HK1038184B - Topical hormonal composition with systemic effect - Google Patents
Topical hormonal composition with systemic effect Download PDFInfo
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- HK1038184B HK1038184B HK01108759.3A HK01108759A HK1038184B HK 1038184 B HK1038184 B HK 1038184B HK 01108759 A HK01108759 A HK 01108759A HK 1038184 B HK1038184 B HK 1038184B
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Description
The present invention relates to the field of therapeutic chemistry and in particular to the development of new galenic forms (galenic forms) for application to the skin.
The invention relates more particularly to galenic formulations, the active principle (active principal) of which is a synthetic progestogen, which is applied to the skin in order to produce a systemic hormonal effect on the perimenopausal or postmenopausal woman.
The present invention therefore relates to topical hormone compositions having systemic action.
In particular, french patent 2.271.833 describes an oral hormonal composition for correcting progestogen deficiencies in pre-or menopausal women.
However, the oral route of natural progesterone and synthetic progestins has certain drawbacks. On the one hand, it requires the administration of very large doses to complement the degradation of the active ingredient both through the intestinal tract and in the liver (known as the "first-pass" effect). On the other hand, it cannot achieve a constant plasma level over a certain period of time because of a plasma peak after oral administration, during which the blood concentration temporarily rises.
Natural progesterone is sometimes administered transdermally. This route produces only a local effect and does not allow remote infiltration of the target tissue, especially the uterine mucosa. This is because the hormone is rapidly degraded by enzymes in the subcutaneous tissue, making it impossible to achieve high enough plasma levels to produce systemic hormonal effects.
Many synthetic progestagens have the same drawbacks and cannot be administered transdermally to achieve a systemic effect. The only exception is norgestimate administered in transdermal patches (patches).
The skin function as a protective barrier against external invading substances makes many substances almost impermeable and allows only certain conditions (size and nature of the molecule, solubility, stability, nature of the carrier containing the molecule, etc.) to permeate the drug molecule.
Thus, the release of the active principle from the carrier and its penetration through the skin to the blood or lymphatic circulation depends on various physicochemical and/or physiological parameters.
The characteristics of the active principle (synthetic progestogen) of the present invention become a major obstacle to penetration through the skin: the main problem is that it is difficult to diffuse through the epidermis due to its lipophilicity. The choice of the carrier used in the composition therefore has a great influence on the transdermal penetration and on the therapeutic activity of the molecule.
Thus, the topical compositions of the present invention achieve systemic effects by optimizing the transdermal channels for the synthesis of progestins (derived from 19-norprogesterone).
The topical compositions of the present invention comprise a synthetic progestin (active ingredient) derived from 19-norprogesterone and excipients (to ensure optimal passage of the active ingredient through the skin).
The invention more particularly relates to a topical hormone composition having a systemic effect, which is capable of correcting progesterone deficiency in pre-menopausal women and is useful as a replacement hormone for menopausal women, characterized in that it comprises:
-as active principle a progestogen derived from 19-norprogesterone,
a carrier capable of allowing the active principle system to pass through, selected from solubilisers, absorption promoters, film formers, gelling agents or mixtures thereof,
in combination or admixture with suitable excipients to produce a gel and/or film pharmaceutical form.
The compositions of the present invention may thus be present in the form of a gel, a film-forming gel or a film-forming solution.
The progestogen derived from 19-norprogesterone for use in the present invention is nomegestrol and/or one of its esters or ethers.
An example of a nomegestrol ether is the tetrahydropyranyl ether of nomegestrol (tetrahydropyranic ether). An example of nomegestrol ester is nomegestrol acetate, a synthetic progestin with oral administration activity whose role includes correcting gynecological disorders caused by a deficiency in hormones that become part of the corpus luteum.
By administration of the compositions of the present invention, nomegestrol acetate may pass through the skin and into the blood circulation to achieve plasma levels (which may be detected by methods for measuring biological mediators). Following transdermal administration, the observed plasma concentrations remained on a plateau (plateau) due to the reservoir effect of the skin.
The plasma levels of nomegestrol acetate obtained with the compositions of the present invention may produce a hormonal effect on tissues remote from the site of administration, particularly the endometrium.
When nomegestrol acetate is administered to a premenopausal woman suffering from a disorder associated with progesterone deficiency or to a menopausal woman receiving estrogen replacement therapy, repeated administration produces a therapeutic effect.
In accordance with the present invention, nomegestrol, or one of its esters or ethers, is present in an amount of 0.05 to 1% by weight of the total composition. Preferably, nomegestrol, or one of its esters or ethers, is present in an amount of 0.1 to 0.8% by weight of the total composition. A preferred systemic topical composition of the invention contains nomegestrol, or one of its esters or ethers, in an amount of 0.4% by weight of the total composition.
Solubilizers and absorption enhancers have different modes of action but they both help the active ingredient to penetrate through the skin.
The solubilizing agent increases the solubility of the active ingredient and modulates its affinity for the skin by acting on the thermodynamic activity of the active molecule.
Absorption enhancers reduce diffusion resistance by altering the structure of the skin barrier.
However, there is no direct link between increasing the solubility of the active ingredient in the carrier and increasing the amount that passes through the skin. Indeed, the use of agents that increase the solubility of the active principle also increases the affinity of the active principle for the carrier and therefore generally reduces its diffusion through the skin.
Thus, the solubility of the active principle in the carrier is the sum, to which a certain affinity is necessary; however, it cannot be too large, so that the partitioning of the active ingredient results from its diffusion through the skin.
Suitable solubilizers according to the invention are water, alcohols, propylene glycol, polyethylene 20 sorbitan monooleate (e.g.commercially available under the name polysorbate DF), C8/C10Polyoxyethylene glycosyl glyceride (such as the product sold under the trade mark Labrasol ) or a mixture thereof.
Increase in useThe solvent is typically a solvent or a mixture of the foregoing solubilizers, which by synergistic effect is more effective than either alone. The solubilizer is preferably selected from water, alcohol, propylene glycol, C8/C10Polyoxyethylene glycosyl glyceride or a mixture thereof. Thus, the solubilizing agent may use a binary mixture of 95 ° ethanol and water, wherein the percentage of 95 ° ethanol is 30-50%, and particularly a binary mixture of 95 ° ethanol and water wherein the percentage of 95 ° ethanol is 45%.
However, according to the present invention, particularly preferred examples of suitable solubilizers for topical compositions having a systemic effect are:
-a ternary mixture of 95 ° ethanol/water/propylene glycol, wherein the percentage of 95 ° ethanol is 30-50%, water 30-60%, propylene glycol 2-20%; preferably 45% ethanol at 95 °, 45% water, 8% propylene glycol,
-a quaternary mixture of 95 ° ethanol/water/Labrasol /propylene glycol, wherein the percentage of 95 ° ethanol is 30-50%, water is 30-60%, Labrasol is 3-7%, propylene glycol is 2-20%;
preferably, the percent of 95 ° ethanol is 45%, water is 33.5%, Labrasol is 5%, and propylene glycol is 15%;
among the substances that are absorption enhancers or "boosters", the most used are derivatives of glycols, sulfoxides, surfactants, fatty acids and terpene derivatives.
Examples of absorption enhancers may be mentioned triglycerides of oleic acid, oleyl alcohol, capric acid and caprylic acid (e.g. marketed under the trade name Miglyol 812 ), isopropyl myristate, propylene glycol dinonanoate, 2 n-nonyl-1, 3-dioxolane, octyldodecyl myristate, isopropylidene glycerol (e.g. marketed under the trade name Solketal), alpha-tocopheryl polyethylene glycol 1000 succinate (e.g. marketed under the trade name vitamin E TPGS), diethylene glycol monoethyl ether (e.g. marketed under the trade name Transcutol ).
