Patent Application
20220241216
The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of an active agent to the systemic circulation, wherein the TTS comprises an active agent-containing layer comprising an acrylic polymer and a skin contact layer comprising a silicone gel adhesive, and an intermediate layer between the active agent-containing layer and the skin contact layer. Further, the present invention relates to processes of manufacture, methods of treatment and uses of the TTS.
It is known in the art that transdermal therapeutic systems (TTS) may cause skin irritation depending on the adhesive layer.
Silicone gel adhesives (SGA) have been described in WO 2011/022199 A2 to address this problem by using an active-free skin contact layer based on silicone gel adhesives on top of an active agent-containing layer, so as to obtain a system with two different adhesive layers. Furthermore, WO 2014/028049 A1 describes a system comprising a backing substrate, an active-containing layer, a support substrate, and an active-free skin contact layer based on a silicone gel adhesive.
However, it has been found that the systems described in the art have disadvantages either in view of an instable connection between the different adhesive layers or between the adhesive layers and the support substrate.
For example, it has been found that if the commercially available rivastigmine-containing TTS Exelon®, which comprises a rivastigmine-containing layer based on acrylate polymers, and a skin contact layer based on silicone polymers, is modified by using a skin contact layer based on silicone gel adhesives, problems arise from the instable connection between the rivastigmine-containing layer and the skin contact layer. In particular, it has been found that the TTS can be damaged upon removal of the release liner.
It is therefore desirable to provide a TTS for the transdermal delivery of an active agent, which overcomes the problem of skin irritation, but nevertheless has advantageous properties regarding the stability as well as the release of the active agent and the adhesiveness.
It is an object of the present invention to provide a TTS for the transdermal administration of an active agent, which is improved in comparison to the systems described in the prior art.
It is a further object of the present invention to provide a TTS for the transdermal administration of an active agent, which reduces the problem of skin irritation.
It is a further object of the present invention to provide a TTS for the transdermal administration of an active agent, which has a high mechanical stability. In particular, it is an object of the present invention that the layers of the TTS stick together also upon removal of the release liner, so that a damage of the TTS can be avoided.
It is a further object of the present invention to provide a TTS for the transdermal administration of an active agent, which avoids a complex structure.
It is a further object of the present invention to provide a TTS for the transdermal administration of an active agent, which provides suitable drug delivery properties and plasma concentrations of the active agent to be therapeutically effective.
It is a further object of the present invention to provide a TTS for the transdermal administration of an active agent, which has the required adhesive properties for administration for at least 24 hours.
It is a further object of the present invention to provide a TTS for the transdermal administration of an active agent, which can be used in a method of treatment.
It has surprisingly been found that at least one of these objects and others are accomplished by the present invention, which according to one aspect relates to a TTS for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing layer comprising at least one acrylic polymer;
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
In a preferred embodiment, the active agent is rivastigmine.
It has surprisingly been found that the TTS according to the present invention, which comprises a silicone gel adhesive based skin contact layer, which is attached to an active agent-containing layer via an intermediate layer has advantageous properties regarding reduced skin irritation, but at the same time has a high stability regarding a potential damage upon removal of a release liner from the system. In particular, it has been found that the intermediate layer provides a strong connection to the active agent-containing layer as well as to the skin contact layer, without negatively affecting the release properties of the TTS.
In a preferred embodiment, the intermediate layer is a membrane or a pressure-sensitive adhesive layer comprising a silicone-based polymer. Particularly preferably, the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer.
In another preferred embodiment, the active agent-containing layer is an active agent-containing matrix layer. Preferably, the active agent is present in an amount of from 5 to 40% by weight, and the acrylic polymer is present in an amount of from 30 to 90% by weight, in each case based on the total weight of the active agent-containing matrix layer.
In another preferred embodiment, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
According to one specific aspect, the present invention therefore relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing layer comprising at least one acrylic polymer;
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive; and wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
In a preferred embodiment, the active agent is rivastigmine.
According to another specific aspect, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing matrix layer comprising an active agent in an amount of from 5 to 40% by weight, and at least one acrylic polymer in an amount of from 30 to 90% by weight in each case based on the total weight of the active agent-containing matrix layer; and
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive;
and wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
In a preferred embodiment, the active agent containing matrix layer has an area weight of from 30 to 200 g/m2, the intermediate layer has an area weight of from 20 to 80 g/m2, and the skin contact layer has an area weight of from 20 to 120 g/m2.
In a more preferred embodiment, the active agent containing matrix layer has an area weight of from 40 to 120 g/m2, the intermediate layer has an area weight of from 20 to 60 g/m2, and the skin contact layer has an area weight of from 30 to 90 g/m2.
In another preferred embodiment, the active agent-containing matrix layer comprises tocopherol in an amount of from 0.01 to 1.0% by weight.
In another preferred embodiment, the active agent is rivastigmine.
In a further aspect, the present invention relates to a TTS as described herein for use in a method of treatment, wherein the transdermal therapeutic system is preferably applied to the skin of the patient for at least 24 hours.
In yet a further aspect, the present invention relates to a process for manufacturing an active agent-containing containing layer structure for use in a transdermal therapeutic system according to the present invention comprising the steps of:
It is to be understood that steps 1.1) to 1.4) are for the preparation of the active agent-containing layer and connecting the same with the intermediate layer, while steps 2.1) to 2.3) are for the preparation of the skin contact layer, and while steps 3.1) to 3.2) are for the preparation of the active agent-containing layer structure comprising the layers prepared before. It is to be understood that the preparation of the active agent-containing layer and the preparation of the skin contact layer may be performed in any order, i.e. the skin contact layer may be prepared before the active agent-containing layer is prepared or vice versa. Furthermore, the preparation of the active agent-containing layer and the preparation of the skin contact layer may also be performed simultaneously. Once the two layers have been prepared and the active agent-containing layer has been laminated with the intermediate layer, steps 3.1) and 3.2) will be performed.
Within the meaning of this invention, the term “transdermal therapeutic system” (TTS) refers to a system by which the active agent (e.g. rivastigmine) 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).
Within the meaning of this invention, the term “active agent-containing layer structure” refers to the layer structure comprising a backing layer, an active agent-containing layer, an intermediate layer, and a skin contact layer as described herein. The active agent-containing layer structure comprises a therapeutically effective amount of an active agent. Preferably, the active agent-containing layer structure is an active agent-containing self-adhesive layer structure.
Within the meaning of this invention, the term “therapeutically effective amount” refers to a quantity of active agent in the TTS sufficient to provide, if administered by the TTS to a patient, the desired pharmacological effect. 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.
Within the meaning of this invention, the terms “active”, “active agent”, and the like, as well as the term “rivastigmine” refers to the respective active agent in any pharmaceutically acceptable chemical and morphological form and physical state. These forms include without limitation the active agent in its free base/free acid form, protonated or partially protonated form, deprotonated or partially deprotonated form, salts, cocrystals and in particular acid/base addition salts formed by addition of an inorganic or organic acid/base such as hydrochloride or tartrate salts, solvates, hydrates, clathrates, complexes and so on, as well as the active agent in the form of particles, which may be micronized, crystalline and/or amorphous, and any mixtures of the aforementioned forms. The active agent, where contained in a medium such as a solvent, may be dissolved or dispersed or in part dissolved and in part dispersed.
When the active agent is mentioned to be used in a particular form in the manufacture of the TTS, this does not exclude interactions between this form of the active agent and other ingredients of the active agent-containing layer structure, e.g. salt formation or complexation, in the final TTS. This means that, even if the active agent is included in its free base/acid form, it may be present in the final TTS in protonated or partially protonated/or deprotonated or partially deprotonated 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 the active agent in the layer structure relates to the amount of the active agent included in the TTS during manufacture of the TTS and is calculated based on the active agent itself, but not on other forms thereof. E.g., when a) 0.1 mmol (equal to 25.03 mg) rivastigmine base orb) 0.1 mmol (equal to 40.04 mg) rivastigmine tartrate is included in the TTS during manufacture, the amount of rivastigmine in the layer structure, within the meaning of the invention, is in both cases 0.1 mmol or 25.03 mg.
The active agent starting material included in the TTS during manufacture of the TTS may be in the form of particles. The active agent may e.g. be present in the active agent-containing layer structure in the form of particles and/or dissolved.
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.
Within the meaning of this invention, the term “dispersing” refers to a step or a combination of steps wherein a starting material (e.g. rivastigmine) is not totally dissolved. Dispersing in the sense of the invention comprises the dissolution of a part of the starting material (e.g. rivastigmine particles), depending on the solubility of the starting material (e.g. the solubility of rivastigmine in the coating composition).
