Transdermal therapeutic system containing estradiol

An active-substance-containing transdermal therapeutic system for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or combined with gestagens consisting of a backing layer, an active-substance-containing reservoir which is bonded thereto and produced by using pressure sensitive adhesives, and a removable protective layer is characterized by the fact that the pressure sensitive adhesive comprises esters of colophony.

BACKGROUND OF THE INVENTION 
The present invention relates to a transdermal therapeutic system for the 
controlled release of estradiol or its pharmaceutically acceptable 
derivatives alone or combined with gestagens, such as levonorgestrel, to 
human or animal skin. The present invention further relates to the use and 
to a process for the production of this system. 
In the therapy of various diseases, transdermal therapeutic systems (TTS) 
have been introduced on the market. Also, transdermal therapeutic systems 
containing the estrogenic active substance 17-.beta.-estradiol used as 
therapeutic agent for climacteric complaints and--for some time 
now--against osteoporosis are commercially available and show good 
therapeutic results. 
Levonorgestrel is a synthetic gestagen derivative which has mainly been 
used in contraceptives in combination with orally effective estrogens. In 
such preparations gestagens, consequently including levonorgestrel, have 
the function to cause a "physiologic" abstraction hemorrhage which is as 
short and rapid as possible by means of an adequate trophic premedication 
of the uterus. There are also hints that the gestagen addition has a 
protective effect against the risk of endometrial tumors. 
For this reason, it is appropriate to use a cyclic treatment also for the 
indication of postmenopausal complaints, i.e., to make use of a temporary 
fixed drug combination consisting of estrogens (e.g., estradiol) and 
gestagens (e.g., levonorgestrel). A combination of the two active 
substances in a common, monolithic transdermal therapeutic system which 
would have to be applied only once a day or even once to twice a week is 
particularly interesting. Owing to its high efficiency and permeativity 
through the skin levonorgestrel is excellently suitable for such a system. 
Experimental systems for the transdermal delivery of levonorgestrel are 
described in literature (Friend et. al., J. Controlled Release 7, 243-250 
(1988)). However, according to this estimation, permeation improvers 
(enhancers), e.g., alkyl esters of short-chain fatty acids, are required 
for the successful transdermal therapy with sufficiently small system 
surfaces (Friend et. al., J. Controlled Release 9, p. 33-40 (1989)). 
Numerous devices for the transdermal application of estrogens and gestagens 
have been disclosed. Nakagawa et al. (EP-A 0 483 370) obtained a 
matrix-type transdermal therapeutic system for estradiol alone by using 
styrene-isoprene block copolymer, moisture-absorbing polymer domains, and 
the enhancer (and antipruritic agent) crotamiton. Another conception is 
the simultaneous application of estradiol and an enhancer (ethanol) in a 
membrane-controlled reservoir system (Campbell et al., U.S. Pat. No. 
4,379,454); this can also be used in a combined administration form 
comprising the gestagen norethisterone acetate (Frankhauser and Schenkel, 
DE 3 810 896). 
However, transdermal therapeutic systems for the release of estradiol 
and/or gestagens have the disadvantage that they either contain ethanol or 
that they exhibit the potential danger of the active substance being 
recrystallized in the course of time. 
It is known from DE-OS 32 05 258 and EP 0 285 563 to administer estradiol 
and ethanol simultaneously in a patch formulation. However, the production 
of this patch is very expensive, and the wearing comfort after application 
is low because of missing flexibility. 
EP 0 285 563 describes a transdermal therapeutic system for the combined 
application of estrogens and gestagens. The reservoir has the active 
substance formulation, optionally a membrane, and ethanol as percutaneous 
absorption improving agent. Since the release of the active substance is 
mainly controlled by the membrane, this transdermal therapeutic system is 
completely different from the active-substance-containing patch according 
to the present invention. In the patch described in said publication, the 
adhesive has the mere function of fastening the patch to the skin. The 
fact that it can contribute to the control of the active substance release 
is not its main function but merely a--probably even undesired--side 
effect. It is a so-called "pouch patch" since the active substance 
preparation is present in a pouch consisting of an impermeable backing 
layer and a membrane having an adhesive layer. As a consequence of its 
complicated structure, the production of this patch is very expensive 
since the individual components have to be produced separately and then 
joined in an additional step to form a patch. 
