(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2003/0099695 Al
`May 29, 2003
`Mueller
`(43) Pub. Date:
`
`US 20030099695A1
`
`(54) STABILISED OVERSATURATED
`TRANSDERMAL THERAPEUTICAL MATRIX
`SYSTEMS
`
`(76)
`
`Inventor: Walter Mueller, Neuwied (DE)
`
`Correspondence Address:
`BIRCH STEWART KOLASCH & BIRCH
`PO BOX 747
`FALLS CHURCH, VA 22040-0747 (US)
`
`(21) Appl. No.:
`
`10/221,650
`
`(22) PCX Filed:
`
`Mar. 5, 2001
`
`(86) PCX No.:
`
`PCT/EP01/02449
`
`(30)
`
`Foreign Application Priority Data
`
`Mar. 16, 2000
`
`(DE).
`
`100 12 908.0
`
`Publication Classification
`
`(51) Int. CI.7
`(52) U.S. CI.
`
`A61K 9/70
`424/449
`
`(57)
`
`ABSTRACT
`
`A transdermal therapeutic system of the matrix type, com­
`prising an active substance-impermeable backing layer, a
`detachable protective layer and an active substance-contain­
`ing matrix based on hydrophobic polymers, the active sub­
`stance having a melting point above room temperature and
`being present at least during part of the application time of
`the TTS in a concentration exceeding the saturation solu­
`bility, is characterized in that a polyacrylate polymer is
`admixed to the hydrophobic base polymers of the active
`substance matrix, or/and in that the matrix layer containing
`the hydrophobic polymers is provided with a self-adhesive
`skin-contact layer based on polyacrylates.
`
`-•-with hydrophile skin contact layer
`-H-without hydrophile skin contact layer
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`US 2003/0099695 A1
`
`1
`
`May 29, 2003
`
`STABILISED OVERSATURATED TRANSDERMAL
`THERAPEUTICAL MATRIX SYSTEMS
`[0001] The invention relates to transdermal therapeutic
`systems (TTSs) of the matrix type comprising an active
`substance-containing matrix based on hydrophobic poly­
`mers. More particularly, the invention relates to TTSs of the
`type mentioned which are at least temporarily oversaturated
`with active substance and wherein measures have been taken
`to prevent the recrystallization of an active substance which
`is solid at room temperature.
`[0002] The invention furthermore relates to processes for
`the production of transdermal therapeutic systems of the
`type mentioned.
`[0003]
`Transdermal therapeutic systems (TTSs) are rela­
`tively new medicinal forms but meanwhile have become
`quite established in a variety of application fields. Their
`general advantages lie in preventing the so-called first-pass
`effect and in maintaining therapeutically useful plasma
`levels over a period of up to 7 days. The application
`possibilities of a transdermal system are, however, fre­
`quently restricted by the fact that they are mainly suitable for
`administering drugs which are very potent and are already
`effective in very small doses. The reason for this lies in the
`barrier properties of the stratum corneum of the skin, which
`limit or prevent the absorption of drugs via the skin.
`[0004] For this reason, a considerable effort has been made
`to at least partially by-pass this obstacle. This can be
`achieved, for example, by employing permeation enhancers
`(also called penetration enhancers), which weaken the skin's
`barrier action. Furthermore, a sufficient active substance
`flow through the skin can also be attained by actively
`transporting the active substance by means of electric cur­
`rent. A further measure through which the absorption of
`active substances through the skin can be promoted consists
`in aiming at a thermodynamic activity of the active sub­
`stance in the transdermal therapeutic system which is as high
`as possible.
`[0005] Permeation enhancers are substances which affect
`the stratum corneum in such a way that its diffusion resis­
`tance is reduced, thus increasing the transdermally admin-
`isterable amount of active substance. A large number of
`substances are suitable as permeation enhancers, for
`example, fatty acids, fatty alcohols, dimethyl sulfoxide,
`partial glycerides and propylene glycol.
`[0006] Transdermal systems enabling an active transport
`of the active substance are known as so-called electrophore­
`sis or iontophoresis systems. Such systems have so far been
`employed first of all for transdermal application of predomi­
`nantly topically active drugs. Recently, efforts are being
`made, however, which focus on minimizing the size of those
`systems for practical use so as to render them suitable for
`application of systemically active drugs too.