The absorption enhancers more suitable for use in the present invention are selected from isopropylidene glycerol, alpha-tocopherol propylene glycol 1000 succinate, diethylene glycol monoethyl ether.
However, the preferred absorption enhancer is isopropylidene glycerol.
The form designed to ensure penetration of the active ingredient through the skin is a gel or an encapsulated gel formulation.
It is also important according to the present invention to select the gelling agent and the film-forming agent in the composition.
A gelling agent is a substance that is capable of thickening and changing the viscosity of a liquid carrier to form a three-dimensional colloidal network (gel).
There are many types of gelling agents: natural gelling agents (minerals, plants, animals), synthetic and semi-synthetic.
Examples of natural gelling agents are guar gum, seaweed extracts (alginates, carrageenans, agar), polysaccharides (xanthan gum, gum arabic, tragacanth), starch, pectin, and the like.
Examples of synthetic or semi-synthetic gelling agents are cellulose derivatives, in particular those obtained by esterification or etherification of cellulose, and also acrylic acid derivatives. Classes of acrylic acid derivatives include carbopol preparations (carbomers), polycarbophils, and acrylates.
The gelling agent of the present invention is selected from cellulose derivatives and acrylic acid derivatives.
The cellulose derivatives include:
-methylcellulose (Methocel, Metholose),
-ethyl cellulose (Ethocel, Aquacoat ),
hydroxypropyl methylcellulose (Kenal Methocel, Hypromelose),
-hydroxyethyl cellulose (Cellosize, Natrosol),
-hydroxypropylcellulose (Klucel),
sodium or calcium form of carboxymethylcellulose (Akucell, Nymcel Tylose CB).
The polymers selected were the Metolose series manufactured by Shin Etsu corporation. For each of these classes, there are different grades (depending on the substituents and substitution rates) that give the polymer solution different viscosities. The celluloses are classified according to their adhesive force. The grade selection is important because the cellulose derivative adhesion varies according to the latter. Particularly suitable cellulose derivatives according to the invention are hydroxypropyl methylcellulose and especially hydroxypropyl methylcellulose of grade 60SH 4000. In fact, class 60SH has the most suitable performance: good solubility in organic solvents and good resistance to electrolytes. It also gives a transparent gel. Among the acrylic acid derivatives, particularly suitable according to the invention are Carbopol preparations, particularly suitable are those sold under the trade names Carbopol or Synthalen .
The resulting formulations of the carbopol formulations remain stable over time and, due to their synthetic nature, give reproducible rheological properties to the formulations.
Different grades or grades result from different molecular weights, degrees of crosslinking, nature of molecular arrangement, and solvents of polymerization. Thus, among the different grades of Carbopol preparations, the products on the market are sold by the company Goodrich under the trade names Carbopol 974P , Carbopol 980 , Carbopol 1382 and Carbopol 2020 , or similar products such as Synthalens of 3V (france), which are (Synthalens K, L, M) or pre-neutralized such as Synthalens PNC .
However, according to the invention, the commercially available Carbomer products under the trade names Carbopol 980 , Carbopol 1382 and Synthalen K are particularly suitable and have the outstanding advantage that they hinder the passage of the active principle, since they are fluidized on contact with the electrolyte on the skin and thus prevent the sedimentation of the polymer.
The film formers used are used to generate solutions for coatings (enrobing) and coatings, since they are mostly obtained by the biomedical or food industry and are suitable for use in humans.
These film formers may be classified into different groups according to their solubility.
Regardless of the film former, the properties of the resulting film-forming gel or film-forming solution depend on the percentage of film former, the type of solvent, the presence and properties of the plasticizer.
According to the invention, the film-forming agent is selected from cellulose derivatives, methacrylic acid derivatives and polyvinylpyrrolidone derivatives.
Cellulose derivatives that we may mention are:
● hydroxypropyl methylcellulose acetate succinate, especially sold under the trade name Aqoat AS-LF by Seppic,
● aqueous dispersion of cellulose acetylphthalate, containing 70% of water, 23% of cellulose acetylphthalate and 7% of Poloxamer, in particular the product sold under the trade name Aqoacoat CPD by the company Seppic,
● aqueous dispersion of ethyl cellulose, cetyl alcohol and sodium lauryl sulphate, in particular the product sold under the trade name Aquacoat ECD30 by the company Seppic,
● Ethyl cellulose.
As methacrylic acid derivatives we may mention:
● aqueous dispersion of an anionic copolymer of methacrylic acid and ethyl acrylate (type C), in particular a product containing 30% of dry copolymer, 0.7% of sodium lauryl sulphate and 2.3% of polyoxyethylene ether NF, under the trade name Eudragit L30D55 (Rohm & Haas),
● copolymer of acrylic acid and methacrylic acid esters (type A), in particular the product with the trade name EudragitRL100 (Rohm & Haas).
Among the polyvinylpyrrolidone derivatives we may mention:
● formula (C)6H9NO)nOf the order of 360000, commercially available under the trade name Kollidon 90
● formula (C)6H9NO)nx(C4H6O2)mOf polyvinylpyrrolidone/vinyl acetate 64 having a molecular weight of (111.1)nx(86.1)m
● homopolymer of polyvinyl alcohol
The cellulose derivative suitable for use in the present invention is hydroxypropyl methylcellulose acetate succinate, the methacrylic acid derivative particularly suitable is an aqueous dispersion of an anionic copolymer of methacrylic acid and ethyl acrylate, and the derivative particularly suitable for polyvinylpyrrolidone is povidone.
The systemic effect topical hormone compositions of the present invention may also contain other excipients which are complexing agents, neutralizing agents such as disodium Ethylenediaminetetraacetate (EDTA), Triethanolamine (TEA) and/or plasticizers such as diethyl phthalate and triacetin.
A particularly suitable topical hormone composition for use in the present invention is in the form of a gel or film-forming gel, wherein nomegestrol or nomegestrol acetate is present in an amount of 0.4% by weight of the total composition, a pH of 6 to 7 and a viscosity of 1000-.
The method of preparation of the compositions with systemic effect of the invention varies according to the specific characteristics of the composition to be prepared, i.e. the gel, the film-forming gel or the film-forming solution.
Drawings
Figure 1 illustrates the main active ingredient nomegestrol acetate (NAc) that passes through the skin as a function of varying amounts of nomegestrol acetate in the compositions of the present invention.
Symbols ■,. diamond-solid, and □ in FIG. 1 represent:
| ■ 0.11.11% NAc gel 0.4% NAc gel □ 0.8.8% NAc gel |
Figure 2 illustrates table 3, the solubility of nomegestrol acetate in different systems containing Propylene Glycol (PG).
Symbols ■,. diamond-solid and a-solidup in FIG. 2 represent:
| ■ solubility in System I solubility in System III solubility in System II |
Figure 3 illustrates the effect of the enhancer (enhancer) and Carbopol on the passage of systemic gels of nomegestrol acetate through the skin.
Symbols ●,. tangle-solidup,. diamond-solid and □ in FIG. 3 represent:
| ● G37-113 (3% Tr). diamond-solid G32-104 (3% Tr) -reference G36-276 (3% Vit E) □ G36-264 (3% Sol) |
Figure 4 shows the distribution of nomegestrol acetate in the skin structure.
