TRANSDERMAL THERAPEUTIC SYSTEM FOR

THE TRANSDERMAL ADMINISTRATION OF BUPRENORPHINE

COMPRISING A SILICONE ACRYLIC HYBRID POLYMER

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of buprenorphine, processes of manufacture and uses thereof, and methods of treatments therewith.

BACKGROUND OF THE INVENTION

[0002] The active ingredient buprenorphine, (5R,6R,7R,9R,l3S,l4S)-l7-Cyclopropylmethyl-7- [(S)-3,3-dimethyl-2-hydroxybutan-2-yl]-6-methoxy-4,5-epoxy-6 ,l4-ethanomorphinan-3-ol) (C ₂₉ H _4I N0 ₄ ), is a partially synthetic opiate with high potency. Despite its rather high molecular weight of 467.64 Daltons, it is currently used for transdermal administration. The commercial TTS product Transtec®, which is a matrix-type TTS wherein buprenorphine is homogeneously dissolved within an acylic polymer matrix, delivers buprenorphine to the skin sufficiently to treat patients in pain for a time period of up to 4 days (about 96 hours) and allows therefore a use of the TTS over a time period of up to 4 days and allows in a fixed dosing regimen a twice-weekly TTS exchange. The commercial matrix-type TTS product Norspan®, also known as BuTrans®, delivers buprenorphine to the skin sufficiently to treat patients in pain for a time period of 7 days (about 168 hours) and allows therefore a use of the TTS over a time period of 7 days and allows in a fixed dosing regimen a once-weekly TTS exchange. A twice-weekly exchange (after about 3.5 days) and a once-weekly exchange (after about 7 days) are specifically beneficial in terms of convenience and patient compliance. Thus, the overall efficacy of the pain medicament is enhanced. However, the long administration periods may cause problems with skin irritation, which in combination with the considerable size (i.e., area of release) of the TTS may be problematic. Also, the large amount of excess drug in the TTS necessary to sustain enough driving force for sustaining the appropriate drug delivery over the long period of time is costly and has the potential to be subject to illicit use.

[0003] It is therefore desirable to reduce the overall size (i.e., area of release) of the TTS as well as the total amount of buprenorphine in the TTS before administration and the amount of buprenorphine remaining in the TTS after proper use, the residual amount. The permeation rate per area of release and the active agent utilization of a TTS thus need to be improved to provide a permeation rate over the desired administration period, e.g. the seven-day administration period, which is comparable to the commercial TTS product, with a smaller TTS which contains less amounts of active agent compared to the commercial TTS product.

[0004] The use of microreservoir TTS is usually characterized by an improved active agent utilization compared to single-phase matrix-type TTS, as the active agent contained in the dispersed inner phase only slightly dissolves in the outer phase of the biphasic layer of a microreservoir TTS, thus supporting the ambition to shift from the microreservoir system towards the skin. A problem of the microreservoir TTS is the insufficient stabilization of the biphasic structure. The dispersed inner phase tends to coalesce and large deposits may release the active agent too fast and provide for an undesired high active agent delivery at the beginning of the dosing period (also known as "drug burst") and a failure of the system in particular for longer dosing periods since the loss of active agent at the beginning will lead to a loss of driving force later in the dosing period. The permeation of the active agent is thus not predictable and may be too fast, not long enough, and not sufficiently continuous.

[0005] WO 2014/195352, which relates to a microreservoir TTS for the transdermal administration of buprenorphine, shows that fusing of the therein contained deposits and the corresponding size increase of the deposits can be controlled by the use of a viscosity-increasing substance. Although it was shown in WO 2014/195352 that the viscosity-increasing substance has a stabilizing effect on the biphasic system, the deposits of the matrix layer are still subject to a certain size increase under high shear forces. The systems may thus still be susceptible to unpredictable variations in the release profile of the active agent. Thus, it is still desirable to provide a TTS with an improved release performance and an improved active agent utilization compared to the commercial TTS product, wherein the variability of the system is sufficiently controlled.

[0006] Further, to reduce the variability of the permeation rate provided by a TTS, it is also required that the TTS, and in particular the area of release of the TTS, remains in contact with the skin during the administration period, in particular during longer administration periods such a seven days. A discontinuous contact of the TTS, and in particular of the active agent- containing layer structure providing the area of release, with the skin may result in a reduced and uncontrolled release of the active agent over the administration period. It is thus desirable to not only provide a TTS with an improved release performance and an improved active agent utilization compared to the commercial TTS product but, in addition, to provide a TTS with a sufficient tack of the active agent-containing layer structure. The provision of the combination of the described beneficial characteristics of a TTS is particularly challenging in view of the basic requirements for a TTS for being chemical and physical stable and feasible to manufacture on a commercial scale.

[0007] There is thus a need in the art for an improved TTS for the transdermal administration of buprenorphine which overcomes the disadvantages of the known TTS for the transdermal administration of buprenorphine.

[0008] All references and publications cited herein are hereby incorporated by reference in their entirety for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

[0009] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine (e.g., buprenorphine base), which requires a relatively small area of release and provides a sufficiently reproducible release of buprenorphine (e.g., buprenorphine base) over the administration period (e.g., about 3.5 days or about 7 days).

[0010] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine (e.g., buprenorphine base), which requires a relatively small amount of buprenorphine (e.g., buprenorphine base) contained therein and provides a sufficiently reproducible release o f buprenorphine (e.g., buprenorphine base) over the administration period (e.g., about 3.5 days or about 7 days).

[0011] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine, which is suitable for providing pain relief for several days (e.g., for about 3 days, for about 3.5 days, for about 4 days, for about 5 days, for about 6 days, or for about 7 days (corresponding to one week).

[0012] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine that provides an improved release performance over the desired administration period (e.g., 7 days) compared to the commercial buprenorphine TTS without negatively affecting the desired physical properties of the TTS (e.g., tackiness and wear properties), in particular without providing a significant reduced tack of the buprenorphine- containing layer structure compared to the commercial buprenorphine TTS.

[0013] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine that provides an increased permeation rate compared to the commercial buprenorphine TTS without providing a significant reduced tack of the buprenorphine-containing layer structure compared to the commercial buprenorphine TTS.

[0014] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine with a high active-agent utilization, i.e. a TTS, which does not require a high excess amount of buprenorphine in order to a sufficient release performance during an administration period (e.g. 7 days).

[0015] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine that provides an improved active agent utilization compared to the commercial buprenorphine TTS without negatively affecting the physical properties (e.g., tackiness and wear properties) of the TTS, in particular without providing a significant reduced tack of the buprenorphine-containing layer structure compared to the commercial buprenorphine TTS.

[0016] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine that provides an increased permeation rate and an improved active agent utilization compared to the commercial buprenorphine TTS without providing a significant reduced tack of the buprenorphine-containing layer structure compared to the commercial buprenorphine TTS.

[0017] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine that provides an improved release performance, an improved active agent utilization, and improved adhesive properties of the buprenorphine- containing layer structure compared to the commercial buprenorphine TTS.

[0018] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine that provides a constant release of the active agent over an extended period of time (e.g., 7 days).

[0019] It is an object of certain embodiments of the present invention to provide a TTS for the transdermal administration of buprenorphine that is easy to manufacture.

[0020] These objects and others are accomplished by the present invention which according to one aspect relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure, the buprenorphine- containing layer structure comprising a backing layer and a buprenorphine- containing layer, wherein the buprenorphine-containing layer comprises a) a therapeutically effective amount of buprenorphine and b) a carboxylic acid, and wherein the transdermal therapeutic system comprises at least one silicone acrylic hybrid polymer.

[0021] It has been found that the TTS according to the present invention, which comprises a silicone acrylic hybrid polymer, buprenorphine (e.g. buprenorphine base) and a carboxylic acid (e.g. levulinic acid), provides advantageous properties in terms of the constant and continuous buprenorphine delivery, the release performance, the active agent utilization, and the adhesive properties. In particular, the TTS according to the present invention provides the advantageous properties over an extended period of time (e.g., 7 days).

[0022] According to further aspects, the TTS according to the invention is for use in a method of treating pain wherein the transdermal therapeutic system is applied to the skin of a patient preferably for more than 3 days, for about 3.5 days, for about 4 days, for about 5 days, for about 6 days, or for about 7 days.

[0023] According to further aspects, the invention relates to a method of treating pain by applying a transdermal therapeutic system in accordance with the invention to the skin of a patient, in particular for more than 3 days, for about 3.5 days, for about 4 days, for about 5 days, for about 6 days, or for about 7 days.

[0024] According to yet another aspect, the invention relates to a method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine in accordance with the invention, comprising the steps of: 1) providing a buprenorphine-containing coating composition comprising a) buprenorphine, b) carboxylic acid, and c) solvent, 2) coating the buprenorphine-containing coating composition onto a release liner in an amount to provide the desired area weight, 3) drying the coated buprenorphine-containing coating composition to provide the buprenorphine-containing layer, 4) laminating the buprenorphine-containing layer to a backing layer to provide an buprenorphine-containing layer structure, 5) optionally providing an additional skin contact layer by coating and drying an active agent- free coating composition according to steps 2 and 3, removing the release liner of the buprenorphine-containing layer and laminating the additional skin contact layer onto the buprenorphine-containing layer to provide a buprenorphine-containing layer structure with the desired area of release, 6) punching the individual systems from the buprenorphine-containing layer structure, 7) optionally adhering to the individual systems an active- free self-adhesive layer structure comprising also a backing layer and an active agent-free pressure-sensitive adhesive layer and which is larger than the individual systems of buprenorphine-containing self-adhesive layer structure, wherein at least one silicone acrylic hybrid polymer composition is added to the buprenorphine-containing coating composition in step 1 , or, if an additional skin contact layer is provided, to the active agent-free coating composition in step 5, or to both the buprenorphine-containing coating composition in step 1 and to the active agent-free coating composition in step 5.

DEFINITIONS

[0025] Within the meaning of this invention, the term“transdermal therapeutic system” (TTS) refers to a system by which the active agent (e.g. buprenorphine) is administered to the systemic circulation via transdermal delivery and refers to the entire individual dosing unit that is applied, after removing an optionally present release liner, to the skin of a patient, and which comprises a therapeutically effective amount of active agent in an active agent-containing layer structure and optionally an additional adhesive overlay on top of the active agent-containing layer structure. The active agent-containing layer structure may be located on a release liner (a detachable protective layer), thus, the TTS may further comprise a release liner. Within the meaning of this invention, the term“TTS” in particular refers to systems providing transdermal delivery, excluding active delivery for example via iontophoresis or microporation. Transdermal therapeutic systems may also be referred to as transdermal drug delivery systems (TDDS) or transdermal delivery systems (TDS).

[0026] Within the meaning of this invention, the term“buprenorphine-containing layer structure” refers to the layer structure containing a therapeutically effective amount of buprenorphine and comprises a backing layer and at least one active agent-containing layer. Preferably, the buprenorphine-containing layer structure is a buprenorphine-containing self- adhesive layer structure.

[0027] Within the meaning of this invention, the term“therapeutically effective amount” refers to a quantity of active agent in the TTS which is, if administered by the TTS to a patient, sufficient to provide a treatment of pain. A TTS usually contains more active in the system than is in fact provided to the skin and the systemic circulation. This excess amount of active agent is usually necessary to provide enough driving force for the delivery from the TTS to the systemic circulation.

[0028] Within the meaning of this invention, the terms“active”,“active agent”, and the like, as well as the term“buprenorphine” refer to buprenorphine in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include without limitation buprenorphine in its free base form, protonated or partially protonated buprenorphine, buprenorphine salts, and in particular acid addition salts formed by addition of an inorganic or organic acid such as buprenorphine hydrochloride or buprenorphine sulphate, phosphate, tartrate, maleinate, oxalate, acetate, lactate, solvates, hydrates, clathrates, complexes and so on, as well as buprenorphine in the form of particles which may be micronized, crystalline and/or amorphous, and any mixtures of the aforementioned forms. The buprenorphine, where contained in a medium such as a solvent, may be dissolved or dispersed or in part dissolved and in part dispersed. In the present invention, buprenorphine base is preferably dissolved in the carboxylic acid (e.g. levulinic acid) to form a buprenorphine- carboxylic acid solution which forms dispersed deposits in the polymer matrix.

[0029] When buprenorphine is mentioned to be used in a particular form in the manufacture of the TTS, this does not exclude interactions between this form of buprenorphine and other ingredients of the buprenorphine-containing layer structure, e.g. salt formation or complexation, in the final TTS. This means that, even if buprenorphine is included in its free base form, it may be present in the final TTS in protonated or partially protonated form or in the form of an acid addition salt, or, if it is included in the form of a salt, parts of it may be present as free base in the final TTS. Unless otherwise indicated, in particular the amount of buprenorphine in the layer structure relates to the amount of buprenorphine included in the TTS during manufacture of the TTS and is calculated based on buprenorphine in the form of the free base. E.g., when a)

0.1 mmol (equal to 46.76 mg) buprenorphine base or b) 0.1 mmol (equal to 50.41 mg) buprenorphine hydrochloride is included in the TTS during manufacture, the amount of buprenorphine in the layer structure is, within the meaning of the invention, in both cases 46.76 mg, i.e. 0.1 mmol.

[0030] Within the meaning of this invention, the term“particles” refers to a solid, particulate material comprising individual particles, the dimensions of which are negligible compared to the material. In particular, the particles are solid, including plastic/deformable solids, including amorphous and crystalline materials.

[0031] Within the meaning of this invention, the term“deposit” as used in reference to “dispersed deposits” refers to distinguishable, e.g., visually distinguishable, areas within the biphasic matrix layer. Such deposits are e.g., droplets and spheres. Within the meaning of this invention, the term droplets is preferably used for deposits in a biphasic coating composition and the term spheres is preferably used for deposits in a biphasic matrix layer. The deposits may be identified by use of a microscope. The sizes of the deposits can be determined by an optical microscopic measurement (for example by Leica MZ16 including a camera, for example Leica DSC320) by taking pictures of the biphasic matrix layer at different positions at an enhancement factor between 10 and 400 times, depending on the required limit of detection. By using imaging analysis software, the sizes of the deposits can be determined.

[0032] Within the meaning of this invention, the size of the deposits refers to the diameter of the deposits as measured using a microscopic picture of the biphasic matrix layer.

[0033] There are two main types of TTS for active agent delivery, i.e. matrix-type TTS and reservoir-type TTS. The release of the active agent in a matrix-type TTS is mainly controlled by the matrix including the active agent itself. In contrast thereto, a reservoir-type TTS typically needs a rate-controlling membrane controlling the release of the active agent. In principle, also a matrix-type TTS may contain a rate-controlling membrane. However, matrix-type TTS are advantageous in that, compared to reservoir-type TTS, usually no rate determining membranes are necessary and no dose dumping can occur due to membrane rupture. In summary, matrix- type transdermal therapeutic systems (TTS) are less complex in manufacture and easy and convenient to use by patients.

[0034] Within the meaning of this invention,“matrix-type TTS” refers to a system or structure wherein the active is homogeneously dissolved and/or dispersed within a polymeric carrier, i.e. the matrix, which forms with the active agent and optionally remaining ingredients a matrix layer. In such a system, the matrix layer controls the release of the active agent from the TTS. Preferably, the matrix layer has sufficient cohesion to be self-supporting so that no sealing between other layers is required. Accordingly, the active agent-containing layer may in one embodiment of the invention be an active agent-containing matrix layer, wherein the active agent is homogeneously distributed within a polymer matrix. In certain embodiments, the active agent- containing matrix layer may comprise two active agent-containing matrix layers, which may be laminated together. Matrix-type TTS may in particular be in the form of a“drug-in-adhesive”- type TTS referring to a system wherein the active is homogeneously dissolved and/or dispersed within a pressure-sensitive adhesive matrix. In this connection, the active agent-containing matrix layer may also be referred to as active agent-containing pressure sensitive adhesive layer or active agent-containing pressure sensitive adhesive matrix layer. A TTS comprising the active agent dissolved and/or dispersed within a polymeric gel, e.g. a hydrogel, is also considered to be of matrix-type in accordance with present invention.

[0035] TTS with a liquid active agent-containing reservoir are referred to by the term “reservoir-type TTS”. In such a system, the release of the active agent is preferably controlled by a rate-controlling membrane. In particular, the reservoir is sealed between the backing layer and the rate- controlling membrane. Accordingly, the active agent-containing layer may in one embodiment be an active agent-containing reservoir layer, which preferably comprises a liquid reservoir comprising the active agent. Furthermore, the reservoir-type TTS typically additionally comprises a skin contact layer, wherein the reservoir layer and the skin contact layer may be separated by the rate-controlling membrane. In the reservoir layer, the active agent is preferably dissolved in a solvent such as ethanol or water or in silicone oil. The skin contact layer typically has adhesive properties.

[0036] Reservoir-type TTS are not to be understood as being of matrix-type within the meaning of the invention. However, microreservoir TTS (biphasic systems having deposits (e.g. spheres, droplets) of an inner active-containing phase dispersed in an outer polymer phase), considered in the art to be a mixed from of a matrix-type TTS and a reservoir-type TTS that differ from a homogeneous single phase matrix-type TTS and a reservoir-type TTS in the concept of drug transport and drug delivery, are considered to be of matrix-type within the meaning of the invention. The sizes of microreservoir deposits can be determined by an optical microscopic measurement as described above. Without wishing to be bound to any theory it is believed that the size and size distribution of the deposits influences the active agent delivery from the TTS. Large deposits release the active agent too fast and provide for an undesired high active agent delivery at the beginning of the dosing period and a failure of the system for longer dosing periods.

[0037] Within the meaning of this invention, the term“active agent-containing layer” refers to a layer containing the active agent and providing the area of release. The term covers active agent-containing matrix layers and active agent-containing reservoir layers. If the active agent- containing layer is an active agent-containing matrix layer, said layer is present in a matrix-type TTS. If the polymer is a pressure-sensitive adhesive, the matrix layer may also represent the adhesive layer of the TTS, so that no additional skin contact layer is present. Alternatively, an additional skin contact layer may be present as adhesive layer, and/or an adhesive overlay is provided. The additional skin contact layer is typically manufactured such that it is active agent- free. However, due to the concentration gradient, the active agent will migrate from the matrix layer to the additional skin contact layer over time, until equilibrium is reached. The additional skin contact layer may be present on the active agent-containing matrix layer or separated from the active agent-containing matrix layer by a membrane, preferably a rate controlling membrane. Preferably, the active agent-containing matrix layer has sufficient adhesive properties, so that no additional skin contact layer is present. If the active agent-containing layer is an active agent- containing reservoir layer, said layer is present in a reservoir-type TTS, and the layer comprises the active agent in a liquid reservoir. In addition, an additional skin contact layer is preferably present, in order to provide adhesive properties. Preferably, a rate-controlling membrane separates the reservoir layer from the additional skin contact layer. The additional skin contact layer can be manufactured such that it is active agent-free or active agent-containing. If the additional skin contact layer is free of active agent the active agent will migrate, due to the concentration gradient, from the reservoir layer to the skin contact layer over time, until equilibrium is reached. Additionally an adhesive overlay may be provided.

[0038] As used herein, the active agent-containing layer is preferably an active agent- containing matrix layer, and it is referred to the final solidified layer. Preferably, an active agent- containing matrix layer is obtained after coating and drying the solvent-containing coating composition as described herein. Alternatively an active-agent containing matrix layer is obtained after melt-coating and cooling. The active agent- containing matrix layer may also be manufactured by laminating two or more such solidified layers (e.g. dried or cooled layers) of the same composition to provide the desired area weight. The matrix layer may be self-adhesive (in the form of a pressure sensitive adhesive matrix layer), or the TTS may comprise an additional skin contact layer of a pressure sensitive adhesive for providing sufficient tack.

Preferably, the matrix layer is a pressure sensitive adhesive matrix layer. Optionally, an adhesive overlay may be present.

[0039] Within the meaning of this invention, the term“pressure-sensitive adhesive” (also abbreviated as“PSA”) refers to a material that in particular adheres with finger pressure, is permanently tacky, exerts a strong holding force and should be removable from smooth surfaces without leaving a residue. A pressure sensitive adhesive layer, when in contact with the skin, is “self-adhesive”, i.e. provides adhesion to the skin so that typically no further aid for fixation on the skin is needed. A“self-adhesive” layer structure includes a pressure sensitive adhesive layer for skin contact which may be provided in the form of a pressure sensitive adhesive matrix layer or in the form of an additional layer, i.e. a pressure sensitive adhesive skin contact layer. An adhesive overlay may still be employed to advance adhesion. The pressure-sensitive adhesive properties of a pressure-sensitive adhesive depend on the polymer or polymer composition used.

[0040] Within the meaning of this invention, the term“silicone acrylic hybrid polymer” refers to a polymerization product including repeating units of a silicone sub-species and an acrylate- sub species. The silicone acrylic hybrid polymer thus comprises a silicone phase and an acrylic phase. The term“silicone acrylic hybrid” is intended to denote more than a simple blend of a silicone-based sub-species and an acrylate-based sub-species. Instead, the term denotes a polymerized hybrid species that includes silicone-based sub-species and acrylate-based subspecies that have been polymerized together. The silicone acrylic hybrid polymer may also be referred to as a“silicone acrylate hybrid polymer” as the terms acrylate and acrylic are generally used interchangeably in the context of the hybrid polymers used in the present invention.

[0041] Within the meaning of this invention, the term“silicone acrylic hybrid pressure- sensitive adhesive” refers to a silicone acrylic hybrid polymer in the form of a pressure-sensitive adhesive. Silicone acrylic hybrid pressure-sensitive adhesives are described, for example, in EP 2 599 847 and WO 2016/130408. Examples of silicone acrylic hybrid pressure-sensitive adhesives include the PSA series 7-6100 and 7-6300 manufactured and supplied in n-heptane or ethyl acetate by Dow Coming (7-61 OX and 7-630X; X=l n-heptane-based / X=2 ethyl acetate- based). It was found that, depending on the solvent in which the silicone acrylic hybrid PSA is supplied, the arrangement of the silicone phase and the acrylic phase providing a silicone or acrylic continuous external phase and a corresponding discontinuous internal phase is different. If the silicone acrylic hybrid PSA is supplied in n-heptane, the composition contains a continuous, silicone external phase and a discontinuous, acrylic internal phase. If the silicone acrylic hybrid PSA composition is supplied in ethyl acetate, the composition contains a continuous, acrylic external phase and a discontinuous, silicone internal phase.

[0042] Within the meaning of this invention, the term“non-hybrid polymer” is used synonymously for a polymer which does not include a hybrid species. Preferably, the non-hybrid polymer is a pressure-sensitive adhesive (e.g. a silicone- or acrylate-based pressure-sensitive adhesives).

