The present invention relates to the field of therapeutic chemistry and more especially to the realization of new galenic forms intended to be applied on the skin. More particularly it relates to a topical hormonal composition with a systemic effect for the hormonal treatment of the perimenopause and of the menopause as well as for the treatment of the ovarian hormonal deficiencies in women with amenorrhea, characterized in that it comprises, as active ingredients, a progestogen derived from 19-nor progesterone and estradiol or one of its derivatives, a vehicle which allows the systemic passage of said active ingredients, chosen from the group constituted by a solubilizing agent, an absorption promoting agent, a film-forming agent, a gelling agent and their mixtures, in combination or in a mixture with suitable excipients for the realization of a gelled and/or film-forming pharmaceutical form.

This application is a 371 of PCT/FR01/02865 filed Sep. 14, 2001.

The present invention relates to the field of therapeutic chemistry and more especially to the realization of new galenic forms intended to be applied on the skin.

A more particular subject of the present invention is cutaneous topical preparations the active ingredients of which are a synthetic progestogen and a natural or synthetic estrogen and the penetrating power of which makes it possible to obtain a systemic hormonal effect.

The invention relates more specifically to a topical estrogen-progestogen composition with a systemic effect for the hormonal treatment of the perimenopause and of the menopause as well as for the treatment of ovarian hormonal deficiencies in women with amenorrhea.

The French patent FR 2 737 411 and the French patent FR 2 754 179 in the name of the Applicant already describes estrogen-progestogen compounds intended for administration by oral route.

However, in the same way for the progestogens as for the oestrogens, the oral route does present some drawbacks. On the one hand, it requires the administration of large doses in order to compensate for the degradation of the active ingredients during passage through the intestines and the liver (so-called <<first pass>> effect). On the other hand, it does not lead to constant plasmatic levels over time as oral administration is followed by a plasmatic peak during the which blood concentrations are transitionally high.

Estradiol and some of its derivatives as well as certain synthetic progestogens are administered by percutaneous route in order to obtain either a substitution within the context of a replacement hormone treatment, or a contraceptive action. However, it requires, particularly for the progestogens, the use of specific galenic forms such as patches combining occlusion, solubilizing agents and powerful passage promoters in order to obtain the plasmatic levels necessary for a systemic effect. These technical solutions are not available for all the progestogens. In addition, the active ingredients interact on the respective percutaneous passage. Because of this, the previously described preparations for the percutaneous passage of a single synthetic progestogen agent, such as described in the French Patent Application published under N° 2 776 191 in the name of the Applicant, are not directly applicable to an estrogen-progestogen combination as each combination of this type requires a specific galenic solution.

The function of the protective barrier of the skin against external aggressions makes it hard to permeate vis-à-vis a number of substances and does not allow medicinal molecules to penetrate except under certain conditions: size and nature of the molecule, solubility, stability, nature of the vehicle containing the molecule; thickness of the skin, state of hydration, pathological condition, location.

Therefore, the release of an active ingredient from a vehicle and its penetration through the skin to the blood or lymphatic circulation depends on a number of physico-chemical and physiological parameters, which are rarely combined or have not yet been defined.

In the present invention, the nature of one of the 2 active ingredients itself, namely synthetic progestogen, represents the main obstacle to percutaneous penetration; thus, the major problem posed for progestogen is its poor diffusion through the epidermis because of its lipophilic nature. A second difficulty lies in the interaction between the two active ingredients vis-à-vis percutaneous passage. The choice of the vehicle used in the compositions according to the invention is therefore of great importance in percutaneous the penetration and the therapeutic activity of the active ingredients.

The topical compositions according to the invention make it possible to obtain a systemic effect by optimization of the percutaneous passage of a synthetic progestogen derived from 19-nor progesterone and a natural or synthetic oestrogen, combined in the same composition.

A more specific subject of the present invention is therefore a topical hormonal composition with a systemic effect for the hormonal treatment of the perimenopause and of the menopause as well as for the treatment of ovarian hormonal deficiency in women with amenorrhea, in the form of a gel or a solution, characterized in that it comprises:

• as active ingredients, a progestogen derived from 19-nor progesterone and an oestrogen, natural or synthetic
• as well as a vehicle allowing the systemic passage of said active ingredients chosen from the group constituted by a solubilizing agent, an absorption promoting agent, a film-forming agent, a gelling agent and their mixtures,
  in combination or in a mixture with suitable excipients for the realization of a gelled and/or film-forming pharmaceutical form.

