MXPA06010705A - Pharmaceutical preparation containing drospirenone for application to the skin - Google Patents

Abstract

The invention relates to a pharmaceutical preparation containing drospirenone for application to the skin. The amount of drospirenone contained in said preparation in an initial state does not exceed saturation solubility. However, one the preparation is applied to the skin, the saturation solubility of drospirenone is exceeded. The pharmaceutical preparation enables inter alia transdermal application of contraceptively effective amounts of drospirenone.

Description

PHARMACEUTICAL PREPARATION FOR APPLYING ON THE SKIN CONTAINING DROSPIRENONE Field of the Invention The invention relates to a pharmaceutical preparation for application to skin containing drospirenone. The amount of drospirenone contained in the preparation in its initial state is not higher than that of saturated solubility, whereas after applying the preparation on the skin, the saturated solubility of the drospirenone is exceeded by release of dissolution-activating components. Background of the Invention As is known, many steroid hormones are now administered transdermally. This application is used within a hormone replacement therapy, both in men and women, or for contraception in women. Although numerous transdermal drug forms are used, the active substances that are applied in this way are few. From the group of estrogens, this is true for estradiol and ethinylestradiol (eg Estraderm, Cli ara®, Fem7, OrthoEVRA®, EstraDOT); from the group of progestins, for levonorgestrel, norethisterone and norethisterone acetate (eg Fem7 Combi, CorabiPatch) and norelgestromin. In andrology, testosterone is available in transdermal drug forms (eg, Androderm®, Testoderm®, Testogel®). However, the feasibility of the transdermal administration does not depend on the good absorption by the skin of the steroid hormones, but exclusively on its potent effect. Ethinylestradiol and levonorgestrel produce an effect with daily doses ranging from 20 to 50 μg. Norethisterone acetate belongs to the group of substances with the weakest effect and a daily transdermal dose of 125-250 μg is typically required. Among the progestins currently used therapeutically include dienogest and drospirenone, which belong to the group of less potent substances, since they must be administered characteristically in oral doses of 2 to 3 mg daily to display its contraceptive effect. Contrary to the so-called high power progestins, such as p. ex. Gestoden or norelgestromina, whose daily dose is in a range of milligrams barely higher than one figure, drospirenone and dienogest should be considered as unsuitable for transdermal administration until the present. The only steroid hormone that can be administered transdermally in daily doses of the milligram range is testosterone. However, the commercial products in Testoderm® and Androderm® patches are known for their poor local tolerance and poor acceptance by patients as a result of the application site - in the scrotum (Testoderm®) or the size of the patch required which is 74 cm2 (Androderm®, 2 patches simultaneously). For transdermal testosterone therapy, the Testogel® gel preparation is also available, which allows resorption of approx. 5-10 mg of testosterone per day with less potential for local irritation and greater comfort of use. From the patent literature a large number of pharmaceutical preparations are known to be applied on the skin which contain gestagen. The patent document WO 97/11680 Al describes a donor for the administration of progestins and estrogens. German patent document 199 06 152 Al claims deposit systems, in which the active substance is dissolved in highly volatile solvents such as ethanol. The transdermal administration of active substances by means of adhesive matrix systems is described. WO 99/15156 Al discloses a method for manufacturing a transdermal administration form, wherein the active substance (s) may be steroid hormones and may be present in the matrix, on the carrier, in a saturated or supersaturated state.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph in which the comparison of the permeation of testosterone and drospirenone can be observed, wherein: A = permeated active substance, B = time T = testosterone D = drospirenone, and Figure 2 shows the mass transport of testosterone and drospirenone, where: C = mass transport.