[0043] Within the meaning of this invention, the term“silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality” comprises the condensation reaction product of a silicone resin, a silicone polymer, and a silicon-containing capping agent which provides said acrylate or methacrylate functionality. It is to be understood that the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality can include only acrylate functionality, only methacrylate

functionality, or both acrylate functionality and methacrylate functionality.

[0044] As used herein, an active agent-containing matrix layer is a layer containing the active agent dissolved or dispersed in at least one polymer, or containing the active agent dissolved in a solvent to form an active agent-solvent mixture that is dispersed in the form of deposits (in particular droplets) in at least one polymer. Preferably, the at least one polymer is a polymer- based pressure-sensitive adhesive (e.g. a silicone acrylic hybrid pressure-sensitive adhesive). Within the meaning of this invention, the term“pressure-sensitive adhesive layer” refers to a pressure-sensitive adhesive layer obtained from a solvent-containing adhesive coating composition after coating on a film and evaporating the solvents.

[0045] Within the meaning of this invention, the term“skin contact layer” refers to the layer included in the active agent-containing layer structure to be in direct contact with the skin of the patient during administration. This may be the active agent-containing layer. When the TTS comprises an additional skin contact layer, the other layers of the active agent-containing layer structure do not contact the skin and do not necessarily have self-adhesive properties. As outlined above, an additional skin contact layer attached to the active agent-containing layer may over time absorb parts of the active agent. The sizes of an additional skin contact layer and the active agent-containing layer are usually coextensive and correspond to the area of release. However, the area of the additional skin contact layer may also be greater than the area of the active agent-containing layer. In such a case, the area of release still refers to the area of the active agent-containing layer.

[0046] Within the meaning of this invention, the term“area weight” refers to the dry weight of a specific layer, e.g. of the matrix layer, provided in g/m ² . The area weight values are subject to a tolerance of ± 10%, preferably ± 7.5%, due to manufacturing variability.

[0047] If not indicated otherwise“%” refers to weight-%.

[0048] Within the meaning of this invention, the term“polymer” refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers which consist of one type of monomer and copolymers which consist of two or more types of monomers. Polymers may be of any architecture such as linear polymers, star polymer, comb polymers, brush polymers, of any monomer arrangements in case of copolymers, e.g. alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the polymer type and is known to the skilled person. Polymers may e.g. have a molecular weight above 2000, preferably above 5000 and more preferably above 10,000 Dalton. Correspondingly, compounds with a molecular weight below 2000, preferably below 5000 or more preferably below 10,000 Dalton are usually referred to as oligomers.

[0049] Within the meaning of this invention, the term“cross-linking agent” refers to a substance which is able to cross-link functional groups contained within the polymer.

[0050] Within the meaning of this invention, the term“adhesive overlay” refers to a self- adhesive layer structure that is free of active agent and larger in area than the active agent- containing structure and provides additional area adhering to the skin, but no area of release of the active agent. It enhances thereby the overall adhesive properties of the TTS. The adhesive overlay comprises a backing layer that may provide occlusive or non-occlusive properties and an adhesive layer. Preferably, the backing layer of the adhesive overlay provides non-occlusive properties.

[0051] Within the meaning of this invention, the term“backing layer” refers to a layer which supports the active agent-containing layer or forms the backing of the adhesive overlay. At least one backing layer in the TTS and usually the backing layer of the active agent-containing layer is substantially impermeable to the active agent contained in the layer during the period of storage and administration and thus prevents active loss or cross-contamination in accordance with regulatory requirements. Preferably, the backing layer is also occlusive, meaning substantially impermeable to water and water-vapor. Suitable materials for a backing layer include

polyethylene terephthalate (PET), polyethylene (PE), ethylene vinyl acetate-copolymer (EVA), polyurethanes, and mixtures thereof. Suitable backing layers are thus for example PET laminates, EVA-PET laminates and PE-PET laminates. Also suitable are woven or non-woven backing materials.

[0052] The TTS according to the present invention can be characterized by certain parameters as measured in an in vitro skin permeation test.

[0053] Where not otherwise indicated, the in vitro permeation test is performed with dermatomed split-thickness human skin with a thickness of 800 pm and an intact epidermis, and with phosphate buffer pH 5.5 as receptor medium (32°C with 0.1% saline azide). The amount of active permeated into the receptor medium is determined in regular intervals using a validated HPLC method with a UV photometric detector by taking a sample volume. The receptor medium is completely or in part replaced by fresh medium when taking the sample volume, and the measured amount of active permeated relates to the amount permeated between the two last sampling points and not the total amount permeated so far.

[0054] Thus, within the meaning of this invention, the parameter“permeated amount” is provided in pg/cm ² and relates to the amount of active permeated in a sample interval at certain elapsed time. E.g., in an in vitro permeation test as described above, wherein the amount of active permeated into the receptor medium has been e.g. measured at hours 0, 8, 24, 32, 48 and 72, the“permeated amount” of active can be given e.g. for the sample interval from hour 32 to hour 48 and corresponds to the measurement at hour 48, wherein the receptor medium has been exchanged completely at hour 32. [0055] The permeated amount can also be given as a“cumulative permeated amount”, corresponding to the cumulated amount of active permeated at a certain point in time. E.g., in an in vitro permeation test as described above, wherein the amount of active permeated into the receptor medium has been e.g. measured at hours 0, 8, 24, 32, 48 and 72, the“cumulative permeated amount” of active at hour 48 corresponds to the sum of the permeated amounts from hour 0 to hour 8, hour 8 to hour 24, hour 24 to hour 32, and hour 32 to hour 48.

[0056] Within the meaning of this invention, the parameter“skin permeation rate” for a certain sample interval at certain elapsed time is provided in pg/cm ² -hr and is calculated from the permeated amount in said sample interval as measured by in vitro permeation test as described above in pg/cm ² , divided by the hours of said sample interval. E.g. the skin permeation rate in an in vitro permeation test as described above, wherein the amount of active permeated into the receptor medium has been e.g. measured at hours 0, 8, 24, 32, 48 and 72, the“skin permeation rate” at hour 48 is calculated as the permeated amount in the sample interval from hour 32 to hour 48 divided by 16 hours.

[0057] A“cumulative skin permeation rate” can be calculated from the respective cumulative permeated amount by dividing the cumulative permeated amount by the elapsed time. E.g. in an in vitro permeation test as described above, wherein the amount of active permeated into the receptor medium has been e.g. measured at hours 0, 8, 24, 32, 48 and 72, the“cumulative skin permeation rate” at hour 48 is calculated as the cumulative permeated amount at hour 48 (see above) divided by 48 hours, unless indicated otherwise. If the cumulative skin permeation rate takes into account a lag time, the elapsed time has to be reduced by the lag time. For example, the“cumulative skin permeation rate over 168 hours taking into account a lag time of 24 hours” is calculated as the cumulative permeated amount at hour 168 (see above) divided by 144 hours (168 hours - 24 hours lag time).

[0058] Within the meaning of this invention, the term“release performance” refers to the parameters which express the release of the active agent per cm ² , such as the“permeated amount”, the“cumulative permeated amount”, the“skin permeation rate” and the“cumulative skin permeation rate”.

[0059] Within the meaning of this invention, the term“active agent utilization” refers to the cumulative permeated amount after a certain elapsed time, e.g. after 168 hours, divided by the initial loading of the active agent.

[0060] Within the meaning of this invention, the above parameters“permeated amount” and “skin permeation rate” (as well as“cumulative permeated amount” and“cumulative skin permeation rate”) refer to mean values calculated from at least 3 in vitro permeation test experiments. Where not otherwise indicated, the standard deviation (SD) of these mean values refer to a corrected sample standard deviation, calculated using the formula:

wherein n is the sample size, are the observed values and x is the mean value of

the observed values.

[0061] Within the meaning of this invention, the term“extended period of time” relates to a period of at least or about 72 hours (3 days), at least or about 84 hours (3.5 days), at least or about 96 hours (4 days), at least or about 120 hours (5 days), at least or about 144 hours (6 days), or at least or about 168 hours (7 days).

[0062] Within the meaning of this invention, the term“room temperature” refers to the unmodified temperature found indoors in the laboratory where the experiments are conducted and usually lies within 15 to 35°C, preferably about 18 to 25°C.

[0063] Within the meaning of this invention, the term“patient” refers to a subject who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.

[0064] Within the meaning of this invention, the term“coating composition” refers to a composition comprising all components of the matrix layer in a solvent, which may be coated onto the backing layer or release liner to form the matrix layer upon drying.

[0065] Within the meaning of this invention, the term“pressure sensitive adhesive

composition” refers to a pressure sensitive adhesive at least in mixture with a solvent (e.g.

n-heptane or ethyl acetate).

[0066] Within the meaning of this invention, the term“dissolve” refers to the process of obtaining a solution, which is clear and does not contain any particles, as visible to the naked eye.

[0067] Within the meaning of this invention, the term“solvent” refers to any liquid substance, which preferably is a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, toluene and mixtures thereof.

[0068] Within the meaning of this invention, the term“viscosity-increasing substance” refers to a substance which when added to the mixture of buprenorphine and carboxylic acid increases the viscosity of the mixture.

[0069] Within the meaning of this invention, the term“soluble polyvinylpyrrolidone” refers to polyvinylpyrrolidone, also known as povidone, which is soluble with more than 10% in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2 propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid and acetic acid. Examples of

polyvinylpyrrolidones which are commercially available include Kollidon® 12 PF, Kollidon®

17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F supplied by BASF, or povidone K90F. The different grades of Kollidon® are defined in terms of the K- Value reflecting the average molecular weight of the polyvinylpyrrolidone grades. Kollidon® 12 PF is characterized by a K- Value range of 10.2 to 13.8, corresponding to a nominal K- Value of 12. Kollidon® 17 PF is characterized by a K- Value range of 15.3 to 18.4, corresponding to a nominal K- Value of 17. Kollidon® 25 is characterized by a K- Value range of 22.5 to 27.0, corresponding to a nominal K- Value of 25, Kollidon® 30 is characterized by a K- Value range of 27.0 to 32.4, corresponding to a nominal K- Value of 30. Kollidon® 90 F is characterized by a K- Value range of 81.0 to 97.2, corresponding to a nominal K- Value of 90. Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F, in particular preferred is Kollidon® 90 F.

[0070] Within the meaning of this invention, the term“K- Value” refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European

Pharmacopoeia (Ph.Eur.) and USP monographs for“Povidone”. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Fig. 1 a depicts the skin permeation rate of Examples la-c and Comparative Examples 1 and 2 over a time interval of 168 hours.

[0072] Fig. lb depicts the cumulative permeated amount of Examples la-c and Comparative Examples 1 and 2 over a time interval of 168 hours.

[0073] Fig. 2a depicts the skin permeation rate of Examples 2b and 2c and Comparative Examples 1 and 2 over a time interval of 168 hours.

[0074] Fig. 2b depicts the cumulative permeated amount of Examples 2b and 2c and

Comparative Examples 1 and 2 over a time interval of 168 hours.

[0075] Fig. 3a depicts the skin permeation rate of Examples 3b and Comparative Example 1 over a time interval of 168 hours.

[0076] Fig. 3b depicts the cumulative permeated amount of Examples 3b and Comparative Example 1 over a time interval of 168 hours.

[0077] Fig. 4a depicts the skin permeation rate of Examples 4a-c and Comparative Example 1 over a time interval of 168 hours.

[0078] Fig. 4b depicts the cumulative permeated amount of Examples 4a-c and Comparative Example 1 over a time interval of 168 hours.

[0079] Fig. 5a depicts the skin permeation rate of Examples 5a-d and Comparative Example 1 over a time interval of 168 hours.

[0080] Fig. 5b depicts the cumulative permeated amount of Examples 5a-d and Comparative Example 1 over a time interval of 168 hours.

[0081] Fig. 6a depicts the skin permeation rate of Examples 6a and 6b and Comparative Example 1 over a time interval of 168 hours.

[0082] Fig. 6b depicts the cumulative permeated amount of Examples 6a and 6b and

Comparative Example 1 over a time interval of 168 hours.

[0083] Fig. 7a depicts the skin permeation rate of Examples 7a and 7b and Comparative Example 1 over a time interval of 168 hours.

[0084] Fig. 7b depicts the cumulative permeated amount of Examples 7a and 7b and

Comparative Example 1 over a time interval of 168 hours.

[0085] Fig. 8a is an exemplary microscopic picture of the buprenorphine-containing layer of Comparative Example 2.

[0086] Fig. 8b is an exemplary microscopic picture of the buprenorphine-containing layer of Example la.

[0087] Fig. 8c is an exemplary microscopic picture of the buprenorphine-containing layer of Example lb.

[0088] Fig. 8d is an exemplary microscopic picture of the buprenorphine-containing layer of Example 2a.

[0089] Fig. 8e is an exemplary microscopic picture of the buprenorphine-containing layer of Example 2b.

[0090] Fig. 8f is an exemplary microscopic picture of the buprenorphine-containing layer of Example 3b.

[0091] Fig. 8g is an exemplary microscopic picture of the buprenorphine-containing layer of Example 4a. [0092] Fig. 8h is an exemplary microscopic picture of the buprenorphine-containing layer of Example 4b.

[0093] Fig. 8i is an exemplary microscopic picture of the buprenorphine-containing layer of Example 4c.

[0094] Fig. 8j is an exemplary microscopic picture of the buprenorphine-containing layer of Comparative Example 1.

[0095] Fig. 9 depicts the results of the measurement of the tack, the cumulative permeated amount of active agent and the active agent utilization of Comparative Example 2, Examples la-c, 2b-c, 3b, 4a-c, 5a-d, 6a-b, and 7a-b in comparison to Comparative Examples 1.

DETAILED DESCRIPTION

TTS STRUCTURE

[0096] The present invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine- containing layer structure.

[0097] The buprenorphine-containing layer structure according to the invention comprises A) a backing layer and B) a buprenorphine-containing layer, wherein the buprenorphine-containing layer comprises a) a therapeutically effective amount of buprenorphine and b) a carboxylic acid. The buprenorphine-containing layer structure is preferably a buprenorphine-containing self- adhesive layer structure.

[0098] According to the present invention, the transdermal therapeutic system also comprises at least one silicone acrylic hybrid polymer.

[0099] Thus, in a first aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure,

the buprenorphine-containing layer structure comprising:

A) a backing layer; and

B) a buprenorphine-containing layer;

wherein the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine, and

b) a carboxylic acid,

and

wherein the transdermal therapeutic system comprises at least one silicone acrylic hybrid polymer.

[0100] The backing layer is in particular substantially buprenorphine-impermeable.

Furthermore, it is preferred that the backing layer is occlusive as outlined above.

[0101] The buprenorphine-containing layer may be directly attached to the backing layer, so that no further layer between the backing layer and the buprenorphine-containing layer is present.

[0102] The TTS according to the present invention may be a matrix-type TTS or a reservoir- type TTS, and preferably is a matrix-type TTS. In a certain preferred embodiment of the present invention, the TTS is a microreservoir TTS.

[0103] The buprenorphine-containing layer structure according to the invention is normally located on a detachable protective layer (release liner), from which it is removed immediately before application to the surface of the patient’s skin. Thus, the TTS may further comprise a release liner. A TTS protected this way is usually stored in a blister pack or a seam-sealed pouch. The packaging may be child resistant and/or senior friendly.

[0104] In certain embodiments of the invention, the buprenorphine-containing layer structure provide a tack of from 0.6 N to 8.0 N, preferably from more than 0.8 N to 8.0 N, or from 0.9 N to 8.0 N, or from more than 0.9 N to 8.0 N, or from 1.2 N to 6.0 N, or from more than 1.2 N to 6.0 N preferably determined in accordance with the Standard Test Method for Pressure-Sensitive Tack of Adhesives Using an Inverted Probe Machine (ASTM D 2979 - 01; Reapproved 2009), wherein the transdermal therapeutic system samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity) prior to testing.

[0105] In certain embodiments of the invention, the buprenorphine-containing layer structure provide an adhesion force of from about 2 N/25mm to about 16 N/25mm, preferably of from about 3.5 N/25mm to about 15 N/25mm, more preferably of from about 4 N/25mm to about 15 N/25mm, preferably determined using a tensile strength testing machine with an aluminium testing plate and a pull angle of 90°, wherein the transdermal therapeutic system samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity) prior to testing and are cut into pieces with a fixed width of 25mm.

[0106] In one embodiment of the present invention, the buprenorphine-containing layer is a buprenorphine-containing pressure sensitive adhesive layer and represents the skin contact layer. That is, the buprenorphine-containing layer structure does not comprise an additional skin contact layer attached to the buprenorphine-containing layer. In this connection, the

buprenorphine-containing layer is preferably a buprenorphine-containing matrix layer, which is self-adhesive. The self-adhesive properties of the buprenorphine-containing layer structure are preferably provided by the silicone acrylic hybrid polymer. Thus, in a preferred embodiment of the invention, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure sensitive adhesive. Further details regarding the silicone acrylic hybrid polymer according to the invention are provided further below.

[0107] In another embodiment of the present invention, the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer. The skin contact layer preferably is self-adhesive and provides the adhesive properties.

[0108] In one embodiment, the at least one silicone acrylic hybrid polymer is contained in the buprenorphine-containing layer such that the buprenorphine-containing layer comprises a) a therapeutically effective amount of buprenorphine, b) a carboxylic acid, and c) at least one silicone acrylic hybrid polymer, and wherein the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer. The skin contact layer may also contain silicone acrylic hybrid polymer. Thus, in one embodiment of the present invention, the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer, and the at least one silicone acrylic hybrid polymer is contained in both the buprenorphine-containing layer and the skin contact layer. [0109] In yet another embodiment of the present invention, the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer, wherein the skin contact layer is free of a silicone acrylic hybrid polymer.

[0110] In yet another embodiment of the present invention, the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer, and the at least one silicone acrylic hybrid polymer is contained in the skin contact layer and the buprenorphine-containing layer comprises a non-hybrid polymer.

[0111] In one embodiment of the present invention, at least one additional layer may be between the buprenorphine-containing layer and the additional skin contact layer. It is however preferred that the additional skin contact layer is attached to the buprenorphine-containing layer.

[0112] When the at least one silicone acrylic hybrid polymer is contained in the buprenorphine- containing layer and in the skin contact layer, the at least one silicone acrylic hybrid polymer contained in the buprenorphine-containing layer may be the same as the at least one silicone acrylic hybrid polymer contained in the skin contact layer. The at least one silicone acrylic hybrid polymer contained in the buprenorphine-containing layer may however also be different compared to the at least one silicone acrylic hybrid polymer contained in the skin contact layer.

[0113] According to certain embodiments of the invention, the TTS may further comprise an adhesive overlay. This adhesive overlay is in particular larger in area than the buprenorphine- containing structure and is attached thereto for enhancing the adhesive properties of the overall transdermal therapeutic system. Said adhesive overlay comprises a backing layer and an adhesive layer. The adhesive overlay provides additional area adhering to the skin but does not add to the area of release of the buprenorphine. The adhesive overlay comprises a self-adhesive polymer or a self-adhesive polymer mixture selected from the group consisting of silicone acrylic hybrid polymers, acrylic polymers, polymers based on polysiloxane, polyisobutylenes, styrene-isoprene-styrene copolymers, and mixtures thereof, which may be identical to or different from any polymer or polymer mixture included in the buprenorphine-containing layer structure. In one embodiment, the TTS is free of an adhesive overlay on top of the

buprenorphine-containing layer structure.

[0114] Depending on the dosage, the area of release of the TTS ranges from 1 to 40 cm ² , preferably from about 1 to about 4.8 cm ² , or from about 3 to about 9.5 cm ² , or from about 6 to about 19 cm ² , or from about 12 to about 28.5 cm ² , or from about 16 to about 38 cm ² .

[0115] In one particular embodiment, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure, the buprenorphine-containing layer structure comprising:

A) a backing layer; and

B) a buprenorphine-containing layer; wherein the buprenorphine-containing layer comprises a) buprenorphine in an amount of from 3 to 15% by weight based on the buprenorphine- containing layer,

b) levulinic acid in an amount of from 3 to 15% by weight based on the buprenorphine- containing layer, and

c) a silicone acrylic hybrid pressure-sensitive adhesive containing a continuous, acrylic external phase and a discontinuous, silicone internal phase in an amount of from about 30% to about 85% by weight based on the buprenorphine- containing layer, wherein the buprenorphine-containing layer is a buprenorphine- containing biphasic matrix layer having an inner phase comprising the buprenorphine and the !evulinic acid, and having an outer phase comprising the silicone acrylic hybrid pressure-sensitive adhesive, wherein the inner phase forms dispersed deposits in the outer phase, preferably wherein the buprenorphine-containing biphasic matrix layer is the skin contact layer.

[0116] In another particular embodiment, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine- containing layer structure, the buprenorphine-containing layer structure comprising:

A) a backing layer; and

B) a buprenorphine-containing layer; wherein the buprenorphine-containing layer comprises a) a therapeutically amount of buprenorphine,

b) levulinic acid,

c) a silicone acrylic hybrid pressure-sensitive adhesive, and

d) a non-hybrid pressure- sensitive adhesive based on polysiloxanes,

wherein the non-hybrid polymer and the silicone acrylic hybrid polymer are contained in the buprenorphine-containing layer in an amount ratio of from 0.5:1 to 2:1, and wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the silicone acrylic hybrid polymer and the non-hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase, preferably wherein the buprenorphine- containing biphasic matrix layer is the skin contact layer.

[0117] In another particular embodiment, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine- containing layer structure, the buprenorphine-containing layer structure comprising:

A) a backing layer; and

B) a buprenorphine-containing layer; wherein the buprenorphine-containing layer comprises a) a therapeutically amount of buprenorphine,

b) levulinic acid,

c) a silicone acrylic hybrid pressure-sensitive adhesive,

d) a non-hybrid pressure-sensitive adhesive, and

e) a soluble polyvinylpyrrolidone,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine, the levulinic acid, and the soluble polyvinylpyrrolidone, and having an outer phase comprising the silicone acrylic hybrid polymer and the non-hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase, preferably wherein the buprenorphine-containing biphasic matrix layer is the skin contact layer.

[0118] In another particular embodiment, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine- containing layer structure, the buprenorphine-containing layer structure comprising:

A) a backing layer;

B) a buprenorphine-containing layer; wherein the buprenorphine-containing layer comprises a) a therapeutically effective amount of buprenorphine,

b) levulinic acid, and c) a non-hybrid pressure-sensitive adhesive, preferably a non-hybrid pressure-sensitive adhesive based on polysiloxanes or acrylates; and

C) a skin contact layer on the buprenorphine-containing layer comprising at least one silicone acrylic hybrid pressure-sensitive adhesive,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the non-hybrid pressure-sensitive adhesive, wherein the inner phase forms dispersed deposits in the outer phase.

