MXPA00009299A - Topical hormonal composition with systemic effect - Google Patents

Abstract

The invention concerns the field of therapeutic chemistry and more particularly the production of novel galenic forms designed to be applied on the skin. More specifically, it concerns a topical hormonal composition with systemic effect to remedy progesterone deficiency in the pre-menopausal woman and as hormonal substitute for the post-menopausal woman. The invention is characterised in that it comprises, as active principle, a gestagenic derived from 19-nor progesterone, a carrier for systemic passage of said active principle selected from the group consisting of a solubilizing agent, an agent promoting absorption, a film-forming agent, a gelling agent or their mixtures, associated or mixed with appropriate carriers for producing a gelled and/or film-forming pharmaceutical form.

Description

A TOPICAL HORMONAL COMPOSITION OF SYSTEMATIC EFFECT The present; invention relates to the field of chemical therapy and more particularly to the preparation of new galenic forms intended to be applied to the skin. The present invention more particularly aims at galenic preparations in which the active principle is a synthetic progestogen, intended to be applied to the skin, for the purpose of obtaining a hormonal systemic effect in women before or after menopause. Therefore, the invention deals with a topical hormonal composition with a systemic effect. Normally it is customary to use synthetic progestogens, as well as natural progesterone, orally, for the correction of luteal deficiencies in non-menopausal women and for hormone replacement therapy for menopause. French Patent 2,271,833, among others, describes hormonal compositions for the correction of progestative deficiencies in premenopausal or menopausal women, intended for oral administration. However, the oral route does not fail to present certain drawbacks, not only with respect to natural progesterone, but also for synthetic progestogens. On the one hand, it requires the administration of very high doses to compensate for the degradation of the active principle as it passes through the intestine and the liver (an effect called "first step"). On the other hand, it does not produce constant plasma levels with time, since the oral ingestion results in a plasma peak during which the concentrations in the blood rise transiently. Sometimes, natural progesterone is administered percutaneously. This route produces only local effects, but does not allow impregnation of the distant objective tissues, in particular the uterine mucosa. The reason is the rapid degradation of the hormone caused by the enzymes of the subcutaneous tissue that does not allow to achieve sufficient plasma levels to create a systemic hormonal action. Many synthetic progestogens have the same drawback and can not be used percutaneously to obtain a systemic effect. The only exception is norethisterone acetate administered by patches. The function of the protective barrier of the skin against external aggressions reduces its permeability with respect to numerous substances and does not allow the penetration of medicinal molecules except under certain conditions: the size and nature of the molecule, the nature of the vehicle containing the molecule, etc. Thus, the release of an active ingredient from a vehicle and its penetration through the skin to reach the blood or lymphatic circulation depends on numerous physical-chemical and / or physiological parameters. In the present invention, the very nature of the active principle (synthetic progestogen) presents the main obstacle to percutaneous penetration: the main problem that arises is its low diffusion through the epidermis due to its lipophilic nature. Therefore, the choice of the vehicle to be used in the compositions will have great importance for percutaneous penetration and on the therapeutic activity of the molecule. Thus, the topical compositions according to the invention allow a systemic effect for the optimization of the percutaneous passage of a synthetic progestagen derived from 19-nor progesterone. According to the invention, the topical compositions contain, as an active principle, a synthetic progestogen derived from 19-nor progesterone and excipients which allow the percutaneous passage of the active principle to be optimized. The present invention more specifically has as its object a topical hormonal composition with a systemic effect for the correction of progesterone faults in non-menopausal women and for hormone replacement in menopausal women, characterized in that it contains: as an active ingredient, a progestogen derivative of 19-nor progesterone, - a vehicle that allows the systemic passage of the said active principle chosen from a group composed of a solubilizing agent, an absorption promoting agent, a smoke agent, a gelling agent or mixtures thereof, in association with suitable excipients for carrying out a gelled and / or fumaric pharmaceutical form. The compositions that conform with the invention can, therefore, be in the form of a gel, of a smoke-forming gel or of a smoke solution. The progestogen derived from 19-nor progesterone which is used in the present invention is nomegestrol and / or one of its esters or ethers. An example of an ether of nomegestrol is the tetrahydropyranic ether of nomegestrol. An example of an ester of nomegestrol is nomegestrol acetate, which is a progestogen of oral active synthesis, whose action depends on the correction of gynecological complaints caused by a lack of luteinizing hormones. Administered by the compositions comprising the invention, nomegestrol acetate is able to penetrate the skin and penetrate the bloodstream to produce plasma levels that can be detected with the aid of measurement methods used in biological media. The observed plasma concentrations are maintained at a constant level due to the reserve effect of the skin. The plasma levels of nomegestrol acetate obtained with the compositions which are the object of the present invention are to create an effect on the tissues located at a distance from the application and especially on the endometrium. The nomegestrol acetate thus administered in a repeated manner produces a therapeutic action when it is administered to non-menopausal women who suffer from a symptomatology linked to a lack of progesterone or to menopausal women undergoing estrogen-replacement therapy. According to the present invention, nomegestrol or one of its esters or ethers is present at a concentration that can vary between 0.05 and 1% by weight of the total composition. Preferably, the nomegestrol or one of its esters or ethers is present at a concentration that can vary between 0.1 and 0.8% by weight of the total composition. The compositions according to the invention which have a preferred systemic action are those which contain an amount of their esters or ethers 0.4% by weight of the total composition. The solubilizing agents and the absorption promoting agents have modes of action that are different but allow both to favor the penetration of the skin by the active principle.

The solubilizing agents, through an action on the thermodynamic activity of the active molecule, improve the solubility of the active principle and modify its affinity with the skin. The absorption promoting agents, by modifications at the level of the cutaneous barrier structure, reduce the resistance to diffusion. However, there is no direct relationship between improving the solubility of the principle, active in the vehicle, and increasing its percutaneous passage. In fact, the use of agents that improve the solubility of the active principle also increase its affinity with the vehicle and therefore frequently reduce its diffusion through the skin.

