comparing the release-penetration of ivermectin to 1% incorporated in compositions of classic emulsion (A) or gel-cream type (example 1) applied non-occlusively on samples of human skin. The radiolabeled compositions with tritium compared are a classic emulsion formula A and example 1 according to the invention. Formula A (conventional emulsion) is as follows: The compositions are applied for 16 hours on the human skin samples arranged in continuous flow automatic diffusion cells (Scott / Dick, Unversity of Newcastle upon Tyne, UK). Subsequently, the radioactivity is measured in the different layers of the skin and in the receiving liquid in contact with the skin sample.

The results obtained show, in effect, that the gel-cream composition described in Example 1 significantly increases the penetration of ivermectin into the different layers of the skin.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (20)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Pharmaceutical composition based on a compound of the avermectin family in the form of a gel-cream, characterized in that it comprises, in a medium physiologically acceptable, an oily phase dispersed in an aqueous phase by a non-surfactant polymer emulsifier, and the oily phase is composed of oils having a melting point lower than 30 ° C, and is free of solid fatty substances having a melting point higher than 30 ° C.
2. 2. Pharmaceutical composition according to claim 1, characterized in that the compound of the avermectin family is chosen from ivermectin, invermectin, avermectin, abamectin, doramectin, eprinomectin and selamectin. 3. Pharmaceutical composition according to one of claims 1 or 2, characterized in that the compound of the avermectin family is ivermectin. 4. Composition according to claim 3, characterized in that it comprises: a) an oily phase comprising oils with a melting point lower than 30 ° C, and free of solid fatty substances having a melting point higher than 30 ° C , b) a non-surfactant polymeric emulsifier, c) ivermectin, d) a solvent and / or active propenetrant, e) and water. Composition according to one of claims 3 or 4, characterized in that the amount of ivermectin represents 0.01 to 10%, and preferably 0.01 to 5% by weight, based on the total weight of the composition. Composition according to one of claims 1 to 5, characterized in that the non-surfactant polymer emulsifier is selected from Pemulen TR 1, Pemulen TR 2, Carbopol 1342, Carbopol 1382 or mixtures thereof. Composition according to claim 4, characterized in that the solvent and / or propenetrant is chosen from propylene glycol, ethanol, isopropanol, butanol, benzyl alcohol, N-methyl-2-pyrrolidone or DMSO, polysorbate 80, phenoxyethanol and mixtures thereof. Composition according to one of claims 1 to 7, characterized in that it contains an amount of water ranging from 30 to 95% by weight with respect to the total weight of the composition. Composition according to one of claims 1 to 8, characterized in that it comprises: 5 to 20% oily phase, 0. 25 to 1% non-surfactant polymer emulsifier, 0 to 2% carbomer, 0 to 5% co-emulsifier, 0.01 to 5% ivermectin 0.1 to 20% solvents and / or propenetrating agents, 60 to 80% water purified. Composition according to one of claims 1 to 9, characterized in that it comprises: 8 to 15% of oily phase, 0.25 to 1% of non-surfactant polymer emulsifier, 0 to 2% of carbomer, 1 to 5% of co-polymer emulsifier, 0.01 to 5% ivermectin, 4 to 20% solvents and / or propenetrating agents, 60 to 80% purified water. 