[0119] In another particular embodiment, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine- containing layer structure, the buprenorphine-containing layer structure comprising:

A) a backing layer;

B) a buprenorphine-containing layer; wherein the buprenorphine-containing layer comprises a) a therapeutically effective amount of buprenorphine,

b) levulinic acid, and

c) at least one silicone acrylic hybrid polymer; and

C) a skin contact layer on the buprenorphine-containing layer comprising at least one non-hybrid pressure-sensitive adhesive, preferably a non-hybrid pressure-sensitive adhesive based on polysiloxanes or acrylates,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the at least one silicone acrylic hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

[0120] In another particular embodiment, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine- containing layer structure, the buprenorphine-containing layer structure comprising:

A) a backing layer;

B) a buprenorphine-containing biphasic matrix layer; wherein the buprenorphine-containing biphasic matrix layer comprises

a) a therapeutically effective amount of buprenorphine,

b) levulinic acid, and

c) at least one silicone acrylic hybrid polymer; and

C) a skin contact layer on the buprenorphine-containing biphasic matrix layer comprising at least one silicone acrylic hybrid pressure-sensitive adhesive,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the at least one silicone acrylic hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

[0121] The TTS according to the invention may further comprise one or more anti-oxidants. Suitable anti-oxidants are sodium metabisulfite, ascorbyl palmitate, tocopherol and esters thereof, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or propyl gallate, preferably sodium metabisulfite, ascorbyl palmitate and tocopherol. The anti-oxidants may be conveniently present in the buprenorphine-containing layer, preferably in an amount of from about 0.001 to about 0.5% of the buprenorphine-containing layer.

[0122] The TTS according to the invention may further comprise in addition to the above mentioned ingredients at least one further excipient or additive, for example from the group of cross-linking agents, solubilizers, fillers, tackifiers, film-forming agents, plasticizers, stabilizers, softeners, substances for skincare, permeation enhancers, pH regulators, and preservatives. In general, it is preferred according to the invention that no additional excipients or additives are required. Thus, the TTS has a composition of low complexity. In certain embodiments, no further additive (e.g. a tackifier) is present in the TTS.

BUPRENORPHINE-CONTAINING LAYER

[0123] As outlined in more detail above, the TTS according to the present invention comprises a buprenorphine-containing layer structure comprising a buprenorphine-containing layer. The buprenorphine-containing layer according to the invention comprises a therapeutically effective amount of the buprenorphine and a carboxylic acid.

[0124] The buprenorphine-containing layer may be a buprenorphine-containing matrix layer or a buprenorphine-containing reservoir layer. It is preferred that the buprenorphine-containing layer is a buprenorphine-containing matrix layer. In yet another preferred embodiment, the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer.

[0125] In one embodiment, the buprenorphine-containing layer is a self-adhesive

buprenorphine-containing layer, more preferably a self-adhesive buprenorphine-containing matrix layer.

[0126] In a certain embodiment, the buprenorphine-containing layer is obtainable by coating and drying a buprenorphine-containing coating composition that comprises the buprenorphine in the form of the free base and the carboxylic acid.

[0127] The buprenorphine may be contained in an amount of from 2% to 20%, preferably from 3% to 15%, more preferably from 3% to 12% or from 3% to less than 10%, by weight based on the buprenorphine-containing layer.

[0128] The carboxylic acid may be contained in the buprenorphine-containing layer in an amount sufficient so that the therapeutically effective amount of buprenorphine is solubilized therein. In one embodiment, the therapeutically effective amount of buprenorphine is in solution in the carboxylic acid.

[0129] Thus, in certain embodiments, the carboxylic acid is contained in an amount of from 2% to 20%, preferably from 3% to 15%, more preferably from 4% to 12%, by weight based on the buprenorphine-containing layer.

[0130] In one embodiment, the buprenorphine and the carboxylic acid are contained in different amounts by weight based on the buprenorphine-containing layer. The buprenorphine and the carboxylic acid may however also be contained in the same amounts by weight based on the buprenorphine-containing layer, such that the carboxylic acid and the buprenorphine are e.g. contained in an amount ratio of about 1 :1.

[0131] The carboxylic acid may be contained in less amounts by weight than the buprenorphine based on the buprenorphine-containing layer. The buprenorphine may however also be contained in less amounts by weight than the carboxylic acid based on the buprenorphine-containing layer. Preferably, the carboxylic acid and the buprenorphine are contained in the buprenorphine- containing layer in an amount ratio of from 0.3:1 to 5:1.

[0132] Suitable carboxylic acid may be selected from the group consisting of C ₃ to C ₂₄ carboxylic acids. In certain embodiments, the carboxylic acid contained in the buprenorphine- containing layer is selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid, and mixtures thereof, in particular the carboxylic acid is levulinic acid. In a particular embodiment, the carboxylic acid is levulinic acid and the levulinic acid and the buprenorphine are contained in the buprenorphine-containing layer in an amount ratio of from 0.3:1 to 5:1.

[0133] Since the carboxylic acid, such as e.g., the levulinic acid, can likewise be absorbed through the skin, the amount in the TTS may become less as the time of application elapses, and may lead to a reduction of the solubility of the buprenorphine. As a result, the decrease in the thermodynamic activity of buprenorphine, due to depletion, is then compensated by the reduced drug solubility.

[0134] In one embodiment, the buprenorphine-containing layer, comprising at least one silicone acrylic hybrid polymer, further comprises at least one non-hybrid polymer. In this connection, the at least one silicone acrylic hybrid polymer and at least one non-hybrid polymer may be comprised in the buprenorphine-containing layer in an amount ratio of from 0.1 :1 to 5:1, preferably of from 0.5:1 to 2:1. Further details regarding non-hybrid polymers according to the invention are provided further below.

[0135] In a certain embodiment of the present invention, the buprenorphine-containing layer further comprises a viscosity-increasing substance, which is preferably contained in an amount of from about 0.1% to about 15%, preferably from about 0.1% to about 8%, more preferably of from about 1% to about 6%, by weight of the buprenorphine- containing layer.

[0136] Suitable viscosity-increasing substances may be selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose,

hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, high molecular mass polyacrylic acids and/or their salts and/or their derivatives such as esters, polyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate, tragacanth, xanthan gum, bentonite, carageenan and guar gum, and mixtures thereof.

[0137] In certain embodiments of the present invention where a viscosity-increasing substance is contained, the viscosity-increasing substance is polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone. In particular, the viscosity-increasing substance is a soluble

polyvinylpyrrolidone having a K- Value of 30 or 90, preferably of 90.

[0138] According to certain embodiments, the buprenorphine-containing layer has an area weight of from 10 to 180 g/m ² , from 20 to 160 g/m ² , from 60 to 160 g/m ² , from 30 to 140 g/m ² , from 40 to 140 g/m ² , or from more than 80 to 140 g/m ² .

[0139] In one embodiment, the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine;

b) a carboxylic acid;

c) optionally a viscosity-increasing substance; and

d) the at least one silicone acrylic hybrid polymer. [0140] Thus, in one embodiment, the buprenorphine-containing layer comprises the at least one silicone acrylic hybrid polymer. In this connection, the silicone acrylic hybrid polymer in the buprenorphine-containing layer may contain a continuous, silicone external phase and a discontinuous, acrylic internal phase. In a certain embodiment, the buprenorphine-containing layer has a continuous, silicone external phase and a discontinuous, acrylic internal phase. The silicone acrylic hybrid polymer in the buprenorphine-containing layer may however also contain a continuous, acrylic external phase and a discontinuous, silicone internal phase. In a certain embodiment, the buprenorphine-containing layer has a continuous, acrylic external phase and a discontinuous, silicone internal phase.

[0141] In certain embodiments, the buprenorphine-containing layer may further comprise at least one non-hybrid polymer in addition to the at least one silicone acrylic hybrid polymer.

[0142] In one embodiment, the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the therapeutically effective amount of buprenorphine and the carboxylic acid, and having an outer phase comprising the at least one silicone acrylic hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

[0143] In certain other embodiments, the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine;

b) a carboxylic acid;

c) optionally a viscosity-increasing substance; and

d) at least one non-hybrid polymer,

wherein the buprenorphine-containing layer is free of an silicone acrylic hybrid polymer, preferably wherein the buprenorphine-containing layer is a buprenorphine-containing matrix layer. Thus, within such an embodiment, the at least one acrylic hybrid polymer of the transdermal therapeutic system is comprised in an additional layer.

[0144] In one embodiment, the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the therapeutically effective amount of buprenorphine and the carboxylic acid, and having an outer phase comprising the at least one non-hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

[0145] In a certain embodiment of the present invention, the content of the inner phase in the biphasic matrix layer is from 5 to 40% by volume based on the volume of the biphasic matrix layer.

[0146] The dispersed deposits have preferably a maximum sphere size of from about 1 pm to about 80 pm, more preferably of from about 5 pm to about 65 pm.

[0147] In a certain embodiment, the at least one silicone acrylic hybrid polymer is contained in the buprenorphine-containing layer, wherein the buprenorphine-containing layer further comprises a polyvinylpyrrolidone in an amount of 0.1% to about 8% by weight based on the buprenorphine-containing layer such that the buprenorphine-containing layer comprises a) a therapeutically effective amount of buprenorphine,

b) a carboxylic acid,

c) at least one silicone acrylic hybrid polymer, and

d) a polyvinylpyrrolidone in an amount of 0.1% to about 8% by weight based on the

buprenorphine-containing layer, preferably wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine, the carboxylic acid and the polyvinylpyrrolidone, and having an outer phase comprising the silicone acrylic hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

[0148] In another certain embodiment, the at least one silicone acrylic hybrid polymer is contained in the buprenorphine-containing layer, wherein the buprenorphine-containing layer further comprises at least one non-hybrid polymer and a polyvinylpyrrolidone in an amount of 0.1% to about 8% by weight based on the buprenorphine-containing layer such that the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine,

b) a carboxylic acid,

c) at least one silicone acrylic hybrid polymer,

d) at least one non-hybrid polymer, and

e) a polyvinylpyrrolidone in an amount of 0.1% to about 8% by weight based on the

buprenorphine-containing layer, preferably wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine, the carboxylic acid, and the polyvinylpyrrolidone and having an outer phase comprising the silicone acrylic hybrid polymer and the non-hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

[0149] In another certain embodiment, the buprenorphine-containing layer according to the invention does not contain a viscosity-increasing substance. In particular, the buprenorphine- containing layer is free of a viscosity-increasing substance selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose,

hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, high molecular mass polyacrylic acids and/or their salts and/or their derivatives such as esters, polyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate, tragacanth, xanthan gum, bentonite, carageenan and guar gum, and mixtures thereof.

[0150] When using an additional skin contact layer, the ingredients of the buprenorphine- containing layer such as the carboxylic acid, the buprenorphine, the optional viscosity-increasing substance and optional additional excipients or additives may over time migrate into the additional skin contact layer. This however depends on the ingredients and the material of the skin contact layer.

SKIN CONTACT LAYER

[0151] In one embodiment of the invention, the buprenorphine-containing layer represents the skin contact layer. In another embodiment of the invention, the buprenorphine-containing layer structure comprises an additional skin contact layer.

[0152] In one embodiment, the skin contact layer comprises at least one silicone acrylic hybrid polymer. In this connection, the silicone acrylic hybrid polymer in the skin contact layer may contain a continuous, silicone external phase and a discontinuous, acrylic internal phase. The silicone acrylic hybrid polymer in the skin contact layer may however also contain a continuous, acrylic external phase and a discontinuous, silicone internal phase. Preferably, the silicone acrylic hybrid polymer in the skin contact layer is a pressure-sensitive adhesive silicone acrylic hybrid polymer.

[0153] In one embodiment, the skin contact layer contains the silicone acrylic hybrid polymer in an amount of from about 10% to about 100%, preferably of from about 20% to about 100%, or of from about 50% to about 100%, by weight based on the skin contact layer.

[0154] The skin contact layer may further comprises at least one non-hybrid polymer. In this connection, the at least one non-hybrid polymer may be based on acrylates, polysiloxanes or polyisobutylenes.

[0155] In another embodiment, the skin contact layer is free of a silicone acrylic hybrid polymer. In this connection, the skin contact layer preferably comprises at least one non-hybrid polymer. Preferably, the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on acrylates, polysiloxanes, or polyisobutylenes.

[0156] The at least one non-hybrid polymer is comprised in the skin contact layer in an amount of from about 10% to about 100%, preferably of from about 20% to about 100%, or of from about 50% to about 100%, by weight based on the skin contact layer.

[0157] According to one aspect of the invention, the skin contact layer comprises at least one silicone acrylic hybrid polymer and at least one non-hybrid polymer in an amount ratio of from 0.1 :1 to 5:1, preferably of from 0.5:1 to 2:1.

[0158] The skin contact layer may comprise an active agent. The active agent may be buprenorphine, as well. However, the active agent may be any additional active agent reasonable for an administration together with buprenorphine.

[0159] In a preferred embodiment, the skin contact layer is free of active agent, that is, is prepared without the addition of an active agent.

[0160] According to a certain embodiment, the skin contact layer may have an area weight of from 5 to 120 g/m ² . It is preferred, that the skin contact layer has an area weight of from 5 to 50 g/m ² , preferably of from 10 to 40 g/m ² , more preferably of from more than 10 to 30 g/m ² .

ACTIVE AGENT BUPRENORPHINE

[0161] The TTS according to the invention comprises a therapeutically effective amount of buprenorphine. A therapeutically effective amount may vary from about 1 mg to about 50 mg, in particular from about 2 mg to about 30 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt, or from about 2 mg to about 25 mg of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

[0162] In one embodiment of the invention, the buprenorphine is contained in an amount of from 2% to 20%, preferably from 3% to 15% by weight, more preferably from 3% to less than 10%, by weight based on the buprenorphine-containing layer.

[0163] In one embodiment of the invention, the buprenorphine is contained in the

buprenorphine-containing layer structure in an amount of from 0.3 mg/cm ² to 3.0 mg/cm ² ,

0.5 mg/cm ² to less than 1.2 mg/cm ² , 0.5 mg/cm ² to less than 0.8 mg/cm ² , or more than

0.6 mg/cm ² to 1.6 mg/cm ² based on the buprenorphine-containing layer.

[0164] In one embodiment, the amount of buprenorphine contained in the transdermal therapeutic system, according to five different dosages, ranges from about 1 mg to about 4 mg buprenorphine, or about 3.5 mg to about 8 mg buprenorphine, or about 6.5 mg to about 16 mg buprenorphine, or about 11.5 mg to about 24 mg buprenorphine, or about 15 mg to about 32 mg buprenorphine.

[0165] According to certain embodiments, the amount of buprenorphine contained in the transdermal therapeutic system, according to five different dosages, ranges from about 1 mg to about 4 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranges from about 1 cm ² to about 4.8 cm ² , or the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 3.5 mg to about 8 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranges from about 3 cm ² to about 9.5 cm ² , or the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 6.5 mg to about 16 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranges from about 6 cm ² to about 19 cm ² , or the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 11.5 mg to about 24 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranges from about 12 cm ² to about 28.5 cm ² , or the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 15 mg to about 32 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranges from about 16 cm ² to about 38 cm ² , wherein the five different transdermal therapeutic systems have increasing areas of release and amounts of buprenorphine.

[0166] In other certain embodiments, the buprenorphine in the buprenorphine-containing layer may be included in the form of a pharmaceutically acceptable chemical and morphological form and physical state, such as a pharmaceutically acceptable salt thereof. In one embodiment, the buprenorphine-containing layer comprises a pharmaceutically acceptable salt of buprenorphine, such as buprenorphine hydrochloride. However, it is preferred according to the invention that the buprenorphine in the buprenorphine-containing layer is included in the form of the free base.

[0167] In certain embodiments, the buprenorphine has a purity of at least 95%, preferably of at least 98%, and more preferably of at least 99% as determined by quantitative HPLC.

Quantitative HPLC may be performed with Reversed-Phase-HP LC with UV detection.

SILICONE ACRYLIC HYBRID POLYMER

[0168] The TTS according to the present invention comprises a silicone acrylic hybrid polymer. The silicone acrylic hybrid polymer comprises a polymerized hybrid species that includes silicone-based sub-species and acrylate-based sub-species that have been polymerized together. The silicone acrylic hybrid polymer thus comprises a silicone phase and an acrylic phase. Preferably, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure- sensitive adhesive.

[0169] The silicone acrylic hybrid pressure-sensitive adhesives are usually supplied and used in solvents like n-heptane and ethyl acetate. The solids content of the pressure-sensitive adhesives is usually between 30% and 80%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.

[0170] Preferably, the weight ratio of silicone to acrylate in the silicone acrylic hybrid pressure-sensitive adhesive is from 5:95 to 95:5, or from 20:80 to 80:20, more preferably from 40:60 to 60:40, and most preferably the ratio of silicone to acrylate is about 50:50. Suitable silicone acrylic hybrid pressure-sensitive adhesives having a weight ratio of silicone to acrylate of 50:50 are, for example, the commercially available silicone acrylic hybrid pressure-sensitive adhesives 7-6102, Silicone/Acrylate Ratio 50/50, and 7-6302, Silicone/Acrylate Ratio 50/50, supplied in ethyl acetate by Dow Coming.

[0171] The preferred silicone acrylic hybrid pressure-sensitive adhesives in accordance with the invention are characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of more than about 400 cP, or from about 500 cP to about 3,500 cP, in particular from about 1,000 cP to about 3,000 cP, more preferred from about 1,200 cP to about 1,800, or most preferred of about 1,500 cP or alternatively more preferred from about 2,200 cP to about 2,800 cP, or most preferred of about 2,500 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

[0172] These silicone acrylic hybrid pressure-sensitive adhesives may also be characterized by a complex viscosity at 0.1 rad/s at 30°C of less than about l.0e9 Poise, or from about l.0e5 Poise to about 9.0e8 Poise, or preferably from about 9.0e5 Poise to about l.0e7 Poise, or more preferred from about 9.0e5 Poise to about 7.0e6 Poise, or most preferred about 4.0e6 Poise, or alternatively preferably from about 2.0e6 Poise to about 9.0e7 Poise, or more preferred from about 8.0e6 Poise to about 9.0e7 Poise, or most preferred about l.0e7 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

[0173] In one embodiment of the present invention, the transdermal therapeutic system comprises at least two silicone acrylic hybrid polymers selected from at least two of the silicone acrylic hybrid polymer groups:

silicone acrylic hybrid pressure-sensitive adhesives characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 1,200 cP to about

1.800 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM, and

silicone acrylic hybrid pressure-sensitive adhesives characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 2,200 cP to about

2.800 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

[0174] In another embodiment of the present invention, the transdermal therapeutic system comprises at least two silicone acrylic hybrid polymers selected from at least two of the silicone acrylic hybrid polymer groups:

silicone acrylic hybrid pressure-sensitive adhesives characterized by a complex viscosity at 0.1 rad/s at 30°C of from about 9 0e5 Poise to about 7.0e6 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed, and

silicone acrylic hybrid pressure-sensitive adhesives characterized by a complex viscosity at 0.1 rad/s at 30°C of from about 8.0e6 Poise to about 9.0e7 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

[0175] To prepare samples for measuring the rheological behavior using a Rheometrics ARES rheometer, between 2 and 3 grams of adhesive solution can be poured onto a SCOTCH-PAK 1022 fluoropolymer release liner and allow to sit for 60 minutes under ambient conditions. To achieve essentially solvent-free films of the adhesive, they can be placed in an oven at 110°C +/- lO°C for 60 minutes. After removing from the oven and letting equilibrate to room temperature. The films can be removed from the release liner and folded over to form a square. To eliminate air bubbles the films can be compressed using a Carver press. The samples can then be loaded between the plates and are compressed to 1.5 +/-0.1 mm at 30°C. The excess adhesive is trimmed and the final gap recorded. A frequency sweep between 0.01 to 100 rad/s can be performed with the following settings: Temperature = 30°C; strain = 0.5-1% and data collected at 3 points/decade.

[0176] Suitable silicone acrylic hybrid pressure-sensitive adhesives which are commercially available include the PSA series 7-6100 and 7-6300 manufactured and supplied in n-heptane or ethyl acetate by Dow Coming (7-61 OX and 7-63 OX; X=l n-heptane-based / X=2 ethyl acetate- based). For example, the 7-6102 silicone acrylic hybrid PSA having a silicone/acrylate ratio of 50/50 is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of 2,500 cP and a complex viscosity at 0.1 rad/s at 30°C of l.0e7 Poise. The 7-6302 silicone acrylic hybrid PSA having a silicone/acrylate ratio of 50/50 has a solution viscosity at 25°C and about 50% solids content in ethyl acetate of 1,500 cP and a complex viscosity at 0.1 rad/s at 30°C of 4.0e6 Poise.

[0177] Depending on the solvent in which the silicone acrylic hybrid pressure-sensitive adhesive is supplied, the arrangement of the silicone phase and the acrylic phase providing a silicone or acrylic continuous external phase and a corresponding discontinuous internal phase is different. If the silicone acrylic hybrid pressure-sensitive adhesive is provided in n-heptane, the composition contains a continuous, silicone external phase and a discontinuous, acrylic internal phase. If the silicone acrylic hybrid pressure-sensitive adhesive is provided in ethyl acetate, the composition contains a continuous, acrylic external phase and a discontinuous, silicone internal phase. After evaporating the solvent in which the silicone acrylic hybrid pressure-sensitive adhesive is provided, the phase arrangement of the resulting pressure-sensitive adhesive film or layer corresponds to the phase arrangement of the solvent-containing adhesive coating composition. For example, in the absence of any substance that may induce an inversion of the phase arrangement in a silicone acrylic hybrid pressure sensitive adhesive composition, a pressure-sensitive adhesive layer prepared from a silicone acrylic hybrid pressure-sensitive adhesive in n-heptane provides a continuous, silicone external phase and a discontinuous, acrylic internal phase, a pressure-sensitive adhesive layer prepared from a silicone acrylic hybrid pressure- sensitive adhesive in ethyl acetate provides a continuous, acrylic external phase and a discontinuous, silicone internal phase. The phase arrangement of the compositions can, for example, be determined in peel force tests with pressure-sensitive adhesive films or layers prepared from the silicone acrylic hybrid PSA compositions which are attached to a siliconized release liner. The pressure-sensitive adhesive film contains a continuous, silicone external phase if the siliconized release liner cannot or can only hardly be removed from the pressure-sensitive adhesive film (laminated to a backing film) due to the blocking of the two silicone surfaces. Blocking results from the adherence of two silicone layers which comprise a similar surface energy. The silicone adhesive shows a good spreading on the siliconized liner and therefore can create a good adhesion to the liner. If the siliconized release liner can easily be removed the pressure-sensitive adhesive film contains a continuous, acrylic external phase. The acrylic - 21

adhesive has no good spreading due to the different surface energies and thus has a low or almost no adhesion to the siliconized liner.