Thus, if the solubility of the active principle in a vehicle is total, it must have some affinity to it; however, it should not be too large for a proportion to be directed to diffusion through the skin. According to the present invention, examples of suitable solubilizing agents are water, alcohols, propylene glycol, polyethylene glycol, polyethylene monooleate sorbitan (marketed under the name Polysorbate 80 DF), a glycoside glycoside polyoxyethylene glycosylated (marketed, for example, under the name Labrasol®) or mixtures thereof. In general, a mixture of the solvents or solubilizing agents indicated above is employed as a solubilizing agent, which, by a synergistic action, is more effective than using only one. Preferably the solubilizing agent of a group composed of water, alcohols, propylene glycol, a glycoside in glycosylated polyoxyethylene C8 / Cl or mixtures thereof is chosen. Thus, for example, it could be used, as a solubilizing agent, a mixture - batch of ethanol at 95 ° / water, in which the percentage of ethanol at 95 ° varies between 30 and 50%, and particularly a binary mixture of ethanol at 95 ° / water, in which the percentage of ethanol at 95 ° is 45%. However, examples of particularly preferred solubilizing agents suitable for the topical composition for a systemic effect according to the invention are: a ternary mixture of 95% ethanol / water / propylene glycol, in which the percentage of ethanol at 95 ° varies between 30 and 50%, water between 30 and 60%, and propylene glycol between 2 and 20%; preferably, the percentage of ethanol at 95 ° is 45%, that of water is 45%, and that of propylene glycol is 8%, a quaternary mixture of ethanol at 95 ° / water / Labrasol® / propylene glycol, in which the percentage of ethanol at 95 ° it varies between 30 and 50%, that of water between 30 and 60%, that of Labrasol® between 3 and 7% and that of propylene glycol between 2 and 20%; preferably, the percentage of ethanol at 95 ° is 45%, that of water is 33.5%, that of LabrasolT is 5% and that of propylene glycol is 15%; Among the substances that are considered as "enhancers", the most commonly used are the glycol derivatives, the sulfoxides, the surfactants, the fatty acids and the terpene derivatives, as an example they can be used as absorption agents. oleic acid, oleic alcohol, a triglyceride of capric and caprylic acids (for example, the one sold under the name Miglyol 812 ©), isopropyl myristate, propylene glycol dipelargonate, 2n-nonyl-1, 3 -dioxolane, octyldodecyl myristate, isopropylidene glycol (for example, sold under the name Solketal), a-tocopheryl polyethylene glycol 1000 succinate (for example, the one sold under the name Vitamin E TPGS), ether diethylene glycol monoethyl (for example, that sold under the name Transcutol ©).

The absorption promoting agent most particularly suitable in the present invention has been chosen from the group consisting of isopropylidene glycerol, α-tocopheryl polyethylene glycol 1 000 succinate and diethylene glycol monoethyl ether. However, the preferred absorption promoting agent is isopropylidene glycerol. The forms visualized to ensure the percutaneous penetration of the active principle will be the occlusive gelled preparations. The choice of gelling agents and smoke-killing agents are equally important in the compositions according to the invention. The gelling agents are substances that thicken and modify the viscosity of a liquid vehicle thus producing a three-dimensional colloidal network, the gel. There are many different types of gelling agents: natural gelling agents (minerals, vegetables, animals), synthetic agents and semi-synthetic agents. Natural gelling agents include guar gum, algae extracts (alginates, carrageenans, gelosa), polysaccharides (xanthan gum, gum arabic, gum tragacanth), starches, pectins, etc. As examples of synthetic or semi-synthetic gelling agents there are the cellulose derivatives, especially those obtained by the esterification of cellulose, and the acrylic derivatives. In the category of acrylic derivatives, carbons, polycarbophils, acrylates are classified In the present invention, the gelling agent of the group consisting of cellulose derivatives and acrylic derivatives has been chosen. find: - methylcelluloses (Methocel, Metolose), - ethylcelluloses (Ethocel, Aquacoat®) - hydroxypropylmethylcelluloses (Kenal Methocel, Hypromelose), - hydroxyethylcelluloses (Cellosize, Natrosol), - hydroxypropylcelluloses (Klucel), - Carboxymethylcelluloses in Sodium or calcium form (Akucell, Nymcel Tylose CB), The polymer of the Metolose range is selected from the firm Shin Etsu For each of these types, there are several grades (or types) according to the substituents and the degree of substitution, providing solutions of polymers of different viscosity Celluloses are classified according to their adhesion potential.The selection of grade is important because its power ad hesiva depends on that one. According to the present invention, a particularly suitable cellulose derivative is hydroxypropylmethylcellulose and very particularly hydroxypropylmethylcellulose of grade 60 SH 4000. Indeed, the SH grade 60 offers the most suitable specification: a good solubility in organic solvents and a high resistance to electrolytes In addition, it allows to obtain transparent gels.

Among the acrylic derivatives, carbomers are especially chosen according to the present invention, and especially those marketed under the names Carbopol ® or Synthalen ®. The carbomers create formulations that remain stable over time and provide the formulation with reproducible rheological properties due to its synthetic nature. The existence of different grades or types refer to the difference in molecular weight, the level of crosslinking, the nature of the molecular arrangements and the polymerization solvent. Thus, among the different grades of carbomer, we can mention those marketed by the company Goodrich under the names Carbopol 974 P ®, Carbopol 980 ®, Carbopol 1382 ® and Carbopol 2020 ®, or similar products such as the Synthalen 3 V France, as (Synthalen K, L, M) or preneutralized, such as the Synthalen PNC ©. However, according to the present invention, the carbomers sold under the names Carbopol 980®, Carbopol 1382® and Synthalen K® are particularly suitable and have not insignificant advantages, since they are fluidized in contact with the electrolytes of the skin and avoid this. way the deposition of polymer that could reduce the passage of the active principle.

