EP3007685A1 - Système thérapeutique transdermique (tts) à trois couches - Google Patents

Système thérapeutique transdermique (tts) à trois couches

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Publication number
EP3007685A1
EP3007685A1 EP14741516.0A EP14741516A EP3007685A1 EP 3007685 A1 EP3007685 A1 EP 3007685A1 EP 14741516 A EP14741516 A EP 14741516A EP 3007685 A1 EP3007685 A1 EP 3007685A1
Authority
EP
European Patent Office
Prior art keywords
pib
styrene
layer
silicone
tts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14741516.0A
Other languages
German (de)
English (en)
Inventor
Armin Breitenbach
Michael Horstmann
Sebastian Braun
Ulrich Becker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tesa Labtec GmbH
Original Assignee
Tesa Labtec GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tesa Labtec GmbH filed Critical Tesa Labtec GmbH
Priority to EP14741516.0A priority Critical patent/EP3007685A1/fr
Publication of EP3007685A1 publication Critical patent/EP3007685A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • TTS Thiee-Layer Transdermal Therapy System
  • the invention relates to an at least three-layer transdermal therapy system (TTS), which in particular has a reduced cold flow.
  • TTS transdermal therapy system
  • the invention further relates in particular to a TTS with rotigotine.
  • TTS transdermal therapy systems
  • TTS are e.g. for estradiol, norethisterone acetate, nicotine, fentanyl, tulobuterol, rivastigmine, rotigotine, ethinylestradiol / norelgestromin, buprenorphine and nitroglycerin, as well as an increasing number of other agents introduced into the therapy.
  • Known TTS often have a drug-impermeable backing layer (so-called backing), a drug-containing reservoir layer with control membrane and adhesive layer - or one or more matrix layers optionally with a pressure-sensitive adhesive layer for attachment to the skin - and to be removed before application to the skin effective substance protective film (so-called Release Liner).
  • CONFIRMATION OPT To improve the active ingredient permeation through the skin, in addition to polymers, resins and other pharmaceutical auxiliaries, system components which are liquid at room temperature are also used which partly serve to adjust the adhesive power, to improve the diffusion within the TTS or to improve the active ingredient permeation through the skin.
  • TTS optimization An essential goal of TTS optimization is to improve the cohesion of the adhesive layers, in particular to minimize the so-called cold flow, as non-cohesive - ie, skin-lubricating systems - quickly become unsightly and adhere unreliably. This problem is compounded by the generally softening effect of the active ingredient.
  • the phenomenon of cold flow means the slow release of the viscous adhesive from the edges of the TTS under a slight ambient pressure. This phenomenon is highly undesirable because it can lead to sticking of the TTS in the respective packaging after only a few months of storage. Often it is then no longer possible to remove the TTS from the pack so that it can no longer be used.
  • Multilayered TTSs are also known in the state of the art, but they likewise do not reliably solve the problem of cold flow.
  • a more tensile membrane is placed between a soft plastic reservoir and an adhesive layer to achieve membrane controlled release.
  • corresponding TTS show a significant cold flow.
  • US Pat. No. 4,769,028 discloses a TTS having up to five active ingredient-containing layers, in which special release properties are to be achieved via an active substance concentration gradient for nitroglycerin. These layers are uniformly sticky layers, by which an improvement in the cohesion or reduction of the cold flow is not to be expected, since it is known that these adhesives lose their mechanical strength without further reinforcement measures with increasing total layer thickness.
  • the object of the present invention is therefore to provide a TTS which has at least one improvement with respect to the disadvantages of TTS known from the prior art. This object is achieved by a transdermal therapy system according to claim 1.
  • Advantageous embodiments are the subject of corresponding subclaims.
  • the invention is based on the finding that the use of a hygroscopic polymer or copolymer in the middle, active substance-containing layer can significantly reduce the problem of cold flow.
  • a hygroscopic polymer or copolymer in the active substance-containing layer has a positive influence on the release of the active substance. It is believed that the hygroscopic polymers / copolymers from the environment (e.g., air or skin) absorb moisture and thus increase the water content in the middle layer. In the case of active substances with limited solubility in water, such as rotigotine, their solubility in the active substance-containing layer thereby decreases, and the active substance is thus "forced out" of this layer, which ultimately improves the release of the active substance.
  • This transport process is possibly enhanced by the effect that the absorption of water reduces the diffusion resistance of the hygroscopic phase and thus the active substance, in particular rotigotine, can diffuse out of the hygroscopic layer more easily,
  • this improvement in the release of active substances preferably is particularly useful at the time of application to the patient, ie that the patch is "activated" to a certain extent in an application-related manner hygroscopic polymer by moisture absorption from the air and the skin can increase the water content in the middle layer and thus can also improve the drug release from the patch.
  • the composition of the TTS according to the invention As a result of the composition of the TTS according to the invention, smaller amounts of active substance can remain in the plaster after use compared to conventional patches. This increases drug safety and also reduces the manufacturing costs of such systems. In addition, it has been shown that the plaster according to the invention retains its structural integrity despite considerable absorption of water in the middle layer.
  • rotigotine 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] amino] -1-naphthalenol (INN: rotigotine) within the meaning of the present invention comprises - if not is further differentiated - both the free base and the protonated form, so rotigotine salts, especially the pharmaceutically acceptable salts, such as rotigotine hydrochloride Also called prodrugs of rotigotine, which are first converted in the human organism to the active ingredient, are with includes.
