Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
21978~~
Estradiol-TTS havin4 water-binding additives
SPECIFICATION
The present invention relates to a transdermal therapeutic system
with the active substance estradiol and, optionally, additional ac-
tive substances as well as a water-binding additive substance, and
with a layered structure of a backing layer which is impermeable
to active substances and moisture, an active substance-containing
matrix layer, and, in case of need, a removable protective layer
covering the matrix layer.
In the pharmaceutical therapy of several diseases, Transdermal
Therapeutic Systems (TTS) have been introduced on the market
for some time now.
In the following the term "estradiol" is to be understood as the
anhydrous substance of 17-~3-estradiol in dissolved or crystalline
(anhydrate) form.
In the meantime, TTSs comprising the active substance estradiol
have been on the market as therapeutic agent for climacteric com-
plaints, and, since a short time ago, also against osteoporosis;
they have proved successful in therapy.
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-con-
struction have been taken (use of multilayer systems, use of con-
trolling membranes, variation of the active substance
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2
concentration, modification of the base polymer, and the like).
This finding, i.e., that the transdermal flow of an active substance
from the solid, finely dispersed phase cannot be increased further
in principle, even if high-dissolving vehicles are used, can already
be found in the trailblazing works of Higuchi, e.g., T. Higuchi:
Physical Chemical Analysis of percutaneous process from creams
and ointments. J. Soc. Cosmetic Chem. 11, p. 85-97 (1960).
The systems described in EP 0 421 454 comprise estradiol in an
acrylate polymer under addition of "crystallization inhibitors" and
tackifying resins. Swelling agents are contained to give protection
against premature loss of adhesive force.
With a lot of active substances, so-called "enhancers" may be
added to the TTS during production. These are usually liquid ad-
mixtures improving the absorption properties of human skin; for
this reason, they allow the absorption of the active substance
from a sufficiently small TTS-surface. In particular readily volatile
enhancers, e.g., ethanol used for the active substance estradiol,
involve the problem of softening the TTS's adhesive layers to a
great extent; above all they require additional bulky compartments
in the system, rendering the TTS unacceptably thick. Finally, any
additional non-polymeric additive involves the risk of incompatibil-
ity reactions on the skin, possibly even that of sensitization. The
addition of certain less volatile, however, mostly less active en-
hancers (e.g., glycerol esters, cyclic amides, eucalyptol) allows the
production of matrix systems comprising the active substance and
the absorption-promoting component in one or several monolithic
layers.
US 4 863 738 represents one of many examples claiming the ap-
plication 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.
According to the art, these TTSs do not permit a satisfactory ther-
apy either. The reason is that either the active enhancers are
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3
poorly tolerated by the skin or that the systems require unac-
ceptably large surfaces owing to the still insufficient flow through
the skin.
Another possibility of increasing the active substance flow through
the skin is that an amount of active substance is dissolved
molecularly disperse in the TTS, which exceeds that corresponding
to the saturation solubility. With supersaturation of these systems
the permeation rate of the skin increases to the same extent.
However, since such states are thermodynamically unstable, these
forms of administration are not stable in storage; unforeseeable
recrystallization of active substance particles will take place so
that the flow rate through the skin gradually decreases to the sat-
uration flow level; depending on the starting concentration, this
results in losing a great portion of the initially existent therapeutic
activity.
This process is a characteristic of estradiol.
At room temperature and normal relative air humidity (20-60%
relative humidity), estradiol i~ not present in ohe of the two known
anhydric modifications (I and II) but as a semihydrate (Busetti and
Hospital, Acta Cryst. 1972, B28, 5601. Owing to the layered
structure stabilized via hydrogen bridges, and because of the dif-
fusional compactness of the crystal compound, the semihydrate
can be subjected to a short-term heat treatment to .temperatures
of about 170°C without decomposition thereof (Kuhnert-Brand-
statter and Winkler (1976) Scientia Pharmaceutics 44 (3), 177-
190). However, the anhydrous form can quantitatively be obtained
already at about 120°C by way of enlarging the crystal surface by
means of micronizing. According to own observations, the trans-
formation already takes place at about 90°C if heating is con-
ducted very slowly (0.2-1 K/min) and in case of a particularly fine-
crystalline substance.
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4
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 desir-
able in transdermal therapeutic systems. However, the water in-
troduced with the estradiol-semihydrate is already sufficient to ini-
tiate gradual recrystallization from the solution as estradiol-semi-
hydrate (Kuhnert-Brandstatter and Winkler (1976) Scientia Phar-
maceutica 44 (3), 177-190). After crystallization, the flow rate
from the system to the skin considerably decreases with the di-
minishing concentration.
