ZA200100129B - Plaster which contains steriods, and a method for the production and use thereof. - Google Patents

Description

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Steroid-containing patch, process for its production, and its use

The present invention relates to a medicinal composition for transdermal application of an estrogen in combination with a gestagen.

In cutaneous application of active substances one aims at the systemic action of the pharmaceutical substances. By reason of the limited permeability of the skin, the substances suit- able and preferred for this purpose are those which are ap- . plied in low dosage (daily doses of up to 10 mg).

Cutaneous application is useful in those cases where after oral administration a large portion of the active substance is metabolized during the first passage through the mucous . membranes of the gastrointestinal tract, or is retained by : the liver (first pass effect), and/or where the active sub- stance has a low plasma half time. By contrast, those sub- stances having a high allergising potential as well as those having a locally irritating action are unsuitable. Where the basic requirements are fulfilled, cutaneous application is an alternative to oral administration.

The invention relates to an active substance-containing de- vice, releasing one or more pharmaceutical substances at a pre-determined rate, continuously, over a fixed period of time, to a fixed site. Such a device is characterized by an exact treatment program and is called a therapeutic system. ’ Since the system according to the present invention is ad- hered as a patch to the skin to achieve a systemic effect, the system in this context is called a transdermal therapeu- tic system (TTS).

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The invention relates to a preparation having a high degree of action, that is the preparation leads to a high biocavail- ability of the pharmaceutical substances. This is achieved in that the presystemic elimination is strongly reduced by avoiding the digestive tract, the efficacy of the pharmaceu- tical substances being independent of the gastric emptying rate and the intestinal motility.

The action of the pharmaceutical substances can be stopped at any time - with a certain delay ~- by simply removing the preparation. The plasma concentration can be set within the therapeutic range without any peaks and lows. As a conse- . quence, the preparation is characterized by a controllability of the absorption phenomena.

The preparation according to the invention exhibits high re- liability as regards the observance of the therapy plan by the patient since the frequency of application as compared to : conventional oral pharmaceutical forms is strongly reduced.

Furthermore, the active substance amount applied can gener- ally be reduced. Dose-dependent side effects are thereby re- duced, too, or they are even eliminated. This results in im- proved therapy safety.

Estradiol, estrone (estrogens) and progesterone (gestagen) are the natural female sex hormones. Sex hormones serve to form the primary and secondary sex characteristics. They in- fluence growth and body building as well as the water and mineral balance. Furthermore, sex hormones determine the se- quence of the menstrual cycle in women.

Natural sex hormones, their derivatives as well as structure analogues are used for hormonal contraception, for substitu- tion therapy ox for treatment of various diseases.

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A main area of application of sex hormones is the field of ] postmenopausal hormone substitution. The substitution serves to prevent climacteric complaints (hot flushes, giddiness, tachycardias, sweating, feeling of anxiety, irritability, bad concentration, sleep disturbances, etc.). Furthermore, changes occurring in the urinary and genital organs, cardio- vascular changes caused by hyperlipoproteinemia, skin atro- phies, or osteoporosis, as well as further pathologic phenom- ‘ena are meant to be prevented. For this purpose, an estrogen is administered in combination with a gestagen.

For example, the following estrogens may be used: 1l7-beta- . estradiol, 17-alpha-estradiol, 17-beta-estradiol cypionate; 17-beta-ethinyl estradiol, 3,17-beta-estradiol diene anthate, 17-beta-estradiol valerate, 1l7-beta-estradiol benzoate, 17- beta-estradiol undecylate, 1l7-deacetyl norgestimate, norges- timate, mestranol and quinestrol. The estrogens mentioned are characterized by an aromatic hydroxyl group or the ethers : thereof.

Since the natural gestagen progesterone exhibits insufficient pharmacokinetic properties for substitution therapy, numerous modification products have been synthesized. Examples to be mentioned are: l9-norprogesterone, norethisterone acetate, norethisterone, ethisterone, melengestrol, norgestrel, levo- norgestrel, gestodene, hydroxyprogesterone capronate, me- droxyprogesterone acetate, ethynodiol diacetate, 17-alpha- hydroxyprogesterone, megestrol acetate, lynestrenol, deso- gestrel, allyl estrenol, chlormadinone and chlormadinone ace- tate. A typical structural feature of most of the compounds ‘ is a 3-keto-4-ene structure.

If estradiol is administered orally, only a small portion thereof is absorbed due to its poor water solubility. The portion absorbed is subject to a strong first pass effect. In this process, numerous metabolites are disintegrated which no

. “ longer exhibit an estrogen effect and which lead to side ef- ] fects. Furthermore, oral administration leads to unphysi- ological fluctuation of the hormone blood level. Owing to the first pass effect it is, in addition, necessary to administer large amounts of estradiol. This causes further side effects.