`[0007] With the exception of the electrophoresis or ion­
`tophoresis systems described above, the active substance
`release of transdermal therapeutic systems is in principle
`based on the principle of passive diffusion of the active agent
`from the patch into and through the stratum corneum of the
`skin, and subsequent systemic absorption of the active
`substance.
`[0008]
`The third above-mentioned possibility of improv­
`ing the active substance uptake via the skin consists in
`
`rendering the thermodynamic activity of the active sub­
`stance in the transdermal therapeutic system as high as
`possible. In this way it is possible to increase the flow of
`active substance. A very high thermodynamic activity is
`achieved if the active substance concentration of the active
`substance dissolved in the active substance-containing com­
`ponents of the ITS corresponds to the saturation concen­
`tration of the active substance concerned. Such TTSs, in
`addition, possess good storage stability.
`[0009] A further increase of the thermodynamic activity of
`the active substance can be attained by raising the concen­
`tration of the active substance above its saturation concen­
`tration. However, the advantage of higher thermodynamic
`activity is linked to the disadvantage of such TTSs being
`physically unstable, i.e. the storage stability of such over-
`saturated systems is reduced.
`[0010] The adverse effect on the storage stability is based
`on the fact that active substances which at room temperature
`are present in a solid state have a tendency to recrystallize
`in such oversaturated TTSs. Owing to the crystal growth or
`formation of crystals, the concentration of dissolved active
`substance decreases, with the consequence that the thermo­
`dynamic activity of the active substance is reduced and the
`release rate of the active substance lowered. It is for this
`reason that it is not possible to produce oversaturated TTSs
`containing partially undissolved active substance, as in such
`cases, due to the crystal growth, the concentration of the
`dissolved active substance will correspond to the saturation
`concentration already after a very short time.
`[0011] There are, however, special TTS formulations
`where the state of oversaturation occurs only after applica­
`tion of the TTS to the skin, so that, prior to application, the
`storage stability is not adversely affected. Such systems
`reach the state of oversaturation by the fact that a solubilizer
`contained in the patch is likewise released from the system
`to the skin, respectively by the fact that the uptake of
`moisture from the skin reduces the saturation solubility of
`the active substance in the TTS. The advantage of such
`systems is their storage stability with respect to recrystalli­
`zation. However, in these cases, too, the active substance
`must be prevented from quickly recrystallizing to a consid­
`erable extent during the application time of the TTS. This
`would make it impossible to achieve a sufScient active
`substance release during the intended duration of applica­
`tion.
`[0012] The simplest way to produce TTSs that reach an
`oversaturated state during the application period is to base
`them on polysiloxanes. Polysiloxanes have only a very poor
`solubility for most active substances. To be able to load the
`polysyloxane matrices of such TTSs with sufScient amounts
`of dissolved active substance, it is necessary to add solvents
`to the polysiloxanes. Here, those solvents are used with
`preference which possess only restricted miscibility with the
`polysiloxanes and are present in the matrix in dispersed
`form, as droplets. In this way it is possible to largely prevent
`an adverse effect on the physical properties of the active
`substance matrix. The dispersed solvent droplets at the same
`time contain the predominant portion of the pharmaceutical
`active agent, which is why they can be regarded as micro-
`reservoirs for active substances.
`[0013] Suitable and physiologically safe solvents are, for
`instance, propylene glycol, 1,3-butanediol, dipropylene gly-
`
`

`

`US 2003/0099695 A1
`
`2
`
`May 29, 2003
`
`col, tetrahydrofurfuryl alcohol and diethyleneglycolmono-
`ethyl ether. These solvents are likewise absorbed trough the
`skin, whereby the solvent content in the active substance-
`containing TTS matrix is reduced. At the same time, the
`water released by the skin concentrates in the solvent
`droplets since the polysiloxanes can absorb water only to a
`very limited degree, owing to their extremely hydrophobic
`properties. Both mechanisms lead to oversaturation of the
`system (TTS) with active substance, in conjunction with an
`increased active substance flux through the skin. It must be
`observed, however, that this oversaturated state needs to be
`stabilised over a prolonged period of the application time.