The smoke-forming agents that are used are those used to prepare coating solutions or to form films, since most originate in the food or biomedical industry and allow them to be contemplated for human use. These smoke-forming agents can be classified into different groups according to their solubility. With respect to all the smoke-forming agents, the quality of the fumed gel obtained or of the smoke solution obtained depends on the percentage of the smoke agent, the nature of the solvent and the presence and nature of the plasticizing agent. According to the present invention, the smoke agent of a group composed of cellulose derivatives, methacrylic derivatives and derivatives of polyvinyl pyrrolidone is chosen. Among the cellulose derivatives, there may be mentioned: • the hydroxypropylmethyl cellulose acetate succinate, and particularly the one sold by the company Seppic under the name Aqoat AS-LF ©, • an aqueous dispersion of cellulose acetophthalate containing 70% water, 23% cellulose acetophthalate and 7% poloxamer, and particularly the one marketed by the company Seppic under the name Aquacoat CPD®, • an aqueous dispersion of ethylcellulose, cetyl alcohol and sodium lauryl sulfate, and particularly that marketed by the company Seppic under the name Aquacoat ECD 30®, • ethylcellulose. Among the metacrylic derivatives, we can mention: • an aqueous dispersion of an anionic copolymer of methacrylic acid and ethyl acrylate (type C), particularly that containing 30% dry copolymer, 0.7% sodium lauryl sulfate and 2.3% Polysorbate 80 NF, and is marketed under the name Eudragit L30 D55® (Rohm &Haas), • a copolymer of acrylic acid and methacrylic ester (type A), particularly and sold under the name Eudragit RL 100® (Rohm &Haas) . Among the polyvinylpyrrolidone derivatives, there may be mentioned: • a povidone, of formula (C6H9NO) n with a molecular weight of approximately 360,000, marketed under the name Kollidon 90® • a copolymer of polyvinylpyrrolidone / vinyl acetate 64, of formula ( C6H9NO) nx (C4H602)? with a molecular weight of: (111, l) n x (86, l) ra. • the homopolymers of polyvinyl alcohol In the present invention, the cellulosic derivative which is particularly suitable is hydroxypropylmethylcellulose acetate succinate, the methacrylic derivative which is particularly suitable is an aqueous dispersion of an anionic copolymer of methacrylic acid and ethyl acrylate, and the polyvinylpyrrolidone derivative which is particularly suitable is a povidone. The topical hormonal compositions of systemic effect according to the invention may also contain other excipients such as complexing agents, neutralizing agents such as disodium edetate (EDTA), triethanolamine (TEA) and / or plasticizing agents such as diethyl phthalate and triacetin. A topical hormonal composition according to the invention which is particularly suitable is a composition in the form of a gel or of a fumed gel, containing 0.4% by weight of the total composition of nomegestrol or nomegestrol acetate, a pH between 6 and 7, and a viscosity between 1000 and 2000 mPas. The method of preparing the compositions with systemic effect differs according to the nature of the compositions to be obtained, ie a gel, a smoke-forming gel or a smoke solution. • PROCEDURE FOR THE PREPARATION OF GELS Likewise, when preparing the compositions in gel form, the method of preparation will vary according to the nature of the gelling agent that is used. Thus, when the gels are prepared, they are divided, as far as the gelling agent is concerned, to synthetic acrylic derivatives and cellulose derivatives. Preparation from acrylic derivatives The important phases of the preparation are the dispersion of the gelling agent in the solubilizing agent (the dispersion of which will depend very much on the quality of the preparation obtained), the agitation-, the hydration, the swelling and finally the gelation Dispersion and stirring: moistening The acrylic derivative is placed in suspension in a stirred solvent (solubilizing agent). The agitation must be moderate, so that the acrylic polymer does not degrade by shearing and loses its effectiveness. Hydration and swelling of polymers In order to avoid avoiding the formation of partially hydrated agglomerates, it is recommended to incorporate the polymers by sieving them to facilitate the wetting and hydration of the powder allowing them to disperse in a network form. In this phase, it is preferred to wet the powder beforehand in the more polar solvent when using a solvent system. Gelification: neutralization of the dispersion obtained The pH of a similar suspension is close to 3 (this pH is a function of the concentration of polymer, then its carboxylic groups). Inorganic bases such as sodium, potassium or ammonium hydroxides are used when the solvents are aqueous, and organic bases such as amines (triethanolamine, tromethamine or TRIS etc.) when they are low or non-polar. The addition of these agents produces a spontaneous thickening by the formation of salts of polymer resins which are soluble in water. An example of the preparation of a gel is defined in which the gelling agent is an acrylic derivative in which: - nomegestrol acetate and EDTA are dissolved in a water / ethanol at 95 ° / propylene glycol solvent system with stirring at 300 rpm (# 30 min); the acrylic polymer is dispersed in small portions in the active substance solution, stirring at 100 rpm; - the acrylic polymer is allowed to swell for 2 hours while stirring at 200 rpm; the dispersion is neutralized by triethanolamine dissolved in a fraction of the water taken from the amount to be incorporated in the formulation; the agitation speed is reduced to 100 rpm during the neutralization to avoid the incorporation of air bubbles; - stir for 30 minutes at 150 rpm to homogenize the obtained gel.

