MXPA97005291A - Patch that contains estrad - Google Patents

Abstract

The present invention relates to a patch containing an active ingredient for the controlled release of estradiol or its pharmaceutically tolerable derivatives alone or in combination with progestins. This patch is composed of a backing layer, a reservoir containing the active ingredient secured to it, which is produced using adhesives, and a removable protective layer. It is characterized because the adhesive contains ethylcellulose, esters of anhydrous and / or hydrated colophonium and lauric acid.

Description

PARCH E THAT CONTAINS ESTRADIOL FIELD OF THE INVENTION The invention relates to an active substance carrier patch intended for the controlled administration of estradiol or its pharmaceutically tolerable derivatives alone or in combination with progestins through human skin or the skin of an animal, formed by a pressure adhesive of ethylcellulose, colophonium esters and lauric acid, to its use and to a process for its manufacture.

BACKGROUND Patches containing estrogen are known today. However, they have the disadvantages of containing ethanol or present the potential risk that the active ingredient recrystallizes over time. The simultaneous administration of estradiol and ethanol in a skin patch formulation is known from DE-OS 32 05 258 and EP 0 285 563. However, the manufacture of this patch is very cumbersome and the comfort of use after application is low due to the lack of flexibility. European patent EP 0 285 563 describes a transdermal therapeutic system for the combined application of estrogens and progestins. The reservoir contains the formulation of the active principle and eventually a membrane as well as ethanol as a percutaneous agent that improves the absorption characteristics. Since the release of the active principle is mainly controlled by the membrane, this transdermal therapeutic system differs substantially from the active principle patch of the present invention. In said patch the adhesive exclusively fulfills the function of fixing the patch on the skin. It is not its main function to contribute to the control of the release of the active principle, but only this is a probably undesirable secondary effect. In this case it is the so-called "bag type patch" because the preparation of the active ingredient is in a bag, formed by an impermeable backing layer and a membrane with an adhesive layer. Due to its complex construction the manufacture of the patch is very complex, since it is necessary to separately manufacture the individual components and these must be assembled in a patch in another manufacturing step. Unlike this system of the invention of a single layer, European patent EP 0 275 716 describes a two-layer transdermal system for the simultaneous administration of one or more estrogens. Those that are dissolved or microdispersed in the polymeric layer. In this case, the adhesive layer contains, apart from the active ingredients, substances that improve transdermal absorption. The polymeric layer and the pressure adhesive may be composed of polyacrylates, silicones or polyisobutylenes. European patent EP 0 072 251 discloses a flexible, liquid-absorbing and medicated dressing. The substrate fixed in the flexible backing layer consists of a hydrophilic matrix based on hydrophilic polysaccharides of high molecular weight and / or polyacrylic acid, polyacrylamide, ethylene-vinyl acetate copolymers and other polymers, as well as a liquid phase on the basis of of a solution or emulsion of carbohydrate, proteins and polyvalent alcohols and several active principles, among which are also hormones. The fundamental characteristics of this invention is the moisture absorbing adhesive. European patent EP 0 328 806 describes a transdermal therapeutic system without membrane, whose matrix is formed of a polyacrylate adhesive, a solvent, a penetration and estrogen enhancer, its derivatives and combinations. In the international patent WO 87/07 138 there is described an estradiol patch provided with a backing layer, a matrix carrying the active principle and a pressure adhesive, covered with a removable protective layer. The manufacture of the matrix and the pressure adhesive is carried out in very complex technological processes by means of homogenized, degassing, coating, drying and subdivision. In one embodiment, it is even necessary to coat the backing layer with a pressure adhesive, which requires another processing step. The assembly of the indivl parts is carried out in a separate stage of the process. Consequently, the manufacture of the patch is generally very complex and cumbersome. Through the US patent 46 24 665 systems have been known, which contain in the reservoir the active principle in microencapsulated form. The reservoir has been embedded or lodged between the backing layer and a membrane. The outer edge of the system is provided with a pressure adhesive. The construction and manufacture of this system are very complex, because it is necessary to microencapsulate the active principle and distribute it in a liquid phase homogeneously, which in later stages of processing is included between the back layer and the membrane. Additionally the system must be provided with an adhesive edge and with a protective layer. Furthermore, EP 0 186 019 discloses active substance patches in which expandable polymers are incorporated into a mass of rubber / adhesive resin in water and from which estradiol is released. However, it was found that the release of estradiol from these therapeutic patches is too low and does not correspond to the therapeutic requirements. German patent DE-OS 20 06 969 discloses a patch or an adhesive bandage with systemic effect, where contraceptive substances are included in the adhesive component or in the adhesive film. The adhesive film can be an acrylate. German Patent DE-OS 39 33 460 discloses a therapeutic patch which, as an active ingredient, contains estrogen on the basis of homo- and / or copolymers with at least one acrylic or methacrylic acid derivative in combination with expandable or swellable substances. Water. However, it was found that transdermal pressure adhesive therapeutic matrix systems, those containing the active ingredient partially or totally dissolved, have a too low release capacity of the active principle and also present the potential risk that the active ingredient recrystallizes at the same time. long time Due to this, the release of active principle decreases and the estrogen-carrying patch no longer meets the therapeutic requirements. Therefore, the object of the present invention is to avoid the drawbacks and to provide a stable patch, ie free of recrystallization, containing estrogen with sufficient release, whose release characteristics are not altered during storage. Surprisingly, it was found that the proposed object has been achieved by means of a pressure adhesive carrying estrogen of ethylcellulose, esters of colophonium and lauric acid. Accordingly, the object set forth above has been solved by means of an active agent carrier patch according to the main claim. The secondary claims refer to particularly preferred embodiments of the object of the invention.