`[0014] Stabilizing the oversaturated state during the appli­
`cation time is important, in particular, because it was sur­
`prisingly found that in active substance-oversaturated TTSs
`with hydrophobic matrix formulation, recrystallisation of
`the active substance can not only occur in the matrix itself
`but also in a thin moisture film which can form during the
`application time between the active substance-releasing side
`of the TTS and the skin surface underneath.
`[0015] Since the active substance is not absorbed by the
`skin as quickly as it is released from the TTS, this moisture
`film, too, is oversaturated with active substance. As a
`consequence the active substance can at least partially
`recrystallize during the application time in the area of this
`moisture film, which puts an end to the oversaturated state
`and reduces the thermodynamic activity of the active sub­
`stance. This means that the thermodynamic activity of the
`active substance in the moisture film located immediately
`above the skin is lowered compared to the conditions
`existing in the matrix.
`[0016] The active substance uptake from the TTS through
`the skin is thereby reduced, and the theoretic advantages of
`an active substance-oversaturated matrix are lost. In the
`polymeric matrix layers themselves, the tendency for recrys­
`tallisation is relatively weak due to the diminished diffusion
`coefScient and the generally inhibiting action of polymers
`on the formation of crystal nuclei.
`[0017] The problem underlying the present invention was
`thus to stabilise the oversaturated state in TTSs of the matrix
`type which are based on hydrophobic polymers as matrix
`formulations and which are present at least during a part of
`the application time in the oversaturated state, in such a way
`that the oversaturated state is also maintained during a
`prolonged period of the application time. More particularly,
`the problem consisted in preventing that the active substance
`undergoes recrystallisation after its release from the TTS and
`before it is absorbed through the skin.
`[0018] It was now surprisingly found that in active sub­
`stance-oversaturated, hydrophobic polymer-based matrix
`TTSs having the features mentioned in the introductory
`portion of Claim 1, stabilisation of the oversaturated state
`during the application time is achieved by admixing a
`polyacrylate polymer to the hydrophobic base polymer(s) of
`the active substance matrix, or/and by providing the matrix
`layer containing the hydrophobic polymers with a self-
`adhesive skin-contact layer based on polyacrylates.
`[0019] By means of the measures proposed in Claim 1, the
`formation of the moisture film mentioned above is prevented
`or suppressed and the risk of active substance recrystallisa­
`tion occurring in the area between the active substance-
`
`releasing side of the TTS and the skin is reduced or
`eliminated. In this way, the thermodynamic activity of the
`active substance remains on a high level in such a TTS over
`a prolonged period of time (which is why those TTSs are
`called "stabilized").
`[0020] This in turn has the consequence that the TTS is
`able to deliver the active substance or active substances in
`therapeutic doses over a prolonged period of time, and that
`thereby the application time of the TTS, during which
`sufScient release rates must be achieved, is prolonged.
`[0021] With the stabilised TTSs proposed by the invention
`it is, in particular, possible to maintain a largely constant
`release of active substance during the application time. This
`was proved by permeation studies with the Examples 1 to 3;
`the results are shown in FIGS. 1 to 3.
`[0022] This results in further advantages such as improved
`or facilitated application as a consequence of the prolonged
`application time, higher therapy safety through stabilization
`of the delivery behaviour, as well as more efficient use of
`active substance. By improving the active substance release,
`the present invention further affords the possibility of broad­
`ening the range of applications of transdermal systems
`which are based on passive diffusion. In addition, the
`invention enables the manufacture of transdermal systems
`which can have a smaller surface area due to the high active
`substance release rates which can be achieved with the
`invention; this in turn is of advantage in manufacture and
`application.
`[0023] The present invention is applicable for TTSs of the
`matrix type (matrix TTSs) whose active substance-contain­
`ing matrix is made on the basis of hydrophobic polymers.
`The stabilizing effect achieved by the additional use of
`polyacrylates in principle comes to fruition in all active
`substance-oversaturated hydrophobic matrices.
`[0024]
`In particular, the invention is of advantage in such
`TTSs which reach an oversaturated state in respect of the
`active substance only after application to the skin by way of
`absorption of moisture or by way of the release of solvents.
`[0025] The structure of the TTSs according to the inven­
`tion comprises an active substance-impermeable backing
`layer and a releasable protective layer to be removed prior
`to application, apart from the mentioned active substance-
`containing matrix.