EP 0 275 716 describes a two-layer transdermal therapeutic system--in 
contrast to the single-layer system according to the present 
invention--for the simultaneous administration of one or several estrogens 
which are dissolved or microdispersed in the polymeric layer. In addition 
to the active substances, the pressure sensitive adhesive layer comprises 
substances improving the transdermal absorption. Polymeric and pressure 
sensitive adhesive layer may consist of polyacrylates, silicones, or 
polyisobutylenes. 
EP 0 072 251 describes a flexible, liquid-absorbing medicinal bandage. The 
substrate which is attached to the flexible backing layer consists of a 
hydrophilic matrix based on hydrophilic high-molecular polysaccharides 
and/or polyacrylic acid, polyacrylamide, ethylene-vinyl 
acetate-copolymers, and other polymers as well as of a liquid phase based 
on a solution or emulsion of carbohydrate, proteins, multivalent alcohols, 
and different active substances, amongst others hormones. The main feature 
of this invention is the moisture-absorbing adhesive. 
EP 0 328 806 describes a transdermal therapeutic system without membrane; 
its matrix consists of a polyacrylate adhesive, a solvent, a penetration 
enhancer, and estrogens, the derivatives and combinations thereof. 
WO 87/07 138 describes an estradiol patch based on a backing layer, an 
active-substance-containing matrix and a pressure sensitive adhesive 
covered with a removable protective layer. The matrix and pressure 
sensitive adhesive are manufactured in technologically very expensive 
operations by homogenizing, degassing, coating, drying, and separating. 
According to an embodiment, the backing layer has to be coated with a 
pressure sensitive adhesive, resulting in an additional operation. The 
individual parts are joined in a separate step. For this reason, the 
production of this patch is very expensive and complicated. 
U.S. Pat. No. 4,624,665 describes systems comprising the active substance 
in microencapsulated form within the reservoir. The reservoir is embedded 
between the backing layer and a membrane. The outer edge of the system is 
provided with a pressure sensitive adhesive. The structure and the 
production of this system are very complicated since the active substance 
has to be microencapsulated and homogeneously distributed in a liquid 
phase which is then embedded between backing layer and membrane in 
additional process steps. In addition, this system must then be provided 
with an adhesive edge and covered with a protective layer. 
Additionally, EP 0 186 019 describes active substance patches wherein 
water-swellable polymers are added to a rubber/adhesive-resin-mass and 
from which estradiol can be released. However, it turned out that the 
release of estradiol from these active substance patches is too low and 
does not meet the therapeutic requirements. 
DE-OS 20 06 969 describes a patch or pressure sensitive adhesive dressing 
exhibiting system action; it contains contraceptive substances which are 
incorporated in the adhesive component or in the adhesive film. This 
publication discloses that the adhesive may be an acrylate. 
DE-OS 39 33 460 describes an estrogen-containing active substance patch 
based on homo and/or copolymers with at least one derivative of the 
acrylic acid or with methacrylic acid in combination with water-swellable 
substances. 
However, it turned out that pressure sensitive adhesive transdermal 
therapeutic matrix systems which comprise the active substance in a 
partially or completely dissolved form involve the potential risk that the 
active substance recrystallizes in the course of time. Thus the active 
substance release decreases and the estrogen-containing patch does no 
longer meet the therapeutic requirements. 
Another drawback of systems according to the state of the art is the use of 
enhancers, this results in a fundamentally undesired additional skin 
affection including the risk of irritation. Additional disadvantages lie 
in the expensive construction of these systems (use of several 
active-substance-containing layers, use of controlling membranes), 
generally rendering the finished product unacceptable for the user. 
