WO2020085809A1 - Composition contenant de la rotigotine non cristalline et son procédé de préparation - Google Patents

Composition contenant de la rotigotine non cristalline et son procédé de préparation Download PDF

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Publication number
WO2020085809A1
WO2020085809A1 PCT/KR2019/014036 KR2019014036W WO2020085809A1 WO 2020085809 A1 WO2020085809 A1 WO 2020085809A1 KR 2019014036 W KR2019014036 W KR 2019014036W WO 2020085809 A1 WO2020085809 A1 WO 2020085809A1
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Prior art keywords
rotigotine
weight
detected
drying temperature
patch
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PCT/KR2019/014036
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English (en)
Korean (ko)
Inventor
최원재
김남호
안혜지
유헌승
유종수
박여진
김성혁
Original Assignee
에스케이케미칼 주식회사
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Publication of WO2020085809A1 publication Critical patent/WO2020085809A1/fr

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • 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
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide

Definitions

  • the present invention relates to compositions stably comprising amorphous rotigotine, patches comprising such compositions, and methods of making such compositions.
  • Rotigotine is known to be useful for the treatment of Parkinson's disease, Parkinson's plus syndrome, depression and restless leg syndrome, as well as for the treatment or prevention of dopamine neuronal loss. It is known that such rotigotine-containing medicines can be administered in a transdermal therapeutic system (TTS), patch, depot form, and the like.
  • TTS transdermal therapeutic system
  • WO 94/07468 is essentially a continuous phase formed by a hydrophobic polymeric material, dispersing the hydrophilic phase contained therein, and active in a two-phase matrix mainly comprising drugs and hydrated silica.
  • TTS comprising rotigotine hydrochloride as a material is disclosed.
  • the silica is said to increase the maximum possible loading of TTS together with the hydrophilic salt.
  • the formulation of WO 94/07468 mainly contains additional hydrophobic solvents, permeation promoting substances, dispersing agents and, in particular, emulsifiers necessary to emulsify aqueous solutions of the active ingredient on lipophilic polymers. do. However, this system did not provide satisfactory drug plasma concentrations.
  • WO 99/49852 discloses a TTS comprising an inert backing layer, a self-adhesive matrix layer comprising an effective amount of rotigotine or rotigotine hydrochloride and a protective film that is removed prior to use.
  • the matrix system consists of a non-aqueous polymer adhesion system based on acrylate or silicone.
  • such rotigotine may exist in various forms such as crystalline polymorph Form I, Form II, and is known to be very unstable, such as crystal polymorph changes in the composition and precipitation as crystals.
  • the problem to be solved by the present invention is to provide a rotigotine-containing composition having stability, a patch containing the composition and a method for stabilizing rotigotine.
  • a rotigotine-containing patch capable of securing the above-described stability and a method of manufacturing the same, while not affecting or desirably affecting the skin permeation rate of rotigotine in manufacturing the patch formulation.
  • the present invention provides a solid dispersion containing rotigotine, comprising a mixture of rotigotine and vinylpyrrolidone-vinyl acetate copolymer as an internal phase on the outer side of a silicone adhesive.
  • the present invention also disperses a mixed solution of rotigotine and vinylpyrrolidone-vinyl acetate copolymer forming an internal phase in a silicone-based adhesive solution forming an external phase, and then drying it (preferably, relatively low)
  • a method for stabilizing rotigotine in a silicone-based pressure sensitive adhesive including drying at a temperature, for example, 90 ° C to 100 ° C.
  • the vinylpyrrolidone-vinyl acetate copolymer of the present invention is used as a solubilizing agent for improving stability, in particular, preventing crystallization
  • first it is easy to secure mixing uniformity of the final dispersion before drying, and finally After the dispersion is prepared, rotigotine stability in the dispersion is excellent (mixing stability and stability against related substances), and layer separation does not occur, so it can be used for patch production for a longer time.
  • Second even when the drying temperature is low, it is possible to manufacture a composition and a patch having excellent stability, thereby suppressing the generation of a flexible substance that may occur when drying at a high temperature, and preventing the softening phenomenon of a film used for manufacturing the patch You can.
  • thirdly in the case of a patch manufactured by satisfying the above conditions, it exhibits very excellent stability.
  • a copolymer suitable for the specifications listed as copovidone in USP-NF, PhEur, or BP procedures can be used, for example, Kolidone® (BASF) VA64 Fine, Plasdone® S630, etc. Can be used.
  • a rotigotine free base or a pharmaceutically acceptable salt thereof may be used, and for example, acidic salts such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid may be used.
  • the mixed weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer contained in the dispersion is 9: 6 to 9:12 (rotigotine: vinylpyrrolidone-vinyl acetate copolymer). , More preferably, the mixing weight ratio is 9: 8 to 9:12.
  • the weight ratio of rotigotine to vinylpyrrolidone-vinyl acetate copolymer is about 9: 8 or more, a dried product having stability maintained regardless of the drying temperature can be prepared, and rotigotine to vinylpyrrolidone-vinyl acetate copolymer