  • Rotigotine can exist in various isomeric forms. Accordingly, this term also covers the isomers or mixtures thereof. Thus, the S or R enantiomer or racemate or any other enantiomeric mixture of rotigotine can be used.
  • a "hygroscopic (co) polymer” in the sense of the invention is defined as a (co) polymer that can reversibly bind water molecules under standard conditions (75% relative humidity, 25 ° C. and 1013.25 hPa) and / or preferably when the temperature increases and / or Conversely, the resulting dehydrated (co) polymer is again capable of binding water molecules Under normal conditions (25 ° C and 1013.25 hPa), the vapor pressure of the hydrated hygroscopic (co) polymers is less than 23 hPa, preferably less than 20 hPa, particularly preferably less than 15 hPa and in particular less than 10 hPa.
  • the vapor pressure of the hydrated hygroscopic (co) polymers is between 2 and 20 hPa, and in particular between 5 and 15 hPa.
  • the dehydrated hygroscopic (Co) polymer has the capacity of at least 0.05 g, preferably at least 0.10 g and more preferably at least 0.1 5 g of water per gram of hygroscopic (co) polymer to bind.
  • the dehydrated hygroscopic (co) polymer can bind up to 10 g, preferably up to 25 g, and more preferably up to 35 g, per gram of hygroscopic (co) polymer.
  • hydrophobic refers to those polymers or copolymers which consist of more than 50% (w / w) of monomer residues which contain nonpolar or uncharged groups.
  • the terms "in dissolved form” or “dissolved” are to be understood as meaning that the active ingredient, which is in particular rotigotine, is present as a homogeneous single-phase mixture in the (polymer) matrix of the respective layer. This does not rule out that the dissolved active ingredient (in particular rotigotine) is above the saturation point in its concentration, so that, in addition to the dissolved active ingredient, also undissolved active ingredient, be it in amorphous or crystalline form.
  • the active ingredient which is in particular rotigotine, is not present as a constituent of so-called microreservoirs.
  • Microreservoirs are spatially and functionally separate compartments, for example, consisting of pure active ingredient or a mixture of active ingredient and crystallization inhibitor, which in one Microreservoirs containing rotigotine are described in EP 1524975 B9.
  • homogeneous in the sense of homogeneous mixtures is to be understood as a mixture in which pure substances are mixed at the molecular level, that is to say single-phase, heterogeneous mixtures such as dispersions, in which the pure substances are not completely mixed, but in For the description of the homogeneity, the light-microscopic detectability must be considered.
  • “Homogeneously distributed” therefore means that the active substance (in particular rotigotine) is essentially not present in the form of active substance-containing particles or microreservoirs or crystals, but instead solved present. In particular, homogeneous therefore means the absence of microreservoirs with active ingredient.
  • permeable refers to a layer which, under application conditions, that is to say under conditions on the skin of the patient, is permeable to the active substance (in particular the free base of rotigotine).
  • rotigotine 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] amino] -1-naphthalenol (INN: rotigotine) within the meaning of the present invention comprises - if not is further differentiated - both the free base and the protonated form, so rotigotine salts, in particular the pharmaceutically acceptable salts, such as rotigotine hydrochloride so-called prodrugs of rotigotine, which are first converted into active ingredient in the human organism, are included.
  • Rotigotine can exist in various isomeric forms. Accordingly, this term also covers the isomers or mixtures thereof. Thus, the S or R enantiomer or racemate or any other enantiomeric mixture of rotigotine can be used.
  • the at least one hygroscopic polymer or copolymer at 75% relative humidity, 25 ° C. and 1013.25 hPa has a water absorption of at least 15% by weight, preferably at least 25% by weight after saturation more preferably at least wt.% -35% based on its own weight.
  • the at least one hygroscopic polymer or copolymer has a weight fraction of 50% or more, preferably 60, 70 or 80% or more, more preferably 90% or more, and especially 100% on the weight of the total polymer of the middle layer.
  • the at least one hygroscopic polymer or copolymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, partially hydrolyzed polyvinyl acetate, poly (vinylpyrrolidone-co-vinyl alcohol) and a polysaccharide, preferably a water-soluble starch derivative, a water-soluble cellulose derivative, pullulan and Alginate, or a mixture thereof.
  • the at least one hygroscopic polymer is polyvinylpyrrolidone or polyvinyl alcohol.
  • the inner and / or the outer layer contains at least one hydrophobic polymer, preferably a mixture of different polyisobutylenes and / or a silicone polymer or a mixture of different silicone polymers.
  • the hydrophobic polymers cause the active agent, which is forced out of the hydrated middle layer, to not accumulate in the inner and / or outer layer, but can pass directly through the respective layers to the skin.
  • layers (ii) and (iii) contain identical polymers.
  • the layer (ii) corresponds to the inner layer and the layer (iii) of the outer layer.
  • Such a constructed TTS is easy to prepare, and has a bilaterally symmetric concentration gradient with respect to the at least one active ingredient.
  • thermodynamic solution equilibrium is established between the three layers, it is easier to predict drug release for such a construction with reduced complexity.
  • the number of layers of the TTS can be more than three, more than 5, more than 6, or even more than 7 and more layers.
  • these more than three layers preferably have a basis weight of not more than 100 g / m 2 .
  • two or more different drugs may be included in the TTS. These are preferably present in different layers.
