Transdermal, hormone-delivering therapeutic system

[0002] The invention relates to an active compound-containing patch for the controlled delivery of oestradiol or its pharmaceutically acceptable derivatives, alone or in combination with gestagens, to human or animal skin, having an active compound-containing reservoir based on ethylcellulose and contact adhesives comprising adhesive resins.

[0003] Transdermal therapeutic systems have been known for a relatively long time, in particular also for the transdermal administration of hormones, especially oestrogens, if appropriate in combination with gestagens.

[0004] The active compounds are provided for this in an active compound reservoir based on contact adhesives, whose adhesiveness must guarantee adequate skin contact on application without excessive softening and without skin irritation occurring, and whose absorption and release of active compound must conform to the desired continuous systemic supply of active compound through the skin.

[0005] As a basis for reservoir layers comprising oestradiol, inter alia, different materials based on rubber or polyacrylate, in particular comprising ethanol, have already been proposed (e.g. DE-A-32 05 258 and EP-0 275 716).

[0006] DE-A-39 33 460 describes active compound patches based on homo- and copolymers comprising at least one derivative of acrylic or methacrylic acid, which are additionally intended to contain water-swellable substances.

[0007] DE-B 40 20 144 discloses a transdermal system, optionally also containing hormone, comprising at least one self-adhesive active compound layer, which besides polyacrylate and a film-forming agent compatible therewith should contain a wide quantitative range of plasticizing active compounds and auxiliaries.

[0008] A recently described transdermal therapeutic system (see DE-A 195 00 662) comprises an active compound reservoir, containing an oestradiol and, if appropriate, gestagens, based on ethylcellulose having a high proportion of esters of optionally hydrogenated colophony as a tackifying resin together with up to 20% by weight of lauric acid, which is intended to counteract recrystallization of the active compound and thus a decrease in its release rate.

[0009] Surprisingly, it has now been found that an unexpectedly high active compound release of oestradiol and in particular norethindrone acetate can be achieved from an active compound reservoir based on ethylcellulose and tackifying resin which is provided with an unusually high proportion of plasticizer.

[0010] The patch according to the invention of the type mentioned at the outset is accordingly characterized in that the contact adhesive contains a high proportion of plasticizer.

[0011] In particular, the contact adhesive contains at least 15% by weight, preferably at least 20% by weight, of plasticizer.

[0012] The active compound-containing patch can otherwise contain emulsifiers, antioxidants and absorption enhancers.

[0013] Such a patch can be employed, in particular, for a high combined release of both oestradiol and norethindrone acetate.

[0014] Preferred formulations of such hormone-containing contact adhesive materials according to the invention have the following composition (in % by weight):

[0015] Although the addition of plasticizers to active compound-containing contact adhesive materials is known per se, such as, for example, also according to the said DE-A 40 20 144, addition of plasticizer to the customary contact adhesives based on polyacrylates, block copolymers and polyisobutylenes is only possible to a limited extent, since from a certain concentration the cohesion of the contact adhesives decreases and they thus become unsuitable for transdermal application.

[0016] The fact that just materials based on ethylcellulose/adhesive resin with unusually high additions of plasticizer would afford particularly useful transdermal therapeutic systems with increased skin penetration of the hormones and a particularly low recrystallization tendency thereof together with good wearing properties of the TTS was in no way to be foreseen, as the said, only recently disclosed TTS development having an active compound reservoir based on ethylcellulose/adhesive resin shows, which as an additive contains lauric acid and not—as now—high proportions of plasticizer.

[0017] The composition according to the invention of the active compound reservoir based on ethylcellulose/adhesive resin with a high proportion of plasticizer, but without lauric acid, shows a markedly increased release of hormone compared with the materials according to DE-A 195 00 662, in particular on incorporation of a combination of oestradiol and norethindrone acetate.

[0018] This is illustrated by the results given below (Tables 1 and 2), of which Table 1 shows the composition of the investigated materials and Table 2 the results of series of tests on the release of active compound.

[0019] It is to be seen that by means of the plasticizer content according to the invention a clear improvement in the release and penetration of active compound is achieved.