Preparation using cellulose derivatives It is not necessary to neutralize the gels formulated based on cellulose derivatives, but it may be necessary to adjust the pH using organic amines or inorganic hydroxides, depending on the nature of the solvent in the formulation. The viscosity obtained depends on the nature and amount of the cellulose derivative used. An example of the preparation of a gel is defined in which the gelling agent is a cellulose derivative in which: - the nomegestrol acetate and EDTA are dissolved in a water / ethanol 95 ° / propylene glycol solvent system with stirring at 300 rpm (# 30 min); - the cellulosic polymer is dispersed in small portions in the active ingredient solution, stirring at 100 rpm; - the cellulosic polymer is allowed to swell for 2 hours with stirring at 250 rpm; - the pH is adjusted, if necessary, with triethanolamine dissolved in water by stirring at 100 rpm; - stir for 30 minutes at 150 rpm to homogenize the obtained gel. »FILMOGEN GELS (or" FILMING GELS ") AND FILMOGEN SOLUTIONS (or" FILMING SOLUTIONS ") These forms are proposed because after the application on the skin, they form, after drying, like an occlusive film, enough to increase hydration of the skin and create new sites of passage improving in this way the diffusion of the active principle that they contain. However, the shape obtained should penetrate or dry quickly leaving a pleasant and non-sticky feeling. The smoke-forming agents which are used in the present invention are, in general, those which are used for the preparation of solutions for the coating of tablets. «PROCEDURE FOR PREPARING FILMOGENIC SOLUTIONS As for gels, in the preparation of compositions for a smoke solution, the method of preparation varies according to the nature of the smoke agent used. Preparation from a solid smoke agent: The phases of the preparation are: - The solubilization of a plasticizing agent and the active principle in a solvent mixture: the duration of the stirring of the mixture containing the plasticizer must be sufficient to obtain a solution. - The dispersion and solubilization of the smoke agent: The dispersion must be carried out in small fractions with good agitation. Stirring is continued until the smoke agent has completely dissolved. If necessary, the neutralization of the smoke solution is carried out at the end of the preparation, with reduced agitation. An example of the preparation of a smoke solution in which the smoke agent is solid is defined, in which: - the amounts of ethanol, water and propylene glycol required for the formulation are stirred at 250 rpm for 10 min; - EDTA and nomegestrol acetate are dissolved in the mixture obtained; - the plasticizing agent is added and stirred at 250 rpm for 30 min; the smoke agent is dispersed in small fractions maintaining the same agitation, until the solubilization is complete; then stirring is continued for 1 hour; the pH is adjusted with the aid of a solution of triethanolamine dissolved in a small amount of water taken from the amount to be incorporated in the formulation; the stirring speed is reduced to 100 rpm; The solution obtained is homogenized for 30 min. - Preparation starting from a smoke-forming agent in aqueous dispersion The phases of the preparation are: - Solubilization and plasticization of the smoke-forming agent - Incorporation of the mixture containing the active principle and the other excipients in small fractions with strong agitation. Neutralization is carried out at the end of manufacture, with reduced agitation. An example of the preparation of a smoke solution is defined in which the smoke agent is in an aqueous dispersion, in which: - the water and a plasticizing agent are mixed at 250 rpm; it is stirred for 30 min; - the dispersion of the smoke agent is added in small fractions, stirring at 250 rpm, until a homogeneous solution of the dispersion is obtained; stirring is continued for 1 hour; - independently, EDTA and nomegestrol acetate are dissolved in the mixture of ethanol and propylene glycol; it is stirred until a total solution is achieved; - the alcoholic solution of the active ingredient is added in small fractions to the aqueous solution, stirring at 250 rpm; the solution obtained is stirred for 1 hour to homogenize it; the solution is neutralized with triethanolamine dissolved in water, reducing the stirring speed; The solution obtained is homogenized for 30 min. PROCEDURE FOR THE PREPARATION OF FILMOGEN GELS OR GELIFIED FILMS Phosmogen gels are obtained by gelling the smoke solutions. Begin by preparing the two solutions separately: an aqueous solution contains a dissolved plasticizer, in which the smoke agent is also dissolved with strong agitation; an alcoholic solution contains the other excipients of the formulation and in it the active principle is dissolved; the gelling agent is dispersed and allowed to swell. The alcohol solution is then mixed in the aqueous solution and the solution is gelled with triethanolamine. An example of the preparation of a smoke-forming gel is defined in that: - the plasticizing agent is dissolved in water; it is stirred for 30 min at 250 rpm; - the fumaric agent is dispersed by stirring at 250 rpm until it is completely dissolved (in the case of a solid smoke agent) or until the dispersion is homogeneous; stirring is continued for 1 hour; - independently, EDTA and nomegestrol acetate are dissolved in the mixture of ethanol and propylene glycol, the chosen gelling agent is dispersed and allowed to swell for 2 hours, stirring at 150 rpm; - the alcohol solution is mixed with the aqueous solution and stirred for 1 hour at 150 rpm; the solution is neutralized with triethanolamine dissolved in water, reducing the stirring speed to 100 rpm; the obtained solution is homogenized by stirring for 30 min. METHOD OF EVALUATION OF THE PERCUTANEOUS STEP OF THE ACTIVE PRINCIPLE The efficacy of the topical composition according to the invention is evaluated by showing that the active principle it contains diffuses through the skin and is reabsorbed by the microcirculation in sufficient quantity to obtain the desired therapeutic effect. In the present invention, the percutaneous passage of nomegestrol acetate is evaluated by measuring the radioactivity using a molecule marked with carbon 14. The method of evaluating the passage of the active ingredient using radio-labeled products allows the detection of very small amounts of active principle, which is a considerable advantage if one considers the very small amounts that diffuse through the skin. The skin used during the course of the various evaluation trials of the percutaneous passage of the active ingredient comes from several plastic surgical interventions of the abdomen of women aged 40 to 45 years. It removes excess adipose tissue and cleanses the woman's skin, and is stored in a freezer at -70 ° C. The topical compositions according to the invention are mainly intended for application to the skin of the abdomen, arms, thighs, etc.

EXPERIMENTAL SECTION »EXAMPLE I Figure 1 shows the percutaneous passage of the active principle, nomegestrol acetate (AcN) as a function of different amounts of nomegestrol acetate in the compositions that conform with the invention. The symbols I,, and D of Figure 1 represent: Gel 0, 11% AcN Gel 0.4% AcN O Gel 0, AcN These compositions are in gel form and the formulations are presented in Table 1 below: Table 1 The percutaneous passage of the active principle is evaluated by measuring the cumulative amount of active principle as a function of time. The quantity of cumulative active principle represents the total amount of active substance diffused through the skin during a given period (24 or 48 h). In this example, it is expressed in ng. Figure 1 clearly indicates that the lowest diffusion results are obtained with the gel at 0.11% AcN.

The gel at 0.11% has been checked in preliminary clinical tests: compare Example IV. In this way, it has been established that this gel, in spite of its inferior results, in any way allows to obtain a systemic passage effect.

* EXAMPLE II Study of the solubility of nomesestrol acetate (AcN) 1) - a) In a binary mixture of 95% ethanol / water Determination of the most effective solvent system of the hydro-alcoholic mixture. Table 2: Solubility of .nomegestrol acetate as a function of the percentage of ethanol at 95 ° In the hydro-alcoholic mixture, the solubility increases according to the percentage of alcohol. The solubility profile is quite low until it reaches 40% alcohol, then rapidly increases between 40 and 80%. However, the percentage of authorized alcohol for topical forms is limited. Within these limits, the most effective solvent system for dissolving nomegestrol acetate is between 40 and 60% - b) In a ternary mixture of 95% ethanol / water / propylene glycol The effect of a ternary mixture of solvents, ethanol / water (45:55) / propylene glycol on the solubility of nomegestrol acetate. The possibility of reducing the proportion of alcohol in the solvent has also been examined, thanks to this ternary mixture, retaining a similar solubility; the effect of propylene glycol on the solubility of the ethanol / water systems (40:60 and 30:70) has been selected for this.