`[0026]
`In the simplest case, the active substance matrix of
`the systems according to the invention has a single-layer
`structure and is self-adhesive. But the invention also relates
`to TTSs of a more complicated configuration which have
`multilayered active substance matrices; in this case not all of
`the layers of the matrix have to be adhesive. In addition, the
`systems according to the invention may in special cases also
`contain a special control membrane which on account of its
`thickness and/or composition puts an upper limit on the
`active substance release.
`[0027]
`In the TTSs according to the invention, polysilox­
`anes, preferably self-adhesive polysiloxanes, or polyisobu-
`tylene, polyisoprene, or a styrene-diene-styrene block
`copolymer, or mixtures of such hydrophobic polymers are
`preferably used as hydrophobic polymers which constitute
`the base polymers of the active substance matrix. Among the
`polysiloxanes, amine-resistant polysiloxanes are especially
`preferred.
`
`

`

`US 2003/0099695 A1
`
`3
`
`May 29, 2003
`
`[0028]
`According to the invention, the stabilised TTSs
`contain a polyacrylate which is admixed to the hydrophobic
`matrix layer, and/or an additional skin-contact layer which is
`superimposed on the hydrophobic matrix layer and is manu­
`factured on the basis of polyacrylate adhesives.
`[0029] The polyacrylates used are polymers which possess
`more or less hydrophile properties, depending on the mono­
`mers used. The portion of the polyacrylate polymer admixed
`to the hydrophobic matrix is preferably 40%-wt. at the most,
`relative to the total matrix. A still higher polyacrylate portion
`would lead to the properties of the active substance matrix
`being excessively determined by the polyacrylate. To
`achieve the effect according to the present invention—i.e.
`the reduction of the tendency towards formation of a mois­
`ture film and thus also of the tendency towards recrystalli-
`zation—in a degree which is at least sufScient, the amount
`of the polyacrylate should be at least about 10%-wt., better
`still at least about 15%-wt., relative to the matrix layer. The
`admixed polyacrylate may also be a self-adhesive polyacry­
`late; if the polyacrylate is admixed to a self-adhesive matrix
`layer it does not need to be adhesive itself.
`[0030] It is in principle sufScient to admix a hydrophile
`polyacrylate polymer at least to the matrix layer which is
`near the skin, i.e. the matrix layer which is in contact with
`the skin (skin-contact layer). This particularly applies to
`TTSs with multi-layered active substance matrices. The
`portion of the polyacrylate should amount to at least approx.
`10%-wt., better still at least approx. 15%-wt., relative to the
`skin-contact layer, but maximally 40%-wt. relative to the
`total matrix.
`[0031] Apart from polyacrylates it is also possible to use
`mixtures of polyacrylates with other hydrophile polymers,
`which are, in accordance with the invention, admixed to the
`hydrophobic base polymers(s) of the matrix or used to
`produce an additional skin-contact layer. As further hydro­
`phile polymers, polyvinyl pyrrolidone and copolymers of
`the vinylpyrrolidone with vinyl acetate can be employed for
`instance.
`[0032] Even where, as described above, mixtures of poly­
`acrylates^) with other hydrophile polymers are employed,
`the total portion of the hydrophile polymers admixed to the
`hydrophobic matrix should not exceed a value of 40%-wt.,
`relative to the total matrix.
`[0033] The polyacrylate itself, which is used in accor­
`dance with the present invention, may be a copolymer of any
`acryl and methacryl derivatives and vinyl compounds suit­
`able for the purpose. The following monomers are men­
`tioned by way of example: acrylic acid, methacrylic acid,
`acrylic acid ethyl ester, acrylic acid butyl ester, acrylic acid
`octyl ester, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate
`and vinyl acetate.
`[0034]
`If the hydrophobic polymers-containing matrix
`layer is provided with a self-adhesive skin-contact layer
`based on polyacrylates, the thickness of this layer or film
`should be markedly smaller than that of the hydrophobic
`matrix layer(s). More particularly, the thickness of the said
`layer should not exceed a value corresponding to 50% of the
`thickness of the hydrophobic matrix layer(s), since other­
`wise the properties of the additional hydrophilic skin-contact
`layer—which likewise contains active substance—would
`dominate the properties of the system.