  • the multilayer construction offers the possibility of administering more than one active substance, with in each case individually adjusted release profiles.
  • a long-lasting therapeutic agent can be created by combining a rapidly releasing (and thereby quickly deflating) layer with a slower releasing (and thus longer-lasting) layer that has neither a very long lag time nor a premature exhaustion.
  • layer combinations which, after a certain period of wear, realize a burst-like additional increase in the plasma concentrations of the active substance - useful, for example, in the early morning in the therapy of the patients.
  • the TTS according to the invention comprises an outer layer ("outer layer” or “layer (iii)”).
  • the outer layer is one which directly or indirectly adjoins the middle active substance-containing layer on the side facing away from the skin.
  • the outer layer may preferably be arranged between the middle layer and the back layer.
  • the outer layer is substantially impermeable to the active agent (especially rotigotine). It can be self-adhesive or non-adhesive. Should it be non-adhesive, adhesive may be provided to adhesively bond the outer layer to the backing layer.
  • the outer layer is identical to the inner layer in terms of its polymeric composition. The outer layer is then also permeable to the active ingredient and in particular to rotigotine.
  • the TTS according to the invention comprises at least i) a middle layer having a basis weight of at most 70 g / m 2 , preferably of at most 45 g / m 2 and particularly preferably of at most 30 g / m 2 ii) an inner layer (1 ) having a basis weight of at most 70 g / m 2 , preferably of at most 45 g / m 2 and more preferably of at most 20 g / m 2, and iii) an outer layer (3) having a basis weight of at most 70 g / m 2 , preferably of at most 45 g / m 2 , more preferably of at most 25 g / m 2 and most preferably of at most 10 g / m 2 .
  • the basis weight of none of the layers is more than 45 g / m 2 and in particular more than 30 g / m 2 .
  • the TTS according to the invention consists of exactly three layers, which have the above-mentioned preferred basis weights.
  • basis weights (FG) of the middle, inner and outer layers are preferred (but other combinations are also possible).
  • the TTS exactly comprises a three-layer structure according to one of the examples A1 to A36 given above in the table.
  • the TTSs may preferably consist of these three layers, if appropriate plus a backing layer and a protective layer.
  • the TTS according to the invention preferably has a total weight per unit area of at most 210 g / m 2 , preferably of at most 135 g / m 2 , more preferably of at most 75 g / m 2 and particularly preferably of at most 60 g / m 2 .
  • the basis weights of the active substance-containing middle layer and the inner layer are preferably in a ratio of 5: 1 to 1: 5, more preferably from 3: 1 to 1: 3 and particularly preferably from 3: 2 or 1: 1.
  • the basis weights of the inner and outer layers are preferably in a ratio of 5: 1 to 1: 5, more preferably 4: 1 to 1: 2, and particularly preferably 2: 1.
  • the basis weights of the middle and outer layers are preferably in a ratio of 5: 1 to 1: 5, more preferably from 4: 1 to 1: 2 and particularly preferably from 3: 1.
  • the basis weights of the outer, middle and inner layers are in a ratio of 1: 1: 1.
  • the basis weights are in a ratio of 2: 3: 2.
  • the basis weights are in a ratio of 1: 3: 2.
  • the middle layer is designed as a release layer, ie it has a tensile strength of at least 0.1 N / mm 2 , preferably of at least 2 N / mm 2 and more preferably of 10 N / mm 2 .
  • the tensile strength of the release liners and the adhesive layers can be measured by standard tensile testing machines (e.g., Zwick-Roell PrecisionLine testing machines). For this, it is first necessary to produce active ingredient-free solutions of the base materials (see below), since manufacturing differences in the admixture of the active ingredients to individual layers otherwise give an incorrect picture. After the preparative production of films via a coating process relevant to a person skilled in the art using solvents for the respective base material, blanks of these films of the same size are clamped into the corresponding test apparatuses. Then the force-displacement curves are recorded. For consistency of terminology, the tensile strength (the measured tensile force value) is measured each time a 10 percent strain of the base material is achieved.
  • Zwick-Roell PrecisionLine testing machines e.g., Zwick-Roell PrecisionLine testing machines.
  • the measurement of the tensile strengths is normalized to uniformity and material reference because of the same layer thickness.
  • the bond strength is defined as the peel force at 90 ° on steel (hereinafter also: bond strength (on steel)).
  • the inner layer is configured as an adhesive layer, ie it has an adhesive force (on steel) of at least 1 N / cm 2 , preferably of at least 5 N / cm 2 and particularly preferably of at least 10 N / cm 2 .
  • the outer layer is configured as an adhesive layer, ie it has an adhesive force (on steel) of at least 1 N / cm 2 , preferably of at least 5 N / cm 2 and particularly preferably of at least 10 N / cm 2 .
  • both the outer layer and the inner layer are configured as an adhesive layer, ie they both have a bond strength (on steel) of at least 1 N / cm 2 , preferably of at least 5 N / cm 2 and particularly preferably of at least 10 N / cm 2 .
  • the middle layer is a release layer and the inner and outer layers are each configured as an adhesive layer.
  • the TTS according to the invention comprises at least two, preferably at least three, double layers and optionally a further adhesive layer, the double layers each consisting of a release layer and an adhesive layer.
  • a separating layer and an adhesive layer may be a so-called double layer.