[0178] According to a preferred embodiment of the invention the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive obtainable from a silicon- containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality. It is to be understood that the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality can include only acrylate functionality, only methacrylate functionality, or both acrylate functionality and methacrylate functionality.

[0179] According to certain embodiments of the invention the silicone acrylic hybrid pressure- sensitive adhesive comprises the reaction product of (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality, (b) an ethylenically unsaturated monomer, and (c) an initiator. That is, the silicone acrylic hybrid pressure-sensitive adhesive is the product of the chemical reaction between these reactants ((a), (b), and (c)). In particular, the silicone acrylic hybrid pressure-sensitive adhesive includes the reaction product of (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality, (b) a (meth)acrylate monomer, and (c) an initiator (i.e., in the presence of the initiator). That is, the silicone acrylic hybrid pressure-sensitive adhesive includes the product of the chemical reaction between these reactants ((a), (b), and (c)).

[0180] The reaction product of (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous, silicone external phase and a discontinuous, acrylic internal phase or the reaction product of (a), (b), and (c) may contain a continuous, acrylic external phase and a discontinuous, silicone internal phase.

[0181] The silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality (a) is typically present in the silicone acrylic hybrid pressure-sensitive adhesive in an amount of from 5 to 95, more typically 25 to 75, parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0182] The ethylenically unsaturated monomer (b) is typically present in the silicone acrylic hybrid pressure-sensitive adhesive in an amount of from 5 to 95, more typically 25 to 75, parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0183] The initiator (c) is typically present in the silicone acrylic hybrid pressure-sensitive adhesive in an amount of from 0.005 to 3, more typically from 0.01 to 2, parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.

[0184] According to certain embodiments of the invention the silicon-containing pressure- sensitive adhesive composition comprising acrylate or methacrylate functionality (a) comprises the condensation reaction product of (al) a silicone resin, (a2) a silicone polymer, and (a3) a silicon-containing capping agent which provides said acrylate or methacrylate functionality.

[0185] According to certain embodiments of the invention the silicon-containing pressure- sensitive adhesive composition comprising acrylate or methacrylate functionality (a) comprises the condensation reaction product of:

(al) a silicone resin,

(a2) a silicone polymer, and (a3) a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula

XYR'bSiZ _3-b , wherein

X is a monovalent radical of the general formula LE- where E is -O- or -NH- and A is an acryl group or a methacryl group,

Y is a divalent alkyl ene radical having from 1 to 6 carbon atoms,

R' is a methyl or a phenyl radical,

Z is a monovalent hydrolyzable organic radical or a halogen, and

b is 0 or 1 ;

wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein:

the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or

the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer.

[0186] According to certain embodiments of the invention the silicon-containing pressure- sensitive adhesive composition comprising acrylate or methacrylate functionality comprises the condensation reaction product of a pressure sensitive adhesive and a silicon-containing capping agent which provides said acrylate or methacrylate functionality. That is, the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functionality is essentially a pressure sensitive adhesive that has been capped or end blocked with the silicon- containing capping agent which provides said acrylate or methacrylate functionality, wherein the pressure sensitive adhesive comprises the condensation reaction product of the silicone resin and the silicone polymer. Preferably, the silicone resin reacts in an amount of from 30 to 80 parts by weight to form the pressure sensitive adhesive, and the silicone polymer reacts in an amount of from 20 to 70 parts by weight to form the pressure sensitive adhesive. Both of these parts by weight are based on 100 parts by weight of the pressure sensitive adhesive. Although not required, the pressure sensitive adhesive may comprise a catalytic amount of a condensation catalyst. A wide array of silicone resins and silicone polymers are suitable to make up the pressure sensitive adhesive.

[0187] According to certain embodiments of the invention the silicone acrylic hybrid pressure- sensitive adhesive is the reaction product of:

(a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality that comprises the condensation reaction product of:

(al) a silicone resin,

(a2) a silicone polymer, and

(a3) a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula

XYR' _b SiZ _3-b , wherein

X is a monovalent radical of the general formula AE- where E is -O- or -NH- and A is an acryl group or a methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms,

R' is a methyl or a phenyl radical,

Z is a monovalent hydrolyzable organic radical or a halogen, and

b is 0 or 1 ;

wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein:

the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or

the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer;

(b) an ethylenically unsaturated monomer; and

(c) an initiator.

[0188] The silicone acrylic hybrid composition used in the present invention may be described by being prepared by a method comprising the steps of:

(i) providing a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality that comprises the condensation reaction product of:

a silicone resin,

a silicone polymer, and

a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR' _b SiZ _3-b , wherein

X is a monovalent radical of the general formula AE- where E is -O- or -NH- and A is an acryl group or a methacryl group,

Y is a divalent alkylene radical having from 1 to 6 carbon atoms,

R' is a methyl or a phenyl radical,

Z is a monovalent hydrolyzable organic radical or a halogen, and

b is 0 or 1 ;

wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein:

the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or

the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer;

(ii) polymerizing an ethylenically unsaturated monomer and the silicon-containing pressure- sensitive adhesive composition comprising acrylate or methacrylate functionality of step (i) in the presence of an initiator to form a silicone acrylic hybrid composition, optionally at a temperature of from 50°C to l00°C, or from 65°C to 90°C.

[0189] During the polymerization of the ethylenically unsaturated monomer and the silicon- containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality, the silicone to acrylic ratio can be controlled and optimized as desired. The silicone to acrylic ratio can be controlled by a wide variety of mechanisms in and during the method. An illustrative example of one such mechanism is the rate controlled addition of the ethylenically unsaturated monomer or monomers to the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality. In certain applications, it may be desirable to have the silicone-based sub-species, or the overall silicone content, to exceed the acrylate-based sub-species, or the overall acrylic content. In other applications, it may be desirable for the opposite to be true. Independent of the end application, it is generally preferred, as already described above, that the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality is preferably present in the silicone acrylic hybrid composition in an amount of from about 5 to about 95, more preferably from about 25 to about 75, and still more preferably from about 40 to about 60 parts by weight based on 100 parts by weight of the silicone acrylic hybrid composition.

[0190] According to a certain embodiment of the invention, the silicone acrylic hybrid composition used in the present invention may be described by being prepared by a method comprising the steps of:

(i) providing a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality that comprises the condensation reaction product of:

a silicone resin,

a silicone polymer, and

a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR'bSiZ ₃ -b, wherein

X is a monovalent radical of the general formula AE- where E is -O- or -NH- and A is an acryl group or a methacryl group,

Y is a divalent alkylene radical having from 1 to 6 carbon atoms,

R' is a methyl or a phenyl radical,

Z is a monovalent hydrolyzable organic radical or a halogen, and

b is 0 or 1 ;

wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein:

the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or

the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer;

(ii) polymerizing an ethylenically unsaturated monomer and the silicon-containing pressure- sensitive adhesive composition comprising acrylate or methacrylate functionality of step (i) in a first solvent in the presence of an initiator at a temperature of from 50°C to l00°C to form a silicone acrylic hybrid composition;

(iii) removing the first solvent; and (iv) adding a second solvent to form the silicone acrylic hybrid composition, wherein the phase arrangement of the silicone acrylic hybrid composition is selectively controlled by selection of the second solvent.

[0191] The silicone acrylic hybrid PSA composition used in the present invention may also be described by being prepared by a method comprising the steps of:

(i) providing a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality that comprises the condensation reaction product of:

a silicone resin,

a silicone polymer, and

a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR' _b SiZ _3-b , wherein

X is a monovalent radical of the general formula LE- where E is -O- or -NH- and A is an acryl group or a methacryl group,

Y is a divalent alkylene radical having from 1 to 6 carbon atoms,

R' is a methyl or a phenyl radical,

Z is a monovalent hydrolyzable organic radical or a halogen, and

b is 0 or 1 ;

wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein:

the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or

the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer;

(ii) polymerizing an ethylenically unsaturated monomer and the silicon-containing pressure- sensitive adhesive composition comprising acrylate or methacrylate functionality of step (i) in a first solvent in the presence of an initiator at a temperature of from 50°C to l00°C to form a silicone acrylic hybrid composition;

(iii) adding a processing solvent, wherein the processing solvent has a higher boiling point than the first solvent, and

(iv) applying heat at a temperature of from 70°C to 150°C such that a majority of the first solvent is selectively removed;

(v) removing the processing solvent; and.

(vi) adding a second solvent to form the silicone acrylic hybrid composition, wherein the phase arrangement of the silicone acrylic hybrid composition is selectively controlled by selection of the second solvent.

[0192] The silicone resin according to the previous paragraphs may contain a copolymer comprising triorganosiloxy units of the formula R ^x ₃ SiOi _/2 and tetrafunctional siloxy units of the formula S1O4/2 in a ratio of from 0.1 to 0.9, preferably of about 0.6 to 0.9, triorganosiloxy units for each tetrafunctional siloxy unit. Preferably, each R ^x independently denotes a monovalent hydrocarbon radical having from 1 to 6 carbon atoms, vinyl, hydroxyl or phenyl groups. [0193] The silicone polymer according to the previous paragraphs may comprise at least one polydiorganosiloxane and is preferably end- capped (end-blocked) with a functional group selected from the group consisting of hydroxyl groups, alkoxy groups, hydride groups, vinyl groups, or mixtures thereof . The diorganosubstituent may be selected from the group consisting of dimethyl, methylvinyl, methylphenyl, diphenyl, methylethyl, (3,3,3-tri fluoropropyl)methyl and mixtures thereof. Preferably, the diorganosubstituents contain only methyl groups. The molecular weight of polydiorganosiloxane will typically range from about 50,000 to about 1,000,000, preferably, from about 80,000 to about 300,000. Preferably, the polydiorganosiloxane comprises AR ^x SiO units terminated with endblocking TR ^x ASiOi _/2 units, wherein the polydiorganosiloxane has a viscosity of from about 100 centipoise to about 30,000,000 centipoise at 25°C, each A radical is independently selected from R ^x or halohydrocarbon radicals having from 1 to 6 carbon atoms, each T radical is independently selected from the group consisting of R ^x , OH, H or OR ^Y , and each R ^Y is independently an alkyl radical having from 1 to 4 carbon atoms.

[0194] As an example using forms of the preferred silicone resin and the preferred silicone polymer, one type of pressure sensitive adhesive is made by:

mixing (i) from 30 to 80 inclusive parts by weight of at least one resin copolymer containing silicon-bonded hydroxyl radicals and consisting essentially of R ^x ₃ SiO1 _/2 units and S1O4/2 units in a mole ratio of 0.6 to 0.9 R ^x ₃ SiOi _/2 units for each Si0 _4/2 unit present, (ii) between about 20 and about 70 parts by weight of at least one polydiorganosiloxane comprising AR ^x SiO units terminated with endblocking TR ^x ASiOi _/2 units, wherein the polydiorganosiloxane has a viscosity of from about 100 centipoise to about 30,000,000 centipoise at 25°C and each R ^x is a monovalent organic radical selected from the group consisting of hydrocarbon radicals of from 1 to 6 inclusive carbon atoms, each A radical is independently selected from R ^x or

halohydrocarbon radicals having from 1 to 6 inclusive carbon atoms, each T radical is independently selected from the group consisting of R ^x , OH, H or OR ^Y , and each R ^Y is independently an alkyl radical of from 1 to 4 inclusive carbon atoms; a sufficient amount of (iii) at least one of the silicon-containing capping agents, also referred to throughout as endblocking agents, described below and capable of providing a silanol content, or concentration, in the range of 5,000 to 15,000, more typically 8,000 to 13,000, ppm, when desirable an additional catalytic amount of (iv) a mild silanol condensation catalyst in the event that none is provided by (ii), and when necessary, an effective amount of (v) an organic solvent which is inert with respect to (i), (ii), (iii) and (iv) to reduce the viscosity of a mixture of (i), (ii), (iii), and (iv), and condensing the mixture of (i), (ii), (iii) and (iv) at least until a substantial amount of the silicon-containing capping agent or agents have reacted with the silicon-bonded hydroxyl radicals and T radicals of (i) and (ii). Additional organosilicon endblocking agents can be used in conjunction with the silicon-containing capping agent or agents (iii) of the present invention.

[0195] The silicon-containing capping agent according to the previous paragraphs may be selected from the group of acrylate functional silanes, acrylate functional silazanes, acrylate functional disilazanes, acrylate functional disiloxanes, methacrylate functional silanes, methacrylate functional silazanes, methacrylate functional disilazanes, meth-acrylate functional disiloxanes, and combinations thereof and may be described as to be of the general formula XYR' _b SiZ _3-b , wherein X is a monovalent radical of the general formula AE- where E is -O- or - NH- and A is an acryl group or a methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R' is a methyl or a phenyl radical, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0, 1 or 2. Preferably, the monovalent hydrolyzable organic radical is of the general formula R"0 - where R" is an alkyl ene radical. Most preferably, this particular endblocking agent is selected from the group of 3 -methacryloxypropyldimethylchlorosilane,

3 -methacryloxypropyldichlorosilane, 3 -methacryloxypropyltrichlorosilane,

3 -methacryloxypropyldimethylmethoxysilane, 3 -methacryloxypropylmethyldimethoxysilane,

3 -methacryloxypropyltrimethoxysilane, 3 -methacryloxypropyldimethylethoxysilane,

3 -methacryloxypropylmethyldiethoxysilane, 3 -methacryloxypropyltriethoxysilane,

(methacryloxymethyl)dimethylmethoxysilane, (methacryloxymethyl)methyldimethoxysilane, (methacryloxymethyl)trimethoxysilane, (methacryloxymethyl)dimethylethoxysilane,

(methacryloxymethyl)methyldiethoxysilane, methacryloxymethyltriethoxysilane, methacryloxy- propyltriisopropoxysilane, 3 -methacryloxypropyldimethylsilazane, 3-acryloxy- propyldimethylchlorosilane, 3 -acryloxypropyldichlorosilane, 3 -acryloxypropyl-trichlorosilane, 3-acryloxypropyldimethylmethoxysilane, 3-acryloxy-propylmethyldimethoxysilane, 3- acryloxypropyltrimethoxysilane, 3-acryloxypropyl-dimethylsilazane, and combinations thereof.

[0196] The ethylenically unsaturated monomer according to the previous paragraphs can be any monomer having at least one carbon-carbon double bond. Preferably, the ethylenically unsaturated monomer according to the previous paragraphs may be a compound selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof. It is to be understood that each of the compounds, the aliphatic acrylates, the aliphatic methacrylates, the cycloaliphatic acrylates, and the cycloaliphatic methacrylates, include an alkyl radical. The alkyl radicals of these compounds can include up to 20 carbon atoms. The aliphatic acrylates that may be selected as one of the ethylenically unsaturated monomers are selected from the group consisting of methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylate, tert-butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, iso-octyl acrylate, iso-nonyl acrylate, iso-pentyl acrylate, tridecyl acrylate, stearyl acrylate, lauryl acrylate, and mixtures thereof. The aliphatic methacrylates that may be selected as one of the ethylenically unsaturated monomers are selected from the group consisting of methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl

methacrylate, iso-butyl meth-acrylate, tert-butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, iso-octyl methacrylate, iso-nonyl methacrylate, iso-pentyl methacrylate, tridecyl methacrylate, stearyl methacrylate, lauryl methacrylate, and mixtures thereof. The cycloaliphatic acrylate that may be selected as one of the ethylenically unsaturated monomers is cyclohexyl acrylate, and the cycloaliphatic methacrylate that may be selected as one of the ethylenically unsaturated monomers is cyclohexyl methacrylate.

[0197] It is to be understood that the ethylenically unsaturated monomer used for preparing the silicone acrylic hybrid pressure sensitive adhesive may be more than one ethylenically unsaturated monomer. That is, a combination of ethylenically unsaturated monomers may be polymerized, more specifically co-polymerized, along with the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functionality and the initiator. According to a certain embodiment of the invention, the silicone acrylic hybrid pressure-sensitive adhesive is prepared by using at least two different ethylenically unsaturated monomers, preferably selected from the group of 2-ethylhexyl acrylate and methyl acrylate, preferably in a ratio of from 40:60 to 70:30, more preferably in a ratio of from 65:35 to 55:45 or of from 55:45 to 45:50, particular preferred in a ratio of 50% 2-ethylhexyl acrylate and 50% methyl acrylate, or in a ratio of 60% 2-ethylhexyl acrylate and 40% methyl acrylate, as the acrylic monomer

[0198] The initiator according to the previous paragraphs may be any substance that is suitable to initiate the polymerization of the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functionality and the ethylenically unsaturated monomer to form the silicone acrylic hybrid. For example, free radical initiators selected from the group of peroxides, azo compounds, redox initiators, and photo-initiators may be used.

[0199] Further suitable silicone resins, silicone polymers, silicon-containing capping agents, ethylenically unsaturated monomers, and initiators that can be used in accordance with the previous paragraphs are detailed in WO 2007/145996, EP 2 599 847 Al, and WO 2016/130408.

[0200] According to a certain embodiment of the invention, the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked and covalently bound to the silicone polymer and/or the silicone resin.

[0201] According to a certain other embodiment of the invention, the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the silicone resin contains triorganosiloxy units R ₃ SiOi _/2 where R is an organic group, and tetrafunctional siloxy units Si0 _4/2 in a mole ratio of from 0.1 to 0.9 R ₃ SiOi _/2 units for each Si0 _4/2 .

[0202] The acrylic polymer may comprise at least an alkoxysilyl functional monomer, polysiloxane-containing monomer, halosilyl functional monomer or alkoxy halosilyl functional monomer. Preferably, the acrylic polymer is prepared from alkoxysilyl functional monomers selected from the group consisting of trialkoxylsilyl (meth)acrylates, dialkoxyalkylsilyl

(meth)acrylates, and mixtures thereof, or comprises end-capped alkoxysilyl functional groups. The alkoxysilyl functional groups may preferably be selected from the group consisting of trimethoxylsilyl groups, dimethoxymethylsilyl groups, triethoxylsilyl, diethoxymethylsilyl groups and mixtures thereof.

[0203] The acrylic polymer may also be prepared from a mixture comprising polysiloxane- containing monomers, preferably from a mixture comprising polydimethylsiloxane mono (meth)acrylate.

[0204] The silyl functional monomers will typically be used in amounts of from 0.2 to 20 weight percent of the acrylic polymer, more preferably the amount of silyl functional monomers will range from about 1.5 to about 5 weight percent of the acrylic polymer.

[0205] The amount of polysiloxane-containing monomer will typically be used in amounts of from 1.5 to 50 weight percent of the acrylic polymer, more preferably the amount of

polysiloxane-containing monomers will range from 5 to 15 weight percent of the acrylic polymer.

[0206] Alternatively, the acrylic polymer comprises a block or grafted copolymer of acrylic and polysiloxane. An example of a polysiloxane block copolymer is polydimethylsiloxane- acrylic block copolymer. The preferred amount of siloxane block is 10 to 50 weight percent of the whole block polymer. [0207] The acrylic polymer comprises alkyl (meth)acrylate monomers. Preferred alkyl (meth)acrylates which may be used have up to about 18 carbon atoms in the alkyl group, preferably from 1 to about 12 carbon atoms in the alkyl group. Preferred low glass transition temperature (Tg) alkyl acrylate with a homopolymer Tg of less than about 0°C have from about 4 to about 10 carbon atoms in the alkyl group and include butyl acrylate, amyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, isooctyl acrylate, decyl acrylate, isomers thereof, and combinations thereof. Particularly preferred are butyl acrylate, 2-ethylhexyl acrylate and isooctyl acrylate. The acrylic polymer components may further comprise (meth)acrylate monomers having a high Tg such as methyl acrylate, ethyl acrylate, methyl methacrylate and isobutyl methacrylate.

[0208] The acrylic polymer component may further comprise a polyisobutylene group to improve cold flow properties of the resultant adhesive.

[0209] The acrylic polymer components may comprise nitrogen-containing polar monomers. Examples include N- vinyl pyrrolidone, N- vinyl caprolactam, N-tertiary octyl acrylamide, dimethyl acrylamide, diacetone acrylamide, N-tertiary butyl acrylamide, N-isopropyl acrylamide, cyanoethylacrylate, N-vinyl acetamide and N-vinyl formamide.

[0210] The acrylic polymer component may comprise one or more hydroxyl containing monomers such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate and/or hydroxypropyl methacrylate.

[0211] The acrylic polymer components may, if desired, comprise carboxylic acid containing monomers. Useful carboxylic acids preferably contain from about 3 to about 6 carbon atoms and include, among others, acrylic acid, methacrylic acid, itaconic acid, b-carboxyethyl acrylate and the like. Acrylic acid is particularly preferred.

[0212] Other useful, well known co-monomers include vinyl acetate, styrene, cyclohexyl acrylate, alkyl di(meth)acrylates, glycidyl methacrylate and allyl glycidyl ether, as well as macromers such as, for example, poly(styryl)methacrylate.

[0213] One acrylic polymer component that can be used in the practice of the invention is an acrylic polymer that comprises from about 90 to about 99.5 wt% of butyl acrylate and from about 0.5 to about 10 wt% dimethoxymethylsilyl methacrylate.

[0214] According to a certain embodiment of the invention the silicone acrylic hybrid polymer may be prepared by a) reacting silicone polymer with silicone resin to form a resultant product, b) reacting the resultant product of a) with an acrylic polymer containing reactive functionality, wherein the components are reacted in an organic solvent.

[0215] According to a certain embodiment of the invention the silicone acrylic hybrid polymer may be prepared by a) reacting a silicone resin with an acrylic polymer containing reactive functionality to form a resultant product, b) reacting the resultant product of a) with silicone polymer, wherein the components are reacted in an organic solvent.

[0216] According to a certain embodiment of the invention the silicone acrylic hybrid polymer may be prepared by a) reacting a silicone polymer with an acrylic polymer containing reactive functionality to form a resultant product, b) reacting the resultant product of a) with silicone resin, wherein the components are reacted in an organic solvent.

[0217] Further suitable acrylic polymers, silicone resins, and silicone polymers that can be used for chemically reacting together a silicone polymer, a silicone resin and an acrylic polymer to provide a silicone acrylic hybrid polymer in accordance with the previous paragraphs are detailed in WO 2010/124187.

[0218] According to certain embodiments of the invention, the silicone acrylic hybrid polymer used in the TTS is blended with one or more non-hybrid polymers, preferably the silicone acrylic hybrid polymer is blended with one or more non-hybrid pressure sensitive adhesives (e.g.

pressure-sensitive adhesives based on polysiloxanes or acrylates).