`
`[0035]
`In a specific embodiment of the invention, the
`self-adhesive, hydrophilic skin-contact layer is a mixture of
`a self-adhesive polyacrylate and a hydrophilic polymer,
`preferably a film-forming polymer. As a hydrophilic film-
`forming polymer it is possible to use, for example, polyvinyl
`pyrrolidone or a copolymer of vinylpyrrolidone and vinyl
`acetate.
`[0036] The manufacture of the inventive stabilised TTSs
`can be accomplished such that initially a solution is prepared
`which contains the hydrophobic base polymers and the
`admixed acrylate polymers, as well as, possibly, auxiliary
`substances, in a suitable solvent. The active substance is
`added to this matrix polymer solution and dissolved. If
`necessary, the active substance can be added in dissolved
`form, possibly using solvents suitable specifically for this
`active substance. The active substance-containing matrix
`polymer mass obtained is then coated on a suitable film and
`subjected to drying or to a heat treatment to remove the
`solvents of the polymers. The dried matrix layer is covered
`with a further suitable film, and subsequently the individual
`TTSs are punched from this laminate.
`[0037] The advantage of the method described above
`consists in that no additional coating process is necessary in
`order to provide the TTS with stabilising properties.
`[0038]
`In the manufacture of stabilised TTSs according to
`the invention which are characterized by a self-adhesive
`hydrophile skin-contact layer based on polyacrylates, the
`hydrophobic, active substance-containing matrix layer and
`the hydrophile skin-contact layer are produced in separate
`coating processes. The individual layers are subsequently
`laminated onto each other, which yields the complete sys­
`tem.
`[0039] Here, the skin-contact layer can be loaded with
`active substance already during the manufacture, or it can be
`manufactured free of active substance. In the latter case the
`active substance enters the skin-contact layer by way of
`diffusion from the hydrophobic matrix layer after the lami­
`nate has been prepared.
`[0040] The invention will be explained in the following by
`way of examples.
`
`EXAMPLE 1
`
`TTS Comprising Estradiol
`
`EXAMPLE la
`
`TTS Without Hydrophile Skin-Contact Layer
`
`COMPARISON EXAMPLE 1
`[0041] 1.0 g of estradiol hemihydrate were dissolved in
`22.75 g of 1,3-butanediol, and the solution was thickened by
`adding 0.7 g of hydroxypropyl cellulose. Then, 60 g of a
`solution of an amine-resistant polysiloxane adhesive (BIO-
`PSA 4301; Dow-Corning; solids content: 70%-wt.) were
`added to this solution, and the active substance solution was
`dispersed in the solution of the adhesive by stirring.
`[0042] Subsequently, the mass is coated, using an Erich-
`son doctor knife, in a thickness of 200 /an onto a film which
`has been rendered abhesive (Scotchpak 1022; 3M), and
`dried for 20 min at 40° C. This yields a matrix film with a
`
`

`

`US 2003/0099695 A1
`
`4
`
`May 29, 2003
`
`coating weight of 120 g/m2. The dried matrix film is covered
`with the backing layer of the ITS (Scotchpak 1220; 3M).
`
`EXAMPLE lb
`
`TTS With Hydrophile Skin-Contact Layer
`[0043] 1.0 g of estradiol hemihydrate are dissolved in 20.0
`g of 1,3-butanediol, and subsequently 20.0 g of a Kollidon
`90F solution (Kollidon 90F is a polyvinyl pyrrolidone;
`BASF) having a solids content of 25%-wt. are added while
`stirring.
`[0044] Thereafter, 145 g of a solution of a polyacrylate
`adhesive (Durotak 387-2287; National Starch & Chemical;
`solids content: 51%-wt.) are added, and the mixture is
`homogenized by stirring. The mass is coated in a thickness
`of 50 /im onto a film which has been rendered abhesive
`(Scotchpak 1022; 3M), and is dried at 40° C. for 15 min.
`[0045] The dried film has a coating weight of 16 g/m2.
`[0046] Then, the abhesive-rendered film is removed from
`the hydrophobic matrix layer prepared under la, and the
`matrix layer is laminated onto the skin-contact layer.
`[0047] The finished TTSs are then punched out from this
`total laminate.