DESCRIPTION OF THE INVENTION Accordingly, the invention relates to a carrier patch of active principle suitable for the controlled administration of estradiol or its pharmaceutically tolerable derivatives alone or in combination with progestins, formed by a backing layer, a reservoir carrier of active principle related to said layer, manufactured with the use of pressure or contact adhesives and a removable protective layer, where the pressure adhesive contains ethylcellulose, hydrogenated or unhydrogenated rosin esters and lauric acid. Ethylcellulose is a cellulose ether prepared by the reaction of ethyl chloride with alkali cellulose. In relation to the structure it is generally assumed that a cellulose molecule consists of an anhydroglucose chain or units of cellobiose, linked by means of oxygen bridges. These long chains of anhydroglucose with oxygen bridges have a great resistance together with a good flexibility. These properties are exploited in the case of the estradiol carrier patch according to the invention in order to give the pressure adhesive sufficient cohesion, a requirement for the free removal of the patch residue from the skin, once the application has been completed. The pressure or contact adhesive contains ethylcellulose in a proportion of 5-25% by weight, preferably 8-14% by weight. Among the colophonium esters are, for example, the methyl ester, the glycerin ester, the pentaerythritol ester, the pentaerythritol ester modified by maleinic acid, the glycerin ester modified by maleinic acid and the triethylene glycol ester. The proportion of the rosin esters in the estrogen-bearing pressure adhesive is 50-90% by weight, preferably 60 -. 60-80 in weight. The pressure adhesive may contain hydrogenated rosin esters either alone or in combination with the non-hydrogenated rosin ester. Those particularly preferred rosin esters are the triethylene glycol ester, the glycerin ester and the pentaerythritol ester of the hydrogenated rosin. Lauric acid is a carbonic acid with 12 carbon atoms. It produces an increase in the penetration of estradiol through the skin. The mechanism is unknown. The pressure adhesive contains lauric acid in a proportion of 1-20% by weight, preferably 2 to 15% by weight. The recrystallized free estrogen carrier patch with a sufficient release of active ingredient contains in the reservoir estradiol and its pharmaceutically tolerable derivatives either alone or in combination with progestins, in a concentration of a total of 1-15% by weight with respect to the total of the components of the reservoir, particularly in a molar ratio of 1: 1 to 1: 10. The reservoir carrier of estradiol may contain at least one component of the group comprising the aging protection agents, plasticizers, antioxidants and enhancers of the absorption. The skilled person knows the suitable plasticizers and they are described, for example, in German patent DE 37 43 946. The oestradiol carrier reservoir usually contains plasticizers in a proportion of up to 5% by weight. On the other hand, the carrier reservoir of active principle contains aging protection agents in a concentration of up to 1% by weight. These agents are known to the person skilled in the art and are described, for example, in German patent DE 37 43 946. Those materials for the waterproof backing layer and the release layer are also known to the person skilled in the art (for example German patent DE 38 43 239). The estradiol carrier reservoir can be prepared from the solution or a fusion. On the other hand, the reservoir may consist of several layers. In the case that the reservoir does not have sufficient adhesion on the skin, this can be provided with an adhesive layer of free pressure of active principle or with a perimetral self-adhesive edge. In this way it is ensured that the transdermal patch adheres during the entire period of application on the skin. A particularly preferred construction of the transdermal patch bearing estradiol is a matrix system, where it is known that the matrix controls the release of the active principle and follows the law (t) 1/2 of Higuchi. However, this does not mean that in special cases a membrane system is also advantageous. In this case between the reservoir and the adhesive pressure layer there is a membrane controlling the release of active principle. The thickness of the transdermal patch depends on the therapeutic requirements and can be conveniently adapted. It is generally in the range of 0.03-0.6 mm.