Taking into account these circumstances, transdermal therapeutic
systems are known that offer a pharmacotherapeutically satisfying
solution by exactly regulating the concentration to little less than
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 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 pre-
cipitation of the poorly soluble estradiol-semihydrate. To this end,
a waterproof package having a low water-vapor permeability can
be used in principle. However, owing to the low estradiol concen-
tration 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 anEstradiol (anhydrous) are present in a
TTS in dissolved form, an amount of only 66.1 erg 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.
~19'~~fi~
DE 42 37 453 already proposes to use desiccants in the ready-for-
storage package; however, there are no indications with respect
to using the water-binding additive as a component of the matrix.
Accordingly, it is the object of the present invention to provide a
transdermal therapeutic system comprising estradiol, that protects
the system in the package during storage against precipitation of
the estradiol-semihydrate, and which, if required, is suitable for a
matrix which comprises more active substance in a molecularly
disperse dissolved form than corresponds to the saturation solubil-
ity.
In a transdermal therapeutic system of the kind mentioned in the
introductory part of claim 1, this object is achieved with the pres-
ent invention by the fact that the water-binding additive substance
is a constituent of the matrix.
Integrating water-binding mineral components in the substance of
the matrix according to the present invention can be realized in a
TTS in different manners: the most simple form is a single-layer
matrix system the matrix of which simultaneously has a pressure-
sensitive adhesive function, rendering an additional adhesive layer
superfluous.
The mineral components that are contained in the matrix in dis-
solved form or which are usually dispersed in solid phase, ensure
an equilibrium-moisture content over the storage period that is low
enough to render precipitation of the estradiol-semihydrate impos-
sible.
If direct contact of the skin with the mineral particles is to be
avoided, only the matrix is provided with water-binding mineral
components and an adhesive layer which faces the skin and is
free from particulate estradiol is applied by lamination.
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6
If a membrane which is hardly permeable to estradiol is introduced
between such a matrix, which comprises estradiol and water-
binding mineral constituents, and the adhesive layer, a modified
active substance release is achieved.
In addition to the wide-spread acrylic-acid ester copolymers suit-
able for the use with estradiol, other polymers may also be used
as base material, for example, polyisobutylene, polyvinyl acetate,
and copolymers, synthetic rubber, silicones.
In any case, the characterizing feature of transdermal therapeutic
systems according to the present invention is the presence of
water-binding mineral components in the matrix. In this connec-
tion, the exact amount of said additives in the matrix must be suf-
ficiently large since this increases the total moisture-binding ca-
pacity in the system. The exact amount of added substances will
result for the skilled artisan in a comprehensible manner from the
component's binding power for water. Since the water-binding
capacity of most of the following exemplary substances generally
lies above that of estradiol, an addition in the range of the estra-
diol contained - about 1 to 2 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 20 and 35 percent by weight is de-
sired.
The following substances may be used as water-binding mineral
components, e.g., zinc oxide, silicon dioxide, silica gel (also in
modified, e.g., hydrophobized form), talc, phosphorus pentaoxide,
alumina, aluminum phosphate, magnesium oxide and hydroxide,
calcium oxide and hydroxide; kaolin, molecular sieves, sodium
oxide, calcium and magnesium carbonate, magnesium sulfate,
CA 02197865 2004-06-29
calcium sulfate, copper sulfate, manganese oxides, silicates, aluminates, or
magnesium
perchlorate
In this connection, it must be considered that both chemico-reactive
processes, such as
the reaction of magnesium oxide to magnesium hydroxide, and the physical
changes, e.g.,
inclusion of crystal water into initially anhydrous sodium sulfate, calcium
sulfate, or
calcium chloride, or also pure, nonstoichiometric hygroscopy or adsorptivity
can be
utilized; these are commonly known as such to the skilled artisan.
Substances having a high water-binding capacity in case of low humidity (in
the range of
below about 5% relative humidity) are preferably used. In addition, a high
degree of
physiological compatibility is desired
Fortunately, many hydrates of salts of the alkaline earth metals and alkali
metals comply
with these conditions, for example, calcium and magnesium carbonate, calcium,
sodium,
and magnesium sulfate, or many silicates, aluminates, borates, and phosphates
of the
alkali metals (preferably sodium, potassium, lithium) and alkaline earth
metals (calcium
and magnesium).
In one embodiment, the present invention provides a transdermal therapeutic
system with
the active substance estradiol and, optionally, further active substances and,
optionally,
water-binding additives, having a layered structure comprising a backing layer
which is
impermeable to active substances and moisture, an active substance-containing
matrix
layer, and, optionally, a removable protective layer, characterised in that
the matrix
contains the active substance as water-free estradiol, together with a water-
binding
additive, said water-binding additive ensuring an equilibrium moisture which
prevents
the precipitation of estradiol semihydrate.
