EP3200774A1 - Système thérapeutique transdermique à base de rotigotine pour traiter la maladie de parkinson - Google Patents

Système thérapeutique transdermique à base de rotigotine pour traiter la maladie de parkinson

Info

Publication number
EP3200774A1
EP3200774A1 EP15775423.5A EP15775423A EP3200774A1 EP 3200774 A1 EP3200774 A1 EP 3200774A1 EP 15775423 A EP15775423 A EP 15775423A EP 3200774 A1 EP3200774 A1 EP 3200774A1
Authority
EP
European Patent Office
Prior art keywords
transdermal therapeutic
therapeutic system
rotigotine
weight
microemulsion
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Withdrawn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
EP15775423.5A
Other languages
German (de)
English (en)
Inventor
Thomas Beckert
Rita STEIGMÜLLER
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.)
Neuraxpharm Arzneimittel GmbH
Original Assignee
Neuraxpharm Arzneimittel 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 Neuraxpharm Arzneimittel GmbH filed Critical Neuraxpharm Arzneimittel GmbH
Publication of EP3200774A1 publication Critical patent/EP3200774A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the invention relates to a transdermal therapeutic system comprising a microemulsion with rotigotine, as well as a method for the production of the transdermal therapeutic system and the use of the transdermal therapeutic system for the treatment of Parkinson's disease.
  • Rotigotine is an active ingredient for the treatment of dopamine deficiency disorders, e.g. Parkinson's disease and restless leg syndrome.
  • Rotigotine is a dopamine antagonist, i. it works similar to dopamine. Since the human gastrointestinal tract can not absorb the drug, it is usually administered in the form of patches, so-called transdermal therapeutic systems (TTS).
  • TTS transdermal therapeutic systems
  • acrylate and methacrylate copolymers polyisobutylene polymers (PIB), silicone polymers and styrene polymers are used as adhesive.
  • EP 1 256 339 B1 describes a transdermal therapeutic system based on silicone for the treatment of Parkinson's disease.
  • the patch has a silicone adhesive that reacts to pressure. Since silicone adhesives are less tacky than other adhesives, the patch must be pressed onto the skin for at least 1 minute.
  • TTS transdermal therapeutic system
  • a microemulsion according to the invention is understood to mean a transparent, thermodynamically stable emulsion.
  • the transdermal therapeutic system according to the invention preferably has 8.3-9.6% by weight of rotigotine.
  • the ratio of rotigotine to polyvinylpyrrolidone is preferably ⁇ 1.5: 1 or> 2.57: 1.
  • the transdermal therapeutic system preferably contains 0.1 to 20% by weight, more preferably 0.1 to 13.0% by weight, of at least one uncrosslinked polyvinylpyrrolidone.
  • the transdermal therapeutic system preferably contains exclusively polyvinylpyrrolidone which is not crosslinked, ie uncrosslinked.
  • Kollidon ® 25 or Kollidon ® 90 is the Fa. BASF used as polyvinylpyrrolidone.
  • the only adhesive used is polyisobutylene (PIB).
  • the adhesive PIB is preferably used at 69.5-86.5 wt .-% in the TTS and forms the adhesive matrix, ie the outer phase of the microemulsion in which the active ingredient is dissolved.
  • a suitable PIB is Duro-TAK ® 87-6908 Henkel Limited.
  • the microemulsion contains 0.1-10% by weight of a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a ratio of 2: 1: 1.
  • a suitable cationic copolymer is Eudragit ® E 100 from Evonik.
  • the solvents used are preferably heptane and / or isopropanol.
  • the microemulsion of the transdermal therapeutic system according to the invention contains in one embodiment additional adjuvants, preferably antioxidants.
  • additional adjuvants preferably antioxidants.
  • Suitable antioxidants are, for example, 2- (2-ethoxyethoxy) ethanol, ascorbyl palmitate, DL- ⁇ -tocopherol or sodium metabisulfite.
  • microemulsion of the transdermal therapeutic system according to the invention preferably consists of
  • heptane and isopropanol are preferably used according to the invention.
  • polyisobutylene and polyvinylpyrrolidone can be mixed in solution. Since PIB and polyvinylpyrrolidone show a completely different solubility behavior, a mixture of the two polymers in solution previously appeared unlikely. In particular, it was unexpected that uncrosslinked polyvinylpyrrolidone could be blended with PIB and rotigotine.
  • FIG. 1 shows a picture of the microemulsion of the transdermal therapeutic system according to the invention at 400 ⁇ magnification (ROT-PEP-004). As can be seen in Figure 1, the microemulsion is crystal-free and shows only emulsion drops but no crystal formations.
  • a microemulsion is a very advantageous system for drug permeation.
  • the microemulsion forms in the inner phase a reservoir of liquid droplets, which supplies the outer phase continuously from their active ingredient supply.
  • the active ingredient can be well dosed, so that it is optimally utilized.
  • microemulsion droplets containing the active ingredient are embedded in the adhesive matrix.
  • the diffusion of the drug from the TTS is controlled by the solubility of the drug in the matrix.
  • the microemulsion droplets form the Reservoirs from which the adhesive matrix is supplied. From the adhesive matrix, the drug diffuses through the skin of the patient, thus ensuring the drug level.
  • the system according to the invention shows a good skin permeation. It has been found that an increase in the amount of polyvinylpyrrolidone leads to an acceleration of skin permeation.
  • the combination of polyvinylpyrrolidone with the described cationic copolymer also increases the stability of the microemulsion droplets. It is thereby possible to incorporate larger amounts of the active ingredient rotigotine stably into a transdermal therapeutic system.