BRIEF SUMMARY OF THE INVENTION 
It is accordingly the object of the present invention to avoid the above 
disadvantages and to provide a stable, i.e., recrystallization-free, 
estrogen-containing patch or transdermal therapeutic system whose release 
does not change through storage, wherein the structure is to be designed 
as thin as possible, and during whose therapeutic application the 
skin--beyond the active substances estradiol and gestagen--is not treated 
with skin affecting substances (enhancers). 
DETAILED DESCRIPTION OF THE INVENTION 
Most surprisingly, it turned out that this object is achieved by the fact 
that the estrogen-containing pressure sensitive adhesive is mainly 
composed of esters of colophony. 
In this connection it is of advantage that a styrene-isoprene block 
copolymer and hydrogenated resin acids or their derivatives are 
additionally used in the active layer which, for example, comprises a 
therapeutically required quantity of the active substances estradiol and 
levonorgestrel. 
A combination of the two inactive ingredients, the styrene-isoprene block 
copolymer serving as cohesive component, and the hydrogenated resin acids 
or their derivatives serving as tackifying substances, not only results in 
a rubber adhesive with good tackiness and cohesiveness but also provides 
excellent biopharmaceutical properties, in particular good skin tolerance 
and permeation capability, and avoids recrystallization of the active 
substances. 
Thus, the present invention relates to a transdermal therapeutic system for 
the controlled release of estradiol or its pharmaceutically acceptable 
derivatives alone or combined with gestagens, consisting of a backing 
layer, an active-substance-containing reservoir which is connected thereto 
and is produced by using pressure sensitive adhesives, and a removable 
protective layer, with the pressure sensitive adhesive comprising esters 
of colophony and inactive ingredients. 
Examples of esters of colophony include, for example, methyl esters, the 
glycerol ester, the pentaerythritol ester, the pentaerythritol ester 
modified with maleic acid, the glycerol ester modified with maleic acid, 
and the triethylene glycol ester. The proportion of colophony esters in 
the estradiol-containing pressure sensitive adhesive amounts to 
55-92%-wt., preferably 60-90%-wt., and most preferably 70-88%-wt. In 
addition, the pressure sensitive adhesive may comprise esters of 
hydrogenated colophony. Particularly preferred esters of colophony include 
the triethylene glycol ester, the glycerol ester, and the pentaerythritol 
ester of hydrogenated colophony. 
According to another embodiment, the estradiol-containing pressure 
sensitive adhesive may additionally comprise polymers selected from the 
group consisting of styrene-butadiene-styrene block copolymers, 
styrene-isoprene-styrene block copolymers, 
styrene-ethylene-butylene-styrene block copolymers, ethylene-vinyl acetate 
copolymers, polyvinyl pyrrolidone, cellulose derivatives, and polymers 
based on acrylic acid and methacrylic acid derivatives. These polymers are 
contained in the estradiol-containing adhesive mass at a concentration of 
6-25%-wt. 
The reservoir of the estradiol-containing patch, wherein recrystallization 
does not occur, comprises estradiol and its pharmaceutically acceptable 
derivatives alone or in combination with gestagens at a total 
concentration of 2-15%-wt., namely at a molar ratio of 1:1 to 1:10. 
Generally the estradiol is present in the active layer in an amount of 0.2 
to 2% by weight, preferably between 0.7 and 1.4% by weight. The amount of 
levonorgestrel in the active layer is between 0.1 and 1.6% by weight. In 
addition, the levonorgestrel and/or the estradiol may be present partially 
in a suspension. 
The estradiol-containing reservoir may comprise at least one component of 
the group including anti-ageing agents, plasticizers, anti-oxidants, and 
absorption improvers. Suitable plasticizers are known to those skilled in 
the art and are described, for example, in DE 37 43 946. Usually, the 
proportion of plasticizers in the estradiol-containing reservoir amounts 
to 0-5%-wt. 