`[0048] The results of a comparative permeation study
`between samples without skin-contact layer (la) and
`samples with hydrophile skin contact layer (lb) are repre­
`sented in FIG. 1.
`
`EXAMPLE 2
`
`Transdermal System (TTS) With Estradiol
`
`EXAMPLE 2a
`
`TTS Without Flydrophile Skin-Contact Layer
`
`COMPARISON EXAMPLE 2
`[0049] 5.0 g of estradiol hemihydrate are dissolved in 38.5
`g ofdipropylene glycol. To this solution are added 124 g of
`a solution of a polysiloxane adhesive (BIO-PSA 4301;
`Dow-Corning; solids content: 70%-wt.), and the active
`substance solution is dispersed in the adhesive solution
`while stirring.
`[0050] Thereafter, the mass is coated by means of an
`Erichson doctor knife onto a suitable, film which has been
`rendered abhesive (Scotchpak 1022; 3M), and the solvent of
`the adhesive is removed by drying for 20 minutes at 45°. The
`dried film having a coating weight of 80 g/m2 is then covered
`with a suitable film (e.g. Scotchpak 1220; 3M).
`
`EXAMPLE 2b
`
`TTSs With Hydrophilic Skin-Contact Layer
`[0051] 1.0 g of estradiol hemihydrate are dissolved in 10.0
`g of dipropylene glycol, and subsequently 20.0 g of a
`Kollidon 90F solution (Kollidon 90F is a polyvinyl pyrroli­
`done) having a solids content of 25%-wt. are added while
`stirring.
`[0052] Thereafter, 164 g of a solution of a polyacrylate
`adhesive (Durotak 387-2287; National Starch & Chemical;
`
`solids content: 51%-wt.) are added, and the mixture is
`homogenised while stirring. The mass is coated in a thick­
`ness of 50 /im with an Erichson doctor knife onto a film
`which has been rendered abhesive (Scotchpak 1022; 3M),
`and dried at 40° C. for 15 min. The dried film has a coating
`weight of 15 g/m2.
`[0053] The abhesive-rendered protective film is removed
`from the hydrophobic matrix layer prepared under 2a, and
`the said matrix layer is laminated onto the skin-contact layer.
`[0054] The TTSs are then punched out of this total lami­
`nate.
`[0055] The results of a comparative permeation study
`between samples without skin-contact layer (2a) and
`samples with hydrophile skin-contact layer (2b) are repre­
`sented in FIG. 2.
`
`EXAMPLE 3
`
`Monolithic Transdermal System (TTS) Based on
`Silicone Adhesives With Flydrophile Additives
`[0056] 1.2 g of estradiol hemihydrate are dissolved in 9 g
`of dipropylene glycol, and the solution is thickened by
`addition of 0.26 g of hydroxypropyl cellulose (Klucel NF).
`To this solution are added 88.0 g of silicone adhesive
`(BIO-PSA 4301; Dow-Corning; solids content: 70%-wt.),
`10.0 g of a polyacrylate adhesive (Durotak 387-2287; solids
`content 51%-wt.; National Starch) and 1.2 g of a solution of
`Kollidon 90F in ethanol (solids content 25%-wt), and the
`mass is mixed while stirring.
`[0057] The mass is coated in a thickness of 250 /an onto
`a film which has been rendered abhesive (Scotchpak 1022;
`3M), using an Erichson doctor knife, and is dried for 15 min
`at 40° C. The dried film having a coating weight of 115 g/m2
`is then covered with a suitable film (e.g. Scotchpak 1220;
`3M), and the finished patches are punched out of the total
`laminate.
`[0058] Example 2a serves as a comparison example. The
`results of a comparative permeation study between samples
`without hydrophilic additives (2a) and samples with hydro-
`philic additives (3) are represented in FIG. 3.
`[0059] Permeation studies involving the systems prepared
`according to Examples 1 to 3.
`[0060] The results of the comparison measurements are
`represented in FIGS. 1 to 3. These measurements were made
`using Franz diffusion cells and human epidermis. Each point
`is the mean of 3 independent measurements.
`[0061] The time course of the permeation in FIGS. 1 to 3
`clearly shows that in the case of the TTSs according to the
`present invention a constant release rate, and thus a stabi­
`lisation, is achieved for a period of at least 72 h, whereas in
`the case of the comparison examples a marked flattening of
`the permeation profile can be seen already after 32 h.
