EP2646008A1 - Système thérapeutique transdermique contenant de la rotigotine - Google Patents

Système thérapeutique transdermique contenant de la rotigotine

Info

Publication number
EP2646008A1
EP2646008A1 EP11790776.6A EP11790776A EP2646008A1 EP 2646008 A1 EP2646008 A1 EP 2646008A1 EP 11790776 A EP11790776 A EP 11790776A EP 2646008 A1 EP2646008 A1 EP 2646008A1
Authority
EP
European Patent Office
Prior art keywords
rotigotine
tts
tts according
active ingredient
matrix layer
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Withdrawn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
EP11790776.6A
Other languages
German (de)
English (en)
Inventor
Christian Drescher
Christian Janssen
Ulrich Becker
Armin Breitenbach
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.)
Ratiopharm GmbH
Original Assignee
Ratiopharm 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 Ratiopharm GmbH filed Critical Ratiopharm GmbH
Priority to EP11790776.6A priority Critical patent/EP2646008A1/fr
Publication of EP2646008A1 publication Critical patent/EP2646008A1/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Withdrawn legal-status Critical Current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
    • 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
    • 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

Definitions

  • TTS Transdermal Therapeutic System
  • the present invention relates to a rotigotine-containing patch for the transdermal delivery of the pharmaceutical active substance rotigotine, comprising a carrier layer (1), a matrix layer containing the active substance (2), a removable before application to the skin, peelable protective film ( 4), characterized in that between the matrix layer (2) and the peelable protective film (4) an additional intermediate layer (3) is applied over the entire area.
  • Rotigotine (-) - 5,6,7,8-Tetrahydro-6- [propyl [2- (2-thienyl) ethyl] amino] -1-naphthol] is a pharmaceutically active substance useful in the treatment of among others Crohn's
  • Parkinson is used.
  • Drug is a transdermal therapeutic system (TTS).
  • TTS transdermal therapeutic system
  • Neupro from UCB contains the active substance embedded in a polymer matrix, in an amount above the saturation concentration.
  • Supersaturated active substance / polymer systems are known to be metastable, ie under unfavorable conditions, the active substance may crystallize: For example, a recall campaign for NEUPRO had to be started because active ingredients crystallized out of the plasmas (see FIG Crystallized drug can cause a variety of problems: For example, less active ingredient is
  • Crystallized active ingredient may also adversely affect the adhesive properties (adhesion or cohesion) of the adhesive matrix. Even today a cold chain is required for transport and storage of NEUPRO® and it is recommended to keep NEUPRO in the refrigerator.
  • self-adhesive polymers often contain free functional groups, such as hydroxyl (OH) or carboxyl (COOH) groups, which interact with the active ingredient and can thereby adversely affect its crystallization and release behavior.
  • free functional groups such as hydroxyl (OH) or carboxyl (COOH) groups
  • the object is to provide a rotigotine TTS, which allows the independent optimization of the adhesive properties and the release behavior.
  • This object has been achieved by providing a drug containing the active ingredient rotigotine transdermal therapeutic system (TTS) with a drug-impermeable carrier layer (1), containing the active ingredient
  • Matrix layer (2) and a peelable protective film (4) to be removed before application to the skin, characterized in that between the
  • the adhesive properties of the TTS are determined by suitable choice of the intermediate layer (3). Due to the inventive structure of the TTS so the release properties for the drug and the
  • Adhesive properties of the patch are modulated independently.
  • Non-self-adhesive polymers in the context of this invention are those whose
  • Adhesive strength is insufficient, so that a TTS invention over the entire Administration period on the human skin -without further aids-adheres.
  • non-self-adhesive polymers are polymers with longer aliphatic chains and / or those without functional groups.
  • Functional groups such as carboxyl groups, which are usually responsible for the adhesive properties of a polymer, may interact in an undesirable manner with basic drugs such as rotigotine, e.g. through salt formation.
  • polymers without these functional groups may have preferred dissolution and release properties for the active ingredient.
  • a preferred embodiment of the invention therefore relates to a TTS with an active substance-impermeable support layer (1), a matrix layer containing the active substance (2), to be removed before application to the skin,
  • the matrix layer (2) consists of a non-self-adhesive polymer.
  • Another advantage of the invention is that for the intermediate layer (3), such polymers are used, due to a very low
  • Solubility for rotigotine as a material for the stock (2) are not readily considered.
  • FIG. 2 shows the schematic structure of a TTS of a self-adhesive matrix layer containing
  • Fig. 3 shows the schematic structure of a TTS with non-adhesive matrix layer containing An active substance-impermeable support layer (1)