Symbol in fig. 4
Andrepresents:
figure 5 shows the diffusion rate of nomegestrol acetate as a function of time.
The symbols ●, a-solidup, and □ in FIG. 5 are as in FIG. 3 and represent:
| ● G37-113 (3% Tr). diamond-solid G32-104 (3% Tr) -reference G36-276 (3% Vit E) □ G36-264 (3% Sol) |
Fig. 6 illustrates the effect of absorption enhancers and film-forming agents on the passage of nomegestrol acetate system membrane through the skin.
Symbol ●,. diamond-o, ●,. tangle-solidup and ≧ y in FIG. 6:
| ● G32-104 (3% Tr) -reference G36-261 (10% Aqoat.) G36-259 (5% Kol) ● G36-266 (3% Solk/5% Kol) G36-263 (10% Eudrag) G36-277 (3% TPGS/5% Kol) |
Figure 7 shows the distribution of nomegestrol acetate in the skin structure.
Symbol in FIG. 7
And
represents:
figure 8 shows the effect of film forming agents on the passage of a systemic film forming gel of nomegestrol acetate through the skin.
Symbols ∑ □,. diamond-solid,. and a in fig. 8 represent:
| ★G32-104(C1382) ◆G36-260(Kol/C980) ▲G36-262(aq/C980)□G36-267(Eud/HPMC) ◇G37-113(C980) |
figure 9 shows the distribution of the main active ingredient in the skin structure.
Symbol in fig. 9
Represents:
fig. 10 can compare film forming solutions and films forming gels of nomegestrol acetate with systemic effect.
Symbols ■, □,. diamond-solid,. a-up and Δ in FIG. 10 represent:
| film-forming solution■G36-259(5％Kollidon) ◆G36-261(10％Aqoat) ▲G36-263(10％Eudrag)Film-forming gel□G36-260(5％Kol/C980) ◇G36-262(10％Aqoat/C980) △G36-267(10％Eudr/HPMC) |
Figure 11 shows the distribution of the main active ingredient in the skin structure.
Symbol of FIG. 11
(symbols in column 2 of figure 11),
(symbols in column 3 of FIG. 11) and
(last column)
Represents:
figure 12 compares the diffusion of nomegestrol acetate in compositions in the form of film-forming gels with compositions in the form of film-forming solutions.
The symbols used in fig. 12 are the same as those used in fig. 10, i.e.:
symbols ■, □,. diamond-solid,. a-up and Δ in FIG. 12 represent:
| film-forming solution■G36-259(5％Kollidon) ◆G36-261(10％Aqoat) ▲G36-263(10％Eudrag)Film-forming gel□G36-260(5％Kol/C980) ◇G36-262(10％Aqoat/C980) △G36-267(10％Eudr/HPMC) |
● method for preparing gel
Similarly, in the preparation of a composition in the form of a gel, the preparation process will not be exactly the same, depending on the type of gelling agent used. Therefore, in the preparation of the gel, synthetic acrylic acid derivatives and cellulose derivatives are classified according to the gelling agent.
Formulations derived from acrylic acid derivatives
The important steps in the preparation of the gel are the dispersion of the gelling agent into the solubilising agent (which dispersion will largely determine the properties of the obtained formulation), stirring, hydration, swelling and finally gelling.
Dispersing and stirring: moistening
The acrylic acid derivative is suspended in the solvent (solubilizer) under stirring. Moderate agitation is necessary or the acrylic polymer will lose its effectiveness due to shear degradation.
Hydration and swelling of polymers
To prevent the formation of partially hydrated lumps, it is proposed to add the polymer by sieving, thereby promoting wetting and hydration of the powders and forming them into a network. This step can be improved by prior wetting of the powder in the case of solvent systems which are strongly polar solvents.
And (3) gelling: neutralization of the resulting dispersion
The pH of this suspension is close to 3(pH is a function of polymer concentration and thus of carboxyl groups). When the solvent in the formulation is aqueous, inorganic bases such as sodium hydroxide, potassium hydroxide or ammonium hydroxide are used, and when the solvent is non-polar or only slightly polar, organic bases such as amines (triethanolamine, tromethamine or TRIS, etc.) are used. The addition of these agents spontaneously thickens by forming a water-soluble salt of the polymer resin.
In one example of preparing a gel, the gelling agent is an acrylic acid derivative characterized by:
-dissolving nomegestrol acetate and EDTA in a solvent system of water/95 ° ethanol/propylene glycol with stirring at 300rev/min (#30 min);
-dispersing the acrylic polymer in the solution of the active principle in small portions and several times with stirring at 100 rev/min;
swelling the acrylic polymer for 2 hours with stirring at 200 rev/min;
-neutralizing the dispersion with triethanolamine dissolved in a portion of the water (taken in the amount added to the formulation); during neutralization, the stirring speed is reduced to 100rev/min so as to avoid bringing air bubbles;
-stirring for 30 minutes at a rotational speed of 150rev/min to homogenize the resulting gel.
Formulations derived from cellulose derivatives
Gel formulations based on cellulose derivatives do not require neutralization, but sometimes their pH is adjusted by organic amines or inorganic hydroxides depending on the type of solvent in the formulation.
The resulting viscosity depends on the type and amount of cellulose derivative used.
An example of the preparation of a gel (the gelling agent of which is a cellulose derivative) is characterized in that:
-dissolving nomegestrol acetate and EDTA in a solvent system of water/95 ° ethanol/propylene glycol with stirring at 300rev/min (#30 min);
-dispersing the cellulose polymer in small portions into a solution of the active principle with stirring at 100 rev/min;
-swelling the cellulosic polymer for 1 hour with stirring at 250 rev/min;
-if necessary, adjusting the pH with triethanolamine dissolved in water, with stirring at 100 rev/min;
-stirring for 30 minutes at a rotational speed of 150rev/min to homogenize the resulting gel.
● film-forming gel (or "film gel") and film-forming solution (or "film solution")
These forms must be taken into account because, when they are applied to the skin, they form a closed film once dry, which substantially increases the hydration of the skin and creates new channels, thus promoting the diffusion of the active principles they contain. However, the resulting form must either quickly penetrate or dry, producing a pleasant, non-adherent feel.
Film formers useful in the present invention are typically the materials used to form the enrobing solutions of the tablets.
● method for preparing film-forming solution
As with gels, in the preparation of compositions in the form of film forming solutions, the method of preparation varies depending on the nature of the film forming agent employed.
-formulations derived from solid film-forming agents:
the preparation steps are as follows:
-dissolving the plasticizer and the active principle in a solvent mixture: the mixture containing the plasticizer and the active ingredient must be stirred for a sufficient time to obtain a solution.
Dispersions and solutions of film-forming agents:
the dispersion must be carried out in small portions with vigorous stirring. Stirring is continued until the film forming agent is completely dissolved. If desired, at the end of the production, the film-forming solution is neutralized under slow stirring.
An example of a film forming solution (whose film former is a solid) is prepared by:
-stirring the required amount of ethanol, water and propylene glycol of the formulation at a rotational speed of 250rev/min for 10 minutes;
-dissolving EDTA and nomegestrol acetate in the resulting mixture;
adding the plasticizer and continuously stirring for 30 minutes at the rotating speed of 250 rev/min;
-dispersing the film-forming agent in small portions, stirring at the same speed until it is completely dissolved; then stirring is continued for 1 hour;
-adjusting the pH by means of a triethanolamine solution dissolved in a small amount of water (taken from the amount of water added to the formulation) and reducing the stirring rate to 100 rev/min; the resulting solution was homogenized for 30 minutes.