`
`1. Transdermal therapeutic system of the matrix type,
`comprising an active substance-impermeable backing layer,
`a detachable protective layer and an active substance-con­
`taining matrix based on hydrophobic polymers, the active
`substance having a melting point above room temperature
`and being present at least during part of the application time
`of the TTS in a concentration exceeding the saturation
`
`

`

`US 2003/0099695 A1
`
`5
`
`May 29, 2003
`
`solubility, characterized in that a polyacrylate polymer is
`admixed to the hydrophobic base polymers of the active
`substance matrix, or/and in that the matrix layer containing
`the hydrophobic polymers is provided with a self-adhesive
`skin-contact layer based on polyacrylates.
`2. Transdermal therapeutic system of the matrix type
`according to claim 1, characterized in that the active sub­
`stance matrix comprises as hydrophobic base polymers:
`polysiloxanes, preferably self-adhesive polysiloxanes, or
`polyisobutylene, polyisoprene or a styrene-diene-styrene
`block copolymer, or mixtures of such hydrophobic poly­
`mers; amine-resistant polysiloxanes being particularly pre­
`ferred.
`3. Transdermal therapeutic system of the matrix type
`according to claim 1 or 2, characterized in that at least the
`matrix layer coming into contact with the skin comprises a
`portion of a polyacrylate polymer, this portion preferably
`being at least 10%-wt., more preferably 15%-wt, relative to
`the skin contact layer, but maximally 40%-wt. relative to the
`total matrix.
`4. Transdermal therapeutic system of the matrix type
`according to one of the preceding claims, characterized in
`that a polyacrylate is admixed to the hydrophic base poly­
`mers) of the active substance matrix, the total portion of the
`polyacrylate admixed to the hydrophic base polymer pref­
`erably being at least 10%-wt., more preferably 15%-wt., but
`maximally 40%-wt, each relative to the total matrix.
`5. Transdermal therapeutic system of the matrix type
`according to one of the preceding claims, characterized in
`that, in addition, polyvinyl pyrrolidone or a copolymer of
`polyvinyl pyrrolidone and vinyl acetate is/are admixed to the
`hydrophobic base polymer(s) of the active substance matrix
`or at least to the matrix layer which is near the skin, the total
`portion of the polymers admixed to the hydrophobic base
`polymer preferably being at least 10%-wt., more preferably
`15%-wt., but maximally 40%-wt., each relative to the total
`matrix.
`6. Transdermal therapeutic system of the matrix type
`according to claim 1 or 2, characterized in that the skin-
`contact layer is a mixture of a self-adhesive polyacrylate and
`a hydrophile polymer, preferably a film-forming hydrophile
`polymer.
`7. Transdermal therapeutic system of the matrix type
`according to claim 6, characterized in that the film-forming
`hydrophile polymer is polyvinyl pyrrolidone or a copolymer
`of vinylpyrrolidone and vinyl acetate.
`8. Transdermal therapeutic system of the matrix type
`according to one or more of the preceding claims, charac­
`
`terized in that the system reaches an oversaturated state in
`respect of the active substance only after the system is
`applied to the skin, by way of absorption of moisture or by
`way of release of solvents.
`9. Process for the production of transdermal therapeutic
`systems of one or more of claims 1 to 5 and 8, comprising
`the following steps:
`a) Preparing a solution containing the hydrophobic base
`polymers and the admixed acrylate polymers;
`b) adding and dissolving the active substance in the
`matrix polymer solution, or adding an active substance
`solution and mixing the same with the matrix polymer
`solution;
`c) coating this mass on a film;
`d) removing the unwanted solvents by heating or drying;
`e) covering the dried matrix layer with a film;
`f) punching out individual transdermal therapeutic sys­
`tems.
`10. Process for the production of a transdermal therapeu­
`tic system of the matrix type comprising a hydrophile
`skin-contact layer, according to one of claims 1, 2, 6 to 8,
`characterized by the following steps:
`a) Preparing a solution or dispersion containing a hydro­
`phobic base polymer and an active substance;
`b) coating this polymer- and active substance-containing
`mass in a thin layer onto a film which