  • a second intermediate layer (5) which is applied in a covering manner between the matrix layer (2) and the carrier layer (1)
  • Intermediate layer (3) also has the additional advantage of avoiding direct contact of the reservoir with the cut edges of the peelable protective film (4) to be removed before applying to the skin, which obviously led to crystal formation in the marketed product Neupro® (see FIG. 1 ).
  • the active substance-impermeable support layer (1) of the plaster according to the invention is impermeable to the active ingredient and the compounds contained in the active substance-containing layer and inert, i. E. there is also no migration into the carrier layer.
  • the active substance-impermeable carrier layer can be permeable to air and water, but is preferably occlusive. On the one hand, it has to have a certain rigidity so that it sufficiently stabilizes the active substance-containing matrix layer (2) so that the TTS can be handled, but on the other hand it must also have a certain sufficient flexibility so that even larger TTS patches can still adapt to the skin to ensure sufficient comfort.
  • the active substance impermeable carrier layer (1) consists of polymers such as polyesters (for example PET), polyolefins (for example PE), polycarbonates, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyvinyl acetates and polyvinyl chlorides. Preference is given to an aluminum-vapor-deposited PE / PET carrier layer (for example Scotchpak 1 109, 3M).
  • film-forming polymers such as e.g. Polyacrylates, ethylene / ethyl acrylate
  • Poliisobutylene (PIB) Poliisobutylene
  • polysiloxanes Preference is given to acrylate Copolymers, for example those of the Eudragit® type.
  • the rotigotine is preferably used in the form of the free rotigotine base.
  • the active ingredient-containing matrix layer (2) may contain excipients such as antioxidants, plasticizers, permeation promoters, solubilizers, crosslinkers, emulsifiers, preservatives and / or thickeners in addition to the pharmaceutical active ingredient rotigotine.
  • the active ingredient may be dissolved in the matrix layer (2) and / or dispersed. Preferably, the active ingredient is completely in dissolved form.
  • the solubility of the matrix layer (2) for the active ingredient rotigotine is between 4 and 30 wt .-%, preferably between 6 and 20 wt .-%, even more preferably between 8 and 15 wt .-%.
  • the active ingredient content of rotigotine in the matrix layer (2) is 4 to 30 wt .-%, preferably 6 to 20 wt .-%, more preferably 8 to 15 wt .-%, based on the total weight of the matrix layer ,
  • intermediate layer (3) are polymers based on
  • Silicones polyacrylates, polyvinyl ethers, polyisobutylenes (PIB), styrene-isoprene or butadiene-styrene copolymers, polyolefins, polyvinyl acetates, polyamides and / or ethylene-vinyl acetate copolymers.
  • PIB polyisobutylenes
  • styrene-isoprene or butadiene-styrene copolymers polyolefins
  • polyvinyl acetates polyamides and / or ethylene-vinyl acetate copolymers.
  • the intermediate layer (3) is preferably self-adhesive and preferably consists of a pressure-sensitive polymer adhesive ("pressure sensitive adhesive"), preferably of an amine-resistant silicone adhesive such as BIO-PSA Q7-4301 or BIO-PSA Q7-4201 (Dow Corning) ,
  • the intermediate layer (3) may optionally include adjuvants such as
  • Plasticizers for molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding, molding aids, and the like.
  • the thickness of the intermediate layer (3) is between 4 and 25 pm, preferably between 8 and 20 pm and particularly preferably between 10 and 15 pm.
  • the intermediate layer can optionally also serve simultaneously as a control membrane for the active substance flow.
  • the permeation of the active ingredient is reduced by not more than 20%, preferably not more than 10%.
  • the intermediate layer should, in addition to its primary function, namely the
  • the solubility of the intermediate layer for the active ingredient is therefore preferably only 5% to 15% of the solubility of the matrix layer, preferably 5% to 10%.
  • the ratio of the thickness of the matrix layer to the thickness of the intermediate layer is between 20: 1 and 3: 1, preferably between 10: 1 and 5: 1.
  • the peelable protective film (4) to be removed before application to the skin consists of polyethylene, polypropylene, polyesters (PET), polysiloxanes,
  • Paper fibers and is preferably silicone, fluorosilicone or fluorocarbon polymer coated. Preferred is fluoropolymer-coated PET liner
  • the same materials as for the first intermediate layer (3) are suitable for the second intermediate layer (5).
  • both are made of the same material.
  • the TTS preferably has a structure as shown in Fig. 1 or Fig. 2.
  • the TTS may additionally have an adhesive film ("overtape") with which the TTS is fixed on the skin.
  • the TTS has a size of 5 to 100 cm 2 , preferably 10 to 50 cm 2 .
  • the basis weight of the TTS (without the peelable protective film) is 20 to 150 g / cm 2 , preferably 30 to 100 g / cm 2 , particularly preferably 40 to 70 g / cm 2 .
  • the TTS has a bond strength of between 5 N / 25 mm 2 and 100 N / 25 mm 2 , preferably between 10 N / 25 mm 2 and 50 N / 25 mm 2 .
  • the determination of the bond strength is carried out by means of known standard methods (eg ASTM D 1000-99).
  • the patch according to the invention is suitable for transdermal