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.
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. It is to be understood that a TTS comprising an active agent-containing matrix layer may additionally also comprise a skin contact layer.
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 are 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.
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 form 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 droplets 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 microreservoirs 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 microreservoirs can be determined.
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. According to the present invention, an additional skin contact layer is present as adhesive layer. Furthermore, an intermediate layer is present between the skin contact layer and the active agent-containing layer. Moreover, an adhesive overlay may be present. The 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 an equilibrium is reached. 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, a skin contact layer is present, in order to provide adhesive properties. The skin contact layer is typically manufactured such that it is active agent-free. If the 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 an equilibrium is reached. Additionally, an adhesive overlay may be provided.
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. Preferably, the matrix layer is a pressure sensitive adhesive matrix layer. Optionally, an adhesive overlay may be present.
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 according to the present invention includes a pressure sensitive adhesive layer for skin contact which is provided in the form of an additional layer, i.e. a pressure sensitive adhesive skin contact layer. The pressure-sensitive adhesive properties of a pressure-sensitive adhesive depend on the polymer or polymer composition used.
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). A preferred non-hybrid polymer according to the present invention is a “silicone-based polymer”, which, as used herein, is a polymer obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. Another preferred non-hybrid polymer is an acrylate-based polymer, i.e. an acrylic polymer, which, as used herein, is a polymer obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate.
Within the meaning of this invention, the term “silicone gel adhesive” refers to an elastic, jelly-like material formed by lightly crosslinking silicone polymers. It may be prepared from a gel producing composition as described further below upon curing. In particular, the silicone gel adhesive preferably forms upon curing of polysiloxanes comprising reactive groups such as Si—H reactive groups and aliphatic unsaturated groups, which react with each other in the presence of a hydrosilylation catalyst. Thus, the silicone gel adhesive is obtained from a curable gel producing composition, while the silicone-containing polymers according to the present invention are preferably non-curing polymers. Accordingly, the silicone gel adhesive is typically applied by using a curable gel producing composition, which solidifies upon curing.
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. an acrylic polymer). 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.
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. When the TTS comprises a 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 the skin contact layer and the active agent-containing layer are usually coextensive and correspond to the area of release. However, the area of the 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.
Within the meaning of this invention, the term “intermediate layer” refers to a membrane or a polymer layer, which is provided between the active agent-containing layer and the skin contact layer to improve the stability of the TTS. In one embodiment, the intermediate layer is a membrane, which is at least semipermeable for the active agent. Preferred membranes are selected from the group consisting of polyethylene membranes, polyurethane coated polyethylene terephthalate/polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate (EVA) membranes. In another embodiment, the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer. Preferably, the silicone-based polymer is obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. More preferably, the residual silanol functionality of the silicone-based polymer is capped with trimethylsiloxy groups. The sizes of the intermediate layer and the active agent-containing layer are usually coextensive and correspond to the area of release. However, the area of the intermediate 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.
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/m2. The area weight values are subject to a tolerance of ±10%, preferably ±7.5%, due to manufacturing variability.
If not indicated otherwise “%” refers to weight-% (% by weight).
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.
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.
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.
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.
The TTS according to the present invention can be characterized by certain parameters as measured in an in vitro skin permeation test.
In general, the in vitro permeation test is performed in a Franz diffusion cell, with EVA membrane (e.g. 9% vinyl acetate and 50 μm thickness, preferably provided by 3M), and with phosphate buffer pH 5.5 or 7.4 as receptor medium (32° C. with 0.1% saline azide).
Further, in vitro permeation test may be performed in a Franz diffusion cell, with human or animal skin and preferably with dermatomed split-thickness human skin with a thickness of 800 μm and an intact epidermis, and with phosphate buffer pH 5.5 or 7.4 as receptor medium (32° C. with 0.1% saline azide) with or without addition of a maximum of 40 vol-% organic solvent e.g. ethanol, acetonitrile, isopropanol, dipropylenglycol, PEG 400 so that a receptor medium may e.g. contain 60 vol-% phosphate buffer pH 5.5, 30 vol-% dipropylenglycol and 10 vol-% acetonitrile.
Where not otherwise indicated, the in vitro permeation test is performed with EVA membrane (9% vinyl acetate, 50 μm), 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 (column: stainless steel column 150 mm×4.6 mm internal diameter with C18 base and acid deactivated stationary phase, 3.5 μm particle size, e.g. Zorbax SB C18 (Agilent); column temperature: 25° C.; mobile phase: acetonitrile/water/TEA=20:80:0.35 (v/v/v) pH 3.5; flow rate: 1.0 ml/min; pressure: 135 bar; injection volume: 50 μL; stop time: 8 min) 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.
Thus, within the meaning of this invention, the parameter “permeated amount” is provided in μg/cm2 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, 2, 4, 8, 12 and 24, the “permeated amount” of active can be given e.g. for the sample interval from hour 8 to hour 12 and corresponds to the measurement at hour 12, wherein the receptor medium has been exchanged completely at hour 8.
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, 2, 4, 8, 12 and 24, the “cumulative permeated amount” of active at hour 12 corresponds to the sum of the permeated amounts from hour 0 to hour 2, hour 2 to hour 4, hour 4 to hour 8 and hour 8 to hour 12.
Within the meaning of this invention, the parameter “skin permeation rate” for a certain sample interval at certain elapsed time is provided in μg/(cm2*h) and is calculated from the permeated amount in said sample interval as measured by in vitro permeation test as described above in μg/cm2, 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, 2, 4, 8, 12 and 24, the “skin permeation rate” at hour 12 is calculated as the permeated amount in the sample interval from hour 8 to hour 12 divided by 4 hours.
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, 2, 4, 8, 12 and 24, the “cumulative skin permeation rate” at hour 12 is calculated as the cumulative permeated amount for hour 12 (see above) divided by 12 hours.
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, {x1, x2, . . . xn} are the observed values and
The TTS according to the present invention can also be characterized by certain parameters as measured in an in vivo clinical study.
Within the meaning of this invention, the parameter “mean release rate” refers to the mean release rate in μg/h (μg/hour) or in mg/day over the period of administration (e.g., 1 to 7 days) by which the active agent is released through the human skin into the systemic circulation and is based on the AUC obtained over said period of administration in a clinical study.
Within the meaning of this invention, the term “extended period of time” relates to a period of at least or about 24 hours, at least or about 48 hours, at least or about 84 hours, at least or about 168 hours, at least or about 1 day, at least or about 3.5 days, or at least or about 7 days, or to a period of about 24 hours to about 168 hours or 1 to 7 day(s), or about 24 hours to about 84 hours or 1 to 3.5 day(s).
For a continuous drug treatment, the frequency of drug administration is preferably kept sufficiently high so as to maintain therapeutically effective blood plasma concentration. In other words, the interval between two dosage form administrations, also called dosing interval, needs to be adapted accordingly. Within the meaning of the present invention, the term “dosing interval” refers to the period of time between two consecutive TTS administrations, i.e. the interval between two consecutive points in time a TTS is applied to the skin of the patient. Once applied, the TTS is usually maintained on the skin of the patient for the entire dosing interval and only removed at the end of the dosing interval, at which time a new TTS is applied to the skin. E.g., if the dosing interval is 24 hours or 1 day, the TTS is applied to and maintained on the skin of the patient for 24 hours or 1 day. After 24 hours or 1 day, the TTS is removed from the skin and a new TTS is applied. Thus, a dosing interval of 24 hours or 1 day allows a daily TTS exchange mode in an around-the-clock treatment.
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.
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.
Within the meaning of this invention the term “pharmacokinetic parameters” refers to parameters describing the blood plasma curve, e.g. Cmax, Ct and AUCt1-t2 obtained in a clinical study, e.g. by single-dose, multi-dose or steady state administration of the active agent-containing TTS, e.g. the rivastigmine-containing TTS to healthy human subjects. The pharmacokinetic parameters of the individual subjects are summarized using arithmetic and geometric means, e.g. a mean Cmax, a mean AUCt and a mean AUCINF, and additional statistics such as the respective standard deviations and standard errors, the minimum value, the maximum value, and the middle value when the list of values is ranked (Median). In the context of the present invention, pharmacokinetic parameters, e.g. the Cmax, Ct and AUCt1-t2 refer to geometric mean values if not indicated otherwise. It cannot be precluded that the absolute mean values obtained for a certain TTS in a clinical study vary to a certain extent from study to study. To allow a comparison of absolute mean values between studies, a reference formulation, e.g. in the future any product based on the invention, may be used as internal standard. A comparison of the AUC per area of release of the respective reference product in the earlier and later study can be used to obtain a correction factor to take into account differences from study to study.