  • Double layer in the sense of the invention means that these layers follow one another directly.
  • the transdermal therapy system (TTS) comprises at least two such bilayers and optionally a protective film and / or backing layer.
  • the TTS according to the invention may comprise a total of at least two separating layers conferring special mechanical stability to the TTS and at least two separate adhesive layers. The separation of the adhesive layer of the TTS into at least two adhesive layers and their combination with the at least two separating layers can further improve the reduction of the unwanted cold flow.
  • a construction of the TTS according to the invention with at least two bilayers can further facilitate the setting of specific and complex profiles of the release of active substance or make it possible in the first place.
  • the separating layer and the adhesive layer differ in their respective tensile strength.
  • the release layer may have a higher tensile strength than the adhesive layer. This is preferably at least a factor of 2, particularly preferably at least a factor of 5, even higher at least by a factor of 10 or by a factor of 20. In a particularly preferred embodiment, the tensile strength of the release layer is at least a factor of 30 higher than the tensile strength of the adhesive layer.
  • the at least two bilayers of the TTS according to the invention according to this embodiment can with respect to the tensile strengths of their respective separation or Adhesive layers may be identical or different.
  • the relations of the tensile strengths may in particular vary in adaptation to the respective layer thickness.
  • the adhesive layer and the release layer differ in their respective bond strength.
  • the adhesive layer preferably has an adhesive force which is at least a factor of 1, 5-2, preferably at least a factor of 3, and more preferably at least a factor of 5, relative to the respective separating layer.
  • the tensile strength of the adhesive layer is at most 0.1 N / mm 2 and the bond strength (on steel) of the release layer is at most 0.01 N / cm 2 , preferably at most 0.001 N / cm 2 .
  • the double layer can be present simply or even several times (at least twice) in a TTS according to the invention.
  • the adhesive layer has a bond strength (on steel) of at least 1 N / cm 2 , preferably of at least 10 N / cm 2 and a tensile strength of at most 0.1 N / mm 2 and a basis weight of at most 70 g / m 2 , preferably of at most 45 g / m 2 , more preferably of at most 25 g / m 2 .
  • the release layer has a tensile strength of more than 0.1 N / mm 2 , preferably more than 2 N / mm 2 and a bond strength (on steel) of at most 0.01 N / cm 2 , preferably at most 0.001 N / cm 2 and a basis weight of at most 30 g / m 2 , preferably of at most 20 g / m 2 , more preferably of at most 10 g / m 2 .
  • the TTS according to the invention may have at least two, preferably at least three, more preferably at least four bilayers, each having a release layer and an adhesive layer, and optionally a further adhesive layer.
  • the bilayers may be identical or different in adhesive strength, tensile strength and basis weight properties. At least two bilayers which are identical with regard to these properties are preferred.
  • the at least two double layers according to this embodiment of the invention can follow one another directly in alternation, so that there is a sequence of release layer / adhesive layer / release layer (or a multiple thereof).
  • the respective double layers can also be separated from one another by at least one further layer.
  • a base polymer which is selected from the group of the following polymers: polyisobutylene (PIB), a mixture of different polyisobutylenes (PIBs), silicone polymer, a mixture of different silicone polymers, acrylate copolymers, acrylic ester copolymers, butyl rubber, polybutylene, styrene copolymers, in particular styrene Butadiene-styrene block copolymers and styrene-isoprene copolymers, in particular styrene-isoprene, in particular styrene-isoprene-styrene block copolymers, ethylene-vinyl acetate copolymers (EVA), mixtures and copolymers thereof.
  • PIB polyisobutylene
  • PIBs polyisobutylene
  • silicone polymer a mixture of different silicone polymers
  • acrylate copolymers acrylic ester copolymers
  • the base polymer of the inner layer are PIB, a mixture of various PIBs, silicone polymer, a mixture of various acrylate copolymers, butyl rubber, polybutylene, styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, EVA, blends and copolymers thereof.
  • PIB particularly preferred are a PIB, a mixture of different PIBs, a silicone polymer and a mixture of different silicone polymers.
  • PIB and a mixture of different PIBs are particularly preferred.
  • a higher molecular weight PIB is used.
  • the molecular weight (or molecular weight) of the individual molecules is distributed over a more or less broad range due to the different degrees of polymerization.
  • a molecular weight distribution (often MWD, molecular weight distribution).
  • MWD molecular weight distribution
  • the skilled worker is familiar with various averages for defining the molecular weight, such as the number average, the viscosity average or the weight average and their determination.
  • the molecular weights of the polymers are defined in particular by the weight average and the number average.
  • the higher molecular weight PIB preferably has a weight-average molecular weight M w of from 100,000 to 1,000,000 g / mol, preferably from 150,000 to 800,000 g / mol, more preferably from 200,000 to 700,000 g / mol and particularly preferably from 250,000 to 600,000 g / mol on.
  • the higher molecular weight PIB preferably has a number average molecular weight M w of from 100,000 to 1,000,000 g / mol, preferably from 150,000 to 800,000 g / mol, more preferably from 200,000 to 700,000 g / mol and particularly preferably from 250,000 up to 600,000 g / mol.
  • a PIB having an M w of about 250,000 g / mol or a PIB having an M w of about 600,000 g / mol may be used.
  • a mixture of two different molecular weight PIBs is used.
  • a mixture of a higher molecular weight PIB with a lower molecular weight PIB is used.