In addition, the active-substance-containing reservoir comprises 
anti-ageing agents at a concentration of 0-1%-wt. These are known to those 
skilled in the art and described, for example, in DE 37 43 946. 
The estradiol-containing reservoir may either be produced from solution or 
from a melt. 
In case the reservoir fails to exhibit sufficient self-tackiness to the 
skin, it may be provided with a pressure-sensitive adhesive layer or with 
a pressure-sensitive adhesive edge. This ensures that the transdermal 
patch adheres to the skin over the whole application period. 
A particularly preferred construction of the transdermal 
estradiol-containing patch is the matrix system wherein, as is generally 
known, the matrix controls the active substance release which complies 
with the .sqroot.t-law according to Higuchi. However, this is not to 
exclude the possibility that particular cases might require the membrane 
system. In this case, a membrane controlling the active substance release 
is located between the reservoir and the pressure sensitive adhesive 
layer. 
The thickness of the transdermal patch depends on the therapeutic 
requirements and may be adapted accordingly. Usually, it ranges from 
0.03-0.4 mm. The thickness of the active substance layer of the reservoir 
is between 30 and 300 .mu.m, preferably between 70 and 120 .mu.m. 
In addition, a preferred application form is a monolithic matrix-type 
transdermal therapeutic system which consists of a backing layer 
substantially impermeable to the active substances, the actually active 
matrix layer (comprising the active substances and inactive ingredients 
according to the present invention) and of a removable protective layer. 
The examples will show that these systems--although having a simpler 
construction and being made at lower expenditure than those according to 
the state of the art--have improved and more constant permeation 
characteristics for both active substances. 
Surprisingly, it turned out that such a formulation which is composed of 
mainly lipophilic and comparatively low-diffusible polymers and resins 
results in human blood levels which cannot be obtained with systems 
according to the state of the art at a comparable low expenditure. 
Until today, rubber adhesives have been regarded as being less suitable for 
the release of estradiol to the skin. For example, EP 0 186 019 describes 
the idea to use rubber adhesives (in this case by adding water-swellable 
substances), this is contradicted in EP 0 421 454 (p. 2, line 54 ff.): a 
sufficient release of estradiol is not given in the case of these low 
diffusible and only slightly soluble polymers. 
Both substances which are essential to use according to the present 
invention, styrene-isoprene block copolymer and hydrogenated resin acids 
or their derivatives, have successfully been used for long as classic base 
materials of pressure sensitive adhesive patches and they have a good 
tolerance. The term "hydrogenated resin acids" means compounds derived 
from the natural product "colophony". Colophony is widely used as a 
mixture of native resin acids, above all in chemically modified form, in 
consumer goods, cosmetics, food packages, chewing gum, etc. It is the 
resinous residue of the raw product turpentine balsam remaining after 
distilling off turpentine oil; turpentine balsam originates from different 
pine trees in mainly subtropical-mediterranean climatic zones. 
The crude product is a brittle, resinous mass softening at about 
73-80.degree. C. and having a density of about 1.07 g/ml. The modification 
of colophony for the purpose of using it in transdermal therapeutic 
systems serves to stabilize it against the influence of oxygen by 
hydrogenation and to improve the alkali stability by esterification. 
Hydrogenation and derivatization, if necessary, render the material more 
suitable for the intended purpose. Important esters which can be used for 
the purpose according to the present invention include, for example, 
glycerol esters, pentaerythritol esters, methyl esters, and other 
derivatives of hydrogenated colophony well tolerated by the skin. 