Clinical studies according to the present invention refer to studies performed in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.
Within the meaning of this invention, the term “healthy human subject” refers to a male or female subject with a body weight ranging from 55 kg to 100 kg and a body mass index (BMI) ranging from 18 to 29.4 and normal physiological parameters, such as blood pressure, etc. Healthy human subjects for the purposes of the present invention are selected according to inclusion and exclusion criteria which are based on and in accordance with recommendations of the ICH.
Within the meaning of this invention, the term “subject population” refers to at least five, preferably at least ten individual healthy human subjects.
Within the meaning of this invention, the term “geometric mean” refers to the mean of the log transformed data back-transformed to the original scale.
Within the meaning of this invention, the term “arithmetic mean” refers to the sum of all values of observation divided by the total number of observations.
Within the meaning of this invention, the parameter “AUC” corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the amount of active agent absorbed into the blood circulation in total and is hence a measure for the bioavailability.
Within the meaning of this invention, the parameter “AUCt1-t2” is provided in (ng/ml) h and relates to the area under the plasma concentration-time curve from hour t1 to t2 and is calculated by the linear trapezoidal method, unless otherwise indicated. Other calculation methods are e.g. the logarithmic and linear log trapezoidal method.
Within the meaning of this invention, the parameter “Cmax” is provided in (ng/ml) and relates to the maximum observed blood plasma concentration of the active agent.
Within the meaning of this invention, the parameter “Ct” is provided in (ng/ml) and relates to the blood plasma concentration of the active agent observed at hour t.
Within the meaning of this invention, the parameter “tmax” is provided in hours and relates to the time point at which the Cmax value is reached. In other words, tmax is the time point of the maximum observed plasma concentration.
Within the meaning of this invention, the term “mean plasma concentration” is provided in (ng/ml) and is a mean of the individual plasma concentrations of active agent, e.g. rivastigmine, at each point in time.
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.
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).
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.
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.
The present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing layer comprising at least one acrylic polymer;
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
Preferably, the aforementioned layers of the TTS according to the invention are directly attached to each other, i.e. the backing layer is directly attached to the active agent-containing layer, which is on the other side directly attached to the intermediate layer. Further, the other side of the intermediate layer is directly attached to the skin contact layer. In other words, the TTS according to the present invention comprises its layers in the following order: (i) backing layer, (ii) active agent-containing layer, (iii) intermediate layer, and (iv) skin contact layer. Further, a release liner may optionally be present on the skin contact layer.
The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS. Thus, the active agent-containing layer may preferably be a matrix layer or a reservoir layer. Preferably, the TTS according to the present invention is a matrix-type TTS, wherein the active agent is homogeneously dissolved and/or dispersed within a polymeric carrier, i.e. the matrix, which forms the together with the active agent and optionally further ingredients a matrix layer. Accordingly, it is preferred that the active agent-containing layer is an active agent-containing matrix layer. Thus, in a preferred embodiment of the TTS according to the present invention, the active agent-containing layer is an active agent-containing matrix layer comprising
Thus, in a preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising
A) a backing layer;
B) an active agent-containing matrix layer comprising
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
The at least one acrylic polymer is a polymer obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate. It is preferably a thermoplastic polymer, which is applied by hot-melt or a solvent based process and typically does not undergo further curing to solidify.
Thus, in a more preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising
A) a backing layer;
B) an active agent-containing matrix layer comprising
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
The intermediate layer of the TTS according to the present invention may be a membrane or a polymer layer, in particular a pressure sensitive adhesive layer comprising a silicone-based polymer obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. The intermediate layer is positioned between the active agent-containing layer and the skin contact layer. Thus, one side of the intermediate layer is preferably directly attached to the active agent-containing layer, while the other side is preferably directly attached to the skin contact layer. The intermediate layer improves the stability of the TTS by holding the active agent-containing layer and the skin contact layer together. Typically, the intermediate layer is manufactured active-free. However, due to the concentration gradient, the active agent may migrate from the active agent-containing layer to the intermediate layer over time, until an equilibrium is reached.
Thus, in a preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing layer comprising at least one acrylic polymer;
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
In another preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing matrix layer comprising
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
In a more preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing matrix layer comprising
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
The TTS according to the present invention comprises a skin contact layer. The skin contact layer is an adhesive layer comprising a silicone gel adhesive, which is preferably directly attached to the intermediate layer, which itself is preferably directly attached to the active agent-containing layer. The silicone gel adhesive in the skin contact layer provides for the adhesive properties, while at the same time reducing the problem of skin irritation. Typically, the skin contact layer is manufactured active-free. However, due to the concentration gradient, the active agent may migrate from the active agent-containing layer to the skin contact layer over time, until an equilibrium is reached.
The silicone gel adhesive is an elastic, jelly-like material formed by lightly crosslinking silicone polymers. It may be prepared from a gel producing composition as described further below upon curing. Thus, while the silicone-containing polymer as used in the active agent-containing layer of the TTS of the present invention is preferably a non-curing polymer, i.e. a polymer, which does not undergo a curing reaction to solidify, the silicone gel adhesive forms upon curing of silicones comprising reactive groups such as Si—H reactive groups and aliphatic unsaturated groups, which react with each other in the presence of a hydrosilylation catalyst. Further details in this regard are provided below.
Thus, in a preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing layer comprising at least one acrylic polymer;
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive;
and wherein the silicone gel adhesive is obtained from curable silicones comprising reactive groups, in particular Si—H groups and aliphatic unsaturated groups.
In another preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing matrix layer comprising
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive; and wherein the silicone gel adhesive is obtained from curable silicones comprising reactive groups, in particular Si—H groups and aliphatic unsaturated groups.
In a more preferred embodiment, the present invention relates to a transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing matrix layer comprising
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin;
and wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive; and wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
It is to be understood that the TTS according to the invention contains a therapeutically effective amount of the active agent. A preferred active agent is rivastigmine. In a preferred embodiment, the active agent is present in the active agent-containing layer in an amount of from 5 to 40% by weight, preferably 20 to 35% by weight, based on the total weight of the active agent-containing layer.
In a preferred embodiment, the active agent is rivastigmine. Preferably, the amount of rivastigmine contained in the active agent-containing layer structure ranges from 0.5 to 5 mg/cm2, preferably from 1 to 3 mg/cm2.
The area of release of the TTS according to the invention may be from 1 to 30 cm2, preferably from 2 to 22 cm2.
The layer thicknesses and area weights of the active agent-containing layer, the intermediate layer, and the skin contact layer may vary over a broad range. Surprisingly, it has been found that the skin contact layer does not negatively affect the release properties of the TTS even at greater thicknesses of up to 220 μm. Similarly, the intermediate layer may have a thickness of up to 100 μm.
Thus, in a preferred embodiment, the active agent-containing layer has a thickness of from 50 to 150 μm and/or an area weight of from 30 to 200 g/m2, preferably from 40 to 120 g/m2. In another preferred embodiment, the intermediate layer has a thickness of from 20 to 100 μm, preferably from 25 to 55 μm and/or an area weight of from 20 to 80 g/m2, preferably from 20 to 60 g/m2. In another preferred embodiment, the skin contact layer has a thickness of from 30 to 220 μm, preferably from 40 to 160 μm and/or an area weight of 20 to 120 g/m2, preferably from 30 to 90 g/m2.
The backing layer is preferably substantially impermeable for the active agent. In a preferred embodiment, the backing layer is occlusive as outlined above.
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 active agent-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 active agent. 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, silicone-based polymers, polyisobutylenes, styrene-isoprene-styrene copolymers, and mixtures thereof, which may be identical to or different from any polymer or polymer mixture included in the rivastigmine-containing layer structure.
The active agent-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.
As outlined in more detail above, the TTS according to the present invention comprises an active agent-containing layer structure comprising inter alia an active agent-containing layer, which comprises at least one silicone-containing polymer.
In a preferred embodiment, the active agent-containing layer comprises a therapeutically affective amount of the active agent. In a particular preferred embodiment, the active agent is present in the active agent-containing layer in an amount of from 5 to 40% by weight, preferably 20 to 35% by weight based on the total weight of the active agent-containing layer. Preferably, the active agent is rivastigmine
The active agent is preferably homogeneously distributed within the active agent-containing layer. In a preferred embodiment, the active agent-containing layer is therefore an active agent-containing matrix layer.
In a preferred embodiment, the active agent-containing layer has a thickness of from 50 to 150 μm. In another preferred embodiment, the active agent-containing layer has an area weight of from 30 to 200 g/m2, preferably from 40 to 120 g/m2.