DETAILED DESCRIPTION OF THE INVENTION The object of the invention is to find transdermal administration forms of progestin that are not very potent to be applied on the skin. According to the invention, the object is achieved by means of a pharmaceutical preparation to be applied to the skin with a drospirenone content, in which the amount of drospirenone contained in the preparation in its initial state is not higher than that of saturated solubility and then if applied on the skin, the saturated solubility of the drospirenone is overcome by the release of the components that activate the solution. According to the invention, the saturated solubility of the drospirenone in the preparation can be overcome during its application in at least one factor 5, preferably at least one factor 10. The saturated solubility of the drospirenone in the preparation during application is exceeded, 1 hour, in at least factor 2, preferably in at least factor 5. The pharmaceutical preparation may contain ethanol or isopropanol.

According to the invention, the pharmaceutical preparation may contain a crystallization inhibitor corresponding to the drospirenone and / or may contain at least one permeation activator. It has been found that the crystallization inhibitor additive is a soluble polyvinylpyrrolidone. The pharmaceutical preparation may be a semi-solid preparation in the form of a gel containing alcohol or a liquid preparation containing alcohol in the form of a lotion, foam or spray. The liquid or semi-solid preparation containing alcohol may also be part of a transdermal patch of the deposit system type. It was also found that during the application, the solubility of the drospirenone exceeds the saturation by at least a factor of 1.5, preferably by at least a factor of 2, and that the alcohol preparation has an alcohol content of at least 60% (m / m), preferably at least 65% (m / m). In addition to drospirenone may also contain an estrogen. I also know. found that during application on the skin, the content of estrogen also passes from a semi-saturated or barely saturated state to an oversaturated state. Estrogen can be ethinylestradiol. The preferred embodiment of the invention is a transdermal gel with an ethanol and water content. The active substance drospirenone is present in the fully dissolved state. To ensure sufficient solubility of the drospirenone, with contents of preferably 0.2-1% (m / m), particularly 0.5 to 1% (m / m) in the gel, an ethanol content of at least 60% (m / m), with particular preference up to 65% (m / m). As a result of the high alcohol content, in addition to the ionic gel formers based on polyacrylic acid (carbomers or carbonates, eg carbopol 940, 941 or 980), gel formers from the group of derivatives of cellulose, p. ex. hydroxymethyl-hydroxyethylcellulose or hydroxypropylcellulose. Other additives that may be included are, above all, permeation activators, skin re-fatting substances and antioxidants. In order to allow drospirenone supersaturation of. the systems of the invention during its application is preferred the use of a group of auxiliary substances of low number of molecules that allow a good dissolution of drospirenone or substances that come off the preparation, either by its high volatility or by its capacity of permeation of the skin particularly- good under the conditions of its application, which causes a supersaturation of drospirenone. Finally, these preferred auxiliary substances also favor a good toxicological tolerance when applied to the skin. Such substances are selected preferably but not exclusively from the group consisting of ethanol, isopropanol (2-propanol), 1,2-propanediol (propylene glycol), dipropylene glycol, 1,3-butanediol, diethylene glycol monomethyl- and ethyl ether, propylene carbonate and isopropylidene glycerol, as well as of monoterpene of essential oils. If necessary, these activators of the drospirenone solution which are easily released from the formulation by evaporation or by transdermal absorption can be combined with one or more co-solvents which do not evaporate easily or are absorbed by the dermis.