  • the drying temperature is preferably 90 to 100 ° C from the viewpoint of securing stability.
  • the weight ratio is calculated based on the weight (i.e., reduced) in terms of rotigotine free base.
  • the vinylpyrrolidone-vinyl acetate copolymer of the present invention has an advantage that stability is maintained even at a low drying temperature.
  • an amine-compatible silicone pressure-sensitive adhesive may be used as the silicone-based pressure-sensitive adhesive that forms the external phase.
  • a silicone adhesive DOW CORNING's BIO-PSA TM 7-4101, 7-4201, 7-4301, 7-4102, 7-4202, 7-4302, 7-4103, 7-4203, 7-4303 , 7-4401, 7-4501, 7-4601, 7-4402, 7-4502, 7-4602, 7-4403, 7-4503, 7-4603, or mixtures thereof, more preferably, The silicone adhesive is BIO-PSA 7-4301, 7-4302, 7-4303, 7-4201, 7-4202, 7-4203, 7-4101, 7-4102, 7-4103 or mixtures thereof.
  • the solid dry dispersion of the present invention may optionally further include an antioxidant.
  • an antioxidant sodium metabisulfite, ascorbyl palmitate, DL-alpha-tocopherol, totocophero acetate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, propyl gallate, or a mixture thereof may be used.
  • BHA butylated hydroxyanisole
  • sodium metabisulfite, ascorbyl palmitate, DL-alpha-tocopherol, or a mixture thereof is used.
  • Antioxidants according to the invention are included in the internal phase, for example, From the time of preparing the preparation (dispersion), the antioxidant can be administered by dissolving it in an appropriate solvent and then adding it.
  • sodium metabisulfite is prepared as a 10% aqueous solution, ascorbyl palmitate, and DL-alpha-tocopherol as a 10% ethanol solution, added to the preparation, and mixed into the internal phase.
  • the present invention also includes dispersing a mixed solution of rotigotine and vinylpyrrolidone-vinyl acetate copolymer forming an internal phase in a silicone-based adhesive solution forming an external phase, and then drying it. To provide a method for stabilizing rotigotine in a silicone adhesive.
  • the weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer, silicone-based adhesive, etc. are as mentioned above.
  • the internal phase is first mixed and the internal phase in which the antioxidant is mixed is mixed with the external phase to form a dispersion.
  • the drying temperature is 90 to 120 ° C, preferably 90 to 100 ° C.
  • a related substance may be generated when treated at a temperature exceeding 100 ° C, but the present invention can produce a patch composition having stability even when dried at a low temperature of 90 to 100 ° C.
  • the mixed weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer is 9: 6 to Even when a low amount of 9: 7 is used, it is possible to prepare a composition for patch excellent in stability in which crystals are not produced even when dried at a low temperature of 90 to 100 ° C.
  • the drying temperature is preferably 90 to 100 ° C.
  • the silicone-based pressure-sensitive adhesive solution forming the external phase can be prepared using heptane, ethyl acetate, toluene or a mixture thereof, and the mixed solution containing rotigotine and copolymer forming the internal phase is ethanol, It can be prepared using ethyl acetate, toluene, or a mixed solvent thereof.
  • the present invention also provides a rotigotine patch comprising the solid dispersion.
  • These rotigotine patches include a backing layer inert to the components of the matrix; A self-adhesive matrix layer (corresponding to the solid dispersion) comprising an effective amount of rotigotine or a pharmaceutically acceptable salt; And a protective layer that is removed prior to use.
  • the self-adhesive matrix layer may further include an antioxidant.
  • the backing layer and the release liner materials commonly used for patching may be used.
  • the backing layer may be made of polyurethane as well as polyolefin, especially polyethylene, or polyester. Also, preferably, a polyester foil such as a polyethylene terephthalate film can be used.
  • the backing layer may include a thin aluminum layer.
  • the protective layer is a pull-off layer that is removed immediately before use, for example, polyurethane, polyvinyl acetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, etc.
  • a pull-off layer that is removed immediately before use
  • polyurethane polyvinyl acetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, etc.
  • paper coated with a corresponding polymer may be used.
  • a one-sided siliconized polymer foil is used as the protective layer.
  • the present invention provides a rotigotine-containing composition having a suitable transdermal permeability and a patch containing such a composition, in which stability of rotigotine is secured in a patch composition, particularly a composition containing a silicone-based adhesive.
  • the present invention also provides a method for preparing a composition for transdermal administration that can secure rotigotine stability in a composition containing a silicone-based adhesive and exhibit proper transdermal permeability.
  • the mixed weight ratio of rotigotine and vinylpyrrolidone-vinyl acetate copolymer is a low usage amount of 9: 6 to 9: 7. Even when it is used, even when dried at a low temperature of 90 to 100 ° C, it is possible to prepare a composition for patch excellent in stability in which crystals are not produced.
  • Example 1 is a commercially available Neupro TM patch (2 mg), the results of the transdermal penetration test of Example 3 and Example 9. This is the result of percutaneous permeation experiment using EVA 9715 membrane instead of skin.
  • Figure 2 shows the results of a commercially available Neupro TM patch (2 mg) and percutaneous permeation experiments of some embodiments. It was evaluated using Hairless mouse skin.