In a preferred embodiment, the acrylic polymer is present in the active agent-containing layer in an amount of from 30 to 90% by weight, preferably 60 to 80% by weight based on the total weight of the active agent-containing layer. It is to be understood that the afore-mentioned amounts refer to the overall amount of acrylic polymers in the active agent-containing layer. Thus, if two different acrylic polymers are present, the overall amount is from 30 to 90% by weight, preferably 60 to 80% by weight based on the total weight of the active agent-containing layer.
In a preferred embodiment, the at least one acrylate polymer is obtainable from one or more monomers selected from acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, butylmethacrylate, t-octylacrylamide, and vinylacetate, preferably from one or more monomers selected from acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate, and methylacrylate. Preferably, the active agent-containing layer comprises two acrylate polymers, of which the first acrylate polymer is a copolymer based on acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate, and the second acrylate polymer is a copolymer based on butylmethacrylate and methylmethacrylate. More preferably, the first acrylate polymer is present in an amount of from 10 to 30% by weight based on the total weight of the active agent-containing layer, and the second acrylate polymer is present in an amount of from 40 to 60% by weight based on the total weight of the active agent-containing layer. Particularly preferably, the first acrylate polymer is present in an amount of from 15 to 25% by weight based on the total weight of the active agent-containing layer, and the second acrylate polymer is present in an amount of from 45 to 55% by weight based on the total weight of the active agent-containing layer.
In another preferred embodiment, the active agent-containing layer further comprises at least one additive. Preferred additives are described further below. Preferably, the at least one additive is a stabilizer selected from tocopherol and ester derivatives thereof. In a particularly preferred embodiment, the active agent-containing layer comprises at least one stabilizer selected from tocopherol and ester derivatives thereof in an amount of from 0.001 to 2.0% by weight, preferably from 0.01 to 1.0% by weight, even more preferably from 0.05 to 0.2% by weight based on the total weight of the active agent-containing layer.
As outlined in more detail above, the TTS according to the present invention comprises an active agent-containing layer structure comprising inter alia an intermediate layer between the active agent-containing layer and the skin contact layer. The intermediate layer may be a membrane or a polymer layer, preferably a polymer layer, in particular a silicone-based polymer layer.
In one preferred embodiment, the intermediate layer is a membrane, which is at least semipermeable for the active agent. In another preferred embodiment, the intermediate layer is a membrane selected from the group consisting of polyethylene membranes, polyurethane coated polyethylene terephthalate/polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate (EVA) membranes.
In another preferred embodiment, the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer. In a more preferred embodiment, the silicone-based polymer is obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. In an even more preferred embodiment, the residual silanol functionality of the silicone-based polymer is capped with trimethylsiloxy groups.
In a preferred embodiment, the intermediate layer is provided free of active agent. However, due to the concentration gradient, the active agent may migrate from the active agent-containing layer to the skin contact layer over time, until an equilibrium is reached.
The intermediate layer is decisive for the stability of the TTS as it provides a stable connection between the active agent-containing layer and the skin contact layer. Furthermore, the intermediate layer does not negatively affect the transdermal delivery of the active agent.
In a preferred embodiment, the intermediate layer has a thickness of from 20 to 100 μm, preferably from 25 to 55 μm. In another preferred embodiment, the intermediate layer has an area weight of from 20 to 80 g/m2, preferably from 20 to 60 g/m2.
As outlined in more detail above, the TTS according to the present invention comprises an active agent-containing layer structure comprising inter alia a skin contact layer, wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive. The skin contact layer is preferably directly attached to the intermediate layer, which is itself preferably directly attached to the active agent-containing layer.
The skin contact layer is typically provided free of active agent. However, due to the concentration gradient, the active agent may migrate from the active agent-containing layer to the skin contact layer over time, until an equilibrium is reached.
The silicone gel adhesive in the skin contact layer is decisive for the adhesive properties as well as the reduction of skin irritation inter alia due to its resiliency. Furthermore, the silicone gel adhesive does not negatively affect the transdermal delivery of the active agent. In a preferred embodiment the skin contact layer comprises the silicone gel adhesive in an amount of at least 95% by weight, preferably at least 99% by weight. Particularly preferably, the skin contact layer essentially consists of the silicone gel adhesive.
The silicone gel adhesive is an elastic, jelly-like material formed by lightly crosslinking silicone polymers provided as a so-called gel producing composition. The silicone gel adhesives are generally formed from linear or branched silicones having reactive groups thereon. Such reactive groups undergo a crosslinking reaction during curing. Examples of crosslinking reactions include the hydrosilylation reaction in which a silicone having an Si—H reactive group reacts with a silicone having an aliphatic unsaturated reactive group in the presence of a hydrosilylation catalyst. Typically, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of the Si—H groups with the Si-alkenyl groups. Preferably, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst. Further details in this regard are provided below.
In a preferred embodiment, the skin contact layer has a thickness of from 30 to 220 μm, preferably from 40 to 160 μm. In another preferred embodiment, the skin contact layer has an area weight of from 20 to 120 g/m2, preferably from 30 to 90 g/m2.
As indicated above, the TTS according to the present invention comprises at least one acrylic polymer in the active agent-containing layer.
As used herein, the terms acrylic polymer and acrylate polymer are synonymously used. Preferably, the acrylic polymers are pressure-sensitive adhesives based on acrylates. 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 be provided in the form of a solution with a solids content preferably between 30% and 60%.
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.
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, butylmethacrylate, t-octylacrylamide and vinylacetate, and are provided in ethyl acetate, heptane, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene or xylene or mixtures thereof.
Specific acrylate-based pressure-sensitive adhesives are available as:
Additional polymers may also be added to enhance cohesion and/or adhesion.
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® E100) 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® E100. Eudragit® E100 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. Further, polymers such as Plastoid B, acrylic polymers such as Eudragits, Chitosan, celluloses and derivatives thereof, and polystyrene may be useful to increase the dryness of the adhesive (e.g. the matrix layer).
As indicated above, the TTS according to the present invention may comprise at least one silicone-based polymer in the intermediate layer.
As used herein, the silicone-based polymer is a non-hybrid polymer, i.e. a polymer, which does not include a hybrid species. Silicone-based polymers are based on polysiloxanes. They may therefore also be referred to as polymers based on polysiloxanes. Preferably, the silicone-based polymers are silicone-based pressure sensitive adhesives, i.e. pressure sensitive adhesives based on polysiloxanes.
As the silicone-based polymer is preferably a non-curing polymer, it is typically supplied and used in solvents, such as n-heptane and ethyl acetate. The solids content is usually between 30% and 80%.
Suitable silicone-based polymers are commercially available under the brand names BIO-PSAs (pressure sensitive adhesives based on polysiloxanes).
Pressure-sensitive adhesives based on polysiloxanes 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 the pressure-sensitive adhesives based on polysiloxanes 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 (also referred to as silicate resin), a pressure-sensitive adhesive based on polysiloxane is prepared wherein 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.
In view of the above, silicone-based polymers, and in particular silicone-based pressure sensitive adhesives, are generally obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. Amine-compatible silicone-based polymers, and in particular amine-compatible silicone-based pressure sensitive adhesives, can be obtained by reacting the silicone-based polymer, in particular the silicone-based pressure sensitive adhesive, with trimethylsilyl (e.g. hexamethyldisilazane) in order to reduce the silanol content of the polymer. As a result, the residual silanol functionality is at least partly, preferably mostly or fully capped with trimethylsiloxy groups.
As indicated above, the tackiness of the silicone-based polymer may be modified by the resin-to-polymer ratio, i.e. the ratio of the silanol endblocked polydimethylsiloxane to the silicate resin, which is preferably in the range of from 70:30 to 50:50, preferably from 65:35 to 55:45. The tackiness will be increased with increasing amounts of the polydimethylsiloxane relative to the resin. High tack silicone-based polymers preferably have a resin-to-polymer ratio of 55:45, medium tack silicone-based polymers preferably have a resin-to-polymer ratio of 60:40, and low tack silicone-based polymers preferably have a resin-to-polymer ratio of 65:35. High tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×106 Poise, medium tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×107 Poise, and low tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×108 Poise. High tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×106 Poise, medium tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×108 Poise, and low tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×109 Poise.
Examples of silicone-based PSA compositions which are commercially available include the standard BIO-PSA series (7-4400, 7-4500 and 7-4600 series), the amine compatible (endcapped) BIO-PSA series (7-4100, 7-4200 and 7-4300 series) and the Soft Skin Adhesives series (7-9800) manufactured and typically supplied in n-heptane or ethyl acetate by Dow Corning. 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 1×108 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 5×106 Poise.