  • rotigotine over 12 hours to 3 days, that is, the wearing period of a patch extends over this period.
  • Preferred is a carrying period of 24h to 48h.
  • Preferred release rates are in the range of 0.05 g / h to 1 g / h, preferably 0.1 to 0.5 pg / h, for a substantial portion of the administration period.
  • the TTS calls in a preferred embodiment, an average maximum Plasma concentration (c max ) of rotigotine from 0.1 to 150 ng / mL, preferably 0.5 to 100 ng / mL, forth.
  • c max average maximum Plasma concentration
  • the TTS after repeated single applications, the TTS generates an AUC of 4.0 to 30 ng * h / ml_,
  • the preparation of the patch according to the invention is carried out according to known production methods.
  • the production of rotigotine TTS in the context of this invention comprises, for example, the following steps:
  • the carrier film (1) is first coated with a suitable polymer solution before the application of the matrix layer (process step c) and then dried.
  • One aspect of the present invention relates to a transdermal
  • TTS therapeutic system
  • active ingredient rotigotine in the form of the free base, comprising a drug-impermeable carrier layer (1), a matrix layer containing the active substance (2), a peelable, polymer-coated protective film (4) to be removed before application to the skin a surface-mounted between the matrix layer (2) and the peelable protective film (4)
  • TTS transdermal therapeutic system
  • the matrix layer (2) consists of a pressure-sensitive polymer adhesive in which the active ingredient is completely dissolved.
  • An embodiment of this aspect of the invention relates to a transdermal therapeutic system (TTS) containing the active ingredient rotigotine in the form of the free base, comprising a drug-impermeable carrier layer (1), a matrix layer containing the active substance (2), one before application to the Skin removable, peelable, polymer coated protective film (4) and a between the matrix layer (2) and the peelable protective film (4) surface-mounted intermediate layer (3), characterized in that the matrix layer (2) consists of a pressure-sensitive polyacrylate adhesive and between 8 and 15 wt .-% completely dissolved active ingredient.
  • Basis weight of the TTS between 30 g / cm and 100 g / cm and the ratio of the thickness of the matrix layer (2) to the thickness of the intermediate layer (3) is between 10: 1 and 5: 1.
  • the transdermal therapeutic system is characterized in that between the matrix layer (2) and the carrier layer (1), a second intermediate layer (5) is applied across the surface.
  • rotigotine can also be used as ionic liquid for the preparation of the TTS according to the invention.
  • ionic liquid refers to salts (i.e.
  • compositions comprising organic cations and organic anions) having a melting point below 40 ° C, preferably below 32 ° C.
  • Such an ionic liquid comprises at least one rotigotine cation and at least one type of counterion obtainable from an organic compound, or at least one rotigotine anion and at least one kind of counterion obtainable from an organic compound.
  • rotigotine as a cation or as an anion with organic compounds can form ionic liquids which can be readily prepared with a variety of pharmaceutically acceptable organic compounds.
  • These ionic rotigotine fluids exhibit high thermal stability and, in particular, do not cause any problems due to crystallization, such as exist for the free base and the other salts known in the art.
  • they have the advantage that there are no problems associated with the existence of polymorphic forms of the crystalline compound. Agents that exist in several polymorphic forms are often unstable when stored in the form of pharmaceutical preparations. Since changes in the crystal form can have far-reaching effects on the physicochemical parameters of a substance, it is advantageous to be able to circumvent the solid state.
  • the ionic liquids are composed of at least one rotigotine cation and at least one kind of anion, or alternatively of at least one rotigotine anion and at least one kind of cation. It will be understood by those skilled in the art that the disclosed ionic liquids may contain a rotigotine cation with more than one type of anion (eg, 2, 3, or more different types of anions). However, an anion is preferred. It will also be understood by those skilled in the art that the disclosed ionic liquids may contain a rotigotine anion having more than one type of cation (e.g., 2, 3, or more different types of cations). However, a cation is preferred.
  • the ions are preferably pharmaceutically acceptable.
  • the stoichiometry of the rotigotine ion to the counterion in the ionic liquid is between 1: 3 and 1: 1, preferably 1: 2 or 1: 1, and most preferably close to 1: 1.
  • the ionic liquid comprises a rotigotine cation and at least 50% anions of an organic acid.
  • compositions comprising rotigotine salts having various anions of organic and inorganic acids, such as HCl, of the invention are also included when at least 50% of the anions are from one
  • the organic compound from which the counterion is derived has a lipophilic character which is characterized by a value of
  • Distribution coefficient log P of more than 0 is defined. It is preferred that said lipophilic compound has a log P of> 1, more preferably of more than 2, more preferably more than 3, and most preferably more than 4.