  • the lower molecular weight PIB preferably has a weight-average molecular weight M w of from 10,000 to 100,000 g / mol, preferably from 20,000 to 50,000, more preferably from 30,000 to 40,000 and particularly preferably from about 36,000 g / mol.
  • the lower molecular weight PIB may preferably have a number average molecular weight M w of from 10,000 to 100,000 g / mol, preferably from 20,000 to 50,000, more preferably from 30,000 to 40,000, and particularly preferably about 36,000 g / mol.
  • a mixture of a PIB having a MW of 250,000 to 600,000 g / mol and a PIB of lower MW MW of about 36,000 g / mol is used.
  • this mixture is added to a low molecular weight polybutylene.
  • PIBs from the Oppanol series from the manufacturer BASF and / or from the Durotak series from the manufacturer Henkel can be used. Exemplary are here Oppanol 10, (low molecular weight polyisobutylene), Oppanol 12 (low molecular weight polyisobutylene), Oppanol 100 (high molecular weight polyisobutylene), Oppanol 200, Durotak 87-6908 and Durotak 618a to call.
  • the PIBs of the Durotak series can also be easily mixed by the person skilled in the art, for example from those of the Oppanol series such as B100, B10, etc.
  • DUROTAK adhesive DT-618A can be mixed as follows:
  • DT-618A 12.5% Oppanol B 100 + 62.5% Oppanol B 10 + 25% Polybutene 950.
  • PIBs according to the invention can be mixed as follows:
  • a preferred PIB adhesive is the DK which consists of 23.4% by weight PIB having a number average M w of 600,000 g / mol, 33.5% by weight PIB having a weight average M w of about 51,000 g / mol and 43 Wt .-% polybutene a polybutene having a number average Mw of about 370 g / mol.
  • the silicone polymers used in the inner layer of the TTS are of the type that form a soluble polycondensed polydimethylsiloxane (PDMS) / resin network, wherein the hydroxy groups are attached to e.g. Trimethylsilyl (TMS) groups are capped.
  • PDMS soluble polycondensed polydimethylsiloxane
  • TMS Trimethylsilyl
  • the weight ratio of resin to PDMS is 85:15 to 35:65, preferably 75:25 to 45:55, and more preferably 65:35 to 55:45.
  • x 1: heptane
  • x 2: ethyl acetate
  • x 3: toluene
  • other silicone adhesives can be used.
  • BIO-PSA 07-420x has a 65:35 resin-PDMS ratio of average tack
  • BIO-PSA 07-430x has a high tack ratio of 55:45.
  • two or more silicone adhesives are used as the main adhesive components. It may be advantageous if such a mixture of silicone adhesives is a mixture of highly adhesive, pressure-sensitive Adhesives comprising PDMS with a resin (eg 07-430x) and medium tack adhesive silicone pressure sensitive adhesives comprising PDMS with a resin (eg 07-420x).
  • Such a blend comprising a high and intermediate tack pressure-sensitive silicone adhesive comprising PDMS with a resin is advantageous because it provides an optimum balance between good adhesion and low cold flow. Excessive cold flow can result in too soft a patch which easily sticks to the patient's wrapper or garments. In addition, such a mixture may be especially useful for obtaining higher plasma levels.
  • a blend of the aforementioned 07-420x (medium tack) and 07-430x (high tack) proved to be particularly useful in the inner layer for the TTSs of the present invention. Preference is given here mixing ratios between silicone adhesive with average tackiness to silicone adhesive with high tack of from 1:50 to 50: 1, more preferably from 1:10 to 10: 1 and in particular from about 1: 1.
  • low-tack silicone polymers (440X low-tack), medium-tack 450X or high-tack 460X adhesives are used.
  • These are silicone polymers of the type that form a soluble polycondensed polydimethylsiloxane (PDMS) / resin network
  • the weight ratio of resin to PDMS is 85:15 to 35:65, preferably 75:25 to 45:55, and more preferably 65:35 to 55:45.
  • These three classes of silicone adhesives are summarized in Table 2 under the term "standard silicone adhesive". Selected examples are BIO-PSA 7-4401, BIO-PSA 7-4402, BIO-PSA 7-4501, BIO-PSA 7-4502, BIO-PSA 7-4601 and BIO-PSA 7-4602.
  • the silicone adhesive BIO-PSA 7-4502 is used.
  • low-tack 410X
  • medium-tack 420X
  • high-tack high-tack
  • the amine-compatible silicone adhesive BIO-PSA 7-4202 is used.
  • the silicone adhesive contains an oil which is capable of affecting the adhesive properties of the silicone adhesive.
  • the oil may be added to high, medium or low adhesion silicone adhesives or mixtures thereof.
  • the oil may be selected from silicone oils, paraffin oils and neutral oils.
  • Polydimethylsiloxanes having kinematic viscosities in the range from 100 to 12500 m 2 s -1 can be used in particular as silicone oils.
  • Typical products are Dow Corning Q7-9120 polydimethylsiloxane having a viscosity of 20 m 2 s -1 , 100 m 2 s -1 , 1000 m 2 s -1 and 12,500 m 2 s -1 .
  • Neutral oils are understood to mean medium-chain triglycerides. These are, in particular, triglycerides of caprylic and / or capric acid chains.
  • Pigaffin oils are understood to be medicinal grade white oils (paraffinum liquidum.)
  • white oils which can be used according to the invention are Shell Ondina 933 and 941.