The compositions according to the invention may be in the form of a gel, a film-forming gel or a film-forming solution.

The progestogen derived from 19-nor progesterone used in the present invention is nomegestrol and/or one of its esters or one of its ethers. An example of nomegestrol ether is nomegestrol tetrahydropyranic ether. An example of nomegestrol ester is nomegestrol acetate.

The oestrogen used in the present invention is 17beta estradiol or one of its esters or ethers. An example of a fatty acid ester of estradiol is estradiol valerate. An example of an estradiol ether is promestriene (17-methyl and 3-propyl ethers of estradiol).

Administered in the compositions according to the invention, nomegestrol acetate and estradiol are capable of going through the skin and passing into the blood circulation in order to produce plasmatic levels which can be detected using methods used to determine it in biological mediums.

The plasmatic levels of estradiol and nomegestrol acetate obtained with the compositions which are the subject of the present invention are able to induce a hormonal effect on the tissues located at a distance from the application site and in particular on the endometrium.

The combination of estradiol and nomegestrol acetate, thus administered in a repeated manner, produces a therapeutic action when it is applied in non-menopausal women suffering from an estrogen-progestogen deficiency or in menopausal women who are candidates for hormone replacement therapy.

According to the present invention, nomegestrol or one of its esters or ethers is present in a quantity varying from 0.05 to 5.0%, and preferably from 0.05 to 1.5% by weight of the total composition. The estradiol or one of its esters or ethers is present in a quantity varying from 0.05 to 1.0% by weight of the total composition, and preferably from 0.05 to 0.5% by weight.

In a more preferred manner, nomegestrol or one of its esters or ethers is present in a quantity varying from 0.1 to 2% by weight of the total composition and estradiol or one of its esters or ethers in a quantity varying from 0.1 to 0.3% by weight of the total composition, with a preference for a concentration of nomegestrol or one of its esters or ethers varying from 0.1 to 1% and estradiol from 0.01 to 0.2%.

Topical compositions with a systemic effect currently preferred according to the invention are those containing a quantity of nomegestrol or of one of its esters or ethers of the order of 1.0% by weight of the total composition, and a quantity of estradiol or of one of its esters or ethers of the order of 0.15% by weight of the total composition.

The solubilizing agents and the absorption promoting agents have different modes of action but both make it possible to encourage the penetration of active ingredients through the skin The solubilizing agents, by acting on the thermodynamic activity of the active molecule, improve the solubility of the active ingredient and modify its affinity for the cutaneous structures, in particular the stratum corneum. The absorption promoting agents reduce the resistance to diffusion of the cutaneous barrier by modifying its structure.

The Solubilizing Agents

The solubilizing agents increase the solubility of the active ingredients but there is however no direct relationship between improvement in the solubility of the active ingredient in the vehicle and its increased percutaneous passage. In fact, the agents which improve the solubility of an active ingredient also increase its affinity for the vehicle and can therefore definitively reduce its diffusion through the skin.

For an active ingredient to be completely solubilized in a vehicle, it must have a defined affinity for it; nevertheless, this affinity must not be so great that the partition coefficient of the active ingredient encourages its diffusion through the skin. According to the present invention, the choice of solvents and their concentrations ensures adequate dissolving and percutaneous passage of each of the two active ingredients.

According to the present invention, appropriate examples of solubilizing agents are alcohols, wateralcohol mixtures, propyleneglycol, polyethyleneglycol, polyethylene 20 sorbitan mono-oleate [marketed for example under the name Polysorbate 80 DF], a glycosylated polyoxyethylenated C₈/C₁₀ glyceride (marketed for example under the name Labrasol®). As a solubilizing agent, a mixture of the aforementioned solvents and/or solubilizing agents is generally used, which, thanks to a synergy of action, is more effective that each of them used alone.

Preferably, the solubilizing agent is chosen from the group consisting of water, alcohols, propyleneglycol or their mixtures.

An example of a suitable solubilizing agent for the topical composition with a systemic effect according to the invention is the ethanol/water/propyleneglycol ternary mixture, in which the quantity of ethanol varies from 30 to 60% by weight of the total composition, the quantity of water varies from 20 to 60% by weight of the total composition, and more particularly from 30 to 60% by weight, and that of propyleneglycol from 2 to 20% by weight of the total composition.

More particularly, a suitable solubilizing agent for the composition according to the invention is the mixture comprising 40 to 60% ethanol, 25 to 45% water and 6 to 12% propyleneglycol, and in particular from 40 to 50% ethanol, from 40 to 45% water and from 6 to 12% by weight propyleneglycol.