Formulations derived from film formers in aqueous dispersions
The preparation steps are as follows:
-dissolving the film-forming agent in solution and plasticizing
Adding the mixture containing the active principle and the other excipients in small portions under vigorous stirring,
at the end of the production, neutralization is carried out at a lower stirring rate.
An example of preparing a film former solution (where the film former is an aqueous dispersion) is characterized by:
-mixing water and plasticizer at a rotational speed of 250 rev/min; stirring for 30 minutes;
-adding the dispersion of film-forming agent in small portions with stirring at 250rev/min until a homogeneous solution of the dispersion is obtained; stirring for 1 hour;
-separately dissolving EDTA and nomegestrol acetate in an ethanol/propylene glycol mixture; stirring was continued until they were completely dissolved;
-adding an alcoholic solution of the active principle to said aqueous solution in small portions with stirring at a speed of 250rev/min, stirring the resulting solution for 1 hour to homogenize it;
-neutralizing the solution with triethanolamine dissolved in water at a lower rotation speed; the resulting solution was homogenized for 30 minutes.
● method for preparing film-forming gel or gelated film
The film-forming gel is obtained by gelling the film-forming solution.
First, two solutions were prepared separately:
-an aqueous solution containing dissolved plasticizer, wherein the film-forming agent is completely dissolved under vigorous stirring;
-alcoholic solutions containing other excipients of the formulation, in which the active principle is dissolved; the gelling agent is dispersed therein and swelled.
The alcohol solution is then added to the aqueous solution for mixing and the solution is gelled with triethanolamine.
An example of a film-forming gel is prepared characterized by:
-dissolving a plasticizer in water; stirring for 30 minutes at the rotating speed of 250 rev/min;
-dispersing the film forming agent therein and stirring at a rotational speed of 250rev/min until it is completely dissolved (wherein the film forming agent is solid) or until the dispersion becomes homogeneous; stirring for 1 hour;
-dissolving EDTA and nomegestrol acetate in a mixture of propylene glycol and ethanol, respectively; dispersing the selected gelling agent and allowing it to swell for 2 hours under stirring at a speed of 150 rev/min;
mixing the alcohol solution with the aqueous solution and stirring at a rotation speed of 150rev/min for 1 hour;
neutralizing with water-soluble triethanolamine, and reducing stirring speed to 100 rev/min; the resulting gel was homogenized by stirring for 30 minutes.
Method for evaluating the passage of active ingredients through the skin
The effectiveness of the topical composition of the present invention is evaluated by demonstrating that the active ingredients it contains diffuse through the skin and are well absorbed by the microcirculation to achieve the desired therapeutic effect.
In the present invention, nomegestrol acetate is assessed through the skin by radioactive measurements using carbon 14 labeled molecules. The method of assessing the passage of the active principle by means of the marker product makes it possible to detect low concentrations of active principle, which is a significant advantage in view of the diffusion of small amounts of substance through the skin.
Evaluation of effective ingredients transdermal various tests skin used was taken from female test subjects of abdominal plastic surgery aged 40-45 years. Excess adipose tissue was removed from the skin, which was then cleaned and stored in a freezer at-70 ℃.
The topical composition of the present invention is primarily applied to the skin at the abdomen, arms, thighs, etc.
Experimental part
● example I
Figure 1 illustrates the effective transdermal nomegestrol acetate (NAc) as a function of varying amounts of nomegestrol acetate in the compositions of the present invention.
Symbols ■,. diamond-solid, and □ in FIG. 1 represent:
| ■ 0.11.11% NAc gel 0.4% NAc gel □ 0.8.8% NAc gel |
These compositions are in the form of gels and their formulations are listed in table 1 below:
TABLE 1
| Formulation (%) nomegestrol acetate propylene glycol Transcutol Carbopol 1342 Carbopol 940 EDTA Triethanolamine (TEA) deionized Water ethanol | Gel 0.400.800.116.006.003.005.005.00-0.500.50-// 0.750.050.050.050.300.300.3042.7542.3545.7945.0045.0050.00 |
| Nomegestrol acetate at pH (1%) | 6.7 6.5 6.70.41 0.4 0.403 |
The passage of the active ingredient through the skin is evaluated by measuring the cumulative amount of the active ingredient as a function of time. The cumulative amount of active ingredient represents the total amount of diffusion of the active ingredient through the skin over a particular period of time (24 or 48 hours). In this embodiment, it is denoted by ng.
Figure 1 clearly shows that the least effect is obtained with the gel containing 0.11% NAc.
Preliminary clinical trials were performed with 0.11% gel: reference is made to example IV. Thus, the resulting gel can achieve the throughput of the system despite its poor performance.
● example II
Solubility test of nomegestrol acetate (NAc)
1) -a) in a 95 ° ethanol/water binary mixture
The most effective solvent system in the water-alcohol mixture was determined.
TABLE 2: solubility of nomegestrol acetate as a function of 95% ethanol percentage
| % 95 ° ethanol | Solubility mg/ml of nomegestrol acetate |
| 0 | 0.056 |
| 10 | 0.070 |
| 20 | 0.113 |
| 30 | 0.683 |
| 40 | 2.820 |
| 50 | 7.330 |
| 60 | 17.850 |
| 70 | 24.850 |
| 80 | 29.500 |
| 90 | 26.600 |
| 100 | 32.850 |
In water-alcohol mixtures, solubility increases with increasing percentage of alcohol. The solubility profile shows that up to 40% alcohol it is still rather low, followed by a sharp increase between 40-80%. The percentage of alcohol allowed for topical application is limited. Under these constraints, the most effective solvent system for dissolving nomegestrol acetate has an alcohol content of 40-60%.
-b) in a ternary mixture of 95 ° ethanol/water/propylene glycol
The effect of the ternary mixture solvent ethanol/water (45: 55)/propylene glycol in dissolving nomegestrol acetate was determined.
While maintaining similar solubility, we also tested the possibility of reducing the proportion of alcohol in the solvent in this ternary mixture; for this reason we chose the effect of propylene glycol on solubility in ethanol/water systems (40: 60 or 30: 70).
TABLE 3: solubility of nomegestrol acetate in various systems containing Propylene Glycol (PG)
| % propylene glycol | Solubility (mg/ml) | ||
| System I | System II | System III | |
| 0 | 0.6 | 2.9 | 5.1 |
| 2 | 0.6 | 2.6 | 5.1 |
| 4 | 0.5 | 2.6 | 5.1 |
| 6 | 0.7 | 3.0 | 5.1 |
| 8 | 1.0 | 3.2 | 7.7 |
| 12 | 1.1 | 3.4 | 7.7 |
| 20 | 1.5 | 3.9 | 7.9 |
And (3) system I: "ethanol 95 °: 30% System II: "ethanol 95 °: 40 percent of
Deionized water: 70 percent ofDeionized water: 60 percent of
And (3) system III: "ethanol 95 °: 45 percent of
Deionized water: 55 percent of
Table 3 is illustrated by fig. 2.