EXAMPLE 1 75.0 g of hydrogenated colophonium triethylene glycol ester (Staybelite Ester 3 E / from Hercules) and 10.0 g of hydrogenated colophonium glycerol ester (Staybelite Ester 10E / from Hercules company) are mixed by kneading. 100 ° C for 5 minutes. Subsequently, 2.5 g estradiol and 2.5 g lauric acid are incorporated. Knead for 30 minutes. After heating to 140 ° C, 10.0 g of ethylcellulose N50N F (Hercules company) are added in portions and then kneading is continued for 2.5 hours. The adhesive composition thus obtained is applied by means of a Hotmelt coating system (nozzle applicator system) on the removable protective layer (Hostaphen RN 100 coated on one side with silicone from the company Kalle), which results in a carrier reservoir of active principle with a surface weight EXAMPLE 0 1 75.0 g of hydrogenated colophon triethylene glycol ester (Staybelite Ester 3E / from Hercules) and 10.0 g of hydrogenated colophonium glycerin ester (Staybelite Ester 10E / from Hercules company) are mixed by kneading. ° C for 5 minutes. Then 2.5 g estradiol and 2.5 g lauric acid are incorporated. Knead for 30 minutes. After heating to 140 ° C, 10.0 g of ethylcellulose N50N F (Hercules company) are added in portions and then kneading is continued for 2.5 hours. The adhesive composition thus obtained is applied by means of a Hotmelt coating system (nozzle applicator system) on the removable protective layer (Hostaphen RN 100 coated on one side with silicone from the company Kalle), which results in a carrier reservoir of active principle with a specific surface weight of 80 g / m2. The impermeable backing layer is laminated on this reservoir (polyester sheet, 15 μm thick). Therapeutic patches of 16 cm2 were then stamped.

E J E M P L O S 2 v 3 The manufacture was carried out as described in Example 1, but with the raw materials and the amounts indicated in Table 1 (formulation).

Analytical The release of the active principle by the transdermal patches of 16 cm2 was determined according to the rotary bottle method described in the USP XXI I standard in a 0.9% by weight saline solution at a temperature of 37 ° C. - To measure the penetration through guinea pig skin, the skin was placed in a Franz cell. An estradiol carrier patch with an area of 2.54 cm2 was adhered to the skin and the release of active principle at a temperature of 37 ° C (accepting medium: 0.9% saline) was measured (Bibliography: Umesh V Banakar Pharmaceutical dissolution testing (First edition 1991) - The test of the recrystallization manifestations was carried out visually against the light.The results are shown in Table 2.