NON-HYBRID POLYMERS

[0219] According to a certain embodiment of the invention, the TTS comprises one or more non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) in addition to the silicone acrylic hybrid polymer. Non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) are polymers (e.g. polymer-based pressure-sensitive adhesives) which do not include a hybrid species. Preferred are non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) based on polysiloxanes, acrylates, polyisobutylenes, or styrene-isoprene-styrene block copolymers.

[0220] The non-hybrid polymers (e.g. the non-hybrid pressure-sensitive adhesives) may be contained in the active agent-containing layer structure and/or in the adhesive overlay.

[0221] Non-hybrid pressure-sensitive adhesives are usually supplied and used in solvents like n-heptane and ethyl acetate. The solids content of the pressure-sensitive adhesives is usually between 30% and 80%.

[0222] Suitable non-hybrid polymers according to the invention are commercially available e.g. under the brand names BIO-PSAs (based on polysiloxanes), Oppanol™ (polyisobutylenes), JSR-SIS (a styrene-isoprene-styrene copolymer) or Duro-Tak™ (acrylic polymers).

[0223] Polymers based on polysiloxanes may also be referred to as silicone-based polymers or polysiloxane-based polymers. Pressure-sensitive adhesives based on polysiloxanes may also be referred to as silicone-based pressure-sensitive adhesives, or polysiloxane-based pressure- sensitive adhesives. Pressure-sensitive adhesives based on polysiloxanes may have a solids content preferably between 60% and 80%. Such silicone-based PSAs need, unlike other organic pressure sensitive adhesives, no additives like antioxidants, stabilizers, plasticizers, catalysts or other potentially extractable ingredients. These pressure-sensitive adhesives provide for suitable tack and for quick bonding to various skin types, including wet skin, suitable adhesive and cohesive qualities, long lasting adhesion to the skin, a high degree of flexibility, a permeability to moisture, and compatibility to many actives and film-substrates. It is possible to provide them with sufficient amine resistance and therefore enhanced stability in the presence of amines. Such pressure-sensitive adhesives are based on a resin-in-polymer concept wherein, by condensation reaction of silanol end blocked polydimethylsiloxane with a silica resin, a polysiloxane is prepared which for amine stability the residual silanol functionality is additionally capped with trimethylsiloxy groups. The silanol end blocked polydimethylsiloxane content contributes to the viscous component of the visco-elastic behavior, and impacts the wetting and the spreadability properties of the adhesive. The resin acts as a tackifying and reinforcing agent, and participates in the elastic component. The correct balance between silanol end blocked polydimethylsiloxane and resin provides for the correct adhesive properties.

[0224] Examples of silicone-based PSA compositions which are commercially available include the standard BIO-PSA series (7-4400,7-4500 and 7-4600 series) and the amine compatible (endcapped) BIO-PSA series (7-4100, 7-4200 and 7-4300 series), typically supplied in n-heptane or ethyl acetate by Dow Coming. For example, BIO-PSA 7-4201 is characterized by a solution viscosity at 25°C and about 60% solids content in heptane of 450 mPa s and a complex viscosity at 0.01 rad/s at 30°C of 1 xlO ⁸ Poise. BIO-PSA 7-4301 has a solution viscosity at 25°C and about 60% solids content in heptane of 500 mPa s and a complex viscosity at 0.01 rad/s at 30°C of 5xl0 ⁶ Poise.

[0225] Pressure-sensitive adhesives based on polysiloxanes are supplied and used in solvents like n-heptane, ethyl acetate or other volatile silicone fluids. For the present invention n-heptane is preferred. The solids content of pressure-sensitive adhesives based on polysiloxanes in solvents is usually between 60 and 85%, preferably between 70 and 80%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.

[0226] The preferred pressure-sensitive adhesives based on polysiloxanes in accordance with the invention are characterized by a solution viscosity at 25°C and 60% solids content in n-heptane of more than about 150 mPa s, or from about 200 mPa s to about 700 mPa s, or of about 450 mPa s or of about 500 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 rpm. Theses may also be characterized by a complex viscosity at 0.01 rad/s at 30°C of less than about 1 x 10 ⁹ Poise or from about 1 x 10 ⁵ to about 9 x 10 ⁸ Poise, or of about lxlO ⁸ Poise, or of about 5xl0 ⁶ Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

[0227] In one embodiment of the invention, the transdermal therapeutic system further comprises at least one non-hybrid pressure-sensitive adhesive based on polysiloxanes characterized by a solution viscosity at 25°C and about 60% solids content in n-heptane of from about 200 mPa s to about 700 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM, and the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 1,200 mPa s to about 1,800 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

[0228] In another embodiment of the invention, the transdermal therapeutic system further comprises at least one non-hybrid pressure- sensitive adhesive based on polysiloxanes characterized by a solution viscosity at 25°C and about 60% solids content in n-heptane of from about 200 mPa s to about 700 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM, and the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 2,200 mPa s to about 2,800 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

[0229] Suitable polyisobutylenes according to the invention are available under the tradename Oppanol®. Combinations of high-molecular weight polyisobutylenes (B100/B80) and low- molecular weight polyisobutylenes (B10, Bl l, B12, B13) may be used. Suitable ratios of low- molecular weight polyisobutylene to high-molecular weight polyisobutylene are in the range of from 100:1 to 1 :100, preferably from 95:5 to 40:60, more preferably from 90:10 to 80:20. A preferred example for a polyisobutylene combination is B10/B100 in a ratio of 85/15. Oppanol® B100 has a viscosity average molecular weight M _v of 1,110,000, and a weight average molecular weight M _w of 1,550,000, and an average molecular weight distribution M _w /M _n of 2.9. Oppanol® B10 has a viscosity average molecular weight M _v of 40,000, and a weight average molecular weight M _w of 53,000, and an average molecular weight distribution M _w /M„ of 3.2. In certain embodiments, polybutene may be added to the polyisobutylenes. The solids content of polyisobutylenes in solvents is usually between 30 and 50%, preferably between 35 and 40%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.

[0230] Pressure-sensitive adhesives based on acrylates may also be referred to as acrylate- based pressure-sensitive adhesives, or acrylate pressure-sensitive adhesives. Pressure-sensitive adhesives based on acrylates may have a solids content preferably between 30% and 60%. Such acrylate-based pressure-sensitive adhesives may or may not comprise functional groups such as hydroxy groups, carboxylic acid groups, neutralized carboxylic acid groups and mixtures thereof. Thus, the term“functional groups” in particular refers to hydroxy- and carboxylic acid groups, and deprotonated carboxylic acid groups.

[0231] Corresponding commercial products are available e.g. from Henkel under the tradename Duro Tak®. Such acrylate-based pressure-sensitive adhesives are based on monomers selected from one or more of acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, t-octylacrylamide and vinylacetate, and are provided in ethyl acetate, heptanes, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene or xylene or mixtures thereof. Suitable acrylate-based pressure- sensitive adhesives are based on monomers selected from two or more of acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate,

methylacrylate, methylmethacrylate, t-octylacrylamide and vinylacetate.

[0232] In one embodiment, the at least one non-hybrid polymer is an acrylate-based pressure- sensitive adhesive, which is a copolymer based on 2-ethylhexylacrylate, 2-hydroxyethylacrylate and vinylacetate.

[0233] In one embodiment of the invention, the at least one non-hybrid polymer is an acrylate- based pressure-sensitive adhesive characterized by a solution viscosity at 25°C and about 39% solids content in ethyl acetate of from about 4000 mPa s to about 12000 mPa s, preferably as measured using a e.g. Brookfield SSA, viscometer equipped with a spindle number 27 at 20 RPM.

[0234] Specific acrylate-based pressure-sensitive adhesives are available as:

- Duro-Tak™ 87-4287 (a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, and

2-hydroxyethyl-acrylate provided as a solution in ethyl acetate without cross-linking agent),

- Duro-Tak™ 387-2287 or Duro-Tak™ 87-2287 (a copolymer based on vinyl acetate,

2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate provided as a solution in ethyl acetate without cross-linking agent),

- Duro-Tak™ 387-2516 or Duro-Tak™ 87-2516 (a copolymer based on vinyl acetate,

2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate provided as a solution in ethyl acetate, ethanol, n-heptane and methanol with a titanium cross-linking agent), - Duro-Tak™ 387-2051 or Duro-Tak™ 87-2051 (a copolymer based on acrylic acid, butylacrylate, 2-ethylhexylacrylate and vinyl acetate, provided as a solution in ethyl acetate and heptane),

- Duro-Tak™ 387-2353 or Duro-Tak™ 87-2353 (a copolymer based on acrylic acid,

2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate, provided as a solution in ethyl acetate and hexane),

- Duro-Tak™ 87-4098 (a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate, provided as a solution in ethyl acetate).

[0235] Additional polymers may also be added to enhance cohesion and/or adhesion.

[0236] Certain polymers in particular reduce the cold flow and are thus in particular suitable as additional polymer. A polymeric matrix may show a cold flow, since such polymer compositions often exhibit, despite a very high viscosity, the ability to flow very slowly. Thus, during storage, the matrix may flow to a certain extent over the edges of the backing layer. This is a problem with storage stability and can be prevented by the addition of certain polymers. A basic acrylate polymer (e.g. Eudragit® El 00) may e.g. be used to reduce the cold flow. Thus, in certain embodiments, the matrix layer composition comprises additionally a basic polymer, in particular an amine-functional acrylate as e.g. Eudragit® El 00. Eudragit® El 00 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2:1 :1. The monomers are randomly distributed along the copolymer chain. Based on SEC method, the weight average molar mass (Mw) of Eudragit® E100 is approximately

47,000 g/mol.

[0237] According to one aspect of the invention, the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in an amount ratio of from 0.1 :1 to 5:1, preferably of from 0.5:1 to 2:1.

[0238] In one embodiment, the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in different amounts by weight.

In another embodiment, the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in the same amounts by weight. In a certain embodiment, the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in an amount ratio of about 1 :1.

[0239] In one embodiment, the at least one silicone acrylic hybrid polymer and the at least one non-hybrid polymer are contained in the same layer of the buprenorphine-containing layer structure. In another embodiment, the at least one silicone acrylic hybrid polymer and the at least one non-hybrid polymer are contained in different layers of the buprenorphine-containing layer structure.

RELEASE CHARACTERISTICS

[§240] The TTS in accordance with the invention are designed for transdermally administering buprenorphine to the systemic circulation for a predefined extended period of time (e.g. for at least 72 hours, for about 84 hours, or for about 168 hours), preferably for about 168 hours.

Whether the skin permeation rate of buprenorphine is sufficient for a therapeutic effect can be determined by comparing the Franz diffusion cell skin permeation rates of a commercially available reference TTS, also including buprenorphine, with the Franz diffusion cell skin permeation rates of the TTS in accordance with the invention.

[0241] In accordance with the invention, the skin permeation rates are measured in a Franz diffusion cell with dermatomed human skin with a thickness of 800 pm, with an intact epidermis, in accordance with the OECD Guideline (adopted April 13, 2004) when a phosphate buffer solution pH 5.5 with 0.1 % saline azide as antibacteriological agent is used at a

temperature of 32 ± l°C. Absolute mean values obtained from different in vitro permeation studies can be compared by using the reference TTS (e.g. Transtec® or BuTrans®) as an internal standard.

[0242] In a certain embodiment, the TTS according to the invention provides a permeation rate of the buprenorphine when measured in a comparable test with a commercial buprenorphine reference TTS (e.g. BuTrans®) that is therapeutically effective, preferably over 48 hours, 72 hours, 84 hours, 96 hours, or 168 hours.

[0243] In a certain embodiment, the TTS according to the invention provides a skin permeation rate of buprenorphine when measured in a comparable test with a commercial buprenorphine reference transdermal therapeutic system (e.g. Transtec® or BuTrans®) in a 36-hour time interval from hour 48 to hour 84 that is therapeutically effective,

[0244] In a certain embodiment, the TTS according to the invention provides a skin permeation rate of buprenorphine when measured in a comparable test with a commercial buprenorphine reference transdermal therapeutic system (e.g. BuTrans®) in a 72-hour time interval from hour 96 to hour 168 that is therapeutically effective, and/or provides a skin permeation rate of buprenorphine when measured in a comparable test with a commercial buprenorphine reference transdermal therapeutic system (e.g. BuTrans®) in a 96-hour time interval from hour 72 to hour 168 that is therapeutically effective, and/or provides a skin permeation rate of buprenorphine when measured in a comparable test with a commercial buprenorphine reference transdermal therapeutic system (e.g. BuTrans®) in a 120-hour time interval from hour 48 to hour 168 that is therapeutically effective.

[0245] The TTS in accordance with the invention provide an improved release performance compared to the commercial buprenorphine TTS in that the permeation rate is increased over the administration period (e.g. 7 days) and the fluctuation of the permeation rate is decreased over the administration period (e.g. 7 days). In particular, the TTS in accordance with the invention maintain a relatively high permeation rate until the end of the administration period (e.g. 7 days), thus providing a constant permeation rate for buprenorphine, in particular towards the end of the administration period.

[0246] In a certain embodiment, the TTS according to the invention provides a permeation rate of buprenorphine that is constant within 20% points over about the last two-thirds of the administration period, preferably over the last 4 days of a 7-day administration period, i.e. from hour 72 to hour 168, preferably as measured in a Franz diffusion cell with dermatomed human skin with a thickness of 800 pm, with an intact epidermis, in accordance with the OECD

Guideline (adopted April 13, 2004) when a phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent is used at a temperature of 32 ± 1°C. The permeation rate is preferably constant within less than 19% points, less than 18% points, or less than 17% points, over about the last two-thirds of the administration period, e.g. from hour 72 to hour 168. [0247] For the purpose of determining whether the permeation rate is constant within 20% points in accordance with the present invention, the relative amendment of the cumulative skin permeation rate from a certain point of elapsed time, e.g. 72 hours, to the end of the

administration period, e.g. 168 hours, is calculated by subtracting the cumulative skin permeation rate over the entire administration period, e.g. at 168 hours, from the cumulative skin permeation rate at a certain elapsed time, e.g. at 72 hours, and dividing the result by the calculated cumulative skin permeation rate at the certain elapsed time, e.g. at 72 hours.

METHOD OF TREATMENT/ MEDICAL USE

[0248] In accordance with a specific aspect of the present invention, the TTS according to the invention is for use in a method of treating a human patient, preferably for use in a method of treating pain.

[0249] According to certain aspects of the present invention, the TTS is for use in a method of treating pain wherein the TTS is applied for more than 3 days, for about 3.5 days, for about 4 days, for about 5 days, for about 6 days, or for about 7 days to the skin of a human patient. In one embodiment, the TTS according to the invention is for use in a method of treating pain wherein the transdermal therapeutic system is applied for about 3.5 days to the skin of a patient. In a preferred embodiment, the TTS according to the invention is for use in a method of treating pain wherein the transdermal therapeutic system is applied for about 7 days to the skin of a patient.

[0250] According to one aspect, the invention relates to the use of a TTS according to the present invention for the manufacture of a medicament. In particular, the invention relates to the use of a TTS according to the present invention for the manufacture of a medicament for treating pain, which preferably is applied to the skin of a patient for more than 3 days, for about 3.5 days, for about 4 days, for about 5 days, for about 6 days, or for about 7 days. In one embodiment, the application period is about 3.5 days. In a preferred embodiment, the application period is about 7 days.

[0251] According to another aspect, the present invention relates to a method of treatment. Preferably, the present invention relates to a method of treating pain by applying to the skin of a patient a transdermal therapeutic system according to the invention. In this connection, the TTS is preferably applied to the skin of a patient for more than 72 hours (or for more than 3 days), or for about 84 hours (3.5 days), or for about 96 hours (4 days), or for about 120 hours (5 days), or for about 144 hours (6 days), or for about 168 hours (7 days or for one week). In one

embodiment, the TTS is applied on the skin of a human patient for about 3.5 days. In a preferred embodiment, the TTS is applied on the skin of a patient for about 7 days.

METHOD OF MANUFACTURE

[0252] The invention further relates to a method of manufacture of a transdermal therapeutic system according to the invention comprising the steps of:

1) providing a buprenorphine-containing coating composition comprising

a) buprenorphine (e.g. buprenorphine base),

b) carboxylic acid (e.g. levulinic acid), and

c) a solvent (e.g. ethanol), 2) coating the buprenorphine-containing coating composition onto a release liner in an amount to provide the desired area weight,

3) drying the coated buprenorphine-containing coating composition to provide the buprenorphine-containing layer,

4) laminating the buprenorphine-containing layer to a backing layer to provide a

buprenorphine-containing layer structure,

5) optionally providing an additional skin contact layer by coating and drying an active agent-free coating composition according to steps 2 and 3, removing the release liner of the buprenorphine-containing layer and laminating the additional skin contact layer onto the buprenorphine-containing layer to provide a buprenorphine-containing layer structure with the desired area of release,

6) punching the individual systems from the buprenorphine- containing layer structure,

7) optionally adhering to the individual systems an active-free self-adhesive layer structure comprising also a backing layer and an active agent-free pressure-sensitive adhesive layer and which is larger than the individual systems of buprenorphine-containing self-adhesive layer structure,

wherein at least one silicone acrylic hybrid polymer composition is added to the

buprenorphine-containing coating composition in step 1), or, if an additional skin contact layer is provided, to the active agent-free coating composition in step 5), or to both the buprenorphine-containing coating composition in step 1) and to the active agent-free coating composition in step 5)

[0253] In a preferred embodiment, the at least one silicone acrylic hybrid polymer composition is a silicone acrylic hybrid pressure-sensitive adhesive, preferably in ethyl acetate or n-heptane.

[0254] In one embodiment, buprenorphine in step 1) is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane or in ethyl acetate to provide the buprenorphine-containing coating composition.

[0255] In a further embodiment, in step 1) a non-hybrid pressure-sensitive adhesive based on polysiloxanes in n-heptane or in ethyl acetate is added. In yet another embodiment, in step 1) a non-hybrid pressure-sensitive adhesive based on acrylate is added.

[0256] In a certain aspect, the invention relates to a method of manufacture according to the invention, wherein in step 1) buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with a non-hybrid pressure-sensitive adhesive based on polysiloxanes in n-heptane or ethyl acetate to provide the buprenorphine-containing coating composition, and in step 5), the additional skin contact layer is provided by coating and drying the active agent-free coating composition comprising the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane or in ethyl acetate.

[0257] In another certain aspect, the invention relates to a method of manufacture according to the invention, wherein in step 1) buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane or ethyl acetate to provide the buprenorphine-containing coating composition, and in step 5), the additional skin contact layer is provided by coating and drying the active agent-free coating composition comprising the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane or in ethyl acetate.

[0258] Preferably, the silicone acrylic hybrid polymer has a solids content of from 40 to 60% by weight.

[0259] In one embodiment, the buprenorphine-containing coating composition of step 1) further comprises an auxiliary polymer, preferably selected from the group consisting of alkyl methacrylate copolymers, amino alkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic ester copolymers, ammonioalkyl methacrylate copolymers, polyvinylpyrrolidones, vinylpyrrolidone-vinyl acetate copolymers, polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol copolymer, and mixtures thereof, preferably the auxiliary polymer is a polyvinylpyrrolidone.

[0260] In step 3) and optionally in step 5) of the above method of manufacture, drying is performed preferably at a temperature of from 20 to 90°C, more preferably from 30 to 80°C.

EXAMPLES

[0261] The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention. Numerical values provided in the examples regarding the amount of ingredients in the composition or the area weight may vary slightly due to manufacturing variability.

COMPARATIVE EXAMPLE 1

[0262] The commercially available product BuTrans ^® , also known as Norspan ^® , is used as a reference TTS (Comp. 1). In particular, absolute mean values obtained from in vitro permeation studies (which may vary from study to study) can be compared by using BuTrans ^® as an internal standard. BuTrans ^® is a homogeneous matrix system based on polyacrylates having an area weight of 80 g/m ² and containing buprenorphine in an amount of 800 pg/cm ² (API loading).

COMPARATIVE EXAMPLE 2

[0263] The formulation of the buprenorphine base-containing coating compositions of Comparative Example 2 (Comp. 2) is summarized in Table 1 below.

[0264] Table 1

Preparation of the coating composition

[0265] In a 10 1 vessel, 1.00 kg of polyvinylpyrrolidone and 3.00 kg of ethanol were dissolved to form a 25% PVP pre-solution. In a homogenizing/mixing vessel: Becomix Lab

mixer RW 30 Ex, 1.368 kg of the PVP pre-solution, 0.958 kg levulinic acid, 0.027 kg ascorbyl palmitate and the main part of 0.912 kg ethanol were suspended by stirring. The prescribed amount of the buprenorphine base was weighed and added to the homogenizing/mixing vessel followed by rinsing the weighing container used for buprenorphine with the remaining part of ethanol. The mixture was kept under stirring for at least lh until a buprenorphine base-containing solution was formed. 15.048 kg of the polysiloxane-based adhesive in the form of a solution in n-heptane having a solids content of 73% by weight and 0.319 kg of n-heptane were added to the mixing/homogenizing vessel. The mixture was stirred for at least 2h until a buprenorphine base- containing adhesive mixture with 6.8% of buprenorphine, with a solids content of 68%

(buprenorphine base-containing adhesive mixture) was formed. Afterwards, this mixture was homogenized using a rotor-stator device using homogenizing unit at approx. 2250 rpm.

Coating of the coating composition

[0266] Within 24 hours the buprenorphine base-containing adhesive mixture was coated on a polyethylene terephthalate foil (Scotchpak from 3M) using a pilot plant roll coater including a drying tunnel, several drying sections, an unwinding and laminating station. The solvent was removed by drying at approximately 30-50°C. The matrix layer remained within the drying tunnel at approx. 8 minutes.

[0267] The coating thickness was chosen such that removal of the solvents results in an area weight of the matrix layer of approx. 90 g/m ² . This results in 10% by weight of buprenorphine, 7% by weight of levulinic acid, 2.5% by weight of polyvinylpyrrolidone (PVP), 0.2% by weight of ascorbyl palmitate, and 80.3% by weight of polysiloxane-based adhesive in this matrix layer. The dried film was then laminated with a backing layer (e.g. polyethylenterephthalate (PET) foil 19 pm) to provide the buprenorphine-containing self-adhesive layer structure. Preparation of the TTS

[0268] The individual systems (TTS) were then punched from the buprenorphine-containing self-adhesive layer structure.

[0269] In specific embodiments a TTS as described above can be provided with a further self- adhesive layer of larger surface area, preferably with rounded comers, comprising a pressure- sensitive adhesive matrix layer which is free of active ingredient and has a preferably beige colored backing layer (overtape). This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the buprenorphine- containing matrix layer, for the purpose of avoiding waste, has pronounced comers (square or rectangular shapes.