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the matrix exhibits several active substance-
containing taming
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layers and that at least one of these layers comprises a pharmaceutically
acceptable,
water-binding mineral additive.
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the matrix material comprises the water-binding
additive
substance in finely dispersed suspension.
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the water-binding additive substance is a mineral.
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the water-binding additive is the anhydrate of an
alkaline-earth or
alkali metal salt
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the water-binding additive is the semihydrate or
anhydrate
("anhydrite") of calcium sulfate.
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the estradiol is present as dispersion of an
anhydrous crystallizate.
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that more estradiol is comprised in the matrix base
material in
molecularly disperse dissolved form than corresponds to the saturation
solubility.
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the proportion of the mineral water-binding additive
in the total
matrix material amounts to between 1 and 40%-wt., and preferably to 20%-wt.
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the matrix base material is a polymer which, under
water-free
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9
conditions, has a solubility for the active substance estradiol of between 0.4
and 3.0%
(w/w).
In an additional embodiment, the transdermal therapeutic system of the present
invention
is characterized in that the matrix base material is a polyacrylate polymer.
In a further embodiment, the present invention provides a process for the
production of
the transdermal therapeutic system, characterized by the steps:
- preparing a suspension of estradiol-semihydrate and water-binding mineral
additive
in a solution, dispersion, or melt of the matrix base material,
- using this suspension, applying a layer on a sheet-like substrate,
- carrying out a conversion of estradiol-semihydrate into anhydrous estradiol
in the
layer by heating to 90 to 175°C
In an additional embodiment, the process of the present invention is
characterized in that
the dry layer is heated to 90 to 200°C until a conversion of the
hydrous form of the
mineral water-binding additive into its anhydrous form has taken place.
In an additional embodiment, the process of the present invention is
characterized in that
the transdermal therapeutic system is packed into a moistureproof package
which
comprises a desiccant, if required.
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1
Examples:
Example 1: Production of a system according to the present invention.
2.0 g of 17-(3-estradiol-semihydrate, micronized 60.0 g of CariflexR TR 1107
(styrene-
isoprene-styrene block co-polymer)
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CA 02197865 2004-06-29
i2a.0 g at Staybelite Ester 5E: ttE~ermoptastic ester gum of
toiaphony dari~ratiuesi
S4 g of uiscous paraffin
S~ g of rslclum sulfate dihydrate
are molten in an evacuatable krfeader at 13U°C and brougi~t into . _. ,
,
an extemaily homogeneous form try means of kneading wltt~in ten
hours. Under ~ecuurn Mess than 0.02 tsar! heating to 9 65°C i$ ef- '
fectcd far ans hourr while doing so Crygtai water Is driven off the ,
. active subsiarvce and aaicium sulfate by meant of kneading. ,
Tfie melt is coolcsl dawn to 120°~; in a continuous coating Line
it
is subsequently coated ants a siiicarrfaed polyester film of 300 ~rcn
thicknøss in such a manner that the weight per ur~it area of the
Eager amounts to 200 glm~.
Afterwards g polyest~sr film t5 arm thick is appiied ~aminatedf un-
der rot! pressure on the still hot layer, avoidic~g the formation of air
hubbies.
TransdermaE systems of 16 Gm' are obtaEned by parching using s
vsr2~d punci~.
Exampie 2: Production of a system according to the present En'
rrentlon
3.0 g of 't7-~i-estradloE~semlhydrata, micronized ,
'40b.0 g of acrylic-aold ester copr~lymer solutECn isaEids content
b 09~ wlw~
70.0 g of cglcium sulfate, anhydrous ("anhydrite"1
are stirred at roam temperature In a cylindrical glass vessel until a
homogeneous suspension is aE~tairrad. Afterwards coating 1s ef~
farted at a slit width of 500pm onto a t~Dpm slliconlzed polyes~
tar fHm. Ztxa cis died a~?S.°yC. at 50°C, at 8d'C an4 at
95°C, each
r;~_for I~0 ~aiauces.. A ~5~m poly~gtBrfilm Es immediately applied
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~a
~i8minated~ on the dry layer tinder roller pressure, avpiding tha
forrnatlon of aEr bu>?bles.
Trsnsdermal systems of t 0 cm' ars obtained by p~unchln~ usErig a
wad punch. The3e are tracked into ~ composite packaging material
of.paperlaluminum foillhflt-sealing layer under addition of a desic-
cant tablet cflmprising 0.3 g of calcium sulfate ~prevloualy pret~ried
~t ~ 80°C~. ~ ~ - . . ' . . _ , .
c ~:
.:~, ..
