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, and active substance-containing matrix, and, if necessary, a removable protective layer covering the matrix, is characterized by the fact that the matrix comprises glycerol either comprising a maximum of 1%-wt. of water or being substantially free from water.

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 occurring during storage is due to particular physicochemical 
characteristic features of estradiol. 
At room temperature and normal relative air humidity (20-60% relative 
humidity), estradiol is not present in one of the two known anhydric 
modifications (I and II) but as a semihydrate (Busetta, Acta Cryst. 1972, 
B28, 560). Owing to the layered structure stabilized via hydrogen bridges, 
and because of the diffusional compactness of the crystal compound, the 
hydrate can be subjected to a short-term heat treatment to temperatures of 
about 170.degree. C. without decomposition thereof (Kuhnert-Brandstatter 
and Winkler (1976) Scientia Pharmaceutica 44 (3), 177-190). However, 
estradiol-semihydrate can quantitatively be converted into the anhydrous 
form already at about 120.degree. C. by way of enlarging the crystal 
surface by means of micronizing. According to the inventors' observations, 
the transformation already takes place at about 90.degree. C. if heating 
is conducted slowly (0.2-1 K/min) and in case of a particularly fine 
substance. 
With decreasing partial water vapor pressure, on the other hand, estradiol 
has a higher solubility in some polymers, particularly in polyacrylates. 
According to Fick's law, higher concentrations with otherwise same 
conditions increase the diffusion flow through the skin; for this reason 
such a concentration increase is very desirable in transdermal therapeutic 
systems. However, the water introduced with the estradiol-semihydrate is 
already sufficient to cause gradual recrystallization from the solution as 
estradiol-semihydrate (Kuhnert-Brandstatter and Winkler (1976) Scientia 
Pharmaceutica 44 (3), 177-190). During crystallization, the flow rate from 
the system to the skin considerably decreases with the diminishing 
concentration. 
Accordingly, transdermal therapeutic systems are known that offer a 
pharmacotherapeutically satisfying solution by exactly regulating the 
concentration to below the saturation solubility of the 
estradiol-anhydrate (DE-PS 42 37 453) or by using partially undissolved, 
disperse estradiol-anhydrate (DE-PS 42 23 360). Even in consideration of 
this latest state of the art, it is important to maintain a sufficiently 
low atmospheric humidity during production and storage of an estradiol-TTS 
in order to avoid large-area precipitation of the poorly soluble 
estradiol-semihydrate. 
To this end, a package having a low water-vapor permeability can be used in 
principle. However, owing to the small estradiol amounts contained in 
today's TTSs, very small amounts of humidity are sufficient to cause 
precipitation of the estradiol-semihydrate. If, for example, 2 mg of 
estradiol (anhydrous) are present in a TTS in dissolved form, an amount 
(calculated on the basis of the molecular-weight ratios) of only 66.1 
.mu.g of water can cause complete precipitation. Using conventional 
packaging means, it is therefore very difficult to exclude entry of such 
small quantities of moisture over storage periods of several years. 
DESCRIPTION OF THE INVENTION 
Accordingly, it is the object of the present invention to provide a 
transdermal therapeutic system comprising estradiol, that comprises a 
long-term protection against precipitation of the estradiol-semihydrate, 
said protection being incorporated in the active substance-containing 
layers themselves, and which prevents crystallization to the 
estradiol-semihydrate. 
Glycerol is a very polar compound and miscible with water in any ratio. 
Anhydrous glycerol is very hygroscopic and can be used as dehydrating 
agent under certain conditions. It can be demonstrated by way of 
experiments that its anhydrous form is able to remove crystal water from 
the estradiol-semihydrate. In this connection, the term "anhydrous" or 
"substantially anhydrous or substantially free from water" is to be 
understood as a water content of less than 1%. If estradiof-semihydrate is 
stirred in anhydrous glycerol at room temperature for about 24 hours, the 
flat-shaped crystals of the semihydrate are converted into thin needles. 