Another preferred embodiment of the present invention are transdermal systems of the deposit type. For the semisolid preparations that contain them, the same warnings apply as for transdermal gels. The preparation of the storage systems and their loading can be carried out in a known manner. It has been found that drospirenone applied in a hydroethanolic vehicle on mouse skin, in vitro, is absorbed almost as well as testosterone. From this it can be deduced that also when applied in humans, daily doses of drospirenone of a range of just over 10 mg can be achieved, similarly to testosterone. This unexpected finding is probably related to a very high degree of supersaturation of active substance during drying of the vehicle when the preparation is applied. Although the mechanism of evaporative supersaturation, especially of alcoholic components of transdermal gels, lotions or sprays, is discussed, in the formulations of the invention, unexpectedly high supersaturation levels of drospirenone were appropriate and practicable. Determination of the supersaturation factor presents during the application of the respective preparations: - In gels, lotions, foams and sprays: To simplify the analysis and especially the analytical elaboration of the samples, the determinations of the solubility of drospirenone of these preparations or of the residues of them which are formed by drying, are carried out on a semiteoric basis. The semiteoric approach consists in that only the liquid components of the formulation are used for this aspect. In the case of gels, lotions and sprays, the gel-forming or film-forming polymer component or the thickener is, as a rule, negligible in terms of its quantity, although it often disturbs considerably the processing of the samples. In the context of this invention, a test solution containing only the liquid components of the aforementioned preparations is used. In the specific case of example 2, the following mixture is analyzed substitutively: -Example of test solution (before drying) Parts (m / m) * Sum of 20.0 g water + 3.55 g water of 3.70 g 0.1N NaOH (NaOH is not used, since this only corresponds in the presence of the polymer and in its absence would create a strongly alkaline medium that would decompose it The determination of the solubility of drospirenone in the test solution before it is dried is carried out as follows: 10 g of heavy test solution are combined, while mixing with drospirenone by means of a magnetic mixer until it is formed a sediment clearly visible at the bottom, this mixture is stirred for at least 24 hours, after which the sediment must remain present, otherwise more drospirenone is added and the operation is repeated. Approx 1.0 ml of test solution and placed in a 1.5 ml autosampler (screw-capped autosampler) Finally, the sample is centrifuged for at least 3000 rpm for 10 minutes to separate the undissolved drospirenone at the bottom of the The concentration of drospirenone is then determined with an appropriate HPLC method in an aliquot of the obtained supernatant. The value obtained corresponds to the saturated solubility of drospirenone in the test mixture before drying (drospirenonasa [mg / ml]). The drospirenone condition? Nit = drospirenonasl, where drospirenonainit [mg / ml] is the initial concentration of drospirenone in the preparation, governs the preparations of the invention. The determination of the solubility of drospirenone in the liquid test mixture after drying is carried out as follows: The test solution is spread on a flat inert support with a layer thickness of approx. 50 μm and allowed to dry for a defined period of time at approx. 32 ° C (skin surface temperature) under ambient conditions and without covering it. The period of time depends on the expected use time; for a daily application it is 24 h. You can also select a shorter period of time, p. ex. when the degree of drying must be determined before the end of the application.

For the application area of this invention, the thickness of the 50μm layer is defined as the standard thickness for the transdermal application of gels, lotions or sprays. In the case of commercial Testogel, p. ex.- 5 ml of gel on the arm. With the defined standard thickness of 50 μm, a theoretical application surface of 90 cm2 (assumed density of the gel, approximately 0.9 g / cm3) is obtained for 5 ml, thus achieving a sufficient approximation to the application in vivo . In the case of the example of the mentioned test solution, approx. 4.36 g of test solution - measured exactly - (weight = Gpi) in a tared Petri dish of 10 cm in diameter (corresponds to 78.53 cm2), resulting in a layer thickness of approx. 50 μm. This preparation is dried on a heating plate at approx. 32 ° C for 24 h (corresponding to a daily application). The amount of test solution and the diameter of the tray are mentioned by way of example and are not limiting. The values can be varied within the described context. The test mixture does not move or mix mechanically during the test, but is allowed to stand. No particular air circulation is foreseen on the sample.

