Note: Descriptions are shown in the official language in which they were submitted.
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Estradiol Penetration Enhancers
S P E C I F I C A T I O N
The present invention relates to an active substance-containing
patch for the controlled release of estradiol or its pharmaceutically
acceptable derivatives alone or in combination with gestagens to
the human or animal skin by using pressure sensitive adhesives
and at least one penetration enhancer. The present invention fur-
ther relates to its use and to a process for its production.
Estrogen-containing patches have been known for some time.
However, they have the disadvantages that they either contain
ethanol, or that there is the potential risk that the active substance
recrystallizes in the course of time, or that they do not release es-
tradiol in an amount sufficient for a therapy.
It is known from DE-OS 32 05 258 and EP 0 285 563 to adminis-
ter estradiol and ethanol at the same time in a patch formulation.
However, the production of said patch is very expensive and the
wearing comfort after application is low due to the lack of flexibil-
ity.
EP 0 285 563 describes a transdermal therapeutic system for the
combined application of estrogens and gestagens. The reservoir
comprises an active substance formulation, optionally a mem-
brane, as well as ethanol used as percutaneous absorption improv-
ing agent. The active substance release is mainly controlled by the
membrane. In the patch described therein 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, what is more, this is merely a side effect -
probably not desired at all. The patch described there is a
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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 adhEaive layer. As a consequence of its
complicated structure, the production of this patch is very expen-
sive, since the individual components have to be manufactured
separately and then joined 1:o form a patch in an additional process
step.
EP 0 275 716 describes a two-layer transdermal therapeutic sys-
tem for the simultaneous administration of one or several estro-
gens dissolved or microdispersed in the polymeric layer. In addi-
tion to the active agents, the adhesive layer comprises substances
improving the transdermal absorption. Polymeric and adhesive
layer may consist of polyacrylates, silicones, or polyisobutylenes.
EP 0 072 251 describes a flexible, moisture-absorbing medical
bandage. The substrate attached to the flexible backing layer
consists of a hydrophilic matrix based on hydrophilic, high-molecu-
lar polysaccharides and/or polyacrylic acid, polyacrylamide, ethyl-
ene-vinyl-acetate-copolymers, and other polymers, as well as of a
liquid phase based on a solution or emulsion of carbohydrate,
proteins, and polyhydric alcohols, as well as different active sub-
stances, amongst others hormones. An essential feature of this
invention is the hygroscopic adhesive.
EP 0 328 806 describes a membrane-free, transdermal therapeutic
system whose matrix consists of a polyacrylate adhesive, a sol-
vent, a polyoxyethylene ester as penetration enhancer, and estro-
gens, 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 sen-
sitive adhesive covered with a removable protective layer. The
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production of the matrix and the adhesive is effected in techno-
logically very expensive operations by homogenizing, degassing,
coating, drying and separating. According to an embodiment, the
backing layer must be coated with a pressure sensitive adhesive,
involving another operational step. The individual parts are joined
together in a separate step. For this reason, the manufacture of
this patch is very expensive and complicated.
U.S.-Patent 4 624 665 describes systems containing the active
substance in micro-encapsulated form in the reservoir. The reser-
voir is embedded between a backing layer and a membrane. The
outer edge of the system is provided with a pressure sensitive ad-
hesive. The structure and the production of this system is very
complicated, since the active substance must be micro-encapsu-
lated and homogeneously distributed in a liquid phase which is
then embedded between backing layer and membrane in additional
process steps. Additionally, the system must then be provided
with an adhesive edge and covered with a protective layer.
Additionally, EP 0 186 019 describes active substance patches in
which water-swellable polymers are added to a rubber-adhesive-
resin mass and from which estradiol can be released. It turned out,
however, that the estradiol release from these active substance
patches is too low and does not meet the therapeutic require-
ments.
DE-OS 20 06 969 describes a patch or a pressure sensitive adhe-
sive bandage having systemic action, in which contraceptive sub-
stances are incorporated into the adhesive component or adhesive
film. The adhesive film may consist of an acrylate.
DE-OS 39 33 460 describes an estrogen-containing active sub-
stance patch based on homo and/or copolymers having at least
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one derivative of the acrylic acid or with methacrylic acid in com-
bination with water-swellable substances.
EP 0 430 491 describes a transdermal therapeutic system
comprising components intensifying the penetration of estradiol.