Symbols ■,. diamond-solid and A-solidup in FIG. 2
| ■ solubility in System I solubility in System III solubility in System II |
In a ternary mixture of water/ethanol/propylene glycol, the solubility of the active principle in a mixture containing 45% of alcohol can be increased by 8% of propylene glycol. For this reason, we can obtain the best solubility of the active ingredient. The solubility of nomegestrol acetate in propylene glycol and alcohol produces a synergistic effect.
c) In a 95 ℃ ethanol/water/Labrasol/propylene glycol mixture
TABLE 4: solubility of nomegestrol acetate in propylene glycol containing systems
| % propylene glycol | Solubility of 1' nomegestrol acetate (mg/ml) |
| 0 | 9.4 |
| 10 | 9.5 |
| 15 | 10.2 |
The system comprises the following steps: "ethanol 95 °: 45 percent of
Water |: 50 percent of
Labrasol：5％
Instead of propylene glycol, 5% Labrasol was used alone, with increased solubility compared to the results obtained with propylene glycol. Solubility was further increased by the combination of propylene glycol and Labrasol .
2) A) in a 95 ℃ ethanol/water/propylene glycol/Solketal mixture
TABLE 5(ii) a Solubility of nomegestrol acetate in water-alcohol mixtures containing propylene glycol and/or Solketal
| % propylene glycol | ％Solketal | Solubility of nomegestrol acetate (mg/ml) |
| 0 | 3 | 6.7 |
| 0 | 8 | 8.6 |
| 8 | 0 | 7.7 |
| 8 | 3 | 10.7 |
The solubility of nomegestrol acetate in a water-alcohol solvent mixture in the presence of 8% Solketal is greater than the resulting solubility in the presence of 8% propylene glycol alone. The combination of propylene glycol and Solketal greatly increases the solubility in the water-alcohol solvent mixture in a ratio of 8% propylene glycol/3% Solketal.
-b) in a 95 ° ethanol/water/propylene glycol/vitamin E TPGS mixture
TABLE 6: solubility of nomegestrol acetate in water-alcohol mixtures containing propylene glycol and/or vitamin E TPGS
| % propylene glycol | % vitamin E TPGS | Solubility of nomegestrol acetate (mg/ml) |
| 0 | 3 | 7.65 |
| 0 | 8 | 11.10 |
| 8 | 0 | 7.70 |
| 8 | 3 | 12.50 |
The solubility of nomegestrol acetate was improved in the presence of vitamin E TPGS alone (same ratio 8% with reference to propylene glycol). 3% was added, which gives an effect comparable to the use of 8% propylene glycol.
However, better results were obtained when the two substances were used in combination (8% propylene glycol/3% vitamin E TPGS).
-c) in a 95 ℃ ethanol/water/propylene glycol/Transcutol mixture
TABLE 7: solubility of nomegestrol acetate in water-alcohol mixtures containing propylene glycol and/or Transcutol
| % propylene glycol | ％Transcutol | Solubility of nomegestrol acetate (mg/ml) |
| 8 | 0 | 7.70 |
| 8 | 3 | 7.95 |
| 0 | 8 | 10.70 |
| 3 | 8 | 10.60 |
In the presence of only 8% Transcutol , the solubility of nomegestrol acetate was increased (compared to using the same ratio of propylene glycol). The same solubility can be obtained by combining the two substances using 8% Transcutol/3% propylene glycol.
Reversing the ratio does not improve the solubility of the active ingredient compared to the results obtained with propylene glycol alone.
Conclusion：
Comprises the following steps:
-8% propylene glycol and 3% Solketal,
-or 8% propylene glycol and 3% vitamin E TPGS,
water-alcohol mixtures of-or 3% propylene glycol and 8% Transcutol are particularly suitable for obtaining good solubility of the active principle.
● example III
1/ Testing of formulations in gel form
Among the substances whose properties are chosen as absorption promoters, Solketal and vitamin ETPGS are particularly suitable, since they also prove to improve the solubility of nomegestrol acetate in water-alcohol mixtures and propylene glycol. The three boosters were studied by adding them to a formulation containing a hydro-alcoholic gel (45% alcohol) and containing 8% propylene glycol and 3% of the booster. These gel form formulations were tested through the skin. The gel used meets the requirements of pH, viscosity, concentration and appearance.
The four gels tested were designated G36-264, G36-276, G32-104 and G37-113, and the formulations are given in Table 8 below:
TABLE 8：
| Dosage form refers to formulation% nomegestrol acetate propylene glycol Transcutol Solketal vitamin E TPGSHPMC 60SH4000Carbopol 1382 Carbopol 980 EDTA ethylene diamine tetraacetic acid disodium TEAKLidon 90 Aqoat AS-LF Eudragit L30D55 diethyl phthalate ethanol 95 degree deionized water | Gel G36-264G 36-276G 32-104G 37-113 reference 0.40.40.40.48888// 333///3//////// 0.5/0.50.5/0.60.050.050.050.050.40.30.30.25///////////////////////////////4545454542.6542.7542.7542.85 |
| pH, 1% solution viscosity mPa.sNAc content (%) | 6.9 6.92 6.6 6.371150 1020 1400 14000.41 0.4 0.403 0.393 |
The main differences in the composition of these gels are: first of all for the choice of absorption enhancer ("enhancer") and secondly for the gelling agent, which may be Carbopol 980 or Carbopol 1382 .
The passage of the active ingredient through the skin is assessed by the following measurements:
the active ingredients being as a function of timeCumulative amount(cf. example I) of the present invention,
the active ingredients being as a function of timeCumulative percentage of，
And active principle as a function of timeDiffusion rate。
The cumulative percentage of active ingredient is the total percentage of active ingredient diffusion through the skin over a given time interval.
The diffusion rate of the effective components is measured in μ g/cm2H represents: it can be used to determine the diffusion kinetics of the active principle over a certain time.
Evaluation of the active principle by the method used can also be used to determine the distribution of nomegestrol acetate in the different structures of the skin after diffusion.
Table 9 shows the change in cumulative percentage of nomegestrol acetate as a function of time and the different locations of the distribution of the active principle in the skin structure (see last 3 rows), i.e. the content of nomegestrol acetate in the different layers of the skin (epidermis + dermis).
TABLE 9：
| Cumulative amount% (μ g) | ||||
| Gel | ||||
| G37-113 | G32-104 | G36-276 | G36-264 | |
| 8％PG3％Trans0.6％C980 | 8％PG3％Trans0.5％C1382 | 8％PG3％Vit E0.5％C980 | 8％PG3％Solketal0.5％C980 | |
| Time, hour | ||||
| 024681024 Washing epidermis | 00.0420.0880.1370.190.2390.57510.054.3367.63 | 00.0580.1350.2270.3290.4021.11714.826.9761.15 | 00.1050.1930.2750.3470.4050.6678.154.6872.69 | 00.1830.3710.5540.7320.8941.92616.824.8460.35 |
Table 9 is explained with reference to fig. 3 and 4.
Figure 3 illustrates the effect of the enhancer (enhancer) and Carbopol on the passage of systemic gels of nomegestrol acetate through the skin.
The following promoters were compared: transcutol (Tr), Solketal (Sol), and vitamin E TPGS (Vit E).
Symbols ■, a-solidup,. diamond-solid and □ in FIG. 3
| ■ G37-113 (3% Tr). diamond-solid G32-104 (3% Tr) -reference G36-276 (3% Vit E) □ G36-264 (3% Sol) |
Figure 4 shows the distribution of nomegestrol acetate in the skin structure.
Symbol in fig. 4
And
represents:
the cumulative amount and rate of diffusion values can be inferred from the cumulative percentage (value) of the active ingredient.
Figure 5 shows the diffusion rate of nomegestrol acetate as a function of time.