[0270] The overtape including the TTS are then punched out by only punching the overtape and sealed into pouches of the primary packaging material.

EXAMPLES 1A-C

Coating composition

[0271] The formulations of the buprenorphine base-containing coating compositions of

Examples la-c are summarized in Table 2.1 below. The formulations are based on the weight percent.

[0272] Table 2.1

Preparation of the coating composition

[0273] In a 250 mL wide-neck glass, the buprenorphine base was suspended in levulinic acid, ethanol, if applicable the PVP solution (Ex. lc), ascorbyl palmitate and stirred until complete dissolution of buprenorphine. The silicone acrylic hybrid pressure-sensitive adhesive in the form of a mixture in n-heptane (Ex. la) or in ethyl acetate (Ex. lb and lc) having a solids content of 50% by weight and n-heptane to adjust the solids content were added. The mixture was stirred until homogeneous to give a buprenorphine-containing adhesive mixture with 5.19% (Ex. la and lb) and 5.14% (Ex. lc) by weight of buprenorphine, with a solids content of 51.9% (Ex. 1 a and lb) and 51.4% (Ex. lc), respectively.

Coating of the coating composition

[0274] The buprenorphine-containing adhesive mixture was coated within less than 24 h after the buprenorphine base-containing mixture was finished on an abhesively equipped foil

(Scotchpak 1022 from 23M) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at approx room temperature (23 ± 2°C) for approx. 10 min, followed by a second drying step at approx. 75°C for approx. 10 min. [0275] The coating thickness was chosen such that removal of the solution results in an area weight of the matrix layer of approx. 90 g/m ² . This results in 10% by weight of buprenorphine, 7% by weight of levulinic acid, if applicable 2.5% by weight of polyvinylpyrrolidone (PVP)

(Ex. lc), 0.2% by weight of ascorbyl palmitate and 80.3% (Ex. lc) and 82.8% (Ex. la and lb), respectively, by weight of silicone acrylic hybrid pressure-sensitive adhesive in this matrix layer. The dried film was then laminated with a backing layer (polyethylenterephthalate (PET) foil 19 pm) to provide the buprenorphine-containing self-adhesive layer structure.

[0276] Table 2.2

Preparation of the TTS (concerning all examples)

[0277] The individual systems (TTS) were then punched out from the

buprenorphine-containing self-adhesive layer structure.

[0278] In specific embodiments a TTS as described above can be provided with an adhesive overlay, i.e. a further self-adhesive layer structure of larger surface area, preferably with rounded comers, comprising a pressure-sensitive adhesive matrix layer which is free of active ingredient and a preferably skin-colored backing layer. The TTS are then punched out and sealed into pouches of the primary packaging material.

Measurement of adhesion force (concerning all examples)

[0279] Adhesion force tests were performed with the TTS using a tensile strength testing machine. Prior testing the samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity). Further, the samples were cut into pieces with a fixed width of 25mm and a suitable length. The first millimeters of the abhesively equipped foil was pulled off and a splicing tape is applied to the opened adhesive side of the buprenorphine-containing layer structure. Then, the abhesively foil was totally removed and the sample was placed with the adhesive surface in longitudinal direction onto the center of the cleaned testing plate (aluminum). The testing plate was fixed to the lower clamp of the tensile strength machine. The machine was adjusted to zero, the splicing tape was gripped into the upper clamp of the machine. The pull angle was set to 90°. After measurement of the adhesion force of three samples, the mean value of the adhesion force was calculated. The measurement value is based on units“N/sample width” [N/25mm].

[0280] Table 2.3

partially cohesion fracture

Measurement of Tack (concerning all examples)

[0281] The Tack (the force which is required to separate an object from an adhesive surface after a short time of contact) tests were performed with the TTS in accordance with the Standard Test Method for Pressure- S ensiti ve Tack of Adhesives Using an Inverted Probe Machine (ASTM D 2979 - 01; Reapproved 2009) using a probe tack tester PT-1000 (Chemlnstruments). Prior to testing the samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh. For determining the tack, the tip of a cleaned probe with a diameter of 5 mm was brought into contact with the adhesive surface of the buprenorphine-containing layer structure for 1 second, at a defined rate (10 ± 0.1 mm/s), under defined pressure (9.79 ± 0.10 kPa), at a given temperature (23 ± 2°C) and the bond formed between probe and the adhesive was subsequently broken at the same rate. Tack was measured as the maximum force required, to break the adhesion bond (see ASTM D2979 - 01 ;

Reapproved 2009). After finalization the mean value from the individual results of three associated samples were calculated and the mean tack value reported in [N].

[0282] Table 2.4

Measurement of skin permeation rate

[0283] The permeated amount and the corresponding skin permeation rates of TTS prepared according to Examples la-c and Comparative Examples 1 and 2 were determined by in vitro experiments in accordance with the OECD Guideline (adopted April 13, 2004) carried out with a 9.0 ml Franz diffusion cell. Split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1988) was used. A dermatome was used to prepare skin to a thickness of 800 pm, with an intact epidermis for all TTS. Due to the prolonged test (168 hours) 800 pm skin is used instead of the recommended 200 to 400 pm skin. Die cuts with an area of 1.191 cm ² were punched from the TTS. The concentrations of buprenorphine base in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% saline azide as

antibacteriological agent) at a temperature of 32 ± l°C were measured and the corresponding skin permeation rate calculated.

[0284] The results for Examples la-c and Comparative Examples 1 and 2 are shown in Tables 2.5 to 2.10, and Figures la and lb.

[0285] Table 2.5

0287] Table 2.7

0288] Table 2.8

Ratio Example TTS/ BuTrans ^® of cumulative permeated amo

after 168 hours of release

Ex. l x. l Ex. l omp. omp.

Tran

1.4 1.7 1.9 1.0 2.0

0289] Table 2.9

0290] Table 2.10

Microscopic pictures

[0291] Microscopic pictures were taken of the buprenorphine base-containing adhesive matrix layers of Examples la-c and Comparative Examples 1 and 2 using a Nikon S/N 237789 Microscope.

[0292] Figure 8a shows an exemplary microscopic picture of the matrix layer of Comp. 2. Figure 8a shows visible spheres within the dried matrix layer.

[0293] Figures 8b-c show exemplary microscopic pictures of the matrix layer of Examples 1 a and lc. Figures 8b-c show visible spheres within the dried matrix layer.

[0294] Figure 8j shows an exemplary microscopic picture of the matrix layer of Comp. 1. The matrix layer of Comp. 1, which is a homogeneous single phase system, shows no spheres. [0295] During the microscopic investigation the size of the spheres (diameter) in the matrix layer were determined if present. The maximum sphere sizes in the matrix layer as determined during microscopic investigation of three different sections of the matrix layer per example are summarized in Table 2.11 below.

[0296] Table 2.11

EXAMPLES 2A-C

Coating composition

[0297] The formulations of the buprenorphine base-containing coating compositions of Examples 2a-c are summarized in Table 3.1 below. The formulations are based on the weight percent.

[0298] Table 3.1

Preparation of the coating composition

[0299] In a 250 mL wide-neck glass, the buprenorphine base was suspended in levulinic acid, ethanol, if applicable the PVP solution (Ex. 2a and 2b), ascorbyl palmitate and stirred until complete dissolution of buprenorphine. The silicone acrylic hybrid pressure-sensitive adhesive in the form of a mixture in n-heptane having a solids content of 50% by weight, if applicable the polysiloxane-based adhesive in the form of a mixture in n-heptane having a solids content of 73% by weight (Ex. 2b and 2c), and n-heptane to adjust the solids content were added. The mixture was stirred until homogeneous to give a buprenorphine-containing adhesive mixture with 5.14% (Ex. 2a), 5.91% (Ex. 2b), and 6.06% (Ex. 2c) by weight of buprenorphine, with a solids content of 51.4% (Ex. 2a), 59.1% (Ex. 2b), and 60.6% (Ex. 2c), respectively.

Coating of the coating composition

[0300] The buprenorphine-containing adhesive mixture was coated within less than 24 h after the buprenorphine base- containing mixture was finished on an abhesively equipped foil using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at approx room temperature (23 ± 2°C) for approx. 10 min, followed by a second drying step at approx. 60°C for approx. 10 min.

[0301] The coating thickness was chosen such that removal of the solution results in an area weight of the matrix layer of approx. 90 g/m ² . This results in 10% by weight of buprenorphine, 7% by weight of levulinic acid, if applicable 2.5% by weight of polyvinylpyrrolidone (PVP)

(Ex. 2a and 2b), 0.2% by weight of ascorbyl palmitate, 80.3% (Ex. 2a), 40.15% (Ex. 2b), and 41.4% (Ex. 2c), respectively, by weight of silicone acrylic hybrid pressure-sensitive adhesive and if applicable 40.15% (Ex. 2b) and 41.4% (Ex. 2c), respectively, of polysiloxane-based adhesive in this matrix layer. The dried film was then laminated with a backing layer

(polyethylenterephthalate (PET) foil 19 pm) to provide a buprenorphine-containing self-adhesive layer structure.

[0302] Table 3.2

Preparation of the TTS

[0303] See Example 1.

Measurement of adhesion force

[0304] For the method of measurement, see Example 1. The mean adhesion force values of the buprenorphine-containing layer structure of Examples 2a-c are summarized in the Table below.

[0305] Table 3.3

Measurement of Tack

[0306] For the method of measurement, see Example 1. The mean tack values of the buprenorphine-containing layer structure of Examples 2a-c are summarized in the Table below.

[0307] Table 3.4

Measurement of skin permeation rate

[0308] For the method of measurement, see Example 1. The results of Examples 2b and 2c, as well as of Comparative Examples 1 and 2, are shown in Tables 3.5 to 3.10, and Figures 2a and 2b. [0309] Table 3.5

[0313] Table 3.9

0314] Table 3.10

Microscopic pictures

[0315] Microscopic pictures were taken of the buprenorphine base-containing adhesive matrix layers of Examples 2a-c using a Nikon S/N 237789 Microscope. Figures 8d and 8e show exemplary microscopic pictures of the matrix layer of Examples 2a and 2b. During the microscopic investigation the size of the spheres (diameter) in the matrix layer were determined if present. Figures 8d and 8e show visible spheres within the dried matrix layer. The maximum sphere sizes in the matrix layer as determined during microscopic investigation of three different sections of the matrix layer per example are summarized in Table 3.11 below.

[0316] Table 3.11

EXAMPLES 3 A, 3B

Coating composition

[0317] The formulations of the buprenorphine base-containing coating compositions of Examples 3a and 3b are summarized in Table 4.1 below. The formulations are based on the weight percent. [0318] Table 4.1

Preparation of the coating composition

[0319] The coating compositions of Examples 3a and 3b were prepared as described in Example 1 , wherein P VP is added to the mixture of Example 3b. A buprenorphine-containing adhesive mixture with 5.19% (Ex. 3b) and 5.10% (Ex. 3b) by weight of buprenorphine, with a solid content of 51.9% (Ex. 3a) and 51% (Ex. 3b) was obtained.

Coating of the coating composition

[0320] See Examples 1. The coating thickness was chosen such that removal of the solution results in an area weight of the matrix layer of approx. 90 g/m ² . This results in 10% by weight of buprenorphine, 7% by weight of levulinic acid, if applicable 3.5% by weight of

polyvinylpyrrolidone (PVP) (Ex. 3b), 0.2% by weight of ascorbyl palmitate, 82.8% (Ex. 3a) and 79.3 (Ex. 3b), respectively, by weight of silicone acrylic hybrid pressure-sensitive adhesive. The dried film was then laminated with a backing layer (polyethylenterephthalate (PET) foil 19 pm) to provide a buprenorphine-containing self-adhesive layer structure.

[0321] Table 4.2

Preparation of the TTS

[0322] See Example 1. Measurement of adhesion force

[0323] For the method of measurement, see Example 1. The mean adhesion force values of the buprenorphine-containing layer structure of Examples 3a and 3b are summarized in the Table below.

[0324] Table 4.3

‘partially cohesion fracture

Measurement of Tack

[0325] For the method of measurement, see Example 1. The mean tack values of the buprenorphine-containing layer structure of Examples 3a and 3b are summarized in the Table below.

[0326] Table 4.4

Measurement of skin permeation rate

[0327] For the method of measurement, see Example 1, wherein a split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1987) was used. The results of Example 3b and Comparative Example 1 are shown in Tables 4.5 to 4.10, and Figures 3a and 3b.

[0328] Table 4.5

[0329] Table 4.6

[0330] Table 4.7

[0333] Table 4.10

Microscopic pictures

[0334] Microscopic pictures were taken of the buprenorphine base-containing adhesive matrix layers of Examples 3a-b using a Nikon S/N 237789 Microscope. Figure 8f shows an exemplary microscopic pictures of the matrix layer of Example 3b. During the microscopic investigation the size of the spheres (diameter) in the matrix layer were determined if present. Figure 8f shows visible spheres within the dried matrix layer. The maximum sphere sizes in the matrix layer as determined during microscopic investigation of three different sections of the matrix layer per example are summarized in Table 4.11 below.

[0335] Table 4.11

EXAMPLES 4A-C

Coating composition

[0336] The formulations of the buprenorphine base-containing coating compositions of Examples 4a to 4c are summarized in Table 5.1 below. The formulations are based on the weight percent.

[0337] Table 5.1

Preparation of the coating composition

[0338] In a 250 mL wide-neck glass, the buprenorphine base was suspended in levulinic acid, ethanol, the PVP solution, ascorbyl palmitate and stirred until complete dissolution of buprenorphine. The silicone acrylic hybrid pressure-sensitive adhesive in the form of a mixture in n-heptane having a solids content of 50% by weight, the polysiloxane-based adhesive in the form of a mixture in n-heptane having a solids content of 73% by weight, and n-heptane to adjust the solids content were added. The mixture was stirred until homogeneous to give a

buprenorphine-containing adhesive mixture with 5.86% (Ex. 4a), 5.98% (Ex. 4b), and 2.92%

(Ex. 4c) by weight of buprenorphine, with a solids content of 58.6% (Ex. 2a), 59.8% (Ex. 4b), and 29.2% (Ex. 4c), respectively.

Coating of the coating composition

[0339] The buprenorphine-containing adhesive mixture was coated within less than 24 h after the buprenorphine base-containing mixture was finished on an abhesively equipped foil using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at approx room temperature (23 ± 2°C) for approx. 10 min, followed by a second drying step at approx. 60°C for approx. 10 min.

[0340] The coating thickness was chosen such that removal of the solution results in an area weight of the matrix layer of approx. 90 g/m ² . This results in 10% (Ex. 4a, b) and 5% (Ex. 4c), respectively, by weight of buprenorphine, 5% (Ex. 4a) and 10% (Ex. 4b, c), respectively, by weight of levulinic acid, 2.5% by weight of polyvinylpyrrolidone (PVP), 0.2% by weight of ascorbyl palmitate, 41.15% (Ex. 4a, c) and 38.65% (Ex. 4b), respectively, by weight of silicone acrylic hybrid pressure-sensitive adhesive and 41.15% (Ex. 4a, c) and 38.65% (Ex. 4b), respectively, by weight of polysiloxane-based adhesive in this matrix layer. The dried film was then laminated with a backing layer (polyethylenterephthalate (PET) foil 19 pm) to provide a buprenorphine-containing self-adhesive layer structure.

[0341] Table 5.2

Preparation of the TTS

[0342] See Example 1.

Measurement of adhesion force

[0343] For the method of measurement, see Example 1. The mean adhesion force values of the buprenorphine-containing layer structure of Examples 4a-c are summarized in the Table below.

[0344] Table 5.3 partially cohesion fracture

Measurement of Tack

[0345] For the method of measurement, see Example 1. The mean tack values of the buprenorphine-containing layer structure of Examples 4a-c are summarized in the Table below.

[0346] Table 5.4

Measurement of skin permeation rate

[0347] For the method of measurement, see Example 1, wherein a split thickness human skin from cosmetic surgeries (male abdomen, date of birth 1960) was used. Die cuts with an area of 1.188 cm ² were punched from Comparative Example 1 and tested against 1.188 cm ² die cuts of Ex. 4a-c. The results of Examples 4a-c, as well as of Comparative Example 1 , are shown in Tables 5.5 to 5.10, and Figures 4a and 4b.

[0348] Table 5.5

[0350] Table 5.7

0351] Table 5.8

0352] Table 5.9

Ratio Cumulative permeated amount after 168 hours

of release / API Loading

[0353] Table 5.10

Microscopic pictures

[0354] Microscopic pictures were taken of the buprenorphine base-containing adhesive matrix layers of Examples 4a- c using a Nikon S/N 237789 Microscope. Figures 8g to 8i show exemplary microscopic pictures of the matrix layer of Examples 4a to 4c. During the

microscopic investigation the size of the spheres (diameter) in the matrix layer were determined. Figures 8g to 8i show visible spheres within the dried matrix layer. The maximum sphere sizes in the matrix layer as determined during microscopic investigation of three different sections of the matrix layer per example are summarized in Table 5.11 below.

[0355] Table 5.11

EXAMPLES 5A-D

Coating composition

[0356] The formulations of the buprenorphine base-containing coating compositions of Examples 5a-d are summarized in Table 6.1 below. The formulations are based on the weight percent.

[0357] Table 6.1

Preparation of the API coating composition

[0358] The API containing coating composition was manufactured according to Comparative Example 2, resulting in a buprenorphine base-containing adhesive mixture with 6.8% of buprenorphine, with a solids content of 68% (buprenorphine base-containing adhesive mixture). Afterwards, this mixture was homogenized using a rotor-stator device using homogenizing unit at approx. 2250 rpm.

Coating of the API coating composition

[0359] The buprenorphine-containing adhesive mixture was coated according to Comparative Example 2. The coating thickness was chosen such that removal of the solvents results in an area weight of the matrix layer of approx. 90 g/m ² . This results in 10% by weight of buprenorphine, 7% by weight of levulinic acid, 2.5% by weight of polyvinylpyrrolidone (PVP), 0.2% by weight of ascorbyl palmitate, and 80.3% by weight of polysiloxane-based adhesive in this matrix layer. The dried film was then laminated with a backing layer (e.g. polyethylenterephthalate (PET) foil 19 pm).

Coating of the API free coating composition (skin contact layer) and lamination

[0360] The compositions of an adhesive solution used for the manufacturing for the active agent free skin contact layer used in the above mentioned examples are summarized in Table 6.1 above (SilAc-PSA 7-6101 (Ex. 5a), SilAc-PSA 7-6102 (Ex. 5b), SilAc-PSA 7-6302 (Ex. 5c), and SilAc-PSA 7-6301 (Ex. 5d), from Dow Coming Healthcare). [0361] The adhesive solutions were coated on an abhesively equipped foil using hand over knife lab coating equipment (erichson coater).

[0362] The coating thickness were each chosen such that removal of the solvents result in an area weight of the skin contact layer of approx. 20 g/m ² . This results in 100% by weight of silicone acrylic hybrid pressure-sensitive adhesive in this skin contact layer.

[0363] The dried film was then laminated with the buprenorphine-containing matrix layer that was laminated with a backing layer. For this purpose, the abhesively equipped foil used for the coating and drying of the buprenorphine-containing matrix layer that was then laminated with a backing layer was removed and the coated and dried buprenorphine-ffee skin contact layer was laminated with that film resulting in a buprenorphine-containing self-adhesive layer structure.

[0364] Table 6.2

Preparation of the TTS

[0365] See Example 1.

Measurement of adhesion force

[0366] For the method of measurement, see Example 1. The mean adhesion force values of the buprenorphine-containing layer structure of Examples 5a-d are summarized in the Table below.

[0367] Table 6.3

Measurement of Tack

[0368] For the method of measurement, see Example 1. The mean tack values of the buprenorphine-containing layer structure of Examples 5a-d are summarized in the Table below.

[0369] Table 6.4

Measurement of skin permeation rate

[0370] For the method of measurement, see Example 1, wherein a split thickness human skin from cosmetic surgeries (female abdomen, date of birth 1953) was used. Die cuts with an area of 1.188 cm ² were punched from Comparative Example 1 and are tested against 1.188 cm ² die cuts of Ex. 5a-d. The results of Examples 5a-d and Comparative Example 1 are shown in Tables 6.5 to 6.10, and Figures 5a and 5b. [0371] Table 6.5

[0373] Table 6.7

[0375] Table 6.9

Ratio Cumulative permeated amount after 168 hours of release

API Loading

Ex. 5d omp.

052 0.30

[0376] Table 6.10

EXAMPLES 6 A, 6B

Coating composition

[0377] The formulations of the buprenorphine base-containing coating compositions of Examples 6a and 6b are summarized in Table 7.1 below. The formulations are based on the weight percent. [0378] Table 7.1

Preparation of the API coating composition

[0379] The API containing coating composition was manufactured according to Example la, resulting in a buprenorphine base-containing adhesive mixture with 5.19% of buprenorphine, with a solids content of 51.9% (buprenorphine base-containing adhesive mixture).

Coating of the API coating composition

[0380] The buprenorphine-containing adhesive mixture was coated according to Example lb. The coating thickness was chosen such that removal of the solvents results in an area weight of the matrix layer of approx. 90 g/m ² . This results in 10% by weight of buprenorphine, 7% by weight of levulinic acid, 0.2% by weight of ascorbyl palmitate, and 82.8% by weight of silicone acrylic hybrid pressure-sensitive adhesive in this matrix layer. The dried film was then laminated with a backing layer (e.g. polyethylenterephthalate (PET) foil 19 pm).

Coating of the API free coating composition (skin contact layer) and lamination

[0381] The compositions of an adhesive solution used for the manufacturing for the active agent free skin contact layer used in above mentioned examples are summarized in Table 7.1 above (SilAc-PSA 7-6301 (Ex. 6a) and SilAc-PSA 7-6302 (Ex. 6b), from Dow Coming

Healthcare).

[0382] The adhesive solutions were coated on an abhesively equipped foil using hand over knife lab coating equipment (erichson coater).

[0383] The coating thickness were each chosen such that removal of the solvents result in an area weight of the skin contact layer of approx. 20 g/m ² . This results in 100% by weight of silicone acrylic hybrid pressure-sensitive adhesive in this skin contact layer.

[0384] The dried film was then laminated with the buprenorphine-containing matrix layer that was laminated with a backing layer. For this purpose, the abhesively equipped foil used for the coating and drying of the buprenorphine-containing matrix layer that was then laminated with a backing layer was removed and the coated and dried buprenorphine-free skin contact layer was laminated with that film resulting in a buprenorphine-containing self-adhesive layer structure. [0385] Table 7.2

Preparation of the TTS

[0386] See Example 1.

Measurement of adhesion force

[0387] For the method of measurement, see Example 1. The mean adhesion force values of the buprenorphine-containing layer structure of Examples 6a and 6b are summarized below.