At the end of the test the weight of the dry residue of the test solution is determined (weight = GP2). From the obtained values, the drying factor of the test solution is calculated by means of equation 1. Equation 1: FE = GP1 / GP2 Accurately weighed approx. 250.0 g (weight = GR1) of the test solution contained in the composition before drying and place in a 500 ml tared wide neck flask. Next, this preparation is concentrated in a Rotavapor at 32 ° C and low pressure until the remaining amount of the preparation is in the same weight ratio with respect to the initial amount, as was found after drying in a tray of Petri for a defined period of time, until the remaining quantity / weight (weight = GR2) meets equation 2. Equation 2: GR2 = GR1 / FE The increased preparation of test solution in the Rotovapor serves to obtain a greater amount of residue for the next determination of the solubility of drospirenone. It is again worked at 32 ° C in order to reproduce the evaporation conditions on the surface of the skin in a quantitatively accelerated but qualitatively as faithful way as possible. From the amount of residue finally obtained in the flask, 1.0 g * is removed and passed to an automatic sampler (autosampler) with a screw cap. To this residue is added 100 mg drospirenone. Then, this preparation is treated for one hour in an ultrasound bath. Then, the sample is left to rest for 24 hours under ambient conditions. Finally, the sample is centrifuged for 10 minutes at least at 3000 rpm in order to separate the undissolved drospirenone at the bottom of the sample. The drospirenone concentration is then determined with an appropriate HPLC method in an aliquot of the obtained supernatant. The value obtained corresponds to the saturated solubility of drospirenone in the dry test solution (drospirenonas2 [mg / ml]). * In the case that only less than 1 g can be removed, typically at FE > 200, the preparation can be increased correspondingly in the Rotavapor or the final determination is reduced p. ex. to 50 mg drospirenone in 0.5 g dry test solution. The supersaturation factor FSs referred to the drospirenone of the test solution during drying is calculated according to equation 3, where the initial concentration of the drospirenone in the preparation is drospirenonamit (mg / ml): Equation 3: Fss = drospirenone? Nit (mg / ml) x FE / drospirenones2 (mg / ml). In the claims of this patent application reference is made to the oversaturation factor Fss • ün value 5 corresponding to FSs means p. ex. , that the saturated solubility of drospirenone during the application of the preparation is exceeded by a factor of 5. - In transdermal patches of the deposit type: The solubility of drospirenone in the formulation of the active substance deposit is considered. Also in this case the semiteoric preparation is used and a test solution formed exclusively by liquid components in substitution form of the semi-solid formulation of the tank is analyzed. The determination of the saturated solubility in the preparation of the deposit is made on this basis and analogous to the determination of drospirenone in the gels, lotions and sprays.

The drying factor FE here replaces the determination of the concentration factor Fc, since the deposit is dried by transdermal permeation of liquid components. The surface of the deposit system that delivers active substance is covered with this film and the deposit system is weighed in this arrangement (GRSa) • Then, the deposit system is exposed for the period of time envisaged and at a temperature of 32 ° C , to pure water, as an acceptor liquid. For a system intended to be applied daily, the period of time foreseen is 24 h. Next, the system is weighed (GRS2) The determined weight loss corresponds to the drying factor FE of the tank preparation according to equation 4: Equation 4: FE = GRF / (GRS1 - GRS2), where GRF is the weight of the amount of formulation of the reservoir containing active substance before the test. The determination of the saturated solubility of drospirenone in the concentrated formulation of the deposit (drospirenonas2) and the supersaturation factor Fss is carried out analogously to that described for gels, lotions and sprays from equation 1, where Fc takes the place of FAITH. EXAMPLES OF EMBODIMENT EXAMPLE 1 - Hydro ethanolic gel Parts (m / m) Drospirenone 1.0 Testogel® 99/0 Drospirenone is mixed directly with Testogel® that is obtained commercially and completely dissolved in this. The composition of Testogel is the same as that of Androgel®: 100 g of gel contains: Testosterone 1.0 g Carbopol 980 0.90 g Isopropylamistate 0.50 g NaOH 0.1 N 4.72 g Ethanol (95% w / w) 72.5 g * Purified water. Ad 100 g * Corresponds to 67 g ethanol Example 2 - Hydro-ethanolic gel based on polyacrylate Parts (m / m Drospirenone 1.0 Ethinylestradiol 0.1 Isopropylmyristate 1.0 Carbopol 940 0.7 NaOH 0.1N 3.7 Water Purified 20 Ethanol 96% Ad 100.0 The preparation is carried out in a manner known to the technician by dissolving / mixing all the components and final neutralization of the gel former with dilute sodium hydroxide, whereby gel formation is initiated. Isopropyl myristate acts as a re-greasing agent on the skin Drospirenone supersaturation occurs during the application by evaporation of ethanol eg 3 - Cellulose-based hydro-ethanolic gel with crystallization inhibitor additive Parts (m / m Drospirenone 0, 5 Ethyl oleate 2.0 Colidon 12 PF 0.5 Hydroxyethylcellulose 1.0 Water 30.0 Ethanol 96% Ad 100.0 The preparation is carried out in a manner known to the artisan by preparing the gel former, methylcellulose, with water and alcohol Y finally adding the auxiliary and active substances. The supersaturation of drospirenone occurs during the application, by evaporation of ethanol. Example 4 - Transdermal patch of the deposit system type.