  • the counterion as the organic compound has the following properties:
  • the invention relates to the
  • compositions comprising a rotigotine salt in the transdermal therapeutic systems (TTS) according to the invention, wherein at least 1%, preferably at least 2%, 5%, 10%, 20%, 30%, 40% or even 50% of the Salt is an ionic liquid.
  • a composition may also include rotigotine salts, such as solid salts, having various anions other than ionic liquids.
  • the ionic liquid content of rotigotine is therefore at least 1%, preferably at least 2%, 5%, 10%, 20%, 30%, 40% or even 50% of the total content of rotigotine salt in this composition.
  • a liquid of rotigotine a rotigotine anion and a cationic counterion selected from the group of cations defined below.
  • Quaternary Ammonium Compounds Specific examples of cations which may be present in the ionic liquid are compounds containing a nitrogen atom. Nitrogen atoms can exist as positively charged quaternary ammonium species or be transformed into such, for example by alkylation or protonation of the nitrogen atom. Accordingly, compounds that are a quaternary
  • Contain nitrogen atom typically cations.
  • Any compound containing a quaternary nitrogen atom or a nitrogen atom that can be transformed into a quaternary nitrogen atom may be a cation of the invention for the disclosed ionic liquids.
  • the ionic liquid comprises a rotigotine anion and at least one quaternary amine of the formula (I)
  • R 1 , R 2 , R 3 , and R 4 may each independently be H, optionally substituted C 1 -C 5 alkyl or alkenyl, optionally substituted C 6 -C 10 cycloalkyl, optionally substituted C 6 -C 12 aryl, optionally substituted C 7 -C 12 aralkyl, or wherein R 1 and R 2 taken together represent an optionally substituted C 4 -C 10 alkylene group and thereby form a 5-membered heterocyclic ring with the nitrogen atom of the formula (I), and wherein the term "optionally substituted” means that the group in question with a or more radicals, preferably between 0 and 6 radicals, selected from OH, SH, SR 5 , Cl, Br, F, I, NH 2 , CN, NO 2 , COOR 5 CHO, COR 5 and OR 5 , wherein R 5 is a C1-C10 alkyl or
  • Cycloalkyl group is substituted or unsubstituted.
  • R 1 is a C 1 -C 5 alkyl or alkenyl radical. Tetraalkyl ammonium
  • the cationic counterion is a tetraalkylammonium cation.
  • a tetraalkylammonium cation may be a long chain alkyl group (eg, having a length of 10 or more
  • Carbon atoms and three short chain alkyl groups (eg, having a length of less than 10 carbon atoms).
  • the ionic liquids may also contain an aliphatic benzylalkyl ammonium cation.
  • An aliphatic benzylalkylammonium cation is a cation comprising an aliphatic group bonded to the nitrogen atom of a benzylalkylamine.
  • the aliphatic group may be as described herein.
  • the benzylalkylamine group may be a benzylamine, wherein the amine is attached to an alkyl or cycloalkyl group as described herein.
  • One or more types of aliphatic benzylalkylammonium cations may be used in the ionic liquids are used.
  • the aliphatic benzylalkylammonium cation is represented by the formula given below:
  • R 10 represents an aliphatic group as described above, and R 11 and R 12 independently represent alkyl or cycloalkyl groups as described herein.
  • one or more of the "R" substituents may be a long chain alkyl group (ie, having 10 or more
  • one or more of the "R" substituents may be a short chain alkyl group (ie, having fewer than 10 carbon atoms). In other embodiments, one of the "R” substituents may be one long chain alkyl group and the other two “R” substituents be short chain alkyl groups.
  • Benzylalkylammonium cation have each of the alkyl groups described herein bonded to each benzylalkylamine group described herein.
  • R 10 in the formula of the aliphatic benzylalkylammonium cation may be an aliphatic group of from 10 to 40 carbon atoms, e.g. A decyl-docecyl (lauryl), tetradecyl (myristyl), hexadecyl (palmityl or cetyl),
  • R 11 and R 12 may each independently be a methyl, ethyl, propyl, butyl, pentyl, or hexyl group.
  • the aliphatic benzylalkylammonium cation may include, but is not limited to, alkyldimethylbenzylammonium cations.
  • alkyldimethylbenzylammonium cations include cetyldimethylbenzylammonium,
  • the aliphatic benzylalkylammonium cation may include, but is not limited to, alkylethylmethylbenzylammonium cations.
  • alkylethylmethylbenzylammonium cations include cetylethylmethylbenzylammonium,
  • dialiphatic dialkylammonium cation is a compound comprising two aliphatic groups and two alkyl groups bonded to the nitrogen atom.
  • the aliphatic groups may be identical or different and may include any aliphatic group as described above.
  • the alkyl groups may be identical or different and may include any alkyl group as described above.
  • the dialkyl dialkyl ammonium cations disclosed the two aliphatic groups may contain ten or more carbon atoms and the two alkyl groups may contain less than ten carbon atoms.
  • the two aliphatic groups may contain less than ten carbon atoms and the two alkyl groups may contain ten or more carbon atoms.
  • One or more types of dialkyl dialkylammonium cations can be used in the ionic liquids.
  • the dialiphatic dialkylammonium cation may be didodecyldimethylammonium, ditetradecyldimethylammonium, dihexadecyldimethylammonium, and the like, including combinations thereof.
  • choline esters e.g., acetylcholine