These include unsaturated fatty acids, their alkyl esters and glyc-
erol or alkanediols, such as propanediol. This formulation has the
disadvantages that the unsaturated fatty acids are sensitive to
oxidation and are thus subject to a chemical modification; addi-
tionally, propanediol evaporates in an uncontrolled manner during
the drying process so that an active substance-containing patch
which meets the required constant composition cannot be manu-
factured.
Also, the transdermal system described in EP 0 371 496 has the
disadvantage that it comprises oleic acid as penetration enhancer,
which is sensitive to oxidation and therefore does not allow the
production of a stable system whose properties do not change
during storage.
EP 0 569 338 describes a patch for the transdermal administration
of estradiol by using penetration enhancers. These include satu-
rated and unsaturated fatty acids and propylene glycol. The un-
saturated fatty acids have the disadvantage that they are sensitive
to oxidation, and that propylene glycol evaporates in an uncon-
trolled manner during the drying process. Far this reason, an es-
tradiol-containing patch having the required constant composition
which does not change during storage cannot be manufactured.
Additionally, it turned out l:hat pressure sensitive adhesive trans-
dermal therapeutic matrix systems comprising the active sub-
stance in a partially or completely dissolved form do not release
estradiol in the amount required for a therapy. There have been
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attempts of eliminating this drawback by enlarging the surface of
the active substance patches. However, this results in the fact
that the patches partially peel off during the application period.
Thus, the all-over contact to the skin which is required for the
therapy is no longer ensured, and the active substance amount
penetrating through the skin varies inadmissibly. For this reason, a
therapy with a constant active substance administration cannot be
ensured.
Accordingly, it is the object of the present invention to avoid the
above-mentioned disadvantages and to provide an estrogen-con-
taining patch releasing the active substance in a sufficient amount
and avoiding the drawback of an unacceptable patch size.
Most surprisingly, it turned out that the object is achieved by
means of an active substance-containing patch for the controlled
release of estradiol or its pharmaceutically acceptable derivatives
alone or combined with gestagens, which consists of a backing
layer, an active substance-containing reservoir which is connected
thereto and has been manufactured by using pressure sensitive
adhesives, and a removable protective layer, with the pressure
sensitive adhesive comprising at least one penetration enhancer of
the group of substances based on carboxylic acids.
The substances based on carboxylic acids include glycollic acid,
malic acid, lactic acid, tartaric acid, citric acid, mandelic acid, 2-
hydroaytcinnamic add, 3-hydroxycinnamic'acid, trans-4--Tne'thoxycin-
namic acid, 2-hydroxyoctanoic acid, tropic acid, gallic acid,
shikimic acid, benzilic acid, benzene-1,2,4-tricarboxylic acid, di-
methyl-3-oxoglutarate, 3-methyl-2-oxo-valerianic acid, 4-methyl-2-
oxo-valerianic acid, 2-oxoglutaric acid, pyruvic acid, 4-amino-
butyric acid, 6-aminohexanoic acid, 11-aminoundecanoic acid, as-
paraginic acid, 2-aminobenzoic acid, 3-aminobenzoic acid, 4'
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aminobenzoic acid, 4-amino-2-salicylic acid, 3-phenylpropionic add,
2-phenylbutyric acid, 4-phenylbutyric acid, succinic acid, glutaric
acid, 3,3-dimethylglutaric acid, adipic acid, pimelic acid, azelainic
acid, sebacic acid, traps-2-dodecenedioic acid, tridecanedioic acid,
tetradecanedioic acid, pentadecanedioic acid, diglycollic acid,
piperidine-4-carboxylic acid, pyrazine-2-carboxylic acid, pyrazine-
2,3-dicarboxylic acid, pyridine-2-carboxylic acid, and nicotinic
acid, pimelic acid monomethyl ester, malonic acid diamide, adipic
acid diamide, succinic acid diamide, pyrazine-2-carboxamide.
The portion of penetration enhancers based on carboxylic acids
amounts to 0.01 - 20%-wt.
In an embodiment of the present invention, components of the
estradiol-containing pressure sensitive adhesive may be polymers
selected from the group consisting of styrene-butadiene-styrene
block copolymers, styrene-isoprene-styrene block copolymers, sty-
rene-ethylene-butylene-styrene block copolymers, polyisobutyl-
enes, ethylene-vinyl acetate copolymers, polyvinyl pyrrolidone,
cellulose derivatives, polycaprolactams, polycaprolactones, ethyl-
ene-ethyl-acrylate copolymer, polyvinylether, polyvinylacetals,
polyvinylacetates, butyl-rubbers, acrylonitrile-butadiene copoly-
mers, polyethylene glycols, and polymers based on acrylic acid
and methacrylic acid derivatives. These polymers are comprised in
the estradiol-containing adhesive mass in a concentration of at
least 6%-wt.