Table 3: Solubility of nomegestrol acetate in different systems containing propylene glycol (PG) System I: 95% ethanol: 30% Demineralized water: 70% System II Ethanol 95 °: 40% Demineralized water: 60% System III: 95% Ethanol: 45% Demineralized water: 55% Figure 2 illustrates Table 3. The symbols M, +, and A of Figure 2 represent: M Solubility of the system I A Solubility of the system III Solubility of the system II In the ternary water / ethanol / propylene glycol mixture, the solubility of the active principle is improved with a proportion of 8% propylene glycol in a mixture of 45% alcohol. It is through this system that the best solubility of the active principle is obtained. Propylene glycol acts synergistically with alcohol, regarding the solubility of nomegestrol acetate. - c) In the mixture of ethanol a 95 ° / water / Labrasol / propylene glycol Table 4: Solubility of nomegestrol acetate in a system containing propylene glycol Ethanol System 95 °: 45% Water: 50% Labrasol®: 5% When using Labrasol® alone, at 5%, without propylene glycol, the solubility increases in the same way as with propylene glycol. This solubility is improved by associating propylene glycol with Labrasol®. 2) - a) In a mixture of 95% ethanol / water / propylene glycol / Solketal Table 5: Solubility of nomegestrol acetate in a hydro-alcoholic mixture containing propylene glycol and / or Solketal The solubility of nomegestrol acetate in the hydro-alcohol solvent mixture in the presence of 8% Solketal is more than that which is obtained in the presence of 8% propylene glycol alone. The association of the two substances propylene glycol and Solketal significantly increases the solubility in the hydro-alcoholic solvent mixture, in the proportion of 8% propylene glycol / 3% Solketal. - b) In a mixture of 95% ethanol / water / propylene glycol / vitamin E TPGS Table 6: Solubility of nomegestrol acetate in a hydro-alcoholic mixture containing propylene glycol and / or vitamin E TPGS The solubility of nomegestrol acetate is improved in the presence of vitamin E TPGS alone, in relation to propylene glycol, at the same proportion of 8%. Incorporated at 3%, it produces equivalent results to propylene glycol used at 8%. However, an even better solubility is obtained when the two substances are combined in the proportion of 8% propylene glycol / 3% vitamin E TPGS. - c) In a mixture of 95% ethanol / water / propylene glycol / Transcutol® Table 7: Solubility of nomegestrol acetate in a hydro-alcoholic mixture containing propylene glycol and / or Transcutol © The solubility of nomegestrol acetate is improved in the presence of 8% Transcutol® alone, relative to propylene glycol, at the same ratio. When these two substances are combined, the same solubility is obtained if the 8% Transcutol / 3% propylene glycol ratio is used.

The inverse proportion does not allow to improve the solubility of the active principle compared to that obtained with propylene glycol alone.

Conclusion: Hydro-alcohol mixtures containing: - 8% propylene glycol and 3% Solketal, - or 8% propylene glycol and 3% vitamin E TPGS, - or 3% propylene glycol and 8% Transcutol®, are particularly suitable for a good solubility of the active principle. • EXAMPLE III 1 / Study of formulations in the form of sels Among the substances chosen for their characteristics as absorption promoting agents, Solketal and vitamin E TPGS are particularly suitable since they are equally capable of improving the solubility of nomegestrol acetate in a hydro-alcoholic and propylene glycol mixture. The promoter action of three promoter agents has been studied by incorporating them in formulations containing a hydro-alcoholic gel at 45% alcohol and containing 8% propylene glycol and 3% promoter. These formulations in gel form have been checked for their percutaneous passage. The verified gels conform to the specifications of pH, viscosity, concentration and appearance.

The four gels studied are called "G36-264, G36-276, G32-104 and G37-113" and their formulations are presented in Table 8 below: Table 8: The main difference between the compositions of these gels is in the choice of the absorption promoter agent ("enhancer") and on the other hand the choice of gelling agent which can be Carbopol 980 © or Carbopol 1382®. The percutaneous passage of the active principle is evaluated by measuring: - the cumulative amount of active ingredient as a function of time (see example I), - the cumulative percentage of the active ingredient as a function of time, - and the diffusion flow of the active principle as a function of time The accumulated active substance percentage is the total percentage of the diffusion of the active principle through the skin during a determined period.The diffusion flow of the active principle is expressed in μg / cm2 / h: this allows to determine the diffusion kinetics of the active ingredient over time The method of evaluating the passage of the active principle that is used also makes it possible to determine the distribution of nomegestrol acetate in the different cutaneous structures after diffusion Table 9 below presents the percentage accumulation of nomegestrol acetate as a function of time, and also (see the last 3 lines) the distribution sites ibución of the active principle in the cutaneous structures, that is to say, the retention of nomegestrol acetate in the different layers (epidermis + dermis) of the skin. Table 9: Table 9 is represented by Figures 3 and 4. Figure 3 depicts the effect of the promoter agent and Carbopol® on the percutaneous passage of the systemic systemic gel of nomegestrol acetate. The following promoter agents are compared: Transcutol® (Tr), Solketal (Sun) and Vitamin E TPGS (Vit E).

The symbols ", A, ^ and D of Figure 3 represent: "G37-113 (3% Tr) * • G32-104 (3% Tr) Ref. A G36-276 (3% Vit E) D G36-264 (3% Sol) Figure 4 represents the distribution of nomegestrol acetate at the level of the cutaneous structures. The symbols and JK? of Figure 4 represent: G37-113 (3% Tr) G32-104 (3% Tr) Ref G36-276 (3% Vit E) G36-264 (3% Sol) From the values of cumulative percentage of active principle, one can deduce from them the cumulative amount and the diffusion flow. Figure 5 represents the diffusion flow of nomegestrol acetate as a function of time. The symbols ", A, ^ and D of Figure 5 have the same meaning as those of Figure 3. The kinetics of diffusion of nomegestrol acetate in the form of gel, is patch type, with constant diffusion.