The pressure-sensitive adhesives based on polysiloxanes are supplied and used in solvents like n-heptane, ethyl acetate or other volatile silicone fluids. The solids content of pressure-sensitive adhesives based on polysiloxanes in solvents is usually between 60 and 85%, preferably between 70 and 80% or between 60 and 75%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.
Pressure-sensitive adhesives based on polysiloxanes, which are, e.g., available from Dow Corning, may be obtained according to the following scheme:
Such pressure-sensitive adhesives based on polysiloxanes are available from Dow Corning, e.g., under the tradenames BIO-PSA 7-4401, BIO-PSA-7-4501, or BIO-PSA 7-4601, which are provided in the solvent n-heptane (indicated by the code “01”), or under the tradenames BIO-PSA 7-4402, BIO-PSA 7-4502, and BIO 7-4602, which are provided in the solvent ethyl acetate (indicated by the code “02”). Typical solids contents in the solvent are in the range of from 60 to 75%. The code “44” indicates a resin-to-polymer ratio of 65:35 resulting in a low tackiness, the code “45” indicates a resin-to-polymer ratio of 60:40 resulting in medium tackiness, the code “46” indicates a resin-to-polymer ratio of 55:45 resulting in high tackiness.
Amine-compatible pressure-sensitive adhesives based on polysiloxanes, which are, e.g., available from Dow Corning may be obtained according to the following scheme:
Such amine-compatible pressure-sensitive adhesives based on polysiloxanes are available from Dow Corning, e.g., under the tradenames BIO-PSA 7-4101, BIO-PSA-7-4201, or BIO-PSA 7-4301, which are provided in the solvent n-heptane (indicated by the code “01”), or under the tradenames BIO-PSA 7-4102, BIO-PSA 7-4202, and BIO 7-4302, which are provided in the solvent ethyl acetate (indicated by the code “02”). Typical solids contents in the solvent are in the range of from 60 to 75%. The code “41” indicates a resin-to-polymer ratio of 65:35 resulting in a low tackiness, the code “42” indicates a resin-to-polymer ratio of 60:40 resulting in medium tackiness, the code “43” indicates a resin-to-polymer ratio of 55:45 resulting in high tackiness.
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, 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 1×109 Poise or from about 1×105 to about 9×108 Poise.
As indicated above, the TTS according to the present invention comprises a skin contact layer, which is an adhesive layer comprising a silicone gel adhesive. The silicone gel adhesive is an elastic, jelly-like solid material formed by lightly crosslinking silicone polymers. Thus, in contrast to the silicone-based polymers as used herein, the silicone gel adhesive is based on a curable gel producing composition. The silicone gel adhesive provides for the adhesiveness of the TTS to the skin, while at the same time reducing the problem of skin irritation. Furthermore, the drug delivery of the TTS is not negatively affected.
Silicone gel adhesives are also referred to as silicone gels and, e.g., described in WO 2011/022199 A2.
The silicone gel adhesive is generally formed from linear or branched silicones having reactive groups thereon. Such reactive groups undergo a crosslinking during curing. Examples of crosslinking reactions include the hydrosilylation reaction in which a silicone having an Si—H group reacts with a silicone having an aliphatic unsaturated reactive group in the presence of a hydrosilylation catalyst. These materials are described, for example in U.S. Pat. Nos. 5,656,279, 5,891,076, EP 0 322 118 and U.S. Pat. No. 4,991,574 which are incorporated herein by reference. An alternative reaction is the condensation cure in which an alkoxy and/or hydroxy containing siloxanes are cured with a catalyst as described in U.S. Pat. No. 4,831,070 which is hereby incorporated by reference.
Typically, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups. These compositions cure at normal ambient temperatures, but curing can be expedited by heating to elevated temperatures, e.g., from 40 to 140° C., or by applying UV light.
Suitable alkenyl groups contain from 2 carbon to about 6 carbon atoms and are exemplified by, but not limited to, vinyl, allyl, and hexenyl. The alkenyl groups in this component may be located at terminal, pendant (non-terminal), or both terminal and pendant positions. The remaining silicon-bonded organic groups in the alkenyl-substituted polydiorganosiloxane are independently selected from the group consisting of monovalent hydrocarbon and monovalent halogenated hydrocarbon groups free of aliphatic unsaturation. These groups typically contain from 1 carbon to about 20 carbon atoms, alternatively from 1 carbon to 8 carbon atoms and are exemplified by, but not limited to, alkyl such as methyl, ethyl, propyl, and butyl; aryl such as phenyl; and halogenated alkyl such as 3,3,3-trifluoropropyl. Typically, at least 50 percent of the organic groups in the alkenyl-substituted polydiorganosiloxane are methyl. The structure of the alkenyl-substituted polydiorganosiloxane is typically linear, however, it may contain some branching due to the presence of trifunctional siloxane units. The viscosity of the alkenyl-substituted polydiorganosiloxane can be any desired. For example, it can be >0 mm2/s to 100,000 mm2/s, alternatively 50 mm2/s to 80,000 mm2/s, alternatively 300 mm2/s-3,000 mm2/s.
Methods for preparing the alkenyl-substituted polydiorganosiloxanes (i) of the present invention, such as condensation of the corresponding halosilanes or equilibration of cyclic polydiorganosiloxanes, are well known in the art.
The alkenyl-substituted polydiorganosiloxanes can be used in the gel producing composition in an amount of 10 wt. %-90 wt. % based on the weight of the composition, alternatively 40 wt. %-90 wt. %, alternatively 50 wt. %-80 wt. %. The amount of alkenyl groups present in the alkenyl-substituted polydiorganosiloxane is typically in the range of 0.05 wt. %-1% wt %, alternatively 0.05 wt. % to 1 wt. % based on the weight of the alkenyl-substituted polydiorganosiloxane.
The organosiloxane containing silicon-bonded hydrogen atoms (ii) are also known in the art as described, for example in U.S. Pat. No. 3,983,298. The hydrogen atoms in this component may be located at terminal, pendant (non-terminal), or both terminal and pendant positions. The remaining silicon-bonded organic groups in this component are independently selected from the group consisting of monovalent hydrocarbon and monovalent halogenated hydrocarbon groups free of aliphatic unsaturation. These groups typically contain from 1 carbon to about 20 carbon atoms, alternatively from 1 carbon to 8 carbon atoms, and are exemplified by, but not limited to, alkyl such as methyl, ethyl, propyl, and butyl; aryl such as phenyl; and halogenated alkyl such as 3,3,3-trifluoropropyl. In one embodiment of the invention, at least 50 percent of the organic groups in the organosiloxane containing silicon-bonded hydrogen atoms are methyl.
The structure of the organosiloxane containing silicon-bonded hydrogen atoms is typically linear however; it may contain some branching due to the presence of trifunctional siloxane units. The viscosity of the organosiloxane containing silicon-bonded hydrogen atoms can be any desired. For example, it can be >0 mm2/s to 100,000 mm2/s, alternatively, 5 mm2/s to 500 mm2/s.
The organosiloxanes containing silicon-bonded hydrogen atoms can be used in the gel producing composition in an amount of 1 wt. %-30 wt. % based on the weight of the composition, alternatively 5 wt. %-20 wt %, and alternatively 5 wt. %-15 wt. %. In one embodiment, the amount of hydrogen group present in the organosiloxane containing silicon-bonded hydrogen atoms is between 0.05 wt. %-1.44 wt % based on the weight of the organosiloxane containing silicon-bonded hydrogen atoms.
Methods of preparing the organosiloxane containing silicon-bonded hydrogen atoms of the present invention by co-hydrolysis of the appropriate chlorosilanes are known in the art; U.S. Pat. No. 2,877,255 to Clark; Japanese Laid Open Patent Application (KOKAI) SHO 62(1987)-39660 to Mogi et al.; and U.S. Pat. Nos. 5,446,185 and 5,493,040 to Cobb et al., which are all hereby incorporated by reference.
In the gel producing compositions (i) and (ii) are present such that the ratio of (H as SiH):(Alkenyl as Si-Alkenyl) is generally in the range of 0.1:1 to 10:1.
The hydrosilylation catalyst (iii) promotes the addition reaction of the alkenyl-substituted polydiorganosiloxane with the organosiloxane containing silicon-bonded hydrogen. The hydrosilylation catalyst can be any of the well known hydrosilylation catalysts comprising a platinum group metal, a compound containing a platinum group metal, or a microencapsulated platinum group metal or compound containing same. These platinum group metals include platinum, rhodium, ruthenium, palladium, osmium and iridium. Platinum and platinum compounds are preferred catalysts based on their high activity level in hydrosilylation reactions. One class of platinum catalysts is the complexes of chloroplatinic acid with certain vinyl-containing organosiloxane compounds disclosed by Willig in U.S. Pat. No. 3,419,593, which is hereby incorporated by reference. A specific catalyst of this type is the reaction product of chloroplatinic acid and 1,3-diethenyl-1,1,3,3-tetramethyldisiloxane.