  • a two-phase system was prepared having an external phase consisting of a self-adhesive polysiloxane polymer and an internal phase consisting of a polyvinylpyrrolidone / drug mixture.
  • the self-adhesive polysiloxane adhesive on the outside is present as n-heptane, ethyl acetate, or a mixed solution thereof.
  • BIO-PSA 7-4301 n-heptane
  • BIO-PSA 7-4302 ethyl acetate
  • the mixture constituting the internal phase was prepared by dissolving an amount selected from 2 to 12% by weight of polyvinyl acetate relative to 9% by weight of rotigotine at a suitable temperature in a 2: 5 mixed solution of ethanol and ethyl acetate (14% by weight).
  • the outer phase and the inner phase were mixed at room temperature to form a homogeneous dispersion.
  • a patch was prepared by drying at various temperature conditions (60 ° C, 80 ° C, 90 ° C, 100 ° C, 120 ° C).
  • a two-phase system was prepared having an external phase consisting of a self-adhesive polysiloxane polymer and an internal phase consisting of a copovidone / drug mixture.
  • the self-adhesive polysiloxane adhesive on the outside is present as n-heptane, ethyl acetate, or a mixed solution thereof.
  • BIO-PSA 7-4301 n-heptane
  • BIO-PSA 7-4302 ethyl acetate
  • the mixture constituting the internal phase was prepared by dissolving an amount selected from 2 to 12% by weight of copovidone relative to 9% by weight of rotigotine at a suitable temperature in a 2: 5 mixed solution of ethanol and ethyl acetate (14% by weight).
  • the outer phase and the inner phase were mixed at room temperature to form a homogeneous dispersion.
  • a patch was prepared by drying at various temperature conditions (60 ° C, 80 ° C, 90 ° C, 100 ° C, 120 ° C).
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6 Rotigotine 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight Copovidone Kollidone® VA64 Fine 2% by weight 4 wt% 6 wt% 8 wt% 10 wt% 12% by weight Ethanol / ethyl acetate (2: 5 w / w) 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight BIO-PSA 7-4301 (heptane) 7-430189% by weight 7-430187 wt% 7-430185 wt% 7-430183 wt% 7-430 181 wt% 7-430179 wt% Remark Heptane solvent was used, and the drying temperature was varied for each Example to perform 5 conditions.
  • Example 7 Example 8
  • Example 9 Example 10
  • Example 11 Rotigotine 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight 9% by weight Copovidone Kollidone® VA64 Fine 2% by weight 4 wt% 6 wt% 8 wt% 10 wt% 12% by weight Ethanol / ethyl acetate (2: 5 w / w) 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight 14% by weight BIO-PSA 7-4201 (ethyl acetate) 7-420189% by weight 7-420187 wt% 7-420 185 wt% 7-420183 wt% 7-420 181 wt% 7-420179 wt% Remark Ethyl acetate solvent was used, and the drying temperature was varied for each example to perform 5 conditions.
  • Solution A pH 9.5 10mM ammonium bicarbonate solution
  • Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Drying temperature 60 °C Detected Detected Detected Detected N / D N / D Drying temperature 80 °C Detected Detected Detected N / D N / D Drying temperature 90 °C Detected Detected Detected Detected N / D N / D Drying temperature 100 °C Detected Detected Detected Detected N / D N / D Drying temperature 120 °C Detected Detected N / D N / D N / D N / D Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Drying temperature 60 °C Detected Detected Detected Detected N / D N / D N / D Drying temperature 80 °C Detected Detected Detected N / D N / D N / D Drying temperature 90 °C Detected Detected N / D N / D N / D
  • Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Drying temperature 60 °C Detected Detected Detected Detected N / D N / D Drying temperature 80 °C Detected Detected Detected N / D N / D Drying temperature 90 °C Detected Detected Detected N / D N / D Drying temperature 100 °C Detected Detected Detected N / D N / D N / D Drying temperature 120 °C Detected Detected N / D N / D N / D N / D Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Drying temperature 60 °C Detected Detected Detected Detected N / D N / D N / D Drying temperature 80 °C Detected Detected Detected N / D N / D N / D Drying temperature 90 °C Detected Detected N / D N / D N / D N
  • Example 1 Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Drying temperature 60 °C Detected Detected Detected N / D N / D N / D Drying temperature 80 °C Detected Detected Detected N / D N / D N / D Drying temperature 90 degrees Detected Detected N / D N / D N / D Drying temperature 100 °C Detected Detected N / D N / D N / D N / D Drying temperature 120 °C Detected Detected N / D N / D N / D N / D N / D
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Drying temperature 60 °C Detected Detected Detected Detected N / D N / D Drying temperature 80 °C Detected Detected Detected N / D N / D N / D Drying temperature 90 degrees Detected Detected N / D N / D N / D Drying temperature 100 °C Detected Detected N / D N / D N / D Drying temperature 120 °C Detected Detected N / D N / D N / D N / D N / D
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Drying temperature 60 °C Detected Detected Detected N / D N / D N / D Drying temperature 80 °C Detected Detected Detected N / D N / D N / D Drying temperature 90 degrees Detected Detected N / D N / D N / D Drying temperature 100 °C Detected Detected N / D N / D N / D Drying temperature 120 °C Detected Detected N / D N / D N / D N / D N / D
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Drying temperature 60 °C Detected Detected Detected N / D N / D N / D Drying temperature 80 °C Detected Detected Detected N / D N / D N / D Drying temperature 90 degrees Detected Detected N / D N / D N / D Drying temperature 100 °C Detected Detected N / D N / D N / D Drying temperature 120 °C Detected Detected N / D N / D N / D N / D N / D
  • Receptor solution solution phosphate buffered saline (PBS, 1.0 M)