  • Shell Ondina 933 is a white oil with a density of 0.883 g / cm 3 at 15 ° C, a dynamic viscosity of 212 mPas at 20 ° C and a molecular weight of 415 g / mol
  • Shell Ondina 941 is a white oil with a density of 0.868 g / cm 3 at 15 ° C, a dynamic viscosity of 268 mPas at 20 ° C and a molecular weight of 530 g / mol.
  • a silicone oil is used in the silicone layer.
  • Particular preference is given to using polydimethylsiloxane having the viscosity 12,500 m 2 s -1 .
  • the concentration of the oil in the silicone adhesive is in the range of 0.01% to 10% by weight of the silicone adhesive. Below 0.01% by weight, the oil has no effect on the properties of the silicone adhesives. More than 10% by weight of oil can not be incorporated into the silicone adhesive.
  • the concentration of the oil is in the range of 0, 1 wt .-% to 5 wt .-%. Above 5%, the oil, if it can be incorporated, lead to a cold flow of silicone adhesive. Below 0.1% by weight the effect achieved with the oil is too low.
  • Particularly preferred concentration of oil is in the range of 0.5% by weight to 1, 5 wt.%. In particular, the concentration of oil in the silicone adhesive is about 1%.
  • hotmelt silicone adhesives which are solvent-free and become liquid by heat treatment. These silicone adhesives are referred to in Table 2 as "HM silicone adhesive”.
  • styrene block copolymer-based adhesives bearing non-elastomeric styrene blocks at the ends and elastomeric blocks at the center are used. These are referred to as "SxS pressure-sensitive adhesives" in Table 2.
  • the elastomeric blocks may, for example, consist of polyethylene butylene, polyethylene-propylene, polybutadiene, polyisobutylene or polyisopropene.
  • Suitable SxS adhesives are described, for example, in US Pat. No. 5,559,165 or US Pat. No. 5,527,536 and are distinguished by good adhesive properties, simple production and processing and good skin compatibility.
  • SxS pressure-sensitive adhesives can be obtained commercially (eg as Duro Tak 378-3500 from National Starch & Chemical) as well as with a hot-melt extrusion equipment in the production of the active ingredient-containing patches themselves.
  • appropriate amounts at least the following constituents of a styrene block copolymer (eg Shell Kraton GX1657 or Kraton D-1107CU) with an aliphatic and / or aromatic resin (eg Keyser Mackay Regalite R1090 or Regalite R1010 or Regalite R1100) and a Oil (eg Shell Ondina 933 or Ondina 94) dosed from the individual metering stations in the extruder, where they are mixed and melted.
  • a styrene block copolymer eg Shell Kraton GX1657 or Kraton D-1107CU
  • an aliphatic and / or aromatic resin eg Keyser Mackay Regalite R1090 or Regalite R1010
  • the active ingredient is metered into the extruder in the pressure-sensitive adhesive thus prepared and the mass is laminated to films.
  • Typical Exemplary Parts by Weight Polymer: Resin: Oil are, for example, 100: 120: 20 or 100: 200: 50.
  • the properties of the SxS pressure-sensitive adhesive can be adapted in each case to the desired properties of the TTS (bond strength, minimum cold flow, adhesive time, release profile of the active substance, etc.).
  • a copolymer of butene and isobutylene is used. This is referred to as "BIB" in Table 2.
  • An example of this is PAR 950.
  • the polymer used for the inner layer is a thermoplastic polymer of butene-1. This is referred to as "polybutene” in Table 2.
  • polybutene in contrast to the branched polyisobutylene, the polybutene monomers are linear and largely isotactic, giving altogether high molar masses of 700,000 to 3,000,000 g / rnol by way of example Called indopol.
  • the polymer used for the inner layer is a copolymer of ethylene and vinyl acetate. This is referred to in Table 2 as "EVA”.
  • hydrophobic polymers and copolymers may comprise further hydrophilic monomers, the proportion of these hydrophilic monomers being at most 50 mol%, preferably at most 30 mol%, particularly preferably at most 10 mol%.
  • the base polymer of the inner layer is preferably hydrophobic.
  • the adhesive layer comprises base polymer of at least 20% by weight, preferably at least 30% by weight, more preferably at least 40% by weight. Most preferably, the inner layer contains at least 80 wt .-% base polymer.
  • a base polymer selected from the group of the following polymers: polyisobutylene (PI), a mixture of different polyisobutylenes, silicone polymer, a mixture of different silicone polymers, acrylate copolymers, acrylic ester copolymers, butyl rubber, polybutylene, styrene copolymers, especially styrene-butadiene-styrene Block copolymers and styrene-isoprene copolymers, in particular styrene-isoprene, in particular styrene-isoprene-styrene block copolymers, ethylene-vinyl acetate copolymers (EVA), mixtures and copolymers thereof.
  • PI polyisobutylene
  • PIB PIB
  • silicone polymer a mixture of various silicone polymers
  • acrylate copolymers butyl rubber, polybutylene, styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, EVA, blends and copolymers thereof.
  • PIB particularly preferred are a PIB, a mixture of different PIBs, a silicone polymer and a mixture of different silicone polymers.
  • PIB and a mixture of different PIBs are particularly preferred.
  • the base polymer of the outer layer is preferably hydrophobic.