[0388] Table 7.3

‘partially cohesion fracture

Measurement of Tack

[0389] For the method of measurement, see Example 1. The mean tack values of the buprenorphine-containing layer structure of Examples 6a and 6b are summarized below.

[0390] Table 7.4

Measurement of skin permeation rate

[0391] See Example 4. The results of Examples 6a and 6b, as well as of Comparative Example 1, are shown in Tables 7.5 to 7.10, and Figures 6a and 6b.

[0396] Table 7.9

[0397] Table 7.10

EXAMPLES 7 A, 7B

Coating composition

[0398] The formulations of the buprenorphine base-containing coating compositions of

Examples 7a and 7b are summarized in Table 8.1 below. The formulations are based on the weight percent.

[0399] Table 8.1

Preparation of the API coating composition

[0400] The API containing coating composition was manufactured according to Example la, resulting in a buprenorphine base-containing adhesive mixture with 5.19% of buprenorphine, with a solids content of 51.9% (buprenorphine base-containing adhesive mixture).

Coating of the API coating composition

[0401] The buprenorphine-containing adhesive mixture was coated according to Example lb. The coating thickness was chosen such that removal of the solvents results in an area weight of the matrix layer of approx. 90 g/m ² . This results in 10% by weight of buprenorphine, 7% by weight of levulinic acid, 0.2% by weight of ascorbyl palmitate, and 82.8% by weight of silicone acrylic hybrid pressure-sensitive adhesive in this matrix layer. The dried film was then laminated with a backing layer (e.g. polyethylenterephthalate (PET) foil 19 pm). Coating of the API free coating composition (skin contact layer) and lamination

[0402] The compositions of an adhesive solution used for the manufacturing for the active agent free skin contact layer used in above mentioned examples are summarized in Table 8.1 above (BIO-PSA 7-4301 from Dow Coming Healthcare (Ex. 7a) and DURO-TAK 87-4287 from Henkel (Ex. 7b)).

[0403] The adhesive solutions were coated on an abhesively equipped foil using hand over knife lab coating equipment (erichson coater).

[0404] The coating thickness were each chosen such that removal of the solvents result in an area weight of the skin contact layer of approx. 20 g/m ² . This results in 100% by weight of polysiloxane-based adhesive (Ex. 7a) and polyacrylate adhesive (Ex. 7b), receptively, in this skin contact layer.

[0405] The dried film was then laminated with the buprenorphine-containing matrix layer that was laminated with the backing layer. For this purpose, the abhesively equipped foil used for the coating and drying of the buprenorphine-containing matrix layer that was then laminated with a backing layer was removed and the coated and dried buprenorphine-free skin contact layer was laminated with that film resulting in a buprenorphine-containing self-adhesive layer structure.

[0406] Table 8.2

Preparation of the TTS

[0407] See Example 1.

Measurement of adhesion force

[0408] For the method of measurement, see Example 1. The mean adhesion force values of the buprenorphine-containing layer structure of Examples 7a and 7b are summarized in the

Table below.

[0409] Table 8.3

Measurement of Tack

[0410] For the method of measurement, see Example 1. The mean tack values of the buprenorphine-containing layer structure of Examples 7a and 7b are summarized in the

Table below.

[0411] Table 8.4 [0412] The ratios of the mean tack value of the TTS prepared according to Examples 7a and 7b to the mean tack value of the Comparative Example 1 (BuTrans ^® ) are shown in Figure 9.

Measurement of skin permeation rate

[0413] For the method of measurement, see Example 4. The results of Examples 7a and 7b, as well as of Comparative Example 1, are shown in Tables 8.5 to 8.10, and Figures 7a and 7b.

[0414] Table 8.5

[0416] Table 8.7

[0417] Table 8.8

0418] Table 8.9

0419] Table 8.10

The invention relates in particular to the following further items:

1. A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure,

the buprenorphine-containing layer structure comprising:

A) a backing layer; and

B) a buprenorphine-containing layer;

wherein the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine, and

b) a carboxylic acid,

and

wherein the transdermal therapeutic system comprises at least one silicone acrylic hybrid polymer.

2. The transdermal therapeutic system according to item 1 ,

wherein the buprenorphine-containing layer is a buprenorphine-containing matrix layer.

3. The transdermal therapeutic system according to any one of items 1 or 2,

which is free of an adhesive overlay on top of the buprenorphine-containing layer structure.

4. The transdermal therapeutic system according to any one of items 1 to 3,

wherein the buprenorphine is contained in an amount of from 2% to 20% by weight based on the buprenorphine-containing layer.

5. The transdermal therapeutic system according to any one of items 1 to 4,

wherein the buprenorphine is contained in an amount of from 3% to 15% by weight based on the buprenorphine-containing layer.

6. The transdermal therapeutic system according to any one of items 1 to 5,

wherein the buprenorphine is contained in an amount of from 3% to less than 10% by weight based on the buprenorphine-containing layer.

7. The transdermal therapeutic system according to any one of items 1 to 6,

wherein the buprenorphine-containing layer is obtainable by coating and drying a

buprenorphine-containing coating composition that comprises the buprenorphine in the form of the free base and the carboxylic acid.

8. The transdermal therapeutic system according to any one of items 1 to 7,

wherein the buprenorphine is present in the buprenorphine-containing layer in the form of the free base. 9. The transdermal therapeutic system according to any one of items 1 to 8,

wherein the carboxylic acid is contained in an amount sufficient so that the therapeutically effective amount of buprenorphine is solubilized therein.

10. The transdermal therapeutic system according to any one of items 1 to 9,

wherein the carboxylic acid is contained in an amount of from 2% to 20% by weight based on the buprenorphine-containing layer.

11. The transdermal therapeutic system according to any one of items 1 to 10,

wherein the carboxylic acid is contained in an amount of from 3% to 15% by weight based on the buprenorphine-containing layer.

12. The transdermal therapeutic system according to any one of items 1 to 11,

wherein the carboxylic acid is contained in an amount of from 4% to 12% by weight based on the buprenorphine-containing layer.

13. The transdermal therapeutic system according to any one of items 1 to 12,

wherein the carboxylic acid is selected from the group consisting of C ₃ to C ₂₄ carboxylic acids.

14. The transdermal therapeutic system according to any one of items 1 to 13,

wherein the carboxylic acid is selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid, and mixtures thereof.

15. The transdermal therapeutic system according to any one of items 1 to 14,

wherein the carboxylic acid is levulinic acid.

16. The transdermal therapeutic system according to any one of items 1 to 15,

wherein the buprenorphine and the carboxylic acid are contained in different amounts by weight based on the buprenorphine-containing layer.

17. The transdermal therapeutic system according to any one of items 1 to 16,

wherein the carboxylic acid and the buprenorphine are contained in an amount ratio of from 0.3:1 to 5:1.

18. The transdermal therapeutic system according to any one of items 1 to 17,

wherein the carboxylic acid is contained in less amounts by weight than the buprenorphine based on the buprenorphine-containing layer.

19. The transdermal therapeutic system according to any one of items 1 to 18,

wherein the buprenorphine is contained in less amounts by weight than the carboxylic acid based on the buprenorphine-containing layer.

20. The transdermal therapeutic system according to any one of items 1 to 19, wherein the buprenorphine and the carboxylic acid are contained in the same amounts by weight based on the buprenorphine-containing layer.

21. The transdermal therapeutic system according to any one of items 1 to 20,

wherein the carboxylic acid and the buprenorphine are contained in an amount ratio of about 1 :1.

22. The transdermal therapeutic system according to any one of items 1 to 21,

wherein the carboxylic acid is levulinic acid and the levulinic acid and the buprenorphine are contained in an amount ratio of from 0.3:1 to 5:1.

23. The transdermal therapeutic system according to any one of items 1 to 22,

wherein the silicone acrylic hybrid polymer contains a continuous, silicone external phase and a discontinuous, acrylic internal phase.

24. The transdermal therapeutic system according to any one of items 1 to 22,

wherein the silicone acrylic hybrid polymer contains a continuous, acrylic external phase and a discontinuous, silicone internal phase.

25. The transdermal therapeutic system according to any one of items 1 to 24,

wherein the at least one silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure- sensitive adhesive.

26. The transdermal therapeutic system according to any one of items 1 to 25,

wherein the at least one silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure- sensitive adhesive having a weight ratio of silicone to acrylate of from 5:95 to 95:5, preferably of from 40:60 to 60:40.

27. The transdermal therapeutic system according to any one of items 25 or 26,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive has a weight ratio of silicone to acrylate of from 40:60 to 60:40, and wherein the ethylenically unsaturated monomers forming the acrylate comprise 2-ethylhexyl acrylate and methyl acrylate in a ratio of from 40:60 to 70:30.

28. The transdermal therapeutic system according to any one of items 25 to 27,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive has a weight ratio of silicone to acrylate of about 50:50.

29. The transdermal therapeutic system according to any one of items 25 to 28,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of more than about 400 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM. 30. The transdermal therapeutic system according to any one of items 25 to 29,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 500 cP to about 3,500 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

31. The transdermal therapeutic system according to any one of items 25 to 30,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 1,000 cP to about 3,000 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

32. The transdermal therapeutic system according to any one of items 25 to 31,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 1,200 cP to about 1,800 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

33. The transdermal therapeutic system according to item 32,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of about 1,500 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

34. The transdermal therapeutic system according to any one of items 25 to 31,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 2,200 cP to about 2,800 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

35. The transdermal therapeutic system according to item 34,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of about 2,500 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

36. The transdermal therapeutic system according to any one of items 25 to 35,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a complex viscosity at 0.1 rad/s at 30°C of less than about l.0e9 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed. 37. The transdermal therapeutic system according to any one of items 25 to 36, wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a complex viscosity at 0.1 rad/s at 30°C of from about l .0e5 Poise to about 9.0e8 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

38. The transdermal therapeutic system according to any one of items 25 to 37,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a complex viscosity at 0.1 rad/s at 30°C of from about 9.0e5 Poise to about l.0e7 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

39. The transdermal therapeutic system according to any one of items 25 to 37,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a complex viscosity at 0.1 rad/s at 30°C of from about 9.0e5 Poise to about 7.0e6 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

40. The transdermal therapeutic system according to item 39,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a complex viscosity at 0.1 rad/s at 30°C of about 4.0e6 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

41. The transdermal therapeutic system according to any one of items 25 to 37,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a complex viscosity at 0.1 rad/s at 30°C of from about 2.0e6 Poise to about 9.0e7 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

42. The transdermal therapeutic system according to any one of items 25 to 37,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a complex viscosity at 0.1 rad/s at 30°C of from about 8.0e6 Poise to about 9.0e7 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

43. The transdermal therapeutic system according to item 42,

wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a complex viscosity at 0.1 rad/s at 30°C of about 1.0e7 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed. 44. The transdermal therapeutic system according to any one of items 1 to 28,

wherein the transdermal therapeutic system comprises at least two silicone acrylic hybrid polymers selected from at least two of the silicone acrylic hybrid polymer groups:

- silicone acrylic hybrid pressure-sensitive adhesives characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 1,200 cP to about

1.800 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM, and

- silicone acrylic hybrid pressure-sensitive adhesives characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 2,200 cP to about

2.800 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

45. The transdermal therapeutic system according to any one of items 1 to 28,

wherein the transdermal therapeutic system comprises at least two silicone acrylic hybrid polymers selected from at least two of the silicone acrylic hybrid polymer groups:

- silicone acrylic hybrid pressure-sensitive adhesives characterized by a complex viscosity at 0.1 rad/s at 30°C of from about 9.0e5 Poise to about 7.0e6 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed, and

- silicone acrylic hybrid pressure-sensitive adhesives characterized by a complex viscosity at 0.1 rad/s at 30°C of from about 8.0e6 Poise to about 9.0e7 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

46. The transdermal therapeutic system according to any one of items 1 to 45,

wherein the silicone acrylic hybrid polymer is obtainable from

(a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or

methacrylate functionality.

47. The transdermal therapeutic system according to any one of items 1 to 46,

wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive comprising the reaction product of

(a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality;

(b) an ethylenically unsaturated monomer; and

(c) an initiator.

48. The transdermal therapeutic system according to any one of items 46 or 47,

wherein the silicon- containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality is the condensation reaction product of

(al) a silicone resin, and

(a2) a silicone polymer, and

(a3) a silicon-containing capping agent comprising acrylate or methacrylate functionality. 49. The transdermal therapeutic system according to any one of items 46 to 48,

wherein the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality is the condensation reaction product of

(al) a silicone resin, and

(a2) a silicone polymer, and

(a3) a silicon-containing capping agent comprising acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR’ _b SiZ _3-b , wherein X is a monovalent radical of the general formula AE, where E is -O- or -NH- and A is an acryl group or methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R’ is a methyl or a phenyl radical, Z is a monovalent hydrolysable organic radical or halogen, and b is 0 or 1 ;

wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted,

and wherein the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive, or the silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.

50. The transdermal therapeutic system according to any one of items 47 to 49,

wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof, each of said compounds having up to 20 carbon atoms in the alkyl radical, and wherein the ethylenically unsaturated monomer is preferably a combination of 2-ethylhexyl acrylate and methyl acrylate, particularly preferably in a ratio of from 40:60 to 70:30.

51. The transdermal therapeutic system according to any one of items 47 to 50,

wherein the reaction product of

(a) the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality;

(b) the ethylenically unsaturated monomer; and

(c) the initiator

contains a continuous, silicone external phase and a discontinuous, acrylic internal phase.

52. The transdermal therapeutic system according to any one of items 47 to 50,

wherein the reaction product of

(a) the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality;

(b) the ethylenically unsaturated monomer; and

(c) the initiator

contains a continuous, acrylic external phase and a discontinuous, silicone internal phase. 53. The transdermal therapeutic system according to any one of items 1 to 45,

wherein the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked and covalently bound to the silicone polymer and/or the silicone resin.

54. The transdermal therapeutic system according to any one of items 1 to 53,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer.

55. The transdermal therapeutic system according to any one of items 1 to 54,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer based on polysiloxanes, polyisobutylenes, styrene-isoprene-styrene block copolymers, acrylates or mixtures thereof.

56. The transdermal therapeutic system according to any one of items 54 or 55,

wherein the at least one non-hybrid polymer is a poymer based on polysiloxanes, a polymer based on polyisobutylenes, a styrene-isoprene-styrene block copolymer, a polyacrylate, or a mixture thereof.

57. The transdermal therapeutic system according to any one of items 54 to 56,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive.

58. The transdermal therapeutic system according to any one of items 54 to 57,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes, polyisobutylenes, styrene-isoprene-styrene block copolymers, acrylates, or mixtures thereof.

59. The transdermal therapeutic system according to any one of items 54 to 58,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes.

60. The transdermal therapeutic system according to any one of items 54 to 59,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes characterized by a solution viscosity at 25°C and about 60% solids content in n-heptane of more than about 150 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

61. The transdermal therapeutic system according to any one of items 54 to 60,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes characterized by a solution viscosity at 25°C and about 60% solids content in n-heptane of from about 200 mPa s to about 700 mPa s, preferably as measured using a

Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

62. The transdermal therapeutic system according to any one of items 54 to 61, wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes characterized by a solution viscosity at 25°C and about 60% solids content in heptane of about 450 mPa s or of about 500 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

63. The transdermal therapeutic system according to any one of items 54 to 62,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes characterized by a complex viscosity at 0.01 rad/s at 30°C of less than about 1 x 10 ⁹ Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

64. The transdermal therapeutic system according to any one of items 54 to 63,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes characterized by a complex viscosity at 0.01 rad/s at 30°C of from about 1 x 10 ⁵ to about 9 x 10 ⁸ Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

65. The transdermal therapeutic system according to item 64,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes characterized by a complex viscosity at 0.01 rad/s at 30°C of 1 xlO ⁸ Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

66. The transdermal therapeutic system according to item 64,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on polysiloxanes characterized by a complex viscosity at 0.01 rad/s at 30°C of 5*l0 ⁶ Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8mm plates and the gap zeroed.

67. The transdermal therapeutic system according to any one of items 54 to 58,

wherein the at least one non-hybrid polymer is a non-hybrid pressure-sensitive adhesive based on acrylates.

68. The transdermal therapeutic system according to any one of items 54 to 58,

wherein the at least one non-hybrid polymer is an acrylate-based pressure-sensitive adhesive based on monomers selected from one or more of acrylic acid, butylacrylate,

2-ethylhexylacrylate, glycidylmethacryl ate, 2-hydroxyethylacrylate, methylacrylate,

methylmethacrylate, t-octylacrylamide and vinylacetate.

69. The transdermal therapeutic system according to any one of items 54 to 58,

wherein the at least one non-hybrid polymer is an acrylate-based pressure-sensitive adhesive based on monomers selected from two or more of acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2 -hydroxyethylacryl ate, methylacrylate, methylmethacrylate, t-octylacrylamide and vinylacetate.

70. The transdermal therapeutic system according to any one of items 67 to 69,

wherein the acrylate-based pressure-sensitive adhesive is a copolymer based on 2- ethylhexylacrylate, 2-hydroxyethylacrylate and vinylacetate.

71. The transdermal therapeutic system according to any one of items 67 to 70,

wherein the acrylate-based pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 39% solids content in ethyl acetate of from about 4000 mPa s to about

12000 mPa s, preferably as measured using a e.g. Brookfield SSA, viscometer equipped with a spindle number 27 at 20 RPM.

72. The transdermal therapeutic system according to any one of items 1 to 59,

wherein the transdermal therapeutic system further comprises at least one non-hybrid pressure- sensitive adhesive based on polysiloxanes characterized by a solution viscosity at 25 °C and about 60% solids content in n-heptane of from about 200 mPa s to about 700 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM, and wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about

1.200 mPa s to about 1,800 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

73. The transdermal therapeutic system according to any one of items 1 to 59,

wherein the transdermal therapeutic system further comprises at least one non-hybrid pressure- sensitive adhesive based on polysiloxanes characterized by a solution viscosity at 25°C and about 60% solids content in n-heptane of from about 200 mPa s to about 700 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM, and wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about

2.200 mPa s to about 2,800 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.

74. The transdermal therapeutic system according to any one of items 1 to 59,

wherein the transdermal therapeutic system further comprises at least one non-hybrid pressure- sensitive adhesive based on acrylates characterized by a solution viscosity at 25°C and about 39% solids content in ethyl acetate of from about 4000 mPa s to about 12000 mPa s, preferably as measured using a e.g. Brookfield SSA, viscometer equipped with a spindle number 27 at 20 RPM,

and wherein the at least one silicone acrylic hybrid pressure-sensitive adhesive is characterized by a solution viscosity at 25°C and about 50% solids content in ethyl acetate of from about 2,200 mPa s to about 2,800 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM. 75. The transdermal therapeutic system according to any one of items 1 to 74,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer and wherein the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in an amount ratio of from 0.1 :1 to 5:1.

76. The transdermal therapeutic system according to any one of items 1 to 75,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer and wherein the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in an amount ratio of from 0.5:1 to 2:1.

77. The transdermal therapeutic system according to any one of items 1 to 76,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer and wherein the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in different amounts by weight.

78. The transdermal therapeutic system according to any one of items 1 to 76,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer and wherein the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in the same amounts by weight.

79. The transdermal therapeutic system according to any one of items 1 to 76,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer and wherein the non-hybrid polymer(s) and the silicone acrylic hybrid polymer(s) are contained in the transdermal therapeutic system in an amount ratio of about 1:1.

80. The transdermal therapeutic system according to any one of items 1 to 79,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer and wherein the at least one silicone acrylic hybrid polymer and the at least one non-hybrid polymer are contained in the same layer of the buprenorphine-containing layer structure.

81. The transdermal therapeutic system according to any one of items 1 to 79,

wherein the transdermal therapeutic system further comprises at least one non-hybrid polymer and wherein the at least one silicone acrylic hybrid polymer and the at least one non-hybrid polymer are contained in different layers of the buprenorphine-containing layer structure.

82. The transdermal therapeutic system according to any one of items 1 to 81,

wherein the at least one silicone acrylic hybrid polymer is contained in the buprenorphine- containing layer such that the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine,

b) a carboxylic acid, and

c) at least one silicone acrylic hybrid polymer. 83. The transdermal therapeutic system according to item 82,

wherein the silicone acrylic hybrid polymer in the buprenorphine-containing layer contains a continuous, silicone external phase and a discontinuous, acrylic internal phase.

84. The transdermal therapeutic system according to item 82,

wherein the silicone acrylic hybrid polymer in the buprenorphine-containing layer contains a continuous, acrylic external phase and a discontinuous, silicone internal phase.

85. The transdermal therapeutic system according to item 1 or 84,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the therapeutically effective amount of buprenorphine and the carboxylic acid, and having an outer phase comprising the at least one silicone acrylic hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

86. The transdermal therapeutic system according to item 85,

wherein the dispersed deposits have a maximum sphere size of from 5 pm to 65 pm.

87. The transdermal therapeutic system according to any one of items 1 to 86,

wherein the therapeutically effective amount of buprenorphine is in solution in the carboxylic acid.

88. The transdermal therapeutic system according to any one of items 1 to 87,

wherein the buprenorphine-containing layer further comprises at least one non-hybrid polymer.

89. The transdermal therapeutic system according to any one of item 88,

wherein the at least one silicone acrylic hybrid polymer and the at least one non-hybrid polymer are contained in the buprenorphine-containing layer such that the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine,

b) a carboxylic acid,

c) at least one silicone acrylic hybrid polymer, and

d) at least one non-hybrid polymer.

90. The transdermal therapeutic system according to item 88 or 89,

wherein the buprenorphine-containing layer is a buprenorphine- containing biphasic matrix layer having an inner phase comprising the therapeutically effective amount of buprenorphine and the carboxylic acid, and having an outer phase comprising the at least one silicone acrylic hybrid polymer and the at least one non-hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

91. The transdermal therapeutic system according to any one of items 1 to 90,

wherein the buprenorphine-containing layer is a buprenorphine- containing pressure sensitive adhesive layer and represents the skin contact layer. 92. The transdermal therapeutic system according to any one of items 1 to 90, wherein the buprenorphine-containing layer structure is a buprenorphine- containing self- adhesive layer structure and does not comprise an additional skin contact layer.

93. The transdermal therapeutic system according to any one of items 1 to 92,

wherein the buprenorphine-containing layer contains the silicone acrylic hybrid polymer in an amount of from about 20% to about 90% by weight based on the buprenorphine-containing layer.

94. The transdermal therapeutic system according to any one of items 1 to 93,

wherein the buprenorphine-containing layer contains the silicone acrylic hybrid polymer in an amount of from about 30% to about 85% by weight based on the buprenorphine-containing layer.