The Absorption Promoting Agents

The absorption promoting agents are substances capable of improving the diffusion of active ingredients in the epidermis, in particular the stratum corneum. These adjuvants can be classified in different families according to their chemical structure. As an example of absorption promoting agents, dioxolane derivatives such as isopropylidene glycerol, marketed under the name Solketal (which is also an excellent solubilizing agent for the hormones of this invention) or 2n-nonyl 1-3 dioxolane; or diethylene glycol monoethyl ether (for example that marketed under the Tradename Transcutol®) can in particular be mentioned. Absorption promoting agents are also described in the following chemical families: polyols, fatty acids, esters of fatty acids alcohols and amides. As an example of substances representative of these families, propylene glycol monocaprylate or Capryol 90, caprylic acid, diisopropyl adipate, polysorbate 80, 2-octyl dodecanol and 1-dodecylazacyclohepta-2-one or Azone, can in particular be mentioned. Substances presenting properties of absorption promoting agents can also be found in the family of sulphoxides (such as for example dimethylsulphoxide), terpenes (for example d-limonene), alkanes (for example N-heptane) or organic acids (salicylic acid and salicylates in particular).

The absorption promoting agent, more particularly suitable in the present invention, is selected from the dioxolane group, such as for example isopropylideneglycerol (Solketal) or from the group of long chain C₆ to C₁₈ fatty acids such as lauric acid, caprylic acid or oleic acid.

The quantity of absorption promoting agent in the compositions according to the invention, varies from 2 to 12% by weight of the total composition.

An absorption promoting agent particularly suitable in the compositions according to the invention is isopropylideneglycerol; the quantity of isopropylideneglycerol is preferably from 3 to 8% by weight of the total composition, and in a more preferred manner from 3 to 6% by weight.

Gelling Agents

The choice of gelling agents and film-forming agents is also important in the compositions according to the invention.

Gelling agents are substances which thicken and modify the viscosity of a liquid vehicle, thus constituting a gel in the form of a three-dimensional colloidal network. There are several types of gelling agent: natural gelling agents (mineral, vegetable, animal), synthetic agents and semi-synthetic agents.

Examples of natural gelling agents are guar gum, algae extract (alginates, carrageenates, gelose), polysaccharides (xanthan gum, arabic gum, tragacanth gum), starches, pectins, etc.

Examples of synthetic or semi-synthetic gelling agents are cellulose derivatives, in particular those obtained by esterification or by etherification of cellulose, and acrylic derivatives. In the category of acrylic derivatives, are carbomers, polycarbophiles and acrylates.

According to the present invention, the gelling agent is preferably chosen from the group consisting of cellulose derivatives and acrylic derivatives.

Among the cellulose derivatives, they are the methylcelluloses (Methocel, Metolose), ethylcelluloses (Ethocel, Aquacoat®), hydroxypropylmethylcelluloses (Kenal, Methocel, Hypromelose), hydroxyethylcelluloses (Cellosize, Natrosol), hydroxypropylcelluloses (Klucel), carboxymethylcelluloses, cross-linked or not, in sodium or calcium form (Akucell, Nymcel, Tylose CB, Croscarmellose, Acdisol).

Among the acrylic derivatives, carbomers can notably be mentioned, in particular those marketed under the names Carbopol® or Synthalen®. According to the invention the preferred carbomers are those that form gels which <<break down>> most easily on contact with electrolytes and the skin.

The carbomers produce formulations which are stable over time and give the formulation rheological properties which can be reproduced because of their synthetic nature.

The existence of different degrees or grades for the products depends on differences in molecular weight, the degree of cross-linking, the nature of the molecular arrangements and the polymerization solvent.

Therefore, from the different grades of carbomer, those marketed by the Goodrich Company under the names Carbopol 974 P®, Carbopol 980®, Carbopol 1382® and Carbopol 2020®, or similar products such as the Synthalens from 3 V France, such as Synthalen K, L, M or preneutralised, such as for example Synthalen PNC®, can be mentioned.

According to the present invention, the carbomer marketed under the name Carbopol 1382® is particularly suitable as it liquefies on contact with the electrolytes of the skin and thus avoids a polymer deposit which risks being an obstacle to the passage of the active ingredients. The quantity of Carbopol 1382 is preferably from 0.3 to 1% by weight of the total composition.