The hydrosilylation catalyst is present in an amount sufficient to cure the composition of the present invention. Typically, the concentration of the catalyst is sufficient to provide from 0.1 ppm to 500 ppm (part per million), alternatively from 1 ppm to 100 ppm, alternatively from 1 ppm to 50 ppm of a platinum group metal, based on the weight of (i) and (ii).
An optional ingredient is a hydroxy substituted silicone resin as described in US. Patent Application No. 2007-0202245, herein incorporated by reference. The resin is typically comprised of groups having the formula R33 SiO1/2 (“M” groups) and groups having the formula SiO4/2 (“Q” groups) where R3 is a alkyl group having 1 carbon to 6 carbon atoms or alkylene group having 1 carbon to 6 carbon atoms, typically methyl or vinyl.
If an alkenyl group is present in the resin, typically the mol-% of R groups present as alkenyl groups is <10 mol-%, alternatively 5 mol-%.
The number ratio of M groups to Q groups is typically in the range of 0.6:1 to 4:1, alternatively 0.6:1 to 1.0:1. The silicone resin typically contains 0.1 wt % to 5 wt %, alternatively 1.0 wt % to 5 wt % silicone-bonded hydroxy groups.
The resin can be used in the gel producing composition in an amount of 2 wt % to 45 wt %, based on the weight of the gel producing composition and resin; alternatively 5 wt % to 40 wt %, alternatively 10 wt % to 35 wt %.
The silicone gel adhesive layer can be made by processes known in the art. For example, the gel may be preformed (e.g. as a sheet) by molding, calendaring, extruding, spraying, brushing, applying by hand, casting or coating on a substrate such as a liner. Or the silicone gel layer can be made by applying the gel producing composition to a substrate by spraying, coating, bar coating, etc. Once applied to the substrate the gel producing composition is cured to produce the silicone gel adhesive on the substrate.
In view of the above, in a preferred embodiment of the invention, the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst. Preferably, (i) and (ii) are present such that the ratio of (H as SiH):(Alkenyl as Si-Alkenyl) is generally in the range of 0.1:1 to 10:1.
Further, in certain preferred embodiments, the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive that contains from about 2 to about 45% by weight of at least one hydroxyl substituted silicate resin.
The TTS according to the invention, and in particular the active agent-containing layer may further comprise at least one additive or excipient. Said additives or excipients are preferably selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers, in particular from crystallization inhibitors, substances for skincare, tackifiers, softeners, stabilizers, and permeation enhancers. More preferably, said additives are selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers, in particular from substances for skincare, tackifiers, softeners, and stabilizers. Such additives may be present in the active agent-containing layer in an amount of from 0.001% to 15% by weight, e.g. from 1 to 10% by weight or from 0.01 to 5% by weight, based on the total weight of the active agent-containing layer.
It should be noted that in pharmaceutical formulations, the formulation components are categorized according to their physicochemical and physiological properties, and in accordance with their function. This means in particular that a substance or a compound falling into one category is not excluded from falling into another category of formulation component. E.g. a certain polymer can be a crystallization inhibitor but also a tackifier. Some substances may e.g. be a typical softener but at the same time act as a permeation enhancer. The skilled person is able to determine based on his general knowledge in which category or categories of formulation component a certain substance or compound belongs to. In the following, details on the excipients and additives are provided which are, however, not to be understood as being exclusive. Other substances not explicitly listed in the present description may be as well used in accordance with the present invention, and substances and/or compounds explicitly listed for one category of formulation component are not excluded from being used as another formulation component in the sense of the present invention.
In one embodiment, the active agent-containing layer further comprises a crystallization inhibitor. In some embodiments, the crystallization inhibitor can be present in an amount of from 0.5 to 10% by weight based on the total weight of the active agent-containing layer. Suitable examples of crystallization inhibitors include polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives. The crystallization inhibitor is preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone. The crystallization inhibitor may increase the solubility of the active agent or inhibit the crystallization of the active agent, e.g., if the active agent is used in the form of a salt.
In one embodiment, the active agent-containing layer further comprises a stabilizer, wherein the stabilizer is preferably selected from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof. In some embodiments, the stabilizer can be present in an amount of from 0.001 to 2.0%, preferably from 0.01 to 1.0%, by weight based on the total weight of the active agent-containing layer. In some embodiments, preferred stabilizers include sodium metabisulfite, ascorbyl esters of fatty acids such as ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, tocopherol, tocopheryl acetate and tocopheryl linoleate. Preferred stabilizers include ascorbyl esters of fatty acids, ascorbic acid, tocopherol, tocopheryl acetate and tocopheryl linoleate. Particularly preferred is tocopherol. Also particularly preferred is a combination of tocopherol and ascorbyl palmitate.
In one embodiment, the active agent-containing layer further comprises a softener/plasticizer. Exemplary softeners/plasticizers include linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides and polyethylene glycols.
In one embodiment, the active agent-containing layer further comprises a solubilizer. The solubilizer preferably improves the solubility of the active agent in the active agent-containing layer. Preferred solubilizers include, e.g., glycerol-, polyglycerol-, propylene glycol- and polyoxyethylene-esters of medium chain and/or long chain fatty acids, such as glyceryl monolinoleate, medium chain glycerides and medium chain triglycerides, non-ionic solubilisers made by reacting castor oil with ethylene oxide, and any mixtures thereof which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose and derivatives thereof such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and derivatives thereof; non-ionic tri-block copolymers having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene known as poloxamers; water-soluble derivatives of vitamin E; pharmaceutical graded or agglomerated spherical isomalt; a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, also abbreviated as PVAc-PVCap-PEG and known as Soluplus®; purified grades of naturally derived castor oil, of polyethylene glycol 400, of polyoxyethylene sorbitan monooleate (such as polysorbate 80) or of propylene glycols; diethylene glycol monoethyl ether; glucono-delta-lactone; maize and potato starch; as well as any of the below mentioned soluble polyvinylpyrrolidones, but also insoluble/cross-linked polyvinylpyrrolidones such as crospovidones.
However, also the permeation enhancers mentioned below can act as solubilizers. Furthermore, also crystallization inhibitors may act as solubilizers.
In one embodiment, the active agent-containing layer further comprises a pH regulator. Suitable pH regulators include mild acids and bases including amine derivatives, inorganic alkali derivatives, and polymers with basic or acidic functionality.
In one embodiment, the active agent-containing layer further comprises a preservative. Suitable preservatives include parabens, formaldehyde releasers, isothiazolinones, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid and anisic acid.
In one embodiment, the active agent-containing layer further comprises a substance for skincare. Such substances may be used to avoid or reduce skin irritation as detectable by the dermal response score. Suitable substances for skincare include sterol compounds such as cholesterol, dexpanthenol, alpha-bisabolol, and antihistamines. Substances for skincare are preferably used in amounts of from 1 to 10% by weight based on the total weight of the active agent-containing layer.
If the active agent-containing layer is required to have self-adhesive properties and one or more polymers is/are selected, which does/do not provide sufficient self-adhesive properties, a tackifier is added. Preferred tackifiers include Miglyol, which is a liquid wax ester based on long-chain, unsaturated, even-numbered fatty acids and long-chain, unsaturated, even-numbered fatty alcohols of vegetable origin, and polyethyleneglycols. In particular, the tackifier may be selected from polyvinylpyrrolidone (which, due to its ability to absorb water, is able to maintain the adhesive properties of the matrix layer and thus can be regarded as a tackifier in a broad sense), triglycerides, polyethylene glycols, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone. Preferably, the tackifier may be selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone. In some embodiments, the tackifier can be present in an amount of from 5 to 15% by weight based on the total weight of the active agent-containing layer.
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.
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”.
Fillers such as silica gels, titanium dioxide and zinc oxide may be used in conjunction with the polymer in order to influence certain physical parameters, such as cohesion and bond strength, in the desired way.
In one embodiment, the active agent-containing layer further comprises a permeation enhancer. Permeation enhancers are substances, which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability. Some examples of permeation enhancers are polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives such as allantoin; polar solvents such as dimethyldecylphosphoxide, methylcetylsulfoxide, dimethylaurylamine, dodecyl pyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide, and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate; and higher molecular weight aliphatic surfactants such as lauryl sulfate salts. Other agents include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate.