95. The transdermal therapeutic system according to any one of items 1 to 94,

wherein the buprenorphine-containing layer contains the silicone acrylic hybrid polymer in an amount of from about 35% to about 85% by weight based on the buprenorphine-containing layer.

96. The transdermal therapeutic system according to any one of items 1 to 90,

wherein the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer.

97. The transdermal therapeutic system according to any one of items 1 to 90,

wherein the at least one silicone acrylic hybrid polymer is contained in the buprenorphine- containing layer such that the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine,

b) a carboxylic acid, and

c) at least one silicone acrylic hybrid polymer,

and wherein the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer.

98. The transdermal therapeutic system according to any one of items 1 to 88, wherein the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer, and wherein the at least one silicone acrylic hybrid polymer is contained in the skin contact layer and the buprenorphine-containing layer comprises a non hybrid polymer.

99. The transdermal therapeutic system according to any one of items 1 to 90, wherein the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer, and wherein the at least one silicone acrylic hybrid polymer is contained in both the buprenorphine-containing layer and the skin contact layer. 100. The transdermal therapeutic system according to item 99, wherein the at least one silicone acrylic hybrid polymer contained in the buprenorphine-containing layer is the same as the at least one silicone acrylic hybrid polymer contained in the skin contact layer.

101. The transdermal therapeutic system according to item 99, wherein the at least one silicone acrylic hybrid polymer contained in the buprenorphine-containing layer is different compared to the at least one silicone acrylic hybrid polymer contained in the skin contact layer.

102. The transdermal therapeutic system according to any one of items 98 to 101,

wherein the silicone acrylic hybrid polymer in the skin contact layer contains a continuous, silicone external phase and a discontinuous, acrylic internal phase.

103. The transdermal therapeutic system according to any one of items 98 to 101,

wherein the silicone acrylic hybrid polymer in the skin contact layer contains a continuous, acrylic external phase and a discontinuous, silicone internal phase.

104. The transdermal therapeutic system according to any one of items 98 to 103,

wherein the skin contact layer contains the silicone acrylic hybrid polymer in an amount of from about 20% to about 100% by weight based on the skin contact layer.

105. The transdermal therapeutic system according to any one of items 1 to 104,

wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.

106. The transdermal therapeutic system according to any one of items 98 to 103,

wherein the skin contact layer further comprises at least one non-hybrid polymer based on acrylates.

107. The transdermal therapeutic system according to any one of items 98 to 103,

wherein the skin contact layer further comprises at least one non-hybrid polymer based on polysiloxanes or polyisobutylenes.

108. The transdermal therapeutic system according to any one of items 1 to 88, wherein the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer which is free of silicone acrylic hybrid polymer.

109. The transdermal therapeutic system according to item 108,

wherein the skin contact layer comprises at least one non-hybrid pressure-sensitive adhesive based on acrylates.

110. The transdermal therapeutic system according to any one of items 108 or 109, wherein the skin contact layer comprises at least one non-hybrid pressure-sensitive adhesive based on polysiloxanes or polyisobutylenes.

111. The transdermal therapeutic system according to any one of items 96 to 110, wherein the additional skin contact layer comprises an active agent.

112. The transdermal therapeutic system according to any one of items 96 to 110, wherein the additional skin contact layer is free of active agent.

113. The transdermal therapeutic system according to any one of items 1 to 112,

wherein the area weight of the buprenorphine-containing layer ranges from 10 to 180 g/m ² .

114. The transdermal therapeutic system according to any one of items 1 to 113,

wherein the area weight of the buprenorphine-containing layer ranges from 60 to 160 g/m ² .

115. The transdermal therapeutic system according to any one of items 1 to 114,

wherein the area weight of the buprenorphine-containing layer ranges from more than 80 to 140 g/m ² .

116. The transdermal therapeutic system according to any one of items 1 to 115,

wherein the buprenorphine-containing layer structure further comprises C) a skin contact layer on the buprenorphine-containing layer having an area weight of from 5 to 50 g/m ² .

117. The transdermal therapeutic system according to item 116,

wherein the area weight of the skin contact layer ranges from 10 to 40 g/m ² .

118. The transdermal therapeutic system according to any one of items 116 or 117, wherein the area weight of the skin contact layer ranges from 10 to 30 g/m ² .

119. The transdermal therapeutic system according to any one of items 1 to 118,

wherein the buprenorphine-containing layer structure contains 0.3 mg/cm ² to 3.0 mg/cm ² buprenorphine based on the buprenorphine-containing layer.

120. The transdermal therapeutic system according to any one of items 1 to 119,

wherein the buprenorphine-containing layer structure contains 0.5 mg/cm ² to less than 1.2 mg/cm ² buprenorphine based on the buprenorphine-containing layer.

121. The transdermal therapeutic system according to any one of items 1 to 120,

wherein the buprenorphine-containing layer structure contains 0.5 mg/cm ² to less than 0.8 mg/cm ² buprenorphine based on the buprenorphine-containing layer. 122. The transdermal therapeutic system according to any one of items 1 to 121, wherein the buprenorphine-containing layer structure contains more than 0.6 mg/cm ² to

1.6 mg/cm ² buprenorphine based on the buprenorphine-containing layer.

123. The transdermal therapeutic system according to any one of items 1 to 122,

wherein the amount of buprenorphine contained in the transdermal therapeutic system ranges from

about 1 mg to about 4 mg buprenorphine, or

about 3.5 mg to about 8 mg buprenorphine, or

about 6.5 mg to about 16 mg buprenorphine, or

about 11.5 mg to about 24 mg buprenorphine, or

about 15 mg to about 32 mg buprenorphine.

124. The transdermal therapeutic system in accordance with any one of items 1 to 123, wherein the size of the buprenorphine-containing layer providing the area of release ranging from

about 1 cm ² to about 4.8 cm ² , or

about 3 cm ² to about 9.5 cm ² , or

about 6 cm ² to about 19 cm ² , or

about 12 cm ² to about 28.5 cm ² , or

about 16 cm ² to about 38 cm ² .

125. The transdermal therapeutic system according to any one of items 1 to 124,

wherein the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 1 mg to about 4 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranging from about 1 cm ² to about 4.8 cm ² .

126. The transdermal therapeutic system according to any one of items 1 to 124,

wherein the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 3.5 mg to about 8 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranging from about 3 cm ² to about 9.5 cm ² .

127. The transdermal therapeutic system according to any one of items 1 to 124,

wherein the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 6.5 mg to about 16 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranging from about 6 cm ² to about 19 cm ² .

128. The transdermal therapeutic system according to any one of items 1 to 124,

wherein the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 11.5 mg to about 24 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranging from about 12 cm ² to about 28.5 cm ² . 129. The transdermal therapeutic system according to any one of items 1 to 124, wherein the amount of buprenorphine contained in the transdermal therapeutic system ranges from about 15 mg to about 32 mg buprenorphine and the size of the buprenorphine-containing layer providing the area of release ranging from about 16 cm ² to about 38 cm ² .

130. The transdermal therapeutic system according to any one of items 1 to 129,

wherein the buprenorphine-containing layer further comprises a viscosity-increasing substance.

131. The transdermal therapeutic system according to item 130,

wherein the viscosity-increasing substance is contained in an amount of from about 0.1% to about 8%, preferably from 1% to 6%, by weight based on the buprenorphine-containing layer.

132. The transdermal therapeutic system according to any one of items 130 or 131,

wherein said viscosity-increasing substance is selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose,

hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, high molecular mass polyacrylic acids and/or their salts and/or their derivatives such as esters, polyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate, tragacanth, xanthan gum, bentonite, carageenan and guar gum, and mixtures thereof.

133. The transdermal therapeutic system according to any one of items 130 to 132,

wherein the viscosity-increasing substance is polyvinylpyrrolidone.

134. The transdermal therapeutic system according to any one of items 130 to 133,

wherein the viscosity-increasing substance is a soluble polyvinylpyrrolidone having a K- Value of 90.

135. The transdermal therapeutic system according to any one of items 1 to 134,

wherein the at least one silicone acrylic hybrid polymer is contained in the buprenorphine- containing layer and wherein the buprenorphine- containing layer further comprises a polyvinylpyrrolidone in an amount of 0.1% to about 8% by weight based on the buprenorphine- containing layer such that the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine,

b) a carboxylic acid,

c) at least one silicone acrylic hybrid polymer, and

d) a polyvinylpyrrolidone in an amount of 0.1 % to about 8% by weight based on the buprenorphine-containing layer.

136. The transdermal therapeutic system according to item 135,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine, the carboxylic acid and the polyvinylpyrrolidone, and having an outer phase comprising the silicone acrylic hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

137. The transdermal therapeutic system according to any one of items 1 to 136,

wherein the at least one silicone acrylic hybrid polymer is contained in the buprenorphine- containing layer, wherein the buprenorphine-containing layer further comprises at least one non- hybrid polymer and a polyvinylpyrrolidone in an amount of 0.1 % to about 8% by weight based on the buprenorphine-containing layer such that the buprenorphine-containing layer comprises a) a therapeutically effective amount of buprenorphine,

b) a carboxylic acid,

c) at least one silicone acrylic hybrid polymer,

d) at least one non-hybrid polymer, and

e) a polyvinylpyrrolidone in an amount of 0.1% to about 8% by weight based on the buprenorphine-containing layer.

138. The transdermal therapeutic system according to item 137,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine, the carboxylic acid, and the

polyvinylpyrrolidone and having an outer phase comprising the silicone acrylic hybrid polymer and the non-hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

139. The transdermal therapeutic system according to any one of items 1 to 129,

wherein no viscosity-increasing substance is contained.

140. The transdermal therapeutic system according to any one of items 1 to 129,

wherein the buprenorphine-containing layer is free of a viscosity-increasing substance selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,

carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, high molecular mass polyacrylic acids and/or their salts and/or their derivatives such as esters, polyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate, tragacanth, xanthan gum, bentonite, carageenan and guar gum, and mixtures thereof.

141. The transdermal therapeutic system according to any one of items 1 to 140,

wherein the tack of the buprenorphine-containing layer structure is from 0.6 N to 8.0 N preferably determined in accordance with the Standard Test Method for Pressure-Sensitive Tack of Adhesives Using an Inverted Probe Machine (ASTM D 2979 - 01; Reapproved 2009), wherein the transdermal therapeutic system samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity) prior to testing. 142. The transdermal therapeutic system according to any one of items 1 to 141, wherein the tack of the buprenorphine-containing layer structure is from more than 0.8 N to

8.0 N preferabyl determined in accordance with the Standard Test Method for Pressure- S ensitive Tack of Adhesives Using an Inverted Probe Machine (ASTM D 2979 - 01 ; Reapproved 2009), wherein the transdermal therapeutic system samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity) prior to testing.

143. The transdermal therapeutic system according to any one of items 1 to 142,

wherein the tack of the buprenorphine-containing layer structure is from 1.2 N to 6.0 N, preferably determined in accordance with the Standard Test Method for Pressure- S ensitive Tack of Adhesives Using an Inverted Probe Machine (ASTM D 2979 - 01; Reapproved 2009), wherein the transdermal therapeutic system samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity) prior to testing.

144. The transdermal therapeutic system according to any one of items 1 to 143,

wherein the adhesion force of the buprenorphine-containing layer structure is from about

2 N/25mm to about 16 N/25mm, preferably determined using a tensile strength testing machine with an aluminium testing plate and a pull angle of 90°, wherein the transdermal therapeutic system samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity) prior to testing and are cut into pieces with a fixed width of 25mm.

145. The transdermal therapeutic system according to any one of items 1 to 144,

wherein the adhesion force of the buprenorphine-containing layer structure is from about

3.5 N/25mm to about 15 N/25mm, preferably determined using a tensile strength testing machine with an aluminium testing plate and a pull angle of 90°, wherein the transdermal therapeutic system samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity) prior to testing and are cut into pieces with a fixed width of 25mm.

146. The transdermal therapeutic system according to any one of items 1 to 145,

wherein the adhesion force of the buprenorphine-containing layer structure is from about

4 N/25mm to about 15 N/25mm, preferably determined using a tensile strength testing machine with an aluminium testing plate and a pull angle of 90°, wherein the transdermal therapeutic system samples were equilibrated 24 hours under controlled conditions at approx room temperature (23 ± 2°C) and approx. 50% rh (relative humidity) prior to testing and are cut into pieces with a fixed width of 25mm. 147. The transdermal therapeutic system according to any one of items 1 to 146, providing a skin permeation rate of buprenorphine when measured in a comparable test with a commercial buprenorphine reference transdermal therapeutic system in a 36-hour time interval from hour 48 to hour 84 that is therapeutically effective, and/or providing a skin permeation rate of buprenorphine when measured in a comparable test with a commercial buprenorphine reference transdermal therapeutic system in a 72-hour time interval from hour 96 to hour 168 that is therapeutically effective.

148. The transdermal therapeutic system according to any one of items 1 to 147,

providing a skin permeation rate of buprenorphine when measured in a comparable test with a commercial buprenorphine reference transdermal therapeutic system in a 96-hour time interval from hour 72 to hour 168 that is therapeutically effective.

149. The transdermal therapeutic system according to any one of items 1 to 148,

providing a skin permeation rate of buprenorphine when measured in a comparable test with a commercial buprenorphine reference transdermal therapeutic system in a 120-hour time interval from hour 48 to hour 168 that is therapeutically effective.

150. The transdermal therapeutic system according to any one of items 1 to 149,

for use in a method of treatment, preferably for use in a method of treating pain.

151. The transdermal therapeutic system according to any one of items 1 to 149,

for use in a method of treating pain wherein the transdermal therapeutic system is applied to the skin of a patient for more than 3 days, for 3.5 days, or for 4 days.

152. The transdermal therapeutic system according to any one of items 1 to 149,

for use in a method of treating pain wherein the transdermal therapeutic system is applied to the skin of a patient for 5 days or for 6 days.

153. The transdermal therapeutic system according to any one of items 1 to 149,

for use in a method of treating pain wherein the transdermal therapeutic system is applied to the skin of a patient for 7 days.

154. Use of a transdermal therapeutic system according to any one of items 1 to 149, for the manufacture of a medicament for treating pain.

155. Use of a transdermal therapeutic system according to any one of items 1 to 149, for the manufacture of a medicament for treating pain that is applied to the skin of a patient for more than 3 days, for 3.5 days, or for 4 days. 156. Use of a transdermal therapeutic system according to any one of items 1 to 149, for the manufacture of a medicament for treating pain that is applied to the skin of a patient for 5 days or for 6 days.

157. Use of a transdermal therapeutic system according to any one of items 1 to 149, for the manufacture of a medicament for treating pain that is applied to the skin of a patient for 7 days.

158. A method of tretament, preferably of treating pain by applying to the skin of a patient a transdermal therapeutic system according to any one of items 1 to 149.

159. A method of treating pain by applying to the skin of a patient a transdermal therapeutic system according to any one of items 1 to 149 for more than 3 days, for 3.5 days, or for 4 days.

160. A method of treating pain by applying to the skin of a patient a transdermal therapeutic system according to any one of items 1 to 149 for 5 days or for 6 days.

161. A method of treating pain by applying to the skin of a patient a transdermal therapeutic system according to any one of items 1 to 149 for 7 days.

162. A method of manufacture of a transdermal therapeutic system according to any one of items 1 to 149 comprising the steps of:

1) providing a buprenorphine-containing coating composition comprising

a) buprenorphine,

b) carboxylic acid, and

c) solvent,

2) coating the buprenorphine-containing coating composition onto a release liner in an amount to provide the desired area weight,

3) drying the coated buprenorphine-containing coating composition to provide the buprenorphine-containing layer,

4) laminating the buprenorphine-containing layer to a backing layer to provide a

buprenorphine-containing layer structure,

5) optionally providing an additional skin contact layer by coating and drying an active agent-free coating composition according to steps 2 and 3, removing the release liner of the buprenorphine-containing layer and laminating the additional skin contact layer onto the buprenorphine-containing layer to provide a buprenorphine-containing layer structure,

6) punching the individual systems from the buprenorphine-containing layer structure,

7) optionally adhering to the individual systems an active-free self-adhesive layer

structure comprising also a backing layer and an active agent-free pressure- sensitive adhesive layer and which is larger than the individual systems of buprenorphine- containing self-adhesive layer structure, wherein at least one silicone acrylic hybrid polymer composition is added to the buprenorphine- containing coating composition in step 1 , or, if an additional skin contact layer is provided, to the active agent-free coating composition in step 5, or to both the buprenorphine-containing coating composition in step 1 and to the active agent- free coating composition in step 5.

163. The method of manufacture according to item 162,

wherein the at least one silicone acrylic hybrid polymer composition is a silicone acrylic hybrid pressure-sensitive adhesive in ethyl acetate or n-heptane.

164. The method of manufacture in accordance with items 162 or 163, wherein in step 1 buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane to provide the buprenorphine-containing coating composition.

165. The method of manufacture in accordance with items 162 or 163, wherein in step 1 buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with the silicone acrylic hybrid pressure-sensitive adhesive in ethyl acetate to provide the buprenorphine-containing coating composition.

166. The method of manufacture in accordance with items 162 to 165, wherein in step 1 a non- hybrid pressure-sensitive adhesive based on polysiloxanes in n-heptane is added.

167. The method of manufacture in accordance with items 162 to 165, wherein in step 1 a non hybrid pressure-sensitive adhesive based on polysiloxanes in ethyl acetate is added.

168. The method of manufacture in accordance with items 162 and 167, wherein in step 1 buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with a non-hybrid pressure- sensitive adhesive based on polysiloxanes in n-heptane or ethyl acetate to provide the

buprenorphine-containing coating composition, and in step 5, the additional skin contact layer is provided by coating and drying the active agent-free coating composition comprising the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane.

169. The method of manufacture in accordance with items 162 and 167, wherein in step 1 buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with a non-hybrid pressure- sensitive adhesive based on polysiloxanes in n-heptane or ethyl acetate to provide the

buprenorphine-containing coating composition, and in step 5, the additional skin contact layer is provided by coating and drying the active agent-free coating composition comprising the silicone acrylic hybrid pressure-sensitive adhesive in ethyl acetate. 170. The method of manufacture in accordance with items 162 and 167, wherein in step 1 buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane or ethyl acetate to provide the buprenorphine-containing coating composition, and in step 5, the additional skin contact layer is provided by coating and drying the active agent-free coating composition comprising the silicone acrylic hybrid pressure- sensitive adhesive in n-heptane.

171. The method of manufacture in accordance with items 162 and 167, wherein in step 1 buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid which are suspended in ethanol and subsequently combined with the silicone acrylic hybrid pressure-sensitive adhesive in n-heptane or ethyl acetate to provide the buprenorphine-containing coating composition, and in step 5, the additional skin contact layer is provided by coating and drying the active agent-free coating composition comprising the silicone acrylic hybrid pressure- sensitive adhesive in ethyl acetate.

172. A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure,

the buprenorphine-containing layer structure comprising:

A) a backing layer; and

B) a buprenorphine-containing layer;

wherein the buprenorphine-containing layer comprises

a) buprenorphine in an amount of from 3 to 15% by weight based on the

buprenorphine-containing layer,

b) levulinic acid in an amount of from 3 to 15% by weight based on the

buprenorphine-containing layer, and

c) a silicone acrylic hybrid pressure-sensitive adhesive containing a continuous, acrylic external phase and a discontinuous, silicone internal phase in an amount of from about 30% to about 85% by weight based on the buprenorphine-containing layer,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the silicone acrylic hybrid pressure-sensitive adhesive, wherein the inner phase forms dispersed deposits in the outer phase.

173. A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure,

the buprenorphine-containing layer structure comprising:

A) a backing layer; and

B) a buprenorphine-containing layer;

wherein the buprenorphine-containing layer comprises

a) a therapeutically amount of buprenorphine,

b) levulinic acid, c) a silicone acrylic hybrid pressure-sensitive adhesive, and

d) a non-hybrid pressure-sensitive adhesive based on polysiloxanes,

wherein the non-hybrid polymer and the silicone acrylic hybrid polymer are contained in the buprenorphine-containing layer in an amount ratio of from 0.5:1 to 2:1, and

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the silicone acrylic hybrid polymer and the non-hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

174. A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure,

the buprenorphine-containing layer structure comprising:

A) a backing layer; and

B) a buprenorphine-containing layer;

wherein the buprenorphine-containing layer comprises

a) a therapeutically amount of buprenorphine,

b) levulinic acid,

c) a silicone acrylic hybrid pressure-sensitive adhesive,

d) a non-hybrid pressure-sensitive adhesive, and

e) a soluble polyvinylpyrrolidone,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine, the levulinic acid, and the soluble polyvinylpyrrolidone, and having an outer phase comprising the silicone acrylic hybrid polymer and the non-hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

175. The transdermal therapeutic systems according to any one of items 172 to 174, wherein the buprenorphine-containing biphasic matrix layer is the skin contact layer.

176. A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure,

the buprenorphine-containing layer structure comprising:

A) a backing layer;

B) a buprenorphine-containing layer;

wherein the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine,

b) levulinic acid, and

c) a non-hybrid pressure-sensitive adhesive, preferably a non-hybrid pressure- sensitive adhesive based on polysiloxanes or acrylates; and

C) a skin contact layer on the buprenorphine-containing layer comprising at least one silicone acrylic hybrid pressure-sensitive adhesive,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the non-hybrid pressure-sensitive adhesive, wherein the inner phase forms dispersed deposits in the outer phase.

177. A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure,

the buprenorphine-containing layer structure comprising:

A) a backing layer;

B) a buprenorphine-containing layer;

wherein the buprenorphine-containing layer comprises

a) a therapeutically effective amount of buprenorphine,

b) levulinic acid, and

c) at least one silicone acrylic hybrid polymer; and

C) a skin contact layer on the buprenorphine-containing layer comprising at least one non-hybrid pressure-sensitive adhesive, preferably a non-hybrid pressure-sensitive adhesive based on polysiloxanes or acrylates,

wherein the buprenorphine-containing layer is a buprenorphine- containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the at least one silicone acrylic hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.

178. A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing layer structure,

the buprenorphine-containing layer structure comprising:

A) a backing layer;

B) a buprenorphine-containing biphasic matrix layer;

wherein the buprenorphine-containing biphasic matrix layer comprises

a) a therapeutically effective amount of buprenorphine,

b) levulinic acid, and

c) at least one silicone acrylic hybrid polymer; and

C) a skin contact layer on the buprenorphine-containing biphasic matrix layer comprising at least one silicone acrylic hybrid pressure-sensitive adhesive,

wherein the buprenorphine-containing layer is a buprenorphine-containing biphasic matrix layer having an inner phase comprising the buprenorphine and the levulinic acid, and having an outer phase comprising the at least one silicone acrylic hybrid polymer, wherein the inner phase forms dispersed deposits in the outer phase.