11. Composition according to one of claims 1 to 10, characterized in that it comprises: Ivermectin 1.0% Mineral oil 10.00% Tocopherol 0.20% Propylparaben 0.10% Disodium edetate 0.10% Glycerol 5.00% Allantoin 0.20% Acrylate / acrylate crosslinked polymer 0.30% C10-30 alkyl Carbomer 0.15% Polysorbate 80 4.00% Propylene glycol 4.00% Phenoxyethanol 1.00% Hydroxide of sodium cs pH 6.30 Purified water cs 100 12. Composition according to one of claims 1 to 10, characterized in that it comprises: Ivermectin 1.00% Mineral oil 10.00% Tocopherol 0.20% Disodium edetate 0.10% Glycerol 5.00% Acrylate / acrylate crosslinked polymer 0.30% C? O-3o alkyl Carbomer 0.15% Polysorbate 80 4.00% Propylene glycol 4.00% Phenoxyethanol 1.00% Triethanolamine cs pH 6.00 Purified water 100% 13. Composition according to one of claims 1 to 10, characterized in that it comprises: Ivermectin 0.50% Capric / Caprylic triglycerides 10.00% Tocopherol 0.20% Disodium edetate. 0.10% Sorbitol 5.00% Zinc acetate 0.50% Acrylate / acrylate crosslinked polymer of 0.30% C? O -3o alkyl Carbomer 0.15% N-methylpyrrolidone 5.00% Phenoxyethanol 1.00% Sodium hydroxide cs pH 6.00 Purified water 100% 14. Composition according to one of claims 1 to 10, characterized by comprising: Ivermectin 1.00 Mineral oil 10.00 Sorbitan laurel 1.00 Tocopherol 0.20 Propyl paraben 0.10 Disodium disodium 0.10 Glycerol 5.00 Allantoin 0.20 Acrylate / acrylate crosslinked polymer 0.30 C10-30 alkyl Carbomer 0.15 Polysorbate 80 3.00 Poloxamer 124 1.00 Propylene glycol 4.00 Phenoxyethanol 1.00 cs pH 6 Hydroxide sodium 6.00 Purified water cs 100 15. Composition according to one of claims 1 to 10, characterized in that it comprises: Ivermectin 1.00 Mineral oil 10.00 Sorbitan laurel 1.00 Tocopherol 0.20 Propyl paraben 0.10 Disodium deodorization 0.10 Glycerol 5.00 Allantoin 0.20 Acrylate / acrylate crosslinked polymer 0.30 C-o-alkyl alkyl Carbomer 0.15 Polysorbate 80 4.00 Propylene glycol 4.00 Benzyl alcohol 3.00 cs pH 6.3 Hydroxide sodium 6.00 Purified water cs 100 16. Composition according to one of claims 1 to 10, characterized in that it comprises: Ivermectin 0.03 Mineral oil 10.00 Sorbitan laurel 1.00 Tocopherol 0.20 Propyl paraben 0.10 Disodium disodium 0.10 Glycerol 5.00 Allantoin 0.20 Acrylate / acrylate crosslinked polymer 0.30 C 0-3 alkyl, Carbomer 0.15 Polysorbate 80 4.00 Propylene glycol 4.00 Benzyl alcohol 3.00 Poly (methacrylate) methyl) 2.00 cs pH 6.3 Sodium hydroxide 6.00 Purified water cs 100 17. Composition according to one of claims 1 to 10, characterized in that it comprises: Ivermectin 0.03 Mineral oil 5.00 Sweet almond oil 5.00 Sorbitan laurel 1.00 Tocopherol 0.20 Propyl paraben 0.10 Disodium deodorization 0.10 Glycerol 5.00 Allantoin 0.20 Acrylate / acrylate crosslinked polymer 0.30 C10-30 alkyl Carbomer 0.15 Polysorbate 80 4.00 Propylene glycol 4.00 Benzyl alcohol 3.00 cs pH 6.
3. 3 Sodium hydroxide 6.00 Purified water cs 100 18. Preparation process at room temperature of a composition according to one of claims 1 to 17, characterized in that it comprises the following steps: a) the constituents of the fatty phase are mixed until it is homogeneous; b) the constituents of the aqueous phase are dissolved in water until a complete homogeneity is achieved; c) the polymeric emulsifier and the optional carbomer are dispersed in the aqueous phase until a homogeneous gel is obtained; d) the fat phase is incorporated under moderate mechanical agitation to the homogeneous gel obtained in c) to form an emulsion; e) the constituents of the active phase are mixed; Ivermectin is solubilized in this mixture; then this phase is incorporated into the emulsion under moderate mechanical agitation; f) the neutralizer is incorporated under moderate mechanical agitation, to obtain a defined pH. 19. Use of a composition according to one of claims 1 to 17, for the manufacture of a pharmaceutical preparation intended to treat dermatological conditions, such as rosacea, acne vulgaris, seborrheic dermitis, or perioral dermatitis, acneiform eruptions, transient acantholytic dermatitis, and necrotic acne miralis. 20. Use according to claim 19, wherein the pharmaceutical preparation is intended to treat rosacea.