If the active agent-containing layer further comprises a permeation enhancer, the permeation enhancer is preferably selected from diethylene glycol monoethyl ether (transcutol), diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, and dimethylpropylene urea.
It has been found that the TTS provides sufficient permeability of the active agent even if no permeation enhancer is present. Therefore, in certain embodiments of the invention, the active agent-containing layer does not comprise a permeation enhancer or solubilizer.
It has been found that the TTS according to the present invention is suitable for the transdermal administration of an active agent, in particular rivastigmine, to the systemic circulation, while at the same time providing good adhesive properties and reduced skin irritation in comparison to other TTS known in the art.
The TTS according to the present invention is suitable for the transdermal administration of an active agent, in particular rivastigmine, to the systemic circulation for a predefined extended period of time, preferably for at least 24 hours.
Preferably, the TTS provides therapeutically effective plasma concentrations of the active agent, preferably rivastigmine, within less than 8 hours, preferably less than 6 hours, more preferably less than 4 hours after application of the TTS to the skin.
Preferably, the TTS provides, after a steady state of the plasma concentration is reached, a therapeutically effective steady state plasma concentration of the active agent, preferably rivastigmine, for at least 12 hours, preferably at least 18 hours, more preferably at least 20 hours, provided that the TTS is administered to the skin for a sufficient time, e.g., for at least 24 hours, so that the steady state can be reached and maintained.
In one embodiment, the TTS provides by transdermal delivery a mean release rate of from 150 to 3500 μg/cm2*day, preferably from 200 to 3000 μg/cm2*day rivastigmine over about 24 hours of administration.
In another embodiment, the TTS provides a cumulative permeated amount of rivastigmine as measured in a Franz diffusion cell with an EVA membrane of about 600 to 1200 μg/cm2 over a time period of about 24 hours.
The TTS according to the present invention is suitable for use in a method of treatment. If the active agent is rivastigmine, the TTS is suitable for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury. Furthermore, the TTS is suitable for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease.
In one embodiment, the TTS according to the invention is for use in a method of treatment, wherein the transdermal therapeutic system is preferably applied to the skin of the patient for at least 24 hours. In another embodiment, the present invention relates to a method of treatment comprising applying a transdermal therapeutic system according to the invention to the skin of a patient, preferably for at least 24 hours.
In one embodiment, the TTS comprises rivastigmine as active agent and is for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury. In a preferred embodiment, the TTS is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours. In another embodiment, the present invention relates to a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury comprising applying a transdermal therapeutic system according to the invention comprising rivastigmine to the skin of a patient, preferably for at least 24 hours, in particular about 24 hours.
In connection with the above uses and methods of treatment, the TTS according to the invention is preferably applied to at least one body surface on the subject selected from the upper outer art, upper chest, upper back or the side of the chest for the defined dosing intervals.
The preferred application time of a TTS according to the invention is at least 24 hours, preferably about 24 hours (1 day). After this time, the TTS may be removed, and optionally a new TTS may be applied, so as to allow an around-the-clock treatment.
The invention further relates to a process of manufacture of an active agent-containing layer structure for use in a transdermal therapeutic system.
In accordance with the invention, the process for manufacturing the active agent-containing layer for use in a transdermal therapeutic system according to the present invention comprises the steps of
If the intermediate layer is a silicone-based polymer layer, the intermediate layer may be prepared in advance by coating a composition comprising at least one silicone-based polymer onto an abhesively equipped foil, and drying the composition to form the intermediate layer.
As explained above, the acrylic polymer as well as the silicone-based polymer as used in the active agent-containing layer and the intermediate layer, respectively, are preferably non-curing polymers and therefore typically applied by a solvent-based process. Accordingly, the acrylic or silicone-based polymer is preferably provided in a solvent, wherein the solids content in the solvent is preferably from 40 to 75% by weight. The solvent is preferably selected from alcoholic solvents, in particular methanol, ethanol, isopropanol and mixtures thereof, and from non-alcoholic solvents, in particular ethyl acetate, hexane, heptane, petroleum ether, toluene, and mixtures thereof, and is more preferably selected from non-alcoholic solvents, and is most preferably ethyl acetate or n-heptane. In case of the coating composition for the active agent-containing layer, the active agent is preferably homogeneously dissolved or dispersed in the coating composition.
The coated coating composition is preferably solidified by drying. Drying is preferably performed at a temperature of from 20 to 90° C., more preferably from 40 to 70° C.
The process for manufacturing the skin contact layer for use in a transdermal therapeutic system according to the present invention comprises the steps of
As explained above, the gel producing composition forms the silicone gel adhesive of the skin contact layer upon curing, i.e. crosslinking of the reactive groups of the silicone polymers.
Crosslinking is preferably performed at a temperature of from 40° C. to 140° C.
The active agent-containing layer, the intermediate layer and the skin contact layer are preferably prepared separately as indicated above, and then laminated together by removing the foils and then laminating the open sides of the layers together in the desired order, so as to give an active agent-containing layer structure.
Accordingly, the process for manufacturing an active agent-containing layer structure for use in a transdermal therapeutic system according to the present invention comprises the steps of:
The present invention also relates to a transdermal therapeutic system obtainable by the above described process.
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.
The formulation of the rivastigmine-containing coating compositions of Comparative examples 1A-F (Comp. 1A-F) is summarized in Table 1.1 below. The solids %-values refer to the amounts (Amt) in % by weight.
The active-containing coating composition was taken from the commercial process for preparing Exelon®, wherein the coating composition was applied to a siliconized release liner as abhesively equipped foil.
The coating thickness was chosen such that removal of the solution resulted in an area weight of the active-containing layer of about 60.0 g/m2.
The resulting active-containing layer was then laminated with a backing layer (FO PET 15 μm, transparent).
The formulation of the active-free coating composition of Comp. 1A-F is summarized in Table 1.2 below. The solids %-values refer to the amounts (Amt) in % by weight.
Both components were weighed separately into a suitable vessel, e.g. a glass vessel. Subsequently, component A was added to the mixing vessel followed by component B. Then the mixture was mixed at approx. 200 rpm for approx. 5 min until a homogeneous mixture of Component A and Component B was obtained.
Within a time frame of approx. 30 min, the resulting active-free coating composition was coated on an abhesively equipped foil (DuPont′ Teflon FEP) using hand over knife lab coating equipment, e.g. an erichson coater.
The coating thickness was chosen such that removal of the solvents resulted in a layer thickness of the active-free (skin contact) layer of approx. 150 μm.
The curing conditions according to Table 1.3 were then applied.
The resulting active-free (skin contact) layer was laminated with a release liner (FEP, fluorinated ethylene propylene, 100 μm).
The active-free (skin contact) layer was then laminated with the active-containing layer. For this purpose, the abhesively equipped foils used for the coating and drying of the layers were removed and the resulting open sides of the active-containing layer and the active-free (skin contact) layer were laminated together resulting in an active-containing self-adhesive layer structure comprising the backing layer, the active-containing layer, and the active-free (skin contact) layer, wherein the active-containing layer is attached to the backing layer, and the active-free (skin contact) layer is attached to the active-containing layer, and wherein the structure is closed by a release liner, which is attached to the active-free (skin contact layer).
The individual systems (TTS) were punched out from the active-containing self-adhesive layer structure obtained as described above. Then, the TTS were sealed into pouches of the primary packaging material.
The release liners of the TTS of Comparative examples 1A-F were then peeled off. The results are summarized in table 1.4 below.
The formulation of the rivastigmine-containing coating compositions of Examples 1A-N (Ex. 1A-N) is summarized in Table 2.1 below. The solids %-values refer to the amounts (Amt) in % by weight.
The active-containing coating composition was taken from the commercial process for preparing Exelon®, wherein the coating composition was applied to a siliconized release liner as abhesively equipped foil.
The coating thickness was chosen such that removal of the solution resulted in an area weight of the active-containing layer of about 60.0 g/m2.
The resulting active-containing layer was then laminated with a backing layer (FO PET 23 μm, transparent).
The formulation of the active-free coating composition of Ex. 1A-N is summarized in Table 2.2 below. The solids %-values refer to the amounts (Amt) in % by weight.
Both components were weighed separately into a suitable vessel, e.g. a glass vessel. Subsequently, component A was added to the mixing vessel followed by component B. Then the mixture was mixed at approx. 200 rpm for approx. 5 min until a homogeneous mixture of Component A and Component B was obtained.
Within a time frame of approx. 30 min, the resulting active-free coating composition was coated on a membrane as indicated in Table 2.3 using a coating block.