The active substance patch may comprise tackifying resins in the
concentration of 5 - 94%-wt. These are known to those skilled in
the art and are described in U.S.-Patent 5 126 144.
The active substance patch comprises in the reservoir estradiol or
its pharmaceutically accepl:able derivatives alone or in combination
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with gestagens in the concentration totaling 2 - 15%-wt., that is
in a molar ratio of estradiol or its pharmaceutically acceptable de-
rivatives to gestagens of 1 : 1 to 1 : 10.
The estradiol-containing reservoir may comprise at least one inac-
tive ingredient of the group including dyes, fillers, anti-ageing
agents, plasticizers, and antioxidants. These inactive ingredients
are known to the skilled artisan and are described, for example, in
DE 37 43 946. The estradiol-containing reservoir normally com-
prises inactive ingredients in a portion of up to 5%-wt.
The active substance patch may consist of one single or of several
layers. The thickness of the active substance-containing reservoir
may amount to 0.02 - 1.0 mm.
The materials for the impermeable backing layer and the remov-
able protective layer are also known to the expert (e.g., DE 38 43
239).
The estradiol-containing reservoir may be formed from a solution,
dispersion, or from the melt.
Additionally, the reservoir may consist of several layers.
In case the reservoir should not have a sufficient self-tackiness to
the skin, it can be provided with a pressure sensitive adhesive
layer or with a pressure seinsitive adhesive edge. This ensures ad-
hesion of the transdermal patch to the skin over the whole appli-
cation period.
A particularly preferred structure of the transdermal estradiol-con-
taining patch is the matrix system; here, as is generally known,
the matrix controls the active substance release which follows the
CA 02181072 2004-O1-23
2i81012
a
~t-law according to Higuchi. However, this doss not mean that the
membrane system may me be ezpedieat is particular cases, pop. In tads
case, a membrane controlling the active substance release is pro-
vided between the reservoir and the pressure sensitive adhesive
layer.
The present invention will be illustrated by the following examples.
Example 1:
66.7 g trtethylene glycol ester of hydrogenated colophony
(Staybelite Ester 3E of Hercules)
8.9 g glycerol ester of hydrogenated colophony (Staybe-
lite Ester 10E of Hercules)
8.9 g ethyl cellulose and
1 g butyl hydroxyanisole are homogenized by stirring at
165°C for about 1 Ya hours.
Subsequently, ..
10.0 g DL-matic acid is added and stirring is effected for
about 2 hours. Then
2.5 g estradiol is added and stirring is carried out for an-
other 2 hours at 16~°C.
The active substance-containing adhesive mass thus obtained is
coated in a hotmelt-coating line (nozzle coating system) onto a
removable protective layer (Hostaphari RN 100, coated on one
side with silicone, Kalle) in such a manner that an active sub-
stance-containing reservoir results that has a mass per unit area of
80 g/m'. The impermeable backing layer (polyester film, thickness
15 pm) is laminated on this reservoir. Afterwards active sub-
stances patches having a size of 16 cm' are punched.
*=TM
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Analysis:
The active substance release of the transdermal patches of
a size of 16 cm' is determined according to the Rotating-
Bottle-method described in USP XXII in 0.9% saline at
37°C.
- To measure the mice skin penetration, the skin or hairless
mice is clamped into the Franz-cell. An estradiol-containing
patch having an area of 2.54 cm' is glued on the skin, and
the active substance release at 37°C (acceptor medium:
0.9% saline) is measured (literature: Umesh V. Banakar
Pharmaceutical dissolution testing, 1st edition, 1991).
The results are shown in Table 1.
Table 1: Results of Analysis
Example estradiol in vitro releasepenetration
content through skin
of
guinea pigs
ug/16 cm~ pg/16cm' pg/16cm' 24h
4h
1 2120 367 114
acc. to
DE 39 33 460 3200 1080 96
'' 48-hour-value minus 24-hour-value
The Table shows that a clearly improved penetration through the
mice skin is obtained, as is proved by the comparative example of
DE 39 33 460.