The ideal application for estradiol would be a slow intrave- : nous infusion. This is, however, impractical. By transdermal : : administration it is possible to achieve almost ideal condi- tions. In this case the first pass effect is avoided, and plasma concentrations are obtained which correspond to the physiological hormone blood level of a premenopausal woman . (40 - 60 pg/ml). A further advantage of transdermal admini- stration over oral application is that the daily dose can be reduced to 50 ng/day. : The main risk connected with postmenopausal estradiol admini- stration is hyperstimulation of the endometrium, in conjunc- tion with an increased risk of hyperplasia or degeneration.

Furthermore, in the case of monotherapy with estradiol this is frequently accompanied by disorders of menstruation. To reduce these risks it is useful to administer estradiol in combination with a gestagen. In the case of transdermal ad- ministration, to prevent hyperplasia, about 200 - 300 ng of norethisterone acetate or of a corresponding equivalent are : necessary per day. In comparison thereto, with peroral ad- ministration, 0.7 - 1 mg/day are required [Wiseman, L.R. and

McTavish, D., Transdermal-Estradiol/Norethisterone: A Review of its Pharmacological Properties and Clinical Use in Post~ menopausal Women, Drug & Aging, Vol. 4, No. 3, 1994, 238- ’ 2561].

Combined TTSs having a composition for transdermal applica- tion of an estrogen, especially of estradiol, in combination with a gestagen, especially of norethisterone acetate, are already known and available on the market (e.g. Estracomb®).

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Their complex structure is a disadvantage. Thus, Estracomb® contains two compartments, serving as an active substance reservoir. Furthermore, a control membrane is contained therein for controlled active substance release. Due to the space-consuming compartments, the systems is very thick and is therefore uncomfortable to wear. . Examples for simple-structure matrix systems for transdermal : oo application of estradiol in combination with gestagen are de- scribed in EP 0 695 177 Bl. WO 96/40087 describes a matrix system on the basis of a cross-linked acrylate polymer for transdermal application of estradiol

When storing steroid-containing TTS of the matrix type, two stability problems occur inter alia: the active substances may be recrystallized or disintegrated. ’ . Recrystallization occurs when the saturation concentration of : the corresponding active substance is exceeded. If the satu- : ration concentration is exceeded, this can be a result of a modification change. Thus, estradiol is apt to forming a semihydrate by absorbing crystal water, said semihydrate re- crystallizing by reason of its lower solubility. Furthermore, there is a possibility that mixed crystals are formed. Here, the solubility of the mixed crystals is lower than the satu- ration solubility of the individual components. As a result of the recrystallization, there is a decrease in the thermo- dynamic activity and the permeation rate of the active sub- stances through the skin. The therapeutic efficacy of the preparation is thereby endangered.

To prevent the crystallization of the estradiol, various pos- sibilities have been described. The system described in the

US patent 5,676,268 contains in the active substance- containing compartment auxiliary substances which are de- scribed as "crystallization inhibitors" and which are to

; | ; counteract the crystallization process. In particular, sili- con dioxide and macromolecular substances, such as polyvinyl- pyrrolidone or its copolymers with vinyl acetate are men- tioned there. In US patent 5,711,962 and in WO 97/23227 the addition of octyl dodecanol is described, for preventing crystallization. In WO 96/05814 a system is described con- . taining anhydrous glycerin as a component of the matrix. An- : hydrous glycerin is miscible with water in any ratio, it is : hygroscopic and can be employed as a dehydrating agent. If anhydrous glycerin is stored together with estradiol semihy- drate, it is capable of withdrawing water therefrom. Anhy- drous glycerin is thus a suitable agent for preventing re- . crystallization during storage. In WO 96/05815 the addition of water-binding mineral components to the active substance- containing matrix is described, so that the recrystallization of estradiol semihydrate is prevented. As mineral components . are mentioned, for example, the anhydrate of calcium sulfate, : .. zink oxide, magnesium oxide, silicon dioxide, silica gel, _ talcum and further substances. DE 42 37 453 proposes the use of desiccants in the primary package. EP 0 186 019 Al de- scribes the use of water-swellable polymers for crystal growth inhibition of the active substance, which is present in a concentration above its saturation concentration. EP 0 695 177 Bl describes a system containing estradiol in a con-~ centration near the saturation concentration. The saturation concentration is exceeded, through absorption of water, only after the system is stuck on the skin, thereby increasing thermodynamic activity. Ia this process, alpha-tocopherol de- termines the degree of oversaturation of the hydrogenated ma- trix and thus the diffusion of active substance through the ‘ skin. Alpha-tocopherol in this context serves to improve ac- tive substance solubility and to prevent recrystallization during storage.