  • Transdermal therapeutic systems according to the invention which have been stored for 16 months at room temperature, still show a stable system. It has been found that formulations with PIB prepared without a cationic copolymer are rougher on the surface and the microemulsion droplets are not as stable as voids are formed.
  • the transdermal therapeutic system according to the invention preferably has two films and an adhesive matrix, which is located between the films.
  • the films used are differentiated due to different functions and materials in protective layer (release liner) and cover film (backing).
  • the release liner is coated with the adhesive matrix.
  • Suitable protective layers are, for example, PET films with modified surfaces or silkonized or otherwise non-adhesive coatings, such as Loparex 78 HL, 75 ⁇ layer thickness.
  • the cover film is applied to the TTS after the adhesive matrix has dried.
  • the cover film is eg a PE film with different coatings, such as ethyl vinyl acetate (EVA).
  • the wet layer thickness of the TTS according to the invention is preferably about 120-140 ⁇ and the dry layer thickness preferably 30-50 ⁇ .
  • This applied amount of adhesive matrix corresponds to a rotigotine concentration of, for example, 0.35-0.5 mg / cm 2 , preferably 0.45 mg / cm 2 .
  • the TTS according to the invention additionally contains a membrane which serves to control the release of active ingredient.
  • Figure 2 shows schematically the structure of such a transdermal therapeutic system according to the invention. On the protective layer 1, a layer 2 of the active substance-containing adhesive matrix is applied. This is limited to the other side by the cover layer 3.
  • the invention further provides a process for the preparation of a transdermal therapeutic system according to the invention, comprising the steps of: a) preparing a solution of a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a ratio of 2: 1: 1,
  • step c) mixing the solutions according to step a.) and b.) with the active ingredient rotigotine while stirring until a clear solution is formed
  • step d applying the solution according to step c. on an active substance impermeable protective layer.
  • the adhesive matrix consists of a microemulsion.
  • the components are stirred at temperatures between 30 and 60 ° C, preferably between 35 and 45 ° C for 30 - 60 minutes at 100 rpm with a T-bar stirrer.
  • the invention further relates to the use of a transdermal therapeutic system according to the invention for the treatment of dopamine-related disorders, preferably Parkinson's disease and restless leg syndrome, particularly preferably Parkinson's disease.
  • the daily dose of rotigotine is preferably 4-8 mg / day.
  • the invention further relates to a transdermal therapeutic system according to the invention for the treatment of dopamine-related disorders, preferably Parkinson's disease and Restless Leg syndrome, particularly preferably Parkinson's disease.
  • dopamine-related disorders preferably Parkinson's disease and Restless Leg syndrome, particularly preferably Parkinson's disease.
  • Example 1 Preparation of a microemulsion according to the invention a. Preparation of the stabilizer solution
  • microemulsion 1 12.5 g of polyisobutylene (Durotak 87-6908) were placed in a beaker. 37 g of the according to step b. prepared PVP solution and 7 g of EUDRAGIT solution prepared according to step a were added. Subsequently, 10 g of rotigotine and 20 g of heptane were added. The antioxidants were added in the concentration of 0.0006% sodium metabisulfate, 0.02% palmitoyl ascorbic acid and 0.05% all-rac-alpha-tocopherol.
  • a plaster extract was prepared with a dry coating thickness of 30-50 ⁇ .
  • microemulsions according to the invention were prepared according to the above procedure with the following compositions. Skin permeation was determined in each case for the TTS thus obtained.
  • Table 1 Composition of TTS according to the invention, all data in wt .-% based on the dry weight of the plaster
  • Skin permeation basically follows the principle of a vertically positioned Franz cell.
  • a piece of plaster is adhered to standardized mouse skin.
  • the mouse skin is placed with the non-stick side on a 1 cm 2 opening in an acceptor vessel and fixed.
  • a sample is taken from the acceptor vessel and analyzed.
  • the amount of active ingredient defined by the mouse skin from the patch is determined.
  • Adhesion and release force determination with the T300 tensile tester is a method by which the adhesive and release force of a transdermal therapeutic system (TTS) can be defined.
  • TTS transdermal therapeutic system
  • the bond strength describes the force required to pull a TTS off a steel plate.
  • a TTS is cut to a defined size of 25mm x150mm.
  • the protective foil is now peeled off at one end (10 mm) and the TTS is glued to the steel plate.
  • the protective foil is peeled off at the middle part of the TTS and the TTS is fixed on the steel plate by means of a pressure roller (1 kg). This ensures a consistent adhesion force.
  • the second end of the TTS, which is still provided with the protective film is clamped in a gripper, which is mounted on a tensile tester. This will measure the force needed to pull the TTS off the steel plate.
  • the release force describes the force required to remove a TTS from the protective film.
  • a TTS is cut out in the same dimensions as in the adhesion measurement.
  • a double-sided adhesive tape of the same size is glued to the protective foil.
  • the specimen is fixed in the same manner as in the adhesion measurement on the steel plate. It is only at the middle part of the TTS not the protective film of the TTS, but peeled off the protective film of the double-sided adhesive tape.
  • the force required to pull the TTS from the protective film is measured
  • Table 2 Composition of TTS according to the invention, all data based on the dry weight of the plaster