Drospirenone 5.0 mg * Ethanol 96% approx.196 μl Patch Androderm of 1 patch 2, 5 mg The protective wrap of an Androderm patch previously weighed with accuracy is removed and the content is allowed to evaporate under ambient conditions with the membrane that now is uncovered, upwards, until they have evaporated approx. 180 mg of the content. Then the deposit system is again covered with the protective film. This pretreatment is necessary to create space for the drospirenone solution that is added as described below. 100 mg drospirenone is dissolved in 4 ml ethanol 96% while undergoing the ultrasound action. From this solution, 500 μl is aspirated in a 1 ml disposable syringe with a steel cannula (0.9x40 mm). With this syringe the deposit system of the Androderm patch is then punctured and injected approx. 200 μl of solution in the tank. This is possible thanks to the fact that it is punctured in a supplementary ventilation hole that is in the place where the air bubble of the semisolid deposit is located. The two puncture sites are then covered with a piece of adhesive tape. The content of the deposit is mixed by kneading the deposit carefully with your fingers for a few minutes. Before being used for experimental purposes, the system is left to equilibrate for at least 24 h. The supersaturation of drospirenone occurs during the application of the system, substantially by transdermal absorption of ethanol, which develops substantially faster than that of drospirenone. Example 5 - Transdermal Spray Parts (m / m Drospirenone 0.5 Ethinylestradiol 0.1 Oleylalcohol 1.0 1, 2-Propanediol 0.5 Ethanol 96% 60.0 Dimethylether Ad 100.0 Supersaturation of drospirenone occurs during application , substantially by evaporation of ethanol El-dimethyl ether serves as a propellant for the spray Example 6 The formulation of Example 1 was analyzed for the permeation of drospirenone through mouse skin, as compared to testosterone. applied about 200 mg of the preparation of Example 1 on bare mouse skin which was fixed as permeation membrane in modified Franz permeation cells.The results of Figure 1 are the average values of experiments of n = 7. of hairless mouse, HsdCpb NMRI-nu / nu, Harian Bioservice, Walsrode.Ant acceptor for the cells Franz: Potassium chloride 0.6 g Potassium diphosphate 0.09 g Sodium chloride 10.905 g Sodium bisphosphate dihydrate 0 , 09 g HEPES 8.94 g Gentamicin sulfate 0.075 g? -cyclodextrin 7.5 g Purified water ad 1500 g At 3, 6, 9, 12, 15 and 18 hours samples of 100 μl per time were taken from the acceptor medium of the Franz cells by means of an automatic sampler system and injected into an automatic HPLC device. HPLC method: Column LiChrospher 100 RP 18.5μm, 125x3 mm Mobile phase Acetonitrile / H20 (40/60) Flow 1 ml / min Temperature 40 ° C Injection volume. 100 μl Long. detection wave (UV) 244 nm (testosterone), 261 nm (drospirenone) Example 7: The formulation of example 1 was analyzed comparatively for the permeation of drospirenone and testosterone in human skin (female's abdomen skin from cosmetic reduction , Dermatomized at a layer thickness of approx. 450 μm), see figure 2. A TABLE 1: Testosterone permeation of example 1 through human skin: Average cumulative permeability [μg / cm2] of 1% testosterone in Testogel (K2053) through dermatomized human skin. 10 fifteen TABLE 2: Permeation of drospirenone from example 1 to C through human skin Average cumulative permeation (μg / cm2) of 1% drospirenone in Testogel (K2053) through dermatomized human skin.