Conclusion: Solketal improves the percutaneous passage of nomegestrol acetate in a more effective way than Vitamin E and that TranscutolT when comparing the results obtained with those of the reference gel G32-104. Thus, the best diffusion is achieved if Solketal is used instead of Vitamin E TPGS, since the solubility of the active principle is greater in the latter case (compare Tables 5 and 6). The same can be said when using a hydro-alcoholic system consisting of a propylene glycol / Transcutol® mixture: if the four possible combinations 8: 0 - 8: 3 - 3: 8 and 0: 8 are considered, the best diffusion obtained is using the 8: 3 mixture. This is because the solubility of this is the lower one (compare Table 7). Some affinity between the active principle and the solvent is necessary to achieve total solubilization. However, it is not necessary for it to be very large so that the distribution coefficient between the vehicle and the skin is in favor of diffusion through the skin. Static-flow diffusion tests of the radiolabelled active ingredient were carried out with the gels containing the two retained absorption promoter types, compared with two reference gels: the G32-104 gel (Carbopol grade different from G37-113). and the 2 others), with which the best diffusion was obtained, and the gel G37-113, of the same composition as the two gels tested (same grade of Carbopol®) containing Transcutol®. If the action of retained absorption promoters on the percutaneous passage of labeled nomegestrol acetate is considered, a net increase in diffusion is noted in the presence of Solketal compared to reference gel G32-104 containing Transcutol®. Vitamin E TPGS, used under the same conditions, does not improve the step with respect to the gel G32-104. On the other hand, if the gel G37-113 is considered, the diffusion obtained is slightly improved by vitamin E, and clearly increased by Solketal. If the quantitative distribution of the active principle (see Figure 4) is observed at the level of the cutaneous structures, it is found that the active substance of the gel G36-264 and of the reference gel G32-104, have similar concentrations, at the level of the epidermis and the dermis. This is not so significant at the level of the epidermis in the case of gels G37-113 and G36-276. The tests indicated above also confirm that there is a difference in diffusion of active principle as a function of the carbomer used in the formulation (the formulations of gels G37-113 and G32-104 are quantitatively and qualitatively identical with this exception). Therefore, it seems that the diffusion is better in the presence of Carbopol 1382 ©, both in locality and in the cutaneous structures. If the results obtained in terms of adhesion are considered, when the controls of the gels G36-264 and G36-276 are made, it is noted that the adhesive character of the gel containing Solketal is slightly higher than that of the gel containing vitamin E Now, these two gels contain the same proportions of the same ingredients, with the exception of the nature of the promoter. Conclusion A topical hormonal composition with the hormonal systemic effect that according to the present invention is currently preferred is a gel-like composition containing: - 0, 4% nomegestrol acetate - 8% propylene glycol - 3% Solketal - 0.5% Carbopol 980 or 1382® - 45% ethanol 95 ° - 0.05% EDTA, 0.4% TEA and csp 100% demineralized water. 2 / Study of the formulations in the form of smoke or filming solutions The 5 studied smoke solutions have been called "G36-259, G36-261, G36-263, G36-266 and G36-27-7" and their formulations are presented continued in -Table -10: Table 10 The main difference of composition of the smoke solutions is in the choice of the smoke agent and whether or not an absorption promoter or a plasticizing agent is added. The tests were carried out with smoke solutions comparing them with the G32-104 gel as a reference.

Table 11 below shows the cumulative percentage of nomegestrol acetate as a function of time and the distribution of nomegestrol acetate at the level of the cutaneous structures. Table 11 Table 11 is represented by Figures 6 and 7.

Figure 6 represents the effect of the absorption promoting agent and the smoke agent on the percutaneous passage of nomegestrol acetate through the systemic film. The symbols U,, < > , •, A and "k in Figure 6 represent: m G32 - - 104 (3 feTr) -Réf 0 G36-261 (10 fcAqoat) G36- -259 (5 £ sKol) • G36-266 (3% Sol k / 5s sKol) A G36- -263 (10% Eudrag ) * G36- 277 (3% TPGS / 5% Kol) The amounts of active ingredient that have diffused from these forms are all lower than the amounts obtained by application of the non-smoke smoke G32-104, with all the polymers tested. It is noted that the solution that does not contain Kollidon® is the one that produces the diffusion most similar to the reference gel. The other two polymers produce similar diffusions. Solutions combining Kollidon © and a promoter agent, such as Solketal or vitamin E TPGS, produced lower active substance diffusions than the G36-259 solution without promoter. Figure 7 represents the distribution of nomegestrol acetate at the level of the cutaneous structures. The symbols ¡¡¡, ^ g, ^ - j 'fZJZIZ' ßB y ^ of l a Figure 7 represent: lü G32-104 (3% Tr) -Ref. - rggj G36-261 (10% Aqoat) ^ G36-259 (5% Kol) ITT 1 G36-266 (3% Sol k / 5% Kol) § G36-263 (10% Eudrag) H G36-277 (3 % TPGS / 5% Kol) It is noted that the best distribution is for the use of Kollídon®. It is equivalent to the one observed with the reference gel. The results obtained with the Aqoat® and Eudragit® solutions remain low. The results obtained with the filming solutions are slightly better than those obtained with the 0.11% gel of nomegestrol acetate (see Table 1, Example I). However, it should be noted that with regard to Eudragit © and Aqoat®, the solutions prepared contain only propylene glycol, without another promoter, unlike the reference gel. Conclusion : A systemic topical hormonal composition according to the present invention will be for example a composition in the form of a smoke solution containing: - 0.4% nomegestrol acetate - 8% propylene glycol - 5% Kollidon 90®-43, 35% ethanol 95% 0.05% EDTA and csp 100% demineralized water. 3 / Study of the formulations in the form of smoke gels or gelled films The three studied smoke gels have been named "G36-260, G36-262 and G36-267, and the formulations are presented below in Table 12. Table 12 The main difference in the composition of these smoke gels is in the choice of the gelling agent and the smoke agent. These tests were performed with smoke gels and compared with gels G32-104 and G37-113 as references. Table 13 below shows the cumulative percentage of nomegestrol acetate as a function of time and the distribution of nomegestrol acetate at the level of the cutaneous structures.

Table 13 is represented by Figures 8 and 9.