The symbols ■, a-solidup, diamond-solid and □ in FIG. 5 have the same meaning as in FIG. 3.
The diffusion kinetics of nomegestrol acetate in compositions in gel form are of the patch type with constant diffusion.
Conclusion：
If we compare the results obtained with the G32-104 reference gel, it can be seen that Solketal significantly improves the passage of nomegestrol acetate through the skin compared to vitamin E and Transcutol .
Thus, better diffusion can be obtained with Solketal instead of vitamin E TPGS, since the solubility of the active ingredient is better than the latter (see tables 5 and 6).
For a hydro-alcoholic system containing a propylene glycol/Transcutol mixture, the same comments can be applied: if there are four possible combinations: 8: 0-8: 3-3: 8 and 0: 8, the diffusion obtained with the 8: 3 mixture is the best. However, the latter solubility was the worst (see table 7).
If complete dissolution is desired, the active ingredient must have some affinity with the solvent. However, it should not be so large that the partition coefficient between such a carrier and the skin facilitates diffusion through the skin.
The diffusion test was performed on the static flow of the radiolabeled active ingredient in gels containing two types of absorption enhancers, corresponding to two reference gels: gel G32-104 (different from G37-113 and one Carbopol of the other two) which gave the best diffusion, and gel G37-113, both test gels containing Transcutol (same grade Carbopol ) having the same composition.
By measuring the effect of the absorption enhancer used on the passage of labelled nomegestrol acetate through the skin, we found that diffusion was significantly increased in the presence of Solketal compared to the G32-104 reference gel containing Transcutol .
Vitamin E TPGS was used under the same conditions, and did not improve by comparison with gels G32-104. On the other hand, if gel G37-113 was used, the resulting diffusion was slightly stronger than vitamin E, and the increase was significant when used with Solketal.
When we tested the quantitative distribution of active ingredients in the skin structure (see fig. 4), we found that the active ingredients in gel G36-264 and reference gel G32-104 had the same concentration in the dermis and epidermis. While gels G37-113 and G36-276 were found to be less concentrated in the epidermis.
The above tests also demonstrated that the diffusion of the active principle is differentiated by the difference in the Carbomer grades used in the formulations (in contrast to the gels G37-113 and G32-104 formulations, which are identical in quantity and nature). It can be seen that the diffusion is better in the presence of Carbopol 1382 as well as the distribution in the skin structure. Examining the resulting adhesion results (testing gels G36-264 and G36-276), it was found that the adhesion properties of the gels containing Solketal were slightly better than those of the gels containing vitamin E. It is noted that the two gels contain the same proportions of excipients, except for the different types of enhancers.
Conclusion
The presently preferred topical hormonal composition with systemic effect according to the invention is a composition in the form of a gel comprising:
-0.4% nomegestrol acetate
-8% propylene glycol
-3% of Solketal
0.5% of Carbopol 980 or 1382
-45% 95 ° ethanol
0.05% EDTA, 0.4% TEA and deionized water to 100%.
2/ Formulation testing in film-forming solution form
The 5 film-forming solutions tested, designated G36-259, G36-261, G36-263, G36-266 and G36-277, were formulated as follows in Table 10:
watch 10
| Form reference formulation (%) nomegestrol acetate propylene glycol Transcutol solkataltov E TPGSHPMC 60SH4000Carbopol 1382 Carbopol 980 EDTATEAKollidon 90 Aqoat AS-LF Eudragit L30D55 diethyl phthalate ethanol 95 ° deionized water | Film-forming solutions G36-259G 36-261G 36-263G 36-266G 36-2770.40.40.40.40.488888//////// 3///////////////////////////0.050.050.050.050.05/0.80.30.050.055// 55/10////////// 10///32// 43.35404043.2543.2543.237.7539.2540.2540.25 |
| pH (1%) viscosity MPa.sNAc content (%) | 6.25 6.16 6.24 6.83 6.340.41 0.42 0.43 0.40 0.40 |
The main differences in the composition of these film forming solutions relate to the choice of film forming agent and the choice of adding or not adding absorption promoters or plasticizers.
The film forming solutions were tested with G32-104 as a reference.
Table 11 illustrates the cumulative percentage of nomegestrol acetate and the distribution of nomegestrol acetate in the skin structure as a function of time.
TABLE 11
| Cumulative percentage of | ||||||
| Gel | Film-forming solution | |||||
| G32-104 | G36-261 | G36-263 | G36-259 | G36-266 | G36-277 | |
| 8％PG3％Trans0.5％C1382 | 8％PG10％Aqoat | 8％PG10％Eudr | 8％PG5％Koll | 8％PG3％Solk5％Koll | 8％PG3％TPGS5％Koll | |
| Time h | ||||||
| 024681024 | 00.0620.1230.1850.2520.3420.799 | 00.0880.1530.2060.2510.30.487 | 00.0920.1520.1970.2390.2890.515 | 00.0770.140.2030.2690.3490.699 | 00.0670.1160.1650.2110.2690.539 | 00.0640.1120.1530.1930.2420.474 |
| Epidermis dermis Washing | 8.245.5672.18 | 5.691.9397.96 | 2.782.2698.85 | 9.144.5894.33 | 6.413.291.37 | 4.434.7695.24 |
Table 11 is illustrated by fig. 6 and 7.
Fig. 6 illustrates the effect of absorption enhancers and film-forming agents on the passage of nomegestrol acetate system membrane through the skin.
Symbol ■,. diamond-o, ●,. tangle-solidup and ≧ y in FIG. 6:
| ■ G32-104 (3% Tr) -reference G36-261 (10% Aqoat.) G36-259 (5% Kol) ● G36-266 (3% Solk/5% Kol) G36-263 (10% Eudrag) G36-277 (3% TPGS/5% Kol) |
Regardless of the polymer used, the amount of active ingredient diffused by these forms is in any case less than that obtained with the non-film-forming gels G32-104.
It can be seen that the diffusion of the solution containing Kollidon alone is closest to that of the reference gel. The other two polymers produced similar diffusion.
Solutions combining Kollidon and a promoter (such as Solketal or vitamin E TPGS) have poor diffusion of the active ingredient compared to solutions G36-259 without promoter.
Figure 7 shows the distribution of nomegestrol acetate in the skin structure.
Symbol in FIG. 7
And
represents:
it can be seen that the distribution using Kollidon is the best. It is comparable to the distribution that occurs in the reference gel. The results obtained with the Aqoat and Eudragit solutions were still poor.
The diffusion effect obtained with the film forming solution was slightly better than with the gel containing 0.11% nomegestrol acetate (see table 1, example I). It should be noted, however, that for Eudragit and Aqoat , the solutions prepared contained only propylene glycol, with no other accelerator compared to the reference gel.
Conclusion：
The topical hormonal composition with systemic effect of the present invention is a composition such as a film forming solution comprising:
-0.4% nomegestrol acetate
-8% propylene glycol
5% of Kollidon 90
-43.35% 95 ° ethanol
0.05% EDTA and deionized water to 100%.
3/ Formulation testing of film-forming gels or gelled films
The 3 film-forming gels tested were designated G36-260, G36-262 and G36-267, and their formulations are set forth in Table 12 below.
