Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Patent
1996-06-07
1999-05-11
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
424443, 424446, 424447, 424448, 514943, 514946, 514947, A61F13/02
Patent
active
059026022
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a transdermal therapeutic system comprising the active substance estradiol and having a layered structure of a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix, and, if necessary, a removable protective layer covering the matrix.
BACKGROUND OF THE INVENTION
In the therapy of several diseases, Transdermal Therapeutic Systems (TTS) have been introduced on the market for some time now.
Also, TTSs comprising the active substance estradiol have been on the market as therapeutic agents for climacteric complaints, and, since a short time ago, also against osteoporosis; they have proved successful in therapy.
In the following the term "estradiol" is to be understood as the anhydrous substance of 17-.beta.-estradiol.
A disadvantage of prior art systems is the insufficient capability of the active substance to permeate through the skin. This cannot be increased beyond a certain limit, the so-called "saturation flow", although several galenic measures with respect to the TTS-design have been taken (use of multilayer systems, use of controlling membranes, variation of the active substance concentration, modification of the base polymer, and the like). This finding that the transdermal flow of an active substance from the solid, finely dispersed phase cannot be increased further in principle, can already be found in the still trailblazing works of Higuchi (e.g., T. Higuchi; Physical Chemical Analysis of percutaneous absorption process from creams and ointments. J. Soc. Cosmetic Chem. 11, p. 85-97 (1990).
The systems described in EP 0 421 454 comprise estradiol in an acrylic polymer under addition of "crystallization inhibitors" and tackifying resins. Swelling agents are contained to give protection against premature loss of adhesive force.
In addition, with a lot of active substances, so-called "enhancers" can be added to the TTS during production. These are usually liquid admixtures improving the absorption properties of human skin; for this reason, they allow the absorption of the active substance from a sufficiently small TTS-surface.
Readily volatile enhancers, e.g., ethanol used for the active substance estradiol, particularly involve problems caused by an extreme softening of the TTSs' adhesive layers, and they require additional bulky compartments in the system, rendering the TTS unacceptably thick.
The addition of less volatile, however, mostly less active enhancers (e.g., glycerol esters, cyclic amides, eucalyptol) allows the production of matrix systems comprising active substances and an absorption-promoting component in one or several layers. However, the insufficient adhesive force of these TTSs is disadvantageous. U.S. Pat. No. 4 863 738 represents one of many examples claiming the application of active substances, e.g., estradiol, together with a certain enhancer (in this case glycerol monooleate) in an optional TTS-matrix and in an optional concentration.
However, even such a prior art TTS does not permit a satisfactory therapy either. The reason is that either the chosen enhancers are poorly tolerated by the skin or that the systems have unacceptably large surfaces owing to the still insufficient flow through the skin.
Another (theoretic) possibility of increasing the active substance flow through the skin is to dissolve more active substance molecularly disperse, i.e., crystal-free, in the TTS than corresponds to the saturation solubility. The permeation rate through the skin increases to the same extent as the degree of supersaturation of these systems. However, these physical states are thermodynamically unstable, therefore these forms of administration are not storable. Within some months or years, at the latest, a spontaneous unforeseeable precipitation of active substance will take place so that the flow rate through the skin gradually decreases to the saturation flow level; depending on the starting concentration, this results in losing a great portion of the initial therapeutic activity.
This process
REFERENCES:
patent: 4764379 (1988-08-01), Sanders et al.
patent: 4788062 (1988-11-01), Gale et al.
patent: 4816258 (1989-03-01), Nedberger et al.
patent: 4863738 (1989-09-01), Taskovich
patent: 5518734 (1996-05-01), Stephano et al.
Higuchi, "Physical Chemical Analysis of Percutaneous Absorption Process From Creams and Ointments", J. Soc. Cosmetic Chem., 11, pp. 85-97 (1990).
Brusetta, "Structure Cristalline et Moleculaire de I'Oestradiol Hemihydrate", Acta Cryst. (1972) B28, pp. 560-567.
Kuhnert-Brandstatter et al., "Thermoanalytische und IR-spektroskopische Untersuchungen an verschiedenen Kristallformen von Arzneistoffen aus der Ostradiol-und Androstangruppe" Scientia Pharmaceutica, 44 (3), 1976, pp. 177-190.
Horstmann Michael
Muller Walter
LTS Lohmann Therapie-Systeme GmbH
Page Thurman K.
Shelborne Kathryne E.
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