The Film-Forming Agents

The film-forming agents used are those which are used to realize coating or filming wrapping solutions as each of them are mainly the product of the food or biomedical industry. They make it possible to envisage a cutaneous application with a view to realizing an occlusive film at skin level, preserving a cutaneous hydration known to encourage percutaneous passage. In addition, the film-forming agents make it possible to give the formulation a more pleasant feel.

The film-forming agents can be classed in different groups according to their solubility. According to the present invention, the film-forming agent is selected from the group consisting of silicones, cellulose derivatives, methacrylic derivatives and polyvinylpyrrolidone derivatives.

The silicones used according to the invention can be soluble or insoluble in water. According to the present invention, silicone is chosen from the group constituted by dimethicone, dimethiconol, simethicone, their mixtures, and more particularly:

• the mixture of stearoxytrimethylsilane and stearic alcohol marketed under the name of Silky Wax 10 (Dow Corning) in the presence or not of an emulsifier such as laurylmethicone,
• the dimethiconol (hydroxy(n-blocked)polydimethylsiloxane) mixture in dimethicone (polydimethyl-siloxane) marketed under the name DC Blend 20.

The quantity of silicone varies from 1 to 3% by weight of the total composition.

In the present invention, the silicone which is particularly suitable is that marketed under the name DC Blend 20; the quantity of DC Blend 20 which is particularly suitable is of the order of 2% by weight of the total composition.

Among the cellulose derivatives, the following can be mentioned:

• hydroxypropylmethylcellulose acetate succinate, and in particular that marketed by the Seppic Company under the name Aqoat AS-LF®,
• an aqueous dispersion of cellulose acetophthalate containing 70% water, 23% cellulose acetophthalate and 7% poloxamer, and in particular that marketed by the Seppic Company under the name Aquacoat CPD®,
• an aqueous dispersion of ethylcellulose, cetyl alcohol and sodium lauryl sulphate, in particular that marketed by the Seppic Company under the name Aquacoat ECD 30®,
• ethylcellulose.

Among the methacrylic derivatives, the following can be mentioned:

• an aqueous dispersion of an anionic copolymer of methacrylic acid and ethyl acrylate (type C), in particular that containing 30% dry copolymer, 0.7% of sodium lauryl sulphate and 2.3% Polysorbate 80 NF, marketed under the name Eudragit L30 D55® (Rohm and Haas),
• an acrylic acid and methacrylic ester (type A) copolymer, in particular that marketed under the name Eudragit RL 100® (Rohm and Haas).

Among the polyvinylpyrrolidone derivatives, the following can be mentioned:

• a povidone, the molecular weight of which is of the order of 360 000, marketed under the name Kollidon 90®
• the polyvinylpyrrolidone/vinyl acetate 64 copolymer, of formula (C₆H₉NO)_n×(C₄H₆O₂)_m the molecular weight of which is: (111.1)_n×(86.1)_m.
• the homopolymers of polyvinyl alcohol.
  The other Excipients of the Composition

The topical hormonal compositions with a systemic effect according to the invention can moreover contain other excipients which are complexing agents, neutralizing agents such as disodium edetate (EDTA), neutralising agents such as triethanolamine (TEA) and/or plasticizers such as diethyl phthalate and triacetin.

A particularly suitable topical hormonal composition according to the invention is a composition which is in the form of a gel and which contains in particular, in a hydroalcoholic mixture, 0.4% nomegestrol acetate, 0.15% estradiol, 8% propyleneglycol, 3% isopropylideneglycerol and 2% silicone DC Blend 20.

Preferably, the compositions according to the invention have a pH of between 6 and 7 and a viscosity ranging between 1000 and 2000 mPas.

The invention also relates to processes for the preparation of topical estrogen-progestogen compounds with a systemic effect.

A process for the preparation of the compositions in the form of a gel is given below as an example.

The important stages in the preparation of a gel are the dispersion of the gelling agent in the solubilizing agent (the dispersion of which will considerably influences the quality of the obtained preparation), agitation, hydration, swelling and finally gelation.

Dispersion and Agitation: Wetting

The gelling agent (acrylic derivative) is placed in suspension under agitation in the solvent (solubilizing agent). The agitation must be moderate as the acrylic polymer loses its gelling power if the shear is too great.

Hydration and Swelling of the Polymers

In order to avoid the formation of partially hydrated clusters, the incorporation of the polymers by sieving them is recommended, to facilitate the wettability and the hydration of the powder and allows them to arrange themselves in a network. This stage is encouraged by wetting the powder beforehand in the solvent or in the most polar solvent if a solvent system is used.