TABLE 12
| Form reference formulation (%) nomegestrol acetate propylene glycol Transcutol solkataltov E TPGSHPMC 60SH4000Carbopol 1382 Carbopol 980 EDTATEAKollidon 90 Aqoat AS-LF Eudragit L30D55 diethyl phthalate ethanol 95 ° deionized water | Film-forming gel G36-260G 36-262G 36-2670.40.40.4888///////meaning / // / // / /0.5 0.75 /0.05 0.05 0.050.1 0.9 0.45 / // 10 // / 10/ 3 243 40 4042.95 36.9 38.15 |
| sNAc content (%). in pH 1% solution | 6.36 6.2 6.171750 1050 11500.41 0.405 0.40 |
The main difference in the composition of these film-forming gels relates to the choice of gelling agent and film-forming agent.
These film-forming gels were tested against reference gels G32-104 and G37-113.
Table 13 illustrates the cumulative percentage of nomegestrol acetate and the distribution of nomegestrol acetate in the skin structure as a function of time.
| % cumulative percentage | |||||
| Gel | Film-forming gel | ||||
| G32-104 | G37-113 | G36-260 | G36-262 | G36-267 | |
| 8％PG3％Trans0.5％C1382 | 8％PG3％Trans0.6％C980 | 8％PG5％Kollidon0.5％C980 | 8％PG10％aqoat0.75％C980 | 8％PG10％Eudr1％HPMC | |
| Time h | |||||
| 024681024 | 0.0000.0580.1350.2270.3290.4021.117 | 0.0000.0240.0880.1370.1900.2390.575 | 0.0000.1210.2060.2780.3340.3790.598 | 0.0000.2510.4140.5330.6260.6940.994 | 0.0000.2510.3920.5060.5900.6500.913 |
| Epidermis dermis Washing | 14.826.9761.15 | 10.054.3367.63 | 11.424.8165.83 | 16.361.5372.35 | 11.211.3990.42 |
Fig. 8 and 9 illustrate table 13.
Figure 8 shows the effect of film forming agents on the passage of a systemic film forming gel of nomegestrol acetate through the skin.
Symbols ∑ □,. diamond-solid,. and a in fig. 8 represent:
| ★G32-104(C1382) ◆G36-260(Kol/C980) ▲G36-262(aq/C980)□G36-267(Eud/HPMC) ◇G37-113(C980) |
all polymers were tested and the diffusion of nomegestrol acetate in the Aqoat and Eudragit film-forming gels was superior to the G32-104 "reference" gels over a period of up to 10 hours. Beyond this time, the trend is slightly reversed. If we used a non-film-forming gel 113 (containing different carbopol than gel G32-104), all film-forming gels gave better results regardless of the polymer used.
It should be noted that the diffusion of the active principle is similar to that of Aqoat and Eudragit .
On the other hand, it is much lower than with Kollidon .
Fig. 9 shows the distribution of active ingredients in the skin structure.
Symbol in fig. 9
Represents:
it can be seen that the distribution varies from one polymer to another: compared to the G32-104 reference gel, the distribution in the epidermis was similar to Aqoat , but lower than Kollidon and Eudragit . The distribution in the dermis was lower than Aqoat and Eudragit , but higher than Kollidon .
Conclusion：
Examples of topical hormonal compositions with systemic effect according to the invention are compositions such as in the form of film-forming gels containing:
-0.4% nomegestrol acetate
-8% propylene glycol
0.75% of Carbopol 980
10% of Aqoat AS-LF
-40% ethanol 95 °
3% diethyl phthalate, 0.05% EDTA, 0.9% TEA and deionized water to 100%,
alternatively, a composition in the form of a film-forming gel comprising:
-0.4% nomegestrol acetate
-8% propylene glycol
-1% HPMC 60SH4000
10% Eudragit L30D55
-40% ethanol 95 °
2% diethyl phthalate, 0.05% EDTA, 0.4% TEA and deionized water to 100%.
4/ Comparison of film-Forming solutions and film-Forming gels
Table 14 shows the cumulative percentage of nomegestrol acetate and the distribution of nomegestrol acetate in the skin structure as a function of time.
| Cumulative percentage of | ||||||
| Film-forming solution | Film-forming gel | |||||
| G36-259 | G36-261 | G36-263 | G36-260 | G36-262 | G36-267 | |
| 8％PG％Koll | 8％PG10％Aqoat | 8％PG10％Eudr | 8％PG5％Koll0.5％C980 | 8％PG3％Aqoat0.75％C980 | 8％PG10％Eudr1％HPMC | |
| Time h | ||||||
| 024681024 | 00.0770.140.2030.2690.3490.699 | 00.0880.1530.2060.2510.30.487 | 00.0920.1520.1970.2390.2890.515 | 00.1210.2060.2760.3340.3790.598 | 00.2510.4140.5330.6260.6940.994 | 00.2510.3920.5060.590.650.913 |
| Epidermis dermis Washing | 9.144.5894.33 | 5.691.9397.96 | 2.782.2698.85 | 11.424.8165.83 | 16.361.5372.35 | 11.211.3990.42 |
Table 14 is explained with reference to fig. 10 and 11.
Fig. 10 can compare film forming solutions and films forming gels of nomegestrol acetate with systemic effect.
Symbols ■, □,. diamond-solid,. a-up and Δ in FIG. 10 represent:
| film-forming solution■G36-259(5％Kollidon) ◆G36-261(10％Aqoat) ▲G36-263(10％Eudrag)Film-forming gel□G36-260(5％Kol/C980) ◇G36-262(10％Aqoat/C980) △G36-267(10％Eudr/HPMC) |
Fig. 11 shows the distribution of active ingredients in the skin structure.
Symbol of FIG. 11
(symbols in column 2 of figure 11),
(symbols in column 3 of FIG. 11) and
(last column)
Represents:
figure 12 compares the diffusion of nomegestrol acetate in compositions in the form of film-forming gels with compositions in the form of film-forming solutions.
The symbols in fig. 12 have the same meanings as those in fig. 10.
Comparing fig. 5 (diffusion flux in gel form), the diffusion kinetics were not constant diffusion, but reached maximum diffusion soon (after 2 hours) and then dropped off quickly. This is especially true for film-forming gels G36-262 and G36-267. Thus, two types of traffic can be distinguished: higher or lower flow than fixed diffusion and other forms where the maximum diffusion peak is reached very quickly.
Thus, film-forming gels are more suitable than film-forming solutions in optimizing the distribution of nomegestrol acetate in the skin. More specifically, the only cellulose (Aqoat , G36-262) or acrylic acid (Eudragit , G36-267) film formers present in the film-forming gel allow good diffusion of the active ingredient. In both cases, the resulting film is stronger, more adherent and can release the active ingredient.
Thus, topical hormone compositions in the form of film-forming gels with systemic effect can be combined with 3% Solketal to obtain a synergistic effect and further improve the diffusion of nomegestrol acetate.
4/ Conclusion
The diffusion of the active ingredient in the film-forming or film-forming solution is generally less than that obtained with the reference gels (G32-104).
On the other hand, if we wish to have formulations that do not contain any absorption enhancers, the film-forming gels of Aqoat (G36-262) and Eudragit (G36-267) allow significant diffusion of the active ingredient.
Solketal is an effective absorption enhancer with effect of diffusing nomegestrol acetate through skin; thus, in the hydro-alcoholic system, when combined with propylene glycol in a 3: 8 ratio, its solubility in the vehicle and diffusion through the skin can be significantly improved.
Thus, a particularly suitable example of a topical hormone composition having a systemic effect according to the invention is a composition in the form of a gel or a film-forming gel and containing 8% propylene glycol and 3% isopropylidene glycerol in a water-alcohol mixture.
● Example IV
Preliminary clinical trial
In these examples, the formulation of the clinical trial in women using a gel containing 0.11% nomegestrol acetate is given in Table 1 of example I.