These needles are either the anhydrous estradiol or an 
estradiol-glycerol-solvate. An addition of only 2% of water to the 
glycerol used for this test prevents this reaction. This clearly 
demonstrates that the species resulting during the reaction with anhydrous 
glycerol does not comprise any water. 
The above-mentioned embodiment of a TTS according to the present invention 
can be realized in different manners. The most simple form is a 
single-layer matrix system whose matrix simultaneously has a 
pressure-sensitive adhesive function, rendering a special adhesive layer 
superfluous. The glycerol dispersed in the matrix ensures an 
equilibrium-moisture content over the storage period that is low enough to 
render precipitation of the estradiol-semihydrate impossible. 
If the adhesive force of this layer is insufficient or if direct skin 
contact of this layer is to be avoided, the matrix may be laminated with a 
special skin adhesive layer. 
If a membrane which is hardly permeable to estradiol is introduced between 
such a matrix, which comprises estradiol and water-binding disperse 
glycerol, and the adhesive layer, an active substance release is achieved 
which is controlled by the patch rather than by the skin. 
In addition to the wide-spread acrylic acid copolymers suitable for the use 
with estradiol, other polymers may also be used as base material, such as 
polyisobutylene, polyvinyl acetate and copolymers, synthetic rubber, block 
polymers of styrene and isoprene or of styrene and butadiene, and 
silicones. 
In any case, the characterizing feature of transdermal therapeutic systems 
according to the present invention is the presence of disperse, 
substantially anhydrous glycerol. In this connection, the exact amount of 
glycerol in the system must be chosen such that, on the one hand, the 
solubility of glycerol in the system is exceeded and that it is present as 
separate phase dispersed in small droplets, and, on the other hand, that 
the total moisture-binding capacity in the system is sufficient. An 
addition in the range of 2 or even 1 percent may be considered as minimum 
amount; the upper limit is determined by mechanical values, such as 
flowability of the matrix, adhesive force, and processibility. In general, 
a proportion of 10 to 50 percent by weight, preferably between 10 and 35 
percent by weight is desired.

EXAMPLES 
Example 1 
2.0 g of 17-.beta.-estradiol-semihydrate, micronized is mixed with 
2.75 g of anhydrous glycerol, 
25 g of an acrylic ester copolymer solution (solids content 42%) and 
5.9 g of colophony-glycerol ester derivative (Staybelite Ester 5E, of 
Hercules) 
and subsequently coated on a 100 .mu.m siliconized polyester film in such a 
manner that the coating weight amounts to 120 g/m.sup.2. 
The coating is dried at.25.degree. C., at 50.degree. C., at 80.degree. C. 
and at 95.degree. C., each time for 10 minutes. A 10 .mu.m polyester film 
is immediately applied (laminated) on the dry layer under roller pressure, 
avoiding the formation of air bubbles. 
Transdermal systems of 16 cm.sup.2 are obtained by punching using a wad 
punch. These are immediately packed into moistureproof, heat-sealable 
bags. 
Example 2 
2.0 g of 17-.beta.-estradiol-semihydrate, micronized, 
60.0 g of Cariflex TR 1107.RTM. (styrene-isoprene block polymer), 
120.0 g of Staybelite Ester 5E (thermoplastic ester gum of colophony 
derivatives), 
50.0 g of viscous paraffin 
50.0 g of anhydrous glycerol 
are rendered molten in an evacuatable kneader at 130.degree. C. and brought 
into an externally homogeneous form by means of kneading within ten hours. 
The melt is cooled down to 120.degree. C.; in a continuous coating line it 
is subsequently coated onto a siliconized polyester film of 1 00 .mu.m 
thickness in such a manner that the weight per unit area amounts to 200 
g/m.sup.2. 
Afterwards a polyester film 15 .mu.m thick is applied (laminated) under 
roll pressure on the still hot layer, avoiding the formation of air 
bubbles. 
Transdermal systems of 16 cm.sup.2 are obtained by punching using a wad 
punch.