Figure 8 shows the effect of the smoke agent on the percutaneous passage of nomegestrol acetate through the smoke-forming gel. The symbols *, p, +, 0 and A of Figure 8 represent: * G32-104 (C1382) + G36-260 (Kol / C980) G36-262 (aq / C980) D-G36-267 (Eud / HPMC) 0 G37-113 (C980) If the polymer assembly is considered, the diffusion of nomegestrol acetate from the smoke gels of Aqoat® and Eudragit® is better than for the gel G32-104 of "reference" until 10 o'clock. Afterwards, the trend reverses slightly. If one considers the non-fuming gel 113, which contains a Carbopol® different from that of the G32-104 gel, the results obtained by all the smoke-forming gels are better, if any of the polymers is considered. It is noted that the diffusion of the active principle is similar for Aqoat® and Eudragit®. On the other hand, it is clearly lower with Kollidon®.

Figure 9 represents the locality of the active principle at the level of the cutaneous structures. The symbols m, ^ $ 8, mm, vmm,? ^ l of Figure 9 represent: G32- 104 (C1382) ÜSS¡¡ G36-260 (Kol / C980) G36-262 (aq / C980) G36-267 (Eud / HPMC) -13 G37 - 113 (C980) It is noted that the locality varies from one polymer to another: compared to the reference G32-104 gel, the distribution at the level of the epidermis is similar in the case of Aqoat ©, and lower for Kollidon® and Eudragit®. The distribution at the level of the dermis is lower in the case of Aqoat® and Eudragit®, and higher in the case of Kollidon®. Conclusion: Examples of systemic topical hormonal compositions according to the invention are, for example, the compositions in the form of a fumed gel containing: - 0.4% nomegestrol acetate - 8% propylene glycol - 0.75% Carbopol 980® - 10% of Aqoat AS-LF® - 40% ethanol 95 ° - 3% diethyl phthalate, 0.05% EDTA, 0.9% TEA and csp 100% demineralised water, or, compositions in the form of a smoke-forming gel containing: - 0.4% nomegestrol acetate - 8% propylene glycol - 1% HPMC 60 SH 4000 - 10% Eudragit L 30 D 55® - 40% ethanol 95 ° - 2% diethyl phthalate, 0.05% EDTA, 0.4% TEA and csp 100% demineralized water. 4 / Comparison between smoke and smoke solutions Table 14 below shows the cumulative percentage of nomegestrol acetate as a function of time, and the distribution of nomegestrol acetate at the level of skin structures.

Table 14 is represented by Figures 10 and 11. Figure 10 allows to compare the smoke-producing solutions and the fuminogenic gels of nomegestrol acetate for systemic effects. The symbols M, d,, 0, A and? of Figure 10 represent: Solutions Filmóqenas M G36-259 (5% Kollidon) G36-261 (10% Aqoat) A G36-263 (10% Eudrag) Gum Fumógeno O G36-260 (5% KO1 / C980) 0 G36-262 (10% Aqoat / C980) ^ G36-267 (10% Eudr / HPMC) Figure 11 represents the distribution of the active principle at the level of the cutaneous structures. The symbols ^, \ ¡, - * -? (column 2, Fig. 11), fjjjjjfl, rg (column 3, Fig. 11) and ¡H¡ | (last column) of figure 11 represent: G36-259 (5 * Kollidon) | , "j G36-261 (10% Aqoat) ||| G36-263 (10% Eudrag) G36-260 (5 * KO1 / C980) 1III1IH G36-262 (10% Aqoat / C980) IIÉI G36-267 (10% Eudr / HPMC) Figure 12 compares the diffusion flows of nomegestrol acetate with those of the compositions in the form of a fumed gel and with those of the compositions in the form of a smoke solution. The symbols of Figure 12 have the same meaning as those of Figure 10. Unlike Figure 5 (diffusion flow of the compositions in gel form), the diffusion kinetics is not a constant diffusion kinetics, but produces a maximum diffusion (at the end of 2 hours) that then reduces fairly quickly. This is particularly true in the case of the smoke-forming gels G36-262 and G36-267. Thus, two types of flow can be distinguished: more or less constant diffusion flows and others that arrive very quickly at a peak of maximum diffusion. Thus, smoke-forming gels are better suited than a smoke solution to the optimization of the percutaneous distribution of nomegestrol acetate. Very particularly, only the presence of a smoke-producing agent of cellulose (Aqoat®, G36-262) or acrylic (Eudragit®, G36-267) nature in a smoke-forming gel makes it possible to obtain a good diffusion of the active principle. The film formed, in both cases, is at the same time more resistant, cohesive and seems to allow the release of the active principle. Therefore, the association can be visualized in addition to topical hormonal compositions of systemic effect, under the form of a fumegen gel, 3% of Solketal with the purpose of obtaining an action synergy and also improve the diffusion of nomegestrol acetate. 4 / Conclusion Fuminogenic solutions or filming solutions in general do not produce diffusions of active principle inferior to those produced by the reference gel (G32-104). On the other hand, the smoke gels of Aqoat® (G36-262) and Eudragit® (G36-267) allow obtaining useful active substance diffusions, taking into account that the formulations prepared do not contain any absorption promoter. Solketal is an absorption promoting agent that seems to affect the diffusion of nomegestrol acetate through the skin; in fact, in a hydro-alcoholic system and in association with propylene glycol in a ratio of (3: 8), it allows significantly improving the solubility in the vehicle and the passage through the skin. Thus, a particularly suitable example for a systemic topical hormonal composition according to the invention is a composition in the form of a gel or of a fumegen gel and containing, in a hydro-alcoholic mixture, 8% propylene glycol and 3% isopropylidene glycerol. EXAMPLE IV Preliminary clinical trials In these examples, clinical trials were performed on women using gel containing 0.11% nomegestrol acetate, the formulation of which is presented in Table 1 of Example I. 1 / Clinical Example No. 1 Twenty-four women, Volunteers, in good health, and in a period of ovarian activity, with an average age of 23.5 years, were treated for 15 consecutive days with 4 mg of nomegestrol acetate in a gel applied every day on both breasts. Repeated blood samples were taken during the hours after the first and last administration, as well as 9 samples (6 times before the application of the gel and 3 times 3 hours later), between the 2nd and 14th day of treatment. The nomegestrol acetate was measured in the plasma of these samples by means of liquid chromatography coupled with mass spectrometry. The nomegestrol acetate could be measured from the first day of treatment in all subjects. The maximum concentration was determined at 0.25 ± 0.027 ng / ml and the surface under the curve from 0 to 48 hours, at 6.08 ± 0.775 ng / ml per hour, establishing a constant level between 0.10 and 0. , 17 ng / ml. After the last administration, the maximum concentration was 0.65 ± 0.073 ng / ml and the surface under the curve from 0 to 48 hours, at 18.43 ± 2.091 ng / ml per hour, and acetate was still detected. nomegestrol in the plasma 72 hours after the last application (level of 0.19 ± 0.027 ng / ml). A state of equilibrium was obtained after the 3rd day of treatment. An average value was then observed by leveling and oscillating a little between 0.42 and 0.65 ng / ml. 2 / Clinical example n ° 2 Six menopausal women, aged 56 to 66 years and without hormone replacement therapy for 2 months, were controlled for 2 consecutive cycles of 25 days, separated by a therapeutic window of 6 days. During each day, they received one tablet of oral estradiol per day and, during the 15 days of the second cycle, 4 mg of nomegestrol acetate applied in the form of a gel, on the abdominal skin. At the end of each cycle, nomegestrol acetate was measured in the plasma, the appearance of genital hemorrhages was noted and an endometrial biopsy was performed. In contrast to what was observed during the course of the first cycle (estradiol alone), during the second cycle, it was observed during the administration of nomegestrol acetate gel that progestogen could be detected in the plasma at levels between 0, 39 and 0.76 ng / ml (an average of 0.62 ng / ml) and that the levels were sufficient to cause a secretory change of the endometrium and cause a genital hemorrhage, in an average of 5 days after the second cycle. 3 / Clinical example n "3 One hundred thirty non-menopausal women suffering from breast pain for more than 3 months and for a minimum of 7 S-days per cycle, were treated for an average duration of 130 days with 4 mg of nomegestrol acetate applied every day, during the last 15 days of the menstrual cycle, in the form of a gel, on both breasts, efficacy was judged after 3 months and at the end of the treatment by means of a visual analogical scale that allowed quantifying breast pain. This evaluation made it possible to confirm that nomegestrol acetate gel reduced the intensity and duration of breast pain in a statistically significant manner during the third month after treatment, after 6 cycles of treatment, the intensity had decreased. 48% and duration by 41% During the course of the study, 55 women had benefited from a dosage of nomegestrol acetate in the blood, which has allowed var values of 0.44 ± 0.30 (m ± of) ng / ml.