  • the adhesive layer comprises base polymer of at least 20% by weight, preferably at least 30% by weight, more preferably at least 40% by weight. Most preferably, the outer layer contains at least 80 wt .-% base polymer.
  • the above embodiments of the inner layer are identically transferable to the inner layer.
  • the outer and inner layers may have different polymeric compositions.
  • the outer layer has the same polymeric composition as the inner layer.
  • the base polymer of the middle layer - which in the above-mentioned embodiments of the TTS corresponds to a double layer of the release layer - are in particular all physiologically acceptable hygroscopic polymers, which reaches a layer with the preferred higher tensile strength against the inner and outer layer (adhesive layer).
  • the base polymer of the middle layer is preferably selected from the group of the following polymers: polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), partially hydrolyzed polyvinyl acetate, poly (vinylpyrrolidone-co-vinyl alcohol), polysaccharides, preferably a water-soluble starch derivative, a modified cellulose, which preferably water-soluble, pullulan and alginate and mixtures and copolymers thereof.
  • PVA polyvinyl alcohol
  • PVP polyvinylpyrrolidone
  • partially hydrolyzed polyvinyl acetate partially hydrolyzed polyvinyl acetate
  • poly (vinylpyrrolidone-co-vinyl alcohol) polysaccharides, preferably a water-soluble starch derivative, a modified cellulose, which preferably water-soluble, pullulan and alginate and mixtures and copolymers thereof.
  • PVP PVP
  • PVA PVA
  • mixtures or copolymers of these PVP.
  • the PVP can in principle be used in all available molecular weights.
  • PVPs it is known that the hygroscopic profile, as shown by way of example in FIG. 5 for a soluble PVP, can be applied to all PVP types and is thus independent of the molecular weight of the respective PVP.
  • the concrete selection of one or more PVPs for the middle layer of the TTS according to the invention is familiar to the person skilled in the art and the embodiments taught below are therefore intended to be illustrative only and not limit the invention.
  • PVP having a weight-average molecular weight M w of from 20,000 to 3,000,000 g / mol, preferably from 100,000 to 2,500,000 g / mol, more preferably from 500,000 to 2,000,000 g / mol, and particularly preferably from 1,000,000 to 1,500 .000 g / mol used.
  • sol.-PVP soluble polyvinylpyrrolidone derivative
  • Preferred examples of sol.-PVAs include Kollidon 12 PF, Kollidon 17 PF, Kollidon 25, Kollidon 30, Kollidon 30 LP and Kollidon 90 F.
  • an insoluble, crosslinked polyvinylpyrrolidone derivative is used which is referred to as "CL-PVP" in Table 2.
  • CL-PVAs include Kollidon CL, Kollidon CL-F, Kollidon CL -SF and Kollidon CL-M.
  • a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, preferably in a mass ratio of 6: 4, is used, which is referred to as "VP / VAc" in Table 2.
  • VP / VAc a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, preferably in a mass ratio of 6: 4
  • Preferred Examples of VP / VAc include Kollidon VA64 and Kollidon VA64 fine.
  • PVA used according to the invention
  • PVAs in all available molecular weights, degrees of hydrolysis and degrees of polymerization.
  • the concrete selection of one or more PVAs for the middle layer of the TTS according to the invention is familiar to the person skilled in the art and the embodiments taught below are therefore intended to be illustrative only and not limit the invention.
  • PVA having a weight average molecular weight MW of from 5,000 to 100,000 g / mol, preferably from 10,000 to 50,000 g / mol, more preferably from 20,000 to 40,000 g / mol, and particularly preferably about 31,000 g / mol is used.
  • a preferred PVA has a number average molecular weight M w of from 5,000 to 100,000 g / mol, preferably from 10,000 to 50,000 g / mol, more preferably from 20,000 to 40,000 g / mol, and particularly preferably about 31,000 g / mol.
  • the average degree of polymerization P w of the PVA used is preferably between 100 and 2050, preferably between 200 and 1025, more preferably between 400 and 825 and particularly preferably about 630.
  • the degree of hydrolysis (saponification) of the PVA is preferably 75 to 100 mol%, preferably 80 to 95 mol%, more preferably 85 to 90 mol%, and particularly preferably about 87 ⁇ 1 mol%.
  • partially hydrolyzed polyvinyl alcohol is used, which is referred to as "TH-PVA" in Table 2.
  • ⁇ -PVAs are Mowiol 3-85, Mowiol 4-88, Mowiol 5-88, Mowiol 8- 88, Mowiol 13-88, Mowiol 18-88, Mowiol 23-88, Mowiol 26-88, Mowiol 32-88, Mowiol 40-88, Mowiol 47-88 and Mowiol 30-92
  • VH-PVA fully hydrolyzed polyvinyl alcohol
  • TH-PVA fully hydrolyzed polyvinyl alcohol
  • PVP from the Kollidon series from the manufacturer BASF, in particular Kollidon 90 F, and PVA from the Mowiol series from the manufacturer Clariant, in particular Mowiol 4-88, can be used.
  • polysaccharides used according to the invention it is possible in principle to use polysaccharides in all available molecular weights, degrees of branching and substitution patterns.
  • the concrete selection of one or more Polysaccharides for the middle layer of the TTS according to the invention is familiar to the person skilled in the art and the embodiments taught below are therefore intended to be illustrative only and not limit the invention.
  • the skilled person can suitably use konjac rubber which has an extremely high Water absorption capacity of 1: 50 has.