Synthetic rubber polymers play an important role in the production of 
transdermal therapeutic systems and wound dressings. Their advantage lies 
in the fact that the mechanical properties of transdermal therapeutic 
systems are considerably improved. In this respect, the 
styrene-isoprene-styrene block copolymers have proved to be particularly 
suitable. By dividing the polymer chain into a middle block of still 
mobile long-chain polyisoprene units and the two polystyrene ends as 
"anchor points", a three-dimensional network is formed in the matrix, this 
ensures a substantially constant geometry, even during storage. In this 
connection it is not decisive which molecular weight or which ratio 
between the proportion of the styrene domains and the polyisoprene domains 
really exists. On the contrary, adjusting the correct tackiness and 
cohesion is the important factor. For example, an increased resin 
proportion results in an improved tackiness to the skin but also in a 
softer consistency of the matrix. In general, the proportion of the block 
copolymer will amount to about one third, the rest remaining after the 
active substance addition are biocompatible resin derivatives. Typically, 
the proportion of the styreneisoprene block copolymer in the active layer 
amounts to 10-45% by weight, preferably 15-33% by weight. 
Although a single-layer structure of the transdermal therapeutic system 
exhibits advantages because of the simple function, it is easily possible 
according to the present invention to provide such a matrix system, e.g., 
with a thin additional adhesive layer directed towards the skin. Also, for 
the purpose of obtaining an improved anchoring effect on the backing layer 
a thin pressure sensitive adhesive layer may be laminated. Such additional 
layers may consist of a rubber-resin-mixture but also, for example, of 
acrylic-ester-containing copolymers. They may be used even if not charged 
with active substances prior to lamination, since a diffusion compensation 
takes place during short-time intermediate storage of the complete 
laminate. 
The transdermal patch is prepared by the following steps: 
kneading the mixture of esters of colophony at an elevated temperature 
until homogenization, incorporating active substance(s) and at least one 
polymer at the solution temperature, coating a removable protective layer 
with the active-substance-containing adhesive mass after homogenization, 
and laminating the backing layer.

The present invention will be illustrated in more detail by the following 
examples. 
EXAMPLE 1 
73.1 g triethylene glycol ester of hydrogenated colophony (Staybelite Ester 
3E/by Hercules) and 
9.8 g glycerol ester of hydrogenated colophony (Staybelite Ester 10E/by 
Hercules) 
are mixed by kneading at 100.degree. C. for 5 minutes. Then 2.5 g of 
estradiol are added. Kneading is continued for 30 minutes. After heating 
to 140.degree. C., 14.6 g ethyl cellulose N50NF (by Hercules) are added in 
portions, and then kneading is continued for 2.5 hours. 
In a hot melt coating line (die coating system) the 
active-substance-containing adhesive mass thus obtained is coated onto a 
removable protective layer (Hostaphan RN 100, coated on one side with 
silicone--by Kalle) in such a manner that an active-substance-containing 
reservoir having a mass per unit area of 80 g/m.sup.2 results. An 
impermeable backing layer (polyester sheet, thickness 15 .mu.m) is 
laminated on this reservoir. Subsequently, active substance patches of 16 
cm.sup.2 are punched. 
EXAMPLE 2 
The manufacture is in accordance with Example 1, with the plasticizer being 
kneaded together with the two Staybelite esters 3E and 10E. 
EXAMPLES 3-9 
Manufacture according to Example 1, however with the raw products and 
quantities as listed in Table 1 (manufacturing formula). 
Analytic Procedure 
The active substance release of the transdermal patches having a size of 16 
cm.sup.2 is determined according to the Rotating bottle-method described 
in USP XXII in 0.9% salt solution at 37.degree. C. 
To measure the mice skin penetration, the skin of hairless mice is placed 
in the Franz-cell. An estradiol-containing patch having an area of 2.54 
cm.sup.2 is stuck onto the skin, and the active substance release is 
measured at 37.degree. C. (acceptor medium: 0.9% saline). (literature: 
Umesh V. Banakar Pharmaceutical dissolution testing (1st edition-1991)). 
The recrystallization testing is carried out visually against the light. 
The results are listed in Table 2. 