1/ Clinical example 1
Nomegestrol acetate, 4mg in gel, was administered daily to the double milk of 24 female volunteers (who were healthy and in ovarian activity cycle, average age 23.5 years) for a continuous 15 days of treatment.
Blood was sampled repeatedly every few hours after the first and last dose, 9 times between the second and 14 days of treatment (6 times before gel administration and 3 times 3 hours after administration). These samples were analyzed for nomegestrol acetate in plasma by liquid chromatography coupled to a mass spectrometer.
From the first day of treatment, nomegestrol acetate assays were performed on all test subjects. The maximum concentration was 0.25. + -. 0.027ng/ml and the area under the curve was 6.08. + -. 0.775ng/ml per hour over 0-48 hours, with plateaus formed having an average of 0.10-0.17 ng/ml.
Maximum concentration was 0.65 + -0.073 ng/ml after the last dose, area under the 0-48 hour curve was 18.43 + -2.091 ng/ml/hour, and nomegestrol acetate (0.19 + -0.027 ng/ml) was also detectable in plasma 72 hours after the last dose.
Equilibrium was reached on the third day of treatment. We then observed the average of the small changes between 0.45-0.65ng/ml that remained on the platform.
2/ Clinical example 2
Six menopausal women aged 56-66 years and not treated for 2 months were monitored for 25 days and 2 consecutive cycles, each for 6 days of treatment observation (therapeutic window).
Wherein one tablet of orally administered oestradiol is administered daily and 4mg nomegestrol acetate in gel form is applied to the abdominal skin within 15 days of the second cycle. At the end of each cycle, plasma was analyzed for nomegestrol acetate, noting if the vulva bleeds and taking a biopsy of the endometrium.
In comparison with the behaviour of the first cycle (using oestradiol alone), gel administration of nomegestrol acetate in the second cycle indicated that the progestogen was detectable in plasma at 0.39-0.76ng/ml (mean 0.62ng/ml) and that this level was sufficient to cause secretory translocation of the endometrium and to produce vaginal bleeding on a mean of 5 days after the second cycle.
3/ Clinical example 3
113 pre-menopausal women (having breast pain for more than 3 months and at least 7 days per cycle) were treated for an average period of 130 days with 4mg of nomegestrol acetate per day and the gel was administered to the double breast on the last 15 days of the menstrual cycle.
The effect was assessed after 3 months and the breast pain was quantified at the end of the treatment by visual comparison.
This trial showed that nomegestrol acetate gel statistically significantly reduced the intensity of breast pain and the duration of the cycle from month 3 of treatment. After 6 cycles of treatment, the intensity decreased by 48% and the duration decreased by 41%.
During this study, nomegestrol acetate was analyzed in the blood of 55 women, and the data obtained was 0.44. + -. 0.30 (m. + -. sd) ng/ml.
Claims (18)
1. A topical hormone composition having a systemic effect for correcting progesterone deficiency in pre-menopausal women and for hormone replacement therapy in menopausal women, characterized in that it comprises:
-as active principle nomegestrol and/or one of its esters or ethers,
-a carrier for the active principle system to pass through the skin barrier, said carrier being selected from solubilizers, absorption enhancers, film-forming agents, gelling agents or mixtures thereof,
combined or mixed with suitable excipients to make a gel and/or film-forming pharmaceutical form.
2. Topical hormonal composition with systemic action according to claim 1, characterised in that it comprises:
-as active principle nomegestrol and/or one of its esters or ethers,
-a carrier allowing the active principle system to pass through the skin barrier, said carrier comprising a substance selected from the group consisting of water, alcohol, propylene glycol, polyethylene 20-sorbitan monooleate, C8/C10A solubilizer for the polyoxyethylene glycosyl glyceride or the mixture thereof,
-a film-forming agent and/or a gelling agent,
combined or mixed with suitable excipients to make a gel and/or film-forming pharmaceutical form.
3. Topical hormonal composition with systemic effect according to claim 2, characterised in that it also comprises absorption enhancers.
4. Topical hormone composition with systemic effect according to claim 2 or 3, characterized in that the active ingredient is nomegestrol acetate.
5. A topical hormone composition with systemic effect according to any of claims 1 to 3, characterized in that nomegestrol or one of its esters or ethers is present in an amount of 0.05 to 1% by weight of the total composition.
6. A topical hormone composition with systemic effect according to claim 5, characterized in that nomegestrol or one of its esters or ethers is present in an amount of 0.4% by weight of the total composition.
7. Topical hormonal composition with systemic effect according to claim 5, characterised in that the solubilising agent is selected from the group consisting of water, alcohol, propylene glycol, C8/C10Polyoxyethylene glycosyl glyceride or a mixture thereof.
8. Topical hormone composition with systemic effect according to claim 6, characterized in that the solubilizer is a ternary mixture of 95 ° ethanol/water/propylene glycol, in which the percentage of 95 ° ethanol is 30-50%, water 30-60% and propylene glycol 2-20%.
9. Topical hormonal composition with systemic effect according to claim 6, characterised in that the solubilising agent is 95 ° ethanol/water/C8/C10A quaternary mixture of polyoxyethylene glycosyl glyceride/propylene glycol, wherein the percentage of 95-degree ethanol is 30-50%, the percentage of water is 30-60%, and C8/C10The polyoxyethylene glycosyl glyceride is 3-7% and the propylene glycol is 2-20%.
10. Topical hormonal composition with systemic effect according to claim 5, characterised in that said absorption enhancer is selected from the group consisting of isopropylidene glycerol, alpha-tocopheryl polyethylene glycol 1000 succinate and diethylene glycol monoethyl ether.
11. Topical hormonal composition with systemic effect according to claim 10, characterised in that the absorption enhancer is isopropylidene glycerol.
12. Topical hormonal composition with systemic effect according to claim 5, characterised in that the gelling agent is selected from the group consisting of cellulose derivatives and acrylic acid derivatives.
13. Topical hormone composition with systemic action according to claim 12, characterized in that the cellulose derivative is hydroxypropylmethylcellulose.
14. Topical hormone composition with systemic action according to claim 12, characterized in that the acrylic acid derivative is a carbopol preparation.
15. Topical hormone composition with systemic effect according to claim 5, characterized in that the film forming agent is selected from the group consisting of cellulose derivatives, methacrylic acid derivatives and polyvinylpyrrolidone derivatives.
16. Topical hormone composition with systemic effect according to claim 15, characterized in that the cellulose derivative is hydroxypropyl methylcellulose acetate succinate.
17. Topical hormonal composition with systemic effect according to claim 15, characterised in that said methacrylic acid derivative is an aqueous dispersion of an anionic copolymer of methacrylic acid and ethyl acrylate.
18. Topical hormonal composition according to claim 5, characterised in that it is present in the form of a gel or a film-forming gel and contains 8% propylene glycol and 3% isopropylidene glycerol in a water-alcohol mixture.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9803533A FR2776191B1 (en) | 1998-03-23 | 1998-03-23 | TOPICAL HORMONAL COMPOSITION WITH SYSTEMIC EFFECT |
| FR98/03533 | 1998-03-23 | ||
| PCT/FR1999/000680 WO1999048477A1 (en) | 1998-03-23 | 1999-03-23 | Topical hormonal composition with systemic effect |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1038184A1 HK1038184A1 (en) | 2002-03-08 |
| HK1038184B true HK1038184B (en) | 2005-04-29 |
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