TABLE 1 . Composition (Data in g). Exp. Ethylcellulose Staybelite Ester Ac. laurico Estradiol N50N F 3E 10E 1 10, 00 75.0 10, 0 2, 5 2, 5 2 10.0 70.0 10.0 7, 5 2, 5 3 12, 0 65, 5 9.0 10.0 2, 5 TABLE 2 Results of the analysis Example Cont. Estradiol Liber. in vitro Penetration in Recristaliz. μg / 16cm2 μg / 16cm2.4h in guinea pig skin μg / 16cm2.24h 1 3200 645 179 none 2 3200 843 157 none 3 3200 1368 180 none according to 3200 1125 95 considera.

DE 3933460 As seen in the Table, considerably better penetration is obtained through guinea pig skin compared to the Comparative Example according to DE 3933460. Parallel to this it can be seen that the recrystallization disappears completely in the examples according to the invention.

Claims (15)

1. R E I V I N D I C A C I O N S 1 . An active substance carrier patch for the controlled administration of estradiol or its pharmaceutically tolerable derivatives, alone or in combination with progestins, formed by a backing layer, a carrier reservoir of the active principle related thereto, manufactured by means of the use of adhesives of pressure, and a releasable protective layer, wherein said pressure adhesive contains ethylulose, unhydrogenated and / or hydrogenated rosin esters and lauric acid.
2. 2. The active substance carrier patch according to claim 1, wherein it contains lauric acid in a proportion of 1-20% by weight, preferably 2-15% by weight.
3. The carrier patch of an active ingredient according to claim 2, wherein the pressure adhesive contains 5-25% ethylulose, preferably 8-14% by weight.
4. The carrier patch of an active ingredient according to claim 2, wherein the pressure adhesive contains rosin esters in a proportion of 50-90% by weight, preferably 60-80% by weight.
5. 5. The active substance carrier patch according to claim 4, wherein the pressure adhesive contains estradiol or its pharmaceutically tolerable derivatives, alone or in combinations with progestins in a proportion of 1-15% by weight, preferably 1.5. -5.0% by weight.
6. 6. The active agent carrier patch according to one of claims 1-5, wherein the backup layer is impermeable to the reservoir components.
7. 7. The active substance carrier patch according to any of claims 1-6, wherein the rosin esters are selected from the group consisting of the methyl ester, the glycerin ester, the pentaerythritol ester, the pentaerythritol ester modified by the maleic acid , glycerin ester modified by maleinic acid and triethylene glycol ester.
8. The carrier patch of an active ingredient according to any of claims 1-7, wherein the reservoir contains estradiol or its pharmaceutically tolerable derivatives in combination with gestagens in a molar ratio of 1: 1 to 1: 10.
9. 9. The active agent carrier patch according to any of claims 1-8, wherein the reservoir contains at least one component of the group consisting of aging agents, plasticizers, antioxidants and absorption enhancers.
10. The active agent carrier patch according to any of claims 1-9, wherein the pressure adhesive is a solvent-type contact adhesive or a fusion-type contact adhesive. eleven .
11. The active substance carrier patch according to any of claims 1-10, wherein the reservoir is formed of several layers and may be provided with an additional adhesive layer of free pressure of active principle.
12. 12. The active substance carrier patch according to any of claims 1-11, wherein a membrane controlling the release of the active principle has been placed between the reservoir and the adhesive pressure layer.
13. 13. The active agent carrier patch according to any of claims 1 -12, wherein the reservoir is provided with a perimetral pressure adhesive edge.
14. 14. The active agent carrier patch according to any of claims 1 - 13, wherein the thickness of the active principle carrier patch is in the range of 0.03-0.6 mm.
15. 15. Use of the active agent carrier patch according to any of claims 1-14, wherein it is as a preparation for therapeutic purposes in human and veterinary medicine, as well as in cosmetics.