TABLE 1 
______________________________________ 
manufacturing formula (indications in g) 
Ethyl cellulose 
Staybelite Ester 
Plasticizer 
Estra- 
Anti- 
Ex. N50NF 3E 10E Miglyol 812 
diol oxidants 
______________________________________ 
1 14.6 73.1 9.8 -- 2.5 
2 14.3 71.6 9.6 2.0 2.5 
3 10.1 75.4 10.0 2.0 2.5 
4 7.7 77.5 10.3 2.0 2.5 
5 14.3 71.6 9.5 2.0 2.5 0.1 BHT 
6 14.3 71.6 9.5 2.0 2.5 0.1 BHA 
7 14.3 71.6 9.5 2.0 2.5 0.1 
BHT:BHA = 
1:1 
8 14.3 71.6 9.6 2.0 2.5 
isopropyl 
palmitate 
9 14.3 71.6 9.5X 2.0 2.5 
______________________________________ 
BHT = butyl hydroxytoluene 
BHA = butyl hydroxyanisole 
X = Foral 105 (pentaerythritol ester of hydrogenated colophony) 
TABLE 2 
______________________________________ 
Results of Analysis 
Estradiol 
In-vitro- Mice skin 
content release penetration 
Recrystal- 
Ex. .mu.g/16 cm.sup.2 
.mu.g/16 cm.sup.2 .multidot. 24 h 
.mu.g/16 cm.sup.2 .multidot. 24 
lization 
______________________________________ 
1 3200 614 225 no 
2 3200 1240 300 " 
3 3200 722 235 " 
4 3200 713 268 " 
5 3200 624 228 " 
6 3200 624 249 " 
7 3200 620 205 " 
8 3200 686 232 " 
acc. to 
3200 2400 125 consider- 
DE able 
3933460 
______________________________________ 
The Table shows that a considerably improved penetration through the mice 
skin is obtained, as evidenced by the comparative example under DE 
3933460. Analogously, there is no recrystallization in the Examples 
according to the present invention. 
EXAMPLE 10 
1.0 g 17-.beta.-estradiol 
1.3 g levonorgestrel 
60.0 g Cariflex.RTM. TR 1107 (styrene-isoprene-styrene block copolymer), 
138.0 g Foral.RTM. 85 (thermoplastic ester resin of colophony derivatives) 
200.0 g benzine (boiling range 80-100.degree. C.) 
are stirred in a cylindrical glass vessel at room temperature until an even 
suspension results and then coated on a siliconized polyester sheet of 100 
.mu.m thickness in a continuous coating line in such a manner that a layer 
thickness of 110 g/m.sup.2 (relative to the solvent-free portion) results. 
The coating is dried at 40.degree. C., 60.degree. C., 75.degree. C., and 
125.degree. C. for 3 minutes each. A polyester sheet of 12 .mu.m thickness 
is immediately placed on the dry layer without air-bubbles under roll 
pressure (laminated). Transdermal systems of 20 cm.sup.2 are obtained by 
punching using a wad punch. 
EXAMPLE 11 
Manufacture of a System According to the Invention 
1.5 g 17-.beta.-estradiol 
1.5 g levonorgestrel 
70.0 g styrene-isoprene-styrene block copolymer 
150.0 g thermoplastic ester resin of colophony derivatives 
are melted and combined by kneading in a heatable kneader at 150.degree. C. 
under nitrogen within 24 h. On a continuous coating line, a polyester 
sheet of 19 .mu.m thickness is coated with the melt at a layer thickness 
of 100 .mu.m. This may be effected at 140.degree. C. in a hot melt coater, 
or at about 80-100.degree. C. by means of an extruder. Subsequently, a 
siliconized polyester sheet of 150 .mu.m thickness, precoated with 20 
g/m.sup.2 of an acrylic ester copolymer (Durotak.RTM. 280-2516), is placed 
on the dried layer (laminated) without air-bubbles and under roll 
pressure. Transdermal systems of 20 cm.sup.2 are obtained by punching 
using a wad punch.