Claims (17)

1. - Topical hormonal composition of systemic effect for the correction of progesterone deficiencies in non-menopausal women and for hormone replacement in non-menopausal women characterized by containing: as an active ingredient, a progestogen derived from 19-nor progesterone; a vehicle that allows the systemic passage of said active principle, selected from a group composed of a solubilizing agent, an absorption promoting agent, a smoke agent, a gelling agent or mixtures thereof; associated or mixed with suitable excipients for the preparation of a gelled and / or smoke-containing pharmaceutical form.

2. Topical hormonal composition with systemic effect according to claim 1, characterized in that the progestogen derived from 19-nor progesterone is nomegestrol and / or one of its esters or ethers.

3. Topical hormonal composition of systemic effect according to claim 1 or claim 2, characterized in that the progestogen derived from 19-nor progesterone is nomegestrol acetate. 4.- Topical hormonal composition of systemic effect 1 to 3, characterized in that the amount of nomegestrol or one of its esters or ethers varies between 0.05 to 1% by weight of the total composition. 5. Topical hormonal composition of systemic effect according to claim 4, characterized in that the amount of nomegestrol or one of its esters or ethers is 0.4% by weight of the total composition. 6. Topical hormonal composition of systemic effect according to any of claims 1 to 5, characterized in that the solubilizing agent of a group composed of water, alcohols, propylene glycol, a glycoside C8 / C10 of glycosylated polyoxyethylene or mixtures of these is selected. . 7. Topical hormonal composition of systemic effect according to any of claims 1 to 6, characterized in that the solubilizing agent is a ternary mixture of 95% ethanol / water / propylene glycol, in which the percentage of ethanol at 95 ° varies between 30 and 50%, that of water between 30 and 60% and that of propylene glycol between 2 and 20%. 8. Topical hormonal composition of systemic effect according to any of claims 1 to 6, characterized in that the solubilizing agent is a quaternary mixture of 95% ethanol / water / Labrasol® / propylene glycol, in which the percentage of ethanol at 95 ° it varies between 30 and 50%, that of water between 30 and 60%, that of Labrasol® between 3 to 7% and that of propylene glycol between 2 and 20%. 9. Topical hormonal composition of systemic effect according to any of claims 1 to 8, characterized in that the absorption promoting agent is selected from the group consisting of isopropylidene glycerol, α-tocopheryl polyethylene glycol 1000 succinate and diethylene glycol monoethyl ether. 10. Topical hormonal composition with systemic effect according to claim 9, characterized in that the absorption promoting agent is isopropylidene glycerol. 11. Topical hormonal composition of systemic effect according to any of claims 1 to 10, characterized in that the gelling agent is selected from the group consisting of cellulose derivatives and acrylic derivatives. 12. Topical hormonal composition with systemic effect according to claim 11, characterized in that the cellulose derivative is hydroxypropylmethylcellulose. 13. Topical hormonal composition of systemic effect according to claim 11, characterized in that the acrylic derivative is a carbomer. 1

4. Topical hormonal composition of systemic effect according to any of claims 1 to 13, characterized in that the fumaric agent is selected from the group consisting of cellulose derivatives, methacrylic derivatives and derivatives of polyvinylpyrrolidone. 1

5. Topical hormonal composition of systemic effect according to claim 14, characterized in that the cellulose derivative is hydroxypropylmethylcellulose acetate succinate. 1

6. Topical hormonal composition of systemic effect according to claim 14, characterized in that the methacrylic derivative is an aqueous dispersion of an anionic copolymer of methacrylic acid and ethyl acrylate. 1

7. Topical hormonal composition according to any of claims 1 to 16, characterized in that it is in the form of a gel or a smoke-forming gel and that it contains a hydro-alcoholic mixture of 8% propylene glycol and 3% isopropylidene glycerol.