Steroids (hormones and corticoids) are disintegrated to a lesser or greater degree during storage, dependent on the auxiliary substances used. Various degradation mechanisms must be taken into consideration. On the one hand, saponifi- cation reactions occur, which lead to more strongly hydro- prhile compounds, and on the other hand, oxidation reactions occur, which lead to ineffective products. In particular, steroids, which have a 3-keto-4-ene partial structure, are very sensitive. For this instability, acidic-reacting groups are held responsible inter alia. Thus, WO 97/03629 describes a system having a carrier that has no acid functions and does not develop such functions during storage either. DE 195 48 332 Al describes a hormone patch with norethisterone acetate which exhibits good storage stability. The stability here is : achieved by using a certain polymer mixture. WO 97/23227 de- scribes that the degradation of norethisterone acetate is de- pendent on the moisture content of the matrix. Consequently, it is advantageous to work with dried air during manufacture and to integrate a desiccant (e.g. sodium sulfate or calcium : sulfate) in the primary package. It is further described that the stability of norethisterone acetate is improved if during manufacture the active substance is dissolved in a solvent mixture, consisting of methyl ethyl ketone and ethanol.

Apart from the stability problems mentioned, it is necessary to ensure the therapeutic efficacy of the TTSs. Therapeutic efficacy is determined by the extent of skin permeation. To guarantee that permeation is sufficient, enhancers are fre- : quently used. For example, in US patent 5,676,968 the use of 1, 2~propanediol and isoprepyl myristate for increasing estra- diol permeation is described by way of example. EP 0 811 381

Al describes the use of fatty alcohols in combination with a diethylene glycol monoalkyl ether as enhancer for estradiol and norethisterone acetate. US patent 5,686,097 mentions the use of monoglycerides and lactate esters for enhancing pene- tration of an estrogen/gestagen combination.

The use of enhancers, however, is not always without prob- lems. Many of the substances employed lead to skin irrita- tions. To alleviate such irritations, further substances are frequently used which are to counteract such irritations.

Glycerol and polyglycerol ether are to be mentioned here, for example. Besides its lenitive effect, glycerol also has a positive effect on the permeation rate. It is of disadvantage that glycerin strongly decreases the cohesion of a poly- acrylate matrix. A deterioration in cohesion manifests itself in increased "tack", increased "cold flow", a transfer of ad- hesive to the protective film, or in the fact that residues of adhesive remain on the skin after removal of the system. . To generally improve the cohesion of systems having a high content of liquid or softening components, US patent 5,306,503 mentions the addition of so-called film-formers.

It has been the object of the present invention to provide a

TTS having a simple structure, a so-called matrix system, which has a low-cost composition, for transdermal application of an estrogen, especially of estradiol, in combination with a gestagen, especially of norethisterone acetate, which TTS guarantees an effective pharmaceutic therapy of climacteric complaints.

Matrix systems are characterized in that the active sub- stances are present finely distributed (dissolved or dis- persed) in a polymer matrix. The matrix here has a reservoir function and an adhesive function. Whereas in a membrane sys- tem the transdermal active substance uptake is largely regu- lated by the integrated control membrane, in matrix systems this function is performed by the skin. The production of the active substance-containing matrix is very simple.

This task is solved by a self-adhesive composition based on polyacrylate for transdermal application according to the

: . features of the main claim. Preferred and advantageous em- } bodiments have the features as described in the subclaims.

Polyacrylate-based compositions have a very low allergenic potential and are therefore also suitable for prolonged ap- plication. The adhesiveness of the polymers is brought about here only by the molecular weight distribution and the mono- mers used. :

To produce polyacrylate-based compositions according to the invention, acrylic acid and/or alkyl acrylic acid, especially methacrylic acid or their derivatives, especially the alkyl . esters, are employed. Among the alkyl esters of acrylic acid and/or methacrylic acid are those having 1 to 18 carbon atoms in the alkyl residue, especially methyl, ethyl, n-butyl, iso- butyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, iso- octyl, 2-ethylhexyl, n-decyl, isodecyl, n-dodecyl and stearyl acrylate or methacrylate. Apart from these, further comono- : : mers can participate in the structure of the poly- mer /copolymer. Examples are acrylic and/or methacrylic amide, hydroxyalkyl esters and polyalkylene glycol esters of acrylic and/or methacrylic acid, nitrogen-containing monomers of acrylic and/or methacrylic acid or the salts thereof, ethyl- ene, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl- pyrrolidone, vinyl chloride, vinyl toluene, acrylonitril, styrene and the like.

For producing a system aceording to the invention an acrylate copolymer is advantageously used which contains 2-ethylhexyl acrylate, vinyl acetate, hydroxyethyl acrylate and glycidyl methacrylate.