From these data it can be deduced that when applied to human skin, the permeation of drospirenone is still up to 40% of that of testosterone. Since 5 to 10 mg daily of Testogel can be administered, it can be deduced that drospirenone 3-5 mg / d can also be administered transdermally. In this way transdermal application of drospirenone amounts with contraceptive effect is possible.

Claims (15)

1. Claims 1. Pharmaceutical preparation for application on skin containing Drospirenone CHARACTERIZED BECAUSE the amount of drospirenone contained in the preparation in its initial state is not higher than that of saturated solubility and after being applied to the skin, the saturated solubility of drospirenone it is overcome by detachment of components that activate the solution.
2. 2. Pharmaceutical preparation according to claim 1, CHARACTERIZED BECAUSE the saturated solubility of the drospirenone of the preparation is exceeded during its application in at least a factor of 5, preferably at least a factor of 10.
3. 3. Pharmaceutical preparation in accordance with claim 2, CHARACTERIZED BECAUSE the saturated solubility of the drospirenone of the preparation during the application is exceeded, after 1 hour, in at least factor 2, preferably by at least factor 5.
4. Pharmaceutical preparation according to one or more of the preceding claims, CHARACTERIZ DA PORQUE presents an ethanol or isopropanol content.
5. 5. Pharmaceutical preparation according to one or more of the preceding claims, CHARACTERIZED BECAUSE it contains a crystallization inhibiting additive referred to drospirenone.
6. 6. Pharmaceutical preparation according to one or more of the preceding claims, CHARACTERIZED BECAUSE the crystallization inhibitor additive is soluble polyvinyl pyrrolidone.
7. 7. Pharmaceutical preparation according to one or more of the preceding claims, CHARACTERIZED BECAUSE it contains at least one permeation activator.
8. 8. Pharmaceutical preparation according to one or more of the preceding claims, CHARACTERIZED BECAUSE it is a semisolid preparation in gel form containing alcohol.
9. 9. Pharmaceutical preparation according to one or more of the preceding claims, CHARACTERIZED BECAUSE it is a liquid preparation that contains alcohol in the form of a lotion, a foam or a spray.
10. 10. Pharmaceutical preparation according to one or more of the preceding claims, CHARACTERIZED BECAUSE it is a liquid or semi-solid preparation containing alcohol as part of a transdermal patch of the deposit system type.
11. 11. Pharmaceutical preparation according to claim 10, CHARACTERIZED BECAUSE the saturated solubility of the drospirenone of the preparation is exceeded during the application by at least a factor of 1.5, preferably by at least a factor of 2.
12. 12. Pharmaceutical preparation in accordance with one of claims 9 to 11, characterized in that the alcohol preparation has an alcohol content of at least 60% (m / m), preferably at least 65% (m / m).
13. 13. Pharmaceutical preparation according to one or more of the preceding claims, CHARACTERIZED BECAUSE in addition to drospirenone contains an estrogen.
14. 14. Pharmaceutical preparation according to claim 10, CHARACTERIZED BECAUSE during the application on the skin, the estrogen content also passes from a semi-saturated or barely saturated state to a supersaturated state.
15. 15. Pharmaceutical preparation according to claim 13 or 14, CHARACTERIZED BECAUSE the estrogen is ethinylestradiol.