The coating thickness was chosen such that removal of the solvents resulted in a layer thickness of the active-free (skin contact) layer of approx. 100 μm or 200 μm as indicated above in Table 2.2.
The curing conditions according to Table 2.3 were then applied.
The resulting active-free (skin contact) layer was laminated with a release liner (Scotchpak 9755, AB1F).
Lamination of the Active-Containing Layer and the Active-Free (Skin Contact) Layer with the Membrane in Between
The abhesively equipped foil of the rivastigmine-containing layer was removed and cast away. The rivastigmine-containing layer attached to the PET backing layer was then laminated with its adhesive side onto the membrane side of the active-free (skin contact) layer. The result is an active-containing self-adhesive layer structure comprising the backing layer, the rivastigmine-containing layer, the membrane as an intermediate layer, and the active-free (skin contact) layer, wherein the system is closed by the release liner.
The individual systems (TTS) were punched out from the active-containing self-adhesive layer structure obtained as described above. Then, the TTS were sealed into pouches of the primary packaging material.
The release liners of the TTS of Examples 1A-N were then peeled off. The results are summarized in table 2.4 below.
The formulation of the rivastigmine-containing coating compositions of Examples 2A-G (Ex. 2A-G) is summarized in Table 3.1 below. The solids %-values refer to the amounts (Amt) in % by weight.
The active-containing coating composition was taken from the commercial process for preparing Exelon®, wherein the coating composition was applied to a siliconized release liner as abhesively equipped foil.
The coating thickness was chosen such that removal of the solution resulted in an area weight of the active-containing layer of about 60.0 g/m2.
The resulting active-containing layer was then laminated with a backing layer (FO PET 23 μm, transparent).
The formulation of composition for the intermediate layer of Ex. 2A-G is summarized in Table 3.2 below. The solids %-values refer to the amounts (Amt) in % by weight.
The composition for the intermediate layer was coated on an abhesively equipped foil (Scotchpak 1022 AB1F) using a coating block.
The coating thickness was chosen such that removal of the solvent resulted in an area weight as indicated above in Table 3.2.
The coating was dried at about 50° C. for about 10 min.
The abhesively equipped foil of the rivastigmine-containing layer was removed and cast away. The rivastigmine-containing layer was then laminated with its open side onto the open side of the intermediate layer.
The formulation of the active-free coating composition of Ex. 2A-G is summarized in Table 3.3 below. The solids %-values refer to the amounts (Amt) in % by weight.
Both components were weighed separately into a suitable vessel, e.g. a glass vessel. Subsequently, component A was added to the mixing vessel followed by component B. Then the mixture was mixed at approx. 200 rpm for approx. 5 min until a homogeneous mixture of Component A and Component B was obtained.
Within a time frame of approx. 30 min, the resulting active-free coating composition was coated on an abhesively equipped foil (DuPont′ Teflon FEP) using hand over knife lab coating equipment, e.g. an erichson coater. The coating temperature was set to 120° C. The resulting active-free layer was heated at this temperature for approx. 5 min.
The coating thickness was chosen such that removal of the solvents resulted in a layer thickness of the active-free (skin contact) as indicated in Table 3.3.
The resulting active-free (skin contact) layer was laminated with a release liner (FEP, fluorinated ethylene propylene, 100 μm).
Lamination of the Active-Containing Layer and the Active-Free (Skin Contact) Layer with the Intermediate Layer in Between
The abhesively equipped foil of intermediate layer on top of the rivastigmine-containing layer was removed and cast away. Further, the abhesively equipped foil on top of the active-free (skin contact) layer was removed and cast away. The open side of the intermediate layer being part of the double layer system attached to the PET backing layer was then laminated onto the open side of the active-free (skin contact) layer. The result is an active-containing self-adhesive layer structure comprising the backing layer, the rivastigmine-containing layer, the silicone-based intermediate layer, and the active-free (skin contact) layer, wherein the system is closed by the FEP release liner.
The individual systems (TTS) were punched out from the active-containing self-adhesive layer structure obtained as described above. Then, the TTS were sealed into pouches of the primary packaging material.
The release liners of the TTS of Examples 2A-G were then peeled off. The results are summarized in table 3.4 below.
The permeated amounts of the TTS prepared according to Examples 2A-G were determined by experiments in accordance with the EMA Guideline on quality of transdermal patches (adopted Oct. 23, 2014) carried out with a 10.0 ml Franz diffusion cell, wherein an EVA-membrane (9% vinyl acetate; Nitroderm TTS K-Membrane 343 mm from PetroplastVinora AG) having a thickness of 50 μm was used. Diecuts with an area of release of 1.118 cm2 were punched from the TTS. The permeated amount of rivastigmine in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacteriological agent) at a temperature of 32±1° C. was measured.
The results are shown in Table 3.5 and in
Reference Example 1 (Ref 1) is the commercially available rivastigmine-containing TTS product Exelon®, having a rivastigmine-containing acrylic based layer (60 g/m2) and a rivastigmine-free silicone based skin contact layer (30 g/m2), which is available from Novartis Pharma.
The permeated amount of the commercially available Exelon® TTS (Ref 1) was determined as described for Examples 3A-G
The results are shown in Table 4 and in
The invention relates in particular to the following further items:
1. Transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
A) a backing layer;
B) an active agent-containing layer comprising at least one acrylic polymer;
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive.
2. Transdermal therapeutic system according to item 1, wherein the intermediate layer is a membrane, which is at least semipermeable for the active agent.
3. Transdermal therapeutic system according to item 1 or 2, wherein the intermediate layer is a membrane selected from the group consisting of polyethylene membranes, polyurethane coated polyethylene terephthalate/polyethylene membranes, polyurethane membranes, and ethylene vinyl acetate (EVA) membranes.
4. Transdermal therapeutic system according to any one of items 1 to 3, wherein the intermediate layer is a pressure-sensitive adhesive layer comprising a silicone-based polymer.
5. Transdermal therapeutic system according to item 4, wherein the silicone-based polymer is obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin.
6. Transdermal therapeutic system according to item 5, wherein the residual silanol functionality of the silicone-based polymer is capped with trimethylsiloxy groups.
7. Transdermal therapeutic system according to any one of items 1 or 4 to 6, wherein the intermediate layer has a thickness of from 20 to 100 μm, preferably from 25 to 55 μm.
8. Transdermal therapeutic system according to any one of items 1 or 4 to 7, wherein the intermediate layer has an area weight of from 20 to 80 g/m2, preferably from 20 to 60 g/m2.
9. Transdermal therapeutic system according to any one of items 1 to 8, wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) at least one alkenyl-substituted polydiorganosiloxane, (ii) at least one organosiloxane, which contains silicone-bonded hydrogen atoms, and (iii) at least one catalyst for the reaction of the SiH groups with the Si-alkenyl groups.
10. Transdermal therapeutic system according to any one of items 1 to 9, wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
11. Transdermal therapeutic system according to any one of items 1 to 10, wherein the silicone gel adhesive is a silicate resin-reinforced silicone gel adhesive that contains from about 2 to about 45% by weight, preferably from about 20 to about 30% by weight of at least one hydroxyl substituted silicate resin.
12. Transdermal therapeutic system according to any one of items 1 to 11, wherein the skin contact layer has a thickness of from 30 to 220 μm, preferably from 40 to 160 μm.
13. Transdermal therapeutic system according to any one of items 1 to 12, wherein the skin contact layer has an area weight of from 20 to 120 g/m2, preferably from 30 to 90 g/m2.
14. Transdermal therapeutic system according to any one of items 1 to 13, wherein the active agent-containing layer is an active agent-containing matrix layer comprising
A) a backing layer;
B) an active agent-containing layer comprising at least one acrylic polymer;
C) a skin contact layer; and
an intermediate layer between the active agent-containing layer and the skin contact layer; wherein the skin contact layer is an adhesive layer comprising a silicone gel adhesive; and wherein the silicone gel adhesive is obtainable by reacting a gel producing composition comprising (i) a copolymer of vinylmethylsiloxane and dimethylsiloxane with (ii) methylhydrogen polysiloxane with trimethylsilyl endgroups in the presence of (iii) a platinum catalyst.
31. Transdermal therapeutic system according to item 30, wherein the active agent is rivastigmine, and wherein the active agent is present in a therapeutically effective amount.
32. Transdermal therapeutic system according to item 30 or 31, wherein the skin contact layer does not comprise an active agent.
33. Transdermal therapeutic system for the transdermal administration of an active agent comprising an active agent-containing layer structure, said active agent-containing layer structure comprising:
| Number | Date | Country | Kind |
|---|---|---|---|
| 19185347.2 | Jul 2019 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/069271 | 7/8/2020 | WO | 00 |