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un système thérapeutique transdermique (TTS) comprenant une microémulsion comportant de la rotigotine, ainsi qu'un procédé pour produire ledit système thérapeutique transdermique et l'utilisation du système thérapeutique transdermique dans le traitement de la maladie de Parkinson.Le TTS selon l'invention présente étonnamment de bonnes propriétés d'adhérence tout en garantissant une administration constante de principes actifs.
EP15775423.5A 2014-10-01 2015-09-30 Système thérapeutique transdermique à base de rotigotine pour traiter la maladie de parkinson Withdrawn EP3200774A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102014114282.9A DE102014114282A1 (de) 2014-10-01 2014-10-01 Transdermales therapeutisches System mit Rotigotin zur Behandlung von Morbus Parkinson
PCT/EP2015/072522 WO2016050824A1 (fr) 2014-10-01 2015-09-30 Système thérapeutique transdermique à base de rotigotine pour traiter la maladie de parkinson

Publications (1)

Publication Number Publication Date
EP3200774A1 true EP3200774A1 (fr) 2017-08-09

Family

ID=54256737

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15775423.5A Withdrawn EP3200774A1 (fr) 2014-10-01 2015-09-30 Système thérapeutique transdermique à base de rotigotine pour traiter la maladie de parkinson

Country Status (3)

Country Link
EP (1) EP3200774A1 (fr)
DE (1) DE102014114282A1 (fr)
WO (1) WO2016050824A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018143384A1 (fr) * 2017-02-03 2018-08-09 コスメディ製薬株式会社 Patch de type à absorption percutanée contenant de la rotigotine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1256339E (pt) 2001-05-08 2004-02-27 Lohmann Therapie Syst Lts Sistema terapeutico transdermico para doenca de parkinson que induz niveis plasmaticos altos de rotigotina
CN101147739B (zh) * 2007-07-06 2010-12-08 北京康倍得医药技术开发有限公司 含罗替戈汀的组合物及其制药用途以及含该组合物的透皮贴剂
EA025584B1 (ru) * 2009-12-22 2017-01-30 ЮСиБи ФАРМА ГМБХ Поливинилпирролидон для стабилизации твердой дисперсии некристаллической формы ротиготина
WO2012084969A1 (fr) * 2010-12-22 2012-06-28 Hexal Ag Composition adhésive contenant de la rotigotine et système thérapeutique transdermique comprenant la composition adhésive

Also Published As

Publication number Publication date
DE102014114282A1 (de) 2016-04-07
WO2016050824A1 (fr) 2016-04-07

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