  • Choline esters can pass through
  • choline esters are bethanechol, carbachol, citocolin,
  • choline can be used as a counterion.
  • preferred cations are (2-hydroxyethyl) - dimethylundecyl-oxymethyl-ammonium, (2-acetoxyethyl) -heptyloxymethyldimethyl-ammonium, (2-acetoxyethyl) -dodecyloxymethyldimethyl-ammonium and mepenzolate.
  • the cationic counterions are derived from an arylamine, which is preferably ethyleneamine or piperazine.
  • the cationic counterions are derived from an alkylamine containing hydroxy groups, which is preferably diethanolamine, triethanolamine, tromethamine or N-methylglucamine.
  • ionic liquids based on amine bases of high lipophilicity such as benzathine, 4-phenylcyclohexylamine, benethamine and hydrabamine, are used.
  • an organic acid is used for the preparation of the ionic liquid.
  • This organic acid preferably has the formula R-COOH, where R is a saturated or monounsaturated, branched or unbranched C 3 -C 16 -hydrocarbon radical.
  • This hydrocarbon radical has 3 to 16, more preferably 5 to 16
  • R preferably represents a saturated, monounsaturated or polyunsaturated, unbranched C 3 -C 16 -hydrocarbon radical, more preferably a C 5 -C 6 -hydrocarbon radical.
  • Examples of preferred acids of the formula R-COOH are propionic, butyric, pentanoic, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic, lauric, tridecanoic, myristic,
  • Pentadecanoic acid and palmitic acid.
  • Octanoic acid is particularly preferred.
  • the organic acid has the formula R'- COOH, where R 'represents a polyunsaturated, branched or unbranched C 1-8-C22 hydrocarbon radical.
  • Examples of preferred acids of the formula R'-COOH are linoleic acid, alpha-linoleic acid, arachidonic acid, eicosapentic acid and docosahexenoic acid. Linoleic acid is particularly preferred. Other suitable anions may be long chain
  • Alkyl sulfonic acids for example, lauryl sulfonic acid
  • saccharin for example, saccharin or acesulfame
  • the anionic counterion is derived from a lipophilic monovalent acid.
  • the anionic counterion of a lipophilic monovalent acid represents at least 50% of the anions within the ionic liquid.
  • the lipophilic monovalent acid is preferably octanoic acid.
  • Solvent with optional heating may therefore serve to produce ionic liquids.
  • the ionic liquid of rotigotine and an organic acid as the The anion-forming reagent can be prepared by mixing rotigotine and acid and recovering the ionic liquid.
  • the mixing step is carried out in the absence of any solvent. This has the advantage that it is not necessary to remove the solvent after the formation of the ionic liquid, and also the process
  • Another advantage of the absence of solvent is that the resulting ionic liquid contains no solvent residues.
  • rotigotine and organic acid may also be mixed in the presence of one or more solvents.
  • solvents either the
  • Solvents are suspended or dissolved before the mixing step takes place.
  • the rotigotine can be dissolved in a solvent, and the acid can then be added to this solution.
  • Suitable solvents are, for example, water, alcohols, ethers, ketones, chlorinated
  • Solvents and mixtures thereof.
  • Preferred solvents are the ethers and the ketones.
  • the ionic liquid of rotigotine and an amine as the cation-forming reagent can be prepared by mixing rotigotine or a suitable acid addition salt of rotigotine and the corresponding amine and optionally an additional base in the presence of one or more solvents.
  • the rotigotine, the amine and / or the additional base may be suspended or dissolved in the same or different solvents before the mixing step.
  • rotigotine may be dissolved in the solvent and the amine and optional additional base subsequently added to this solution.
  • Suitable solvents include, for example, water, alcohols, ethers, ketones, chlorinated solvents, and mixtures thereof. Preferred solvents are alcohols.
  • additional base is a strong base, such as hydroxides or hydrides.
  • Preferred optional additional bases are sodium hydroxide and potassium hydroxide.
  • Example 1 Ionic liquid containing a rotigotine cation and an octanoate anion
  • Example 1 a 1 equivalent of octanoic acid is added to a solution of rotigotine (1 equivalent) in diisopropyl ether (5 times the volume) under nitrogen. After stirring (1 h), the solvent is removed in vacuo at 30 ° C. Drying under high vacuum for 2 h gives an oil in quantitative yield.
  • Example 1 b Rotigotine (1 equivalent) is added in a glass ampoule to one equivalent of octanoic acid. The mixture is shaken for 1 h, forming a homogeneous oil.
  • Example 2 Ionic liquid containing a rotigotine anion and a choline cation
  • Example 2a Rotigotine (1 equivalent) is dissolved in a round bottom flask in methanol (5 volumes). Potassium hydroxide (1 equivalent) and choline chloride (1 equivalent) are added and the mixture is stirred at room temperature for 1 h.
  • Example 2b Rotigotinhydrochlond (1 equivalent) is dissolved in a round bottom flask in methanol (5 volumes). Potassium hydroxide (2 equivalents) and choline chloride (1 equivalent) are added and the mixture is stirred at room temperature for 1 h. Acetone (5 volumes) is added and the solution filtered through a fine filter. The filtrate is concentrated in vacuo at room temperature and dried under high vacuum. As the product, an oily residue is obtained in quantitative yield.