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition comprenant de la rotigotine dont la stabilité est assurée, un patch comprenant la composition, et un procédé de stabilisation de la rotigotine. Plus particulièrement, la présente invention concerne un patch contenant de la rotigotine qui possède ou non des effets bénéfiques sur le taux de perméation cutanée de la rotigotine tout en étant capable d'assurer la stabilité susmentionnée tel que préparé dans une formulation de patch, et son procédé de préparation.
PCT/KR2019/014036 2018-10-24 2019-10-24 Composition contenant de la rotigotine non cristalline et son procédé de préparation WO2020085809A1 (fr)

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KR10-2018-0127643 2018-10-24
KR1020180127643A KR20200046461A (ko) 2018-10-24 2018-10-24 비결정 로티고틴 함유 조성물 및 이의 제조 방법

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090024277A (ko) * 2006-06-22 2009-03-06 슈바르츠 파르마 악티엔게젤샤프트 여러 가지 타입의 통증의 예방, 경감 및/또는 치료를 위한 약제의 제조에 있어 치환 2-아미노테트랄린의 사용
KR101041512B1 (ko) * 2002-07-30 2011-06-16 유씨비 파르마 게엠베하 로티고틴 투여를 위한 핫 멜트형 경피제제
WO2012084969A1 (fr) * 2010-12-22 2012-06-28 Hexal Ag Composition adhésive contenant de la rotigotine et système thérapeutique transdermique comprenant la composition adhésive
KR20150094588A (ko) * 2012-11-22 2015-08-19 유씨비 파마 게엠베하 로티고틴의 경피 투여용 멀티 데이 패치
KR20170023772A (ko) * 2009-12-22 2017-03-06 유씨비 파르마 게엠베하 비결정질형 로티고틴의 고체 분산체의 안정화를 위한 폴리비닐피롤리돈

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5989586A (en) 1992-10-05 1999-11-23 Cygnus, Inc. Two-phase matrix for sustained release drug delivery device
DE19814084B4 (de) 1998-03-30 2005-12-22 Lts Lohmann Therapie-Systeme Ag D2-Agonist enthaltendes transdermales therapeutisches System zur Behandlung des Parkinson-Syndroms und Verfahren zu seiner Herstellung

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101041512B1 (ko) * 2002-07-30 2011-06-16 유씨비 파르마 게엠베하 로티고틴 투여를 위한 핫 멜트형 경피제제
KR20090024277A (ko) * 2006-06-22 2009-03-06 슈바르츠 파르마 악티엔게젤샤프트 여러 가지 타입의 통증의 예방, 경감 및/또는 치료를 위한 약제의 제조에 있어 치환 2-아미노테트랄린의 사용
KR20170023772A (ko) * 2009-12-22 2017-03-06 유씨비 파르마 게엠베하 비결정질형 로티고틴의 고체 분산체의 안정화를 위한 폴리비닐피롤리돈
WO2012084969A1 (fr) * 2010-12-22 2012-06-28 Hexal Ag Composition adhésive contenant de la rotigotine et système thérapeutique transdermique comprenant la composition adhésive
KR20150094588A (ko) * 2012-11-22 2015-08-19 유씨비 파마 게엠베하 로티고틴의 경피 투여용 멀티 데이 패치

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