Gelation: Neutralisation of the Dispersion Obtained

The pH of the suspension obtained during the previous stage is close to 3 (this pH is a function of the polymer concentration, and therefore of the carboxylic groups). The medium is neutralised by using mineral bases such as sodium, potassium or ammonium hydroxides when the formulation solvents are aqueous and organic bases such as the amines (triethanolamine, tromethamine or TRIS etc.) when they are slightly polar or non-polar. The addition of these agents causes a spontaneous thickening by formation of the polymer salts, soluble in the water.

A more particular example of preparing a gel according to the invention the gelling agent of which is an acrylic derivative, is characterized in that:

• the active ingredients and the EDTA are solubilized in a water/95° ethanol/propyleneglycol solvent system whilst agitating at 300 rpm (approximately 30 min);
• the acrylic polymer is dispersed in small fractions in the solution of active ingredients by agitating at 100 rpm;
• the acrylic polymer is let to swell for 2 hours under agitation at 200 rpm;
• the dispersion is neutralised by triethanolamine (TEA) dissolved in a fraction of water taken from the quantity to be incorporated in the formulation; the agitation is reduced to 100 rpm during neutralisation to avoid the incorporation of air bubbles;
• agitation is carried out for 30 minutes at 50 rpm to homogenise the gel obtained.

The preparation of the compositions according to the invention in the form of film-forming gels (or filming gels) and film-forming solutions (or filming solutions) can also be envisaged.

Such forms are envisaged, as, during their application on the skin, they form, after drying, an occlusive film sufficient to increase the hydration of the skin and improve the diffusion of the active ingredients that they contain. The form obtained must nevertheless penetrate or dry rapidly whilst having a pleasant and non-sticky feel.

Therefore, an example of preparing a <<film-forming solution>> the film-forming agent of which is solid, is characterized in that:

• the quantities of ethanol, water and propyleneglycol necessary for the formulation are agitated at 250 rpm for 10 min;
• the EDTA and the active ingredients are solubilized in the mixture obtained;
• the plasticizing agent is added and agitation is carried out at 250 rpm for 30 min;
• the film-forming agent is dispersed in small fractions whilst maintaining the same agitation, until it is completely solubilized; agitation is continued for 1 hour;
• the pH is adjusted using a solution of triethanolamine (TEA) dissolved in a small quantity of water, taken from the quantity of water to be incorporated into the formulation, whilst reducing the agitation to 100 rpm; the solution obtained is homogenized for 30 min.

Another example of preparing a <<film-forming solution>> the film-forming agent of which is in an aqueous dispersion, is characterized in that:

• the water and a plasticizing agent are mixed at 250 rpm and agitated for 30 minutes;
• the dispersion of the film-forming agent is added in small fractions whilst agitating at 250 rpm, until a homogenous solution is obtained; agitation is continued for 1 hour;
• the EDTA and the active ingredients are solubilized independently in the ethanol and propyleneglycol mixture; agitation is carried out until total dissolution;
• the alcoholic solution of active ingredients in the aqueous solution is added in small fractions under agitation at 250 rpm; the solution obtained is agitated for 1 hour to homogenise it;
• the solution is neutralised with triethanolamine (TEA) dissolved in water, whilst reducing the agitation; the solution obtained is homogenized for 30 min.

The film-forming gels are obtained by gelation of the film-forming solutions. Two solutions are therefore prepared separately:

• an aqueous solution containing a solubilized plasticizer, in which the film-forming agent is totally solubilized under vigorous agitation;
• an alcoholic solution containing the other excipients of the formulation and in which the active ingredients are solubilized; and the gelling agent is dispersed and left to swell;
• the alcoholic solution is mixed in the aqueous solution and the solution is gelled with triethanolamine.

Claim 1 of 25 Claims

1. A topical composition with a systemic effect, for the hormonal treatment of the perimenopause and of the menopause as well as for the treatment of ovarian hormonal deficiencies in women with amenorrhea, based on a progestogen and an oestrogen agent, comprising

as active ingredientss, nomegestrol and/or one of its esters or its ethers and estradiol and/or one of its esters or its ethers,

and a vehicle allowing the systemic passage of said active ingredients, selected from the group consisting of a solubilizing agent, an absorption agent, a film-forming agent, a gelling agent and their mixture,

in combination or in admixture with suitable excipients for the realization of a pharmaceutical, gelled and/or film-forming agent.
 

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