To ensure the therapeutic efficacy, glycerol is used as en-~ hancer. To this end, glycerol must be incorporated into the matrix in larger amounts. It is problematic that, if present in larger amounts, glycerol diminishes the cohesion of the matrix. To counteract this effect, a further polymer is added to the acrylate base, which polymer is non-adhesive itself, but has very good film-forming properties. This film-forming polymer has a positive influence on the cohesion of the ma- trix. Polymers based on polyacrylic or polymethacrylic acid and their esters have proved to be well suited.

To prepare a system according to the invention, a f£ilm- g forming acrylate copolymer having 10 - 90%-wt. of methacrylic acid and 10 - 90%-wt. of methyl methacrylate are used. It is surprising, that the addition of the acid-reacting components does not lead to increased degradation of the incorporated . hormones having 3-keto-4-ene partial structure. This is in stark contradiction to the test results described in WO 97/03629. By contrast, the use of the polymer mentioned rather contributes to improving stability. FIG. 1 illustrates the influence of Eudragit L100 on the formation of degrada- tion products of norethisterone acetate. The bars designated : with figures 1 - 3 represent known degradation products (Nor- dion, 6-beta-hydroxynorethisterone acetate and norethister- one). The z-axis indicates the associated retention times, corresponding to the RP-HPLC that has been carried through.

The y-axis gives the percentages for the degradation products formed, in relation to the overall surface in the RP-HPLC chromatogram. The second row from the right on the x-axis shows that a formulation containing no Eudragit L100 has the largest number of degradation products. With increasing con- tent of Eudragit L100 (frem right to left, of 1 - 10% Eu- dragit L100, relative to the dry matter), the sum of the deg- radation products decreases. The TTSs are stored for two ‘ months at 40 °C and 27% relative air humidity.

To improve cohesion, advantageously, additives, preferably metal ions, such as aluminium or titanium are incorporated.

If the adhesive power of the matrix has been reduced by the ) addition of film-forming polymers, this can be effectively compensated by admixing of strongly tackifying resins. As tackifying agents, colophony resins, polyterpene resins, pe- troleum resins, coumarone-indene resins, terpene phenol res- ins, hydrocarbon resins, liquid polybutene resins and the like may be used in the production of the composition accord- ing to the invention.

In the following, the invention will be illustrated by means of an example: . EXAMPLE: 1,4 g of estradiol, 7.5 g of norethisterone acetate, 105 g of acrylate adhesive (Durotak® 387-2287), 46 g of adhesive resin (e.g. Hercolyn® DE), 10 g of Eudragit L100, 30 g of glycerin, g of acetyl acetone and 0.1 g of aluminium acetyl aceto- : nate (4%-wt. in ethyl acetate) were mixed. The layer was ap- plied to a siliconized polyester film (e.g. Hostaphan®) with the aid of a doctor knife, at a wet-coating thickness of 200 pm. The moist film was dried for 30 minutes at 50 °C and subsequently laminated with a polyester film (e.g. Hosta- phan®). The weight per unit area of an adhesive film prepared in this manner was about 80.4 g/m2. From the laminate, TTSs of the desired size were punched out by means of a suitable punch. The TTSs were stored at various temperatures for ex- amination of their stability.

Claims (11)

1. Medicinal self-adhesive composition for transdermal ap- plication of an estrogen in combination with a gestagen, con- ~ taining (a) 25-90%-wt. of a self-adhesive acrylate copolymer, (b) 1-15%-wt. of a film-forming acrylate copolymer, characterized in that acid-reacting, : functional groups are contained, (c) 1-30%-wt. of tack-increasing additives, (d) 0.2-2.0%-wt. of estrogen and (e) 1-5%-wt. of gestagen.

2. Composition according to Claim 1, characterized in that the self-adhesive acrylate copolymer contains 2-ethylhexyl acrylate, vinyl acetate, hydroxyethyl acrylate and glycidyl methacrylate.

: 3. Composition according to Claim 1, characterized in that the film-forming acrylate copolymer contains 10-90%-wt. of methacrylic acid and 10-90%~-wt. of methyl methacrylate.

4. Composition according to Claim 1, characterized in that the tack-increasing additive is a derivative of colophony.

5. Composition according to Claim 1, characterized in that the tack-increasing additive is a polyterpene resin.-

6. Composition according to Claim 1, characterized in that a cohesion-increasing additive is contained.

7. Composition according to Claim 1, characterized in that the cohesion-increasing additive is a metal ion, preferably of aluminium or titanium.

8. Composition according to Claim 1, characterized in that the estrogen is a derivative of estradiol, especially 17-beta-estradiol.

9. Composition according to Claim 1, characterized in that the gestagen is a derivative of norethisterone, especially of norethisterone acetate.

10. Composition according to Claim 1, characterized in that it contains 1-20%-wt. of anhydrous glycerin.

11. The use of the composition according to any one of

. Claims 1 to 8 for producing a pharmaceutical product for pro- phylaxis and treatment of climacteric complaints.