Abstract

La présente invention concerne un pansement contenant le principe actif rotigotine pour l'administration transdermique du principe actif pharmaceutique rotigotine. Ledit pansement comprend une couche de support (1), une couche de matrice (2) contenant le principe actif, une feuille de protection pelable (4) à retirer avant l'application sur la peau, et est caractérisé en ce qu'une couche intermédiaire supplémentaire (3) est appliquée entre la couche de matrice (2) et la couche de protection pelable (4) de manière à recouvrir l'ensemble de la surface.
EP11790776.6A 2010-11-29 2011-11-29 Système thérapeutique transdermique contenant de la rotigotine Withdrawn EP2646008A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11790776.6A EP2646008A1 (fr) 2010-11-29 2011-11-29 Système thérapeutique transdermique contenant de la rotigotine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP10015079A EP2457565A1 (fr) 2010-11-29 2010-11-29 Système thérapeutique transdermique comportant de la rotigotine
US41907010P 2010-12-02 2010-12-02
PCT/EP2011/071321 WO2012072650A1 (fr) 2010-11-29 2011-11-29 Système thérapeutique transdermique contenant de la rotigotine
EP11790776.6A EP2646008A1 (fr) 2010-11-29 2011-11-29 Système thérapeutique transdermique contenant de la rotigotine

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EP2646008A1 true EP2646008A1 (fr) 2013-10-09

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EP (2) EP2457565A1 (fr)
EA (1) EA201300648A1 (fr)
WO (1) WO2012072650A1 (fr)

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EA201300648A1 (ru) 2013-12-30
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WO2012072650A1 (fr) 2012-06-07

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