  • polysaccharides are to be understood as meaning molecules in which at least 10 monosaccharide molecules are linked via a glycosidic bond
  • Preferred examples include alginates, agar-agar, carrageenan, guar gum, konjac gum, locust bean gum, oat beta-glucan, pectin, Xanthan gum, guar hydroxypropyltrimonium chloride and sodium hyaluronate.
  • modified celluloses used according to the invention it is possible in principle to use cellulose derivatives in all available molecular weights, degrees of branching and substitution patterns.
  • the specific selection of one or more modified celluloses for the middle layer of the TTS according to the invention is familiar to the person skilled in the art and the embodiments taught below are therefore intended to be illustrative only and do not represent a limitation of the invention.
  • modified celluloses are reported in Table 2 as "Mod. Preferred examples are ethylcellulose (EC), MC (Metolose®, methylcellulose, cellulose methylated), HPMC (Metolose®, MHPC, hypromellose, hydroxypropyl methylcellulose), HPMC phthalate (HPMC-P, hypromellose phthalate), AQOAT (HPMC-AS, hypromellose acetate succinate), L-HPC (hydroxypropyl cellulose, low substituted), USP, carboxy methylcellulose (CMC) and microcrystalline cellulose (MCC).
  • EC ethylcellulose
  • MC Methodolose®, methylcellulose, cellulose methylated
  • HPMC Metolose®, MHPC, hypromellose, hydroxypropyl methylcellulose
  • HPMC phthalate HPMC phthalate
  • HPMC-P hypromellose phthalate
  • AQOAT HPMC-AS, hypromellose acetate succinate
  • hydrophilic polymers and copolymers may comprise further hydrophobic monomers, the proportion of these hydrophobic monomers being at most 50 mol%, preferably at most 30 mol%, particularly preferably at most 10 mol%.
  • the at least one base polymer used in the middle layer is preferably hydrophilic. Furthermore, it is also preferably non-self-adhesive.
  • the middle Layer preferably contains base polymer to at least 20 wt .-%, preferably at least 30 wt .-%, most preferably at least 40 wt .-%.
  • Silicone polymer silicone polymer, especially a polycondensed PDMS / resin network with a resin to PDMS ratio of 65:35 to 55:45
  • Silicone Polym.-Gem Blend of two silicone polymers, esp. Of two polycondensed PDMS / resin networks, one with a resin-PDMS weight ratio of about 65:35 and one with a ratio of about 55:45
  • Styrene-isoprene styrene-isoprene copolymers, in particular styrene-isoprene-styrene block copolymer "styrene-butadiene”: styrene-butadiene-styrene block copolymer
  • PIB poly (vinyl pyrrolidone PIB
  • PIB poly (vinylpyrrolidone-silicone polym. Gem.
  • PIB poly (vinyl pyrrolidone PIB / polybutylene co-vinyl alcohol
  • PIB poly (vinylpyrrolidone-styrene-butadiene co-vinyl alcohol
  • butyl rubber polyvinyl acetate, t.h. butyl rubber
  • butyl rubber polyvinyl acetate, t.h. Styrene-butadiene
  • Styrene-isoprene poly (vinylpyrrolidone-styrene-isoprene

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Abstract

L'invention concerne un système thérapeutique (TTS) à au moins trois couches, contenant notamment de la rotigotine comme principe actif. Le TTS comprend une couche centrale contenant un principe actif et comprenant au moins un polymère ou copolymère hygroscopique, une couche interne perméable au principe actif et une couche externe.
EP14741516.0A 2013-06-14 2014-06-16 Système thérapeutique transdermique (tts) à trois couches Withdrawn EP3007685A1 (fr)

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JPWO2018199015A1 (ja) * 2017-04-26 2020-03-12 ニプロ株式会社 経皮吸収型製剤およびその製造方法
JPWO2018199018A1 (ja) * 2017-04-26 2020-03-12 ニプロ株式会社 経皮吸収型製剤およびその製造方法
DE102018120505A1 (de) * 2017-10-20 2019-04-25 Amw Gmbh Verhinderung der Kristallisation von Wirkstoffen in transdermalen Darreichungssystemen
DE102017124627A1 (de) * 2017-10-20 2019-04-25 Amw Gmbh Transdermales Darreichungssystem enthaltend einen Dopaminagonisten
FI3854388T3 (fi) * 2020-01-24 2023-11-27 Luye Pharma Switzerland Ag Transdermaalinen hoitojärjestelmä, jossa on vaikuttava aine rotigotiini ja ainakin yksi ei-amiiniresistentti silikoniliima
DK180828B1 (en) * 2020-06-25 2022-05-06 Mlmc Therapeutics Aps Method for manufacturing a multi-layered film structure and method for manufacturing multi-layered microstructures
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DE10147036A1 (de) 2001-09-25 2003-04-30 Tesa Ag Verfahren zum Delaminieren einer zumindest einschichtigen ersten Bahn von einem Laminat und zum anschließenden Laminieren einer zumindest einschichtigen weiten Bahn auf das Restlaminat
DE10234673B4 (de) * 2002-07-30 2007-08-16 Schwarz Pharma Ag Heißschmelz-TTS zur Verabreichung von Rotigotin und Verfahren zu seiner Herstellung sowie Verwendung von Rotigotin bei der Herstellung eines TTS im Heißschmelzverfahren
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