Pharmaceutical Research

, Volume 29, Issue 9, pp 2367–2376 | Cite as

Preparation of Rotigotine-Loaded Microspheres and Their Combination Use with L-DOPA to Modify Dyskinesias in 6-OHDA-Lesioned Rats

  • Aiping Wang
  • Lexi Wang
  • Kaoxiang Sun
  • Wanhui Liu
  • Chunjie Sha
  • Youxin Li
Research Paper



To prepare rotigotine loaded microspheres (RoMS) to achieve continuous dopaminergic stimulation (CDS) for the treatment of Parkinson’s disease (PD) and investigate both the therapeutic benefit and inducibility of AIMs of administration of RoMS combination with L-DOPA in 6-OHDA-leisioned rats.


Rotigotine was encapsulated into poly(lactic-co-glycolic acid) (PLGA) microspheres by an oil-in-water emulsion solvent evaporation technique. In vitro characteristics and in vivo pharmacokinetics of RoMS either in rat blood or brain (by microdialysis) were investigated. Contraversive rotations and AIMs were observed to investigate the therapeutic benefit and the propensity to induce dyskinesia of RoMS or RoMS combination with L-DOPA in 6-OHDA-lesioned rats.


RoMS displayed continuous-release characteristics of rotigotine in animals and exhibited a steady efficacy lasted for 2 weeks in 6-OHDA-lesioned rats. No significant difference of the therapeutic benefit between the treatment of RoMS and pulsatile L-DOPA combination and mono L-DOPA was found. While the dyskinesia was significantly decreased with the treatment of RoMS and pulsatile L-DOPA combination compared to mono L-DOPA.


RoMS could supply an alternative of CDS for the treatment of PD and the study indicates a potential advantage of RoMS for the treatment of mild and advanced PD patient in combination with L-DOPA.


combination with L-DOPA continuous dopaminergic stimulation dyskinesia Parkinson’s disease rotigotine loaded microspheres 



abnormal involuntary movements




continuous dopaminergic stimulation


encapsulation efficiency


intramuscular injection


intraperitoneal injection




levodopa induced dyskinesias


Parkinson’s disease


poly(lactic-co-glycolic acid)


per os


rotigotine loaded microspheres


  1. 1.
  2. 2.
    Braak H, Del TK, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211.PubMedCrossRefGoogle Scholar
  3. 3.
    Jenner P. Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation. Neurology. 2004;62:S47–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Rajput AH, Fenton ME, Birdi S, Macaulay R, George D, Rozdilsky B, et al. Clinical-pathological study of levodopa complications. Mov Disord. 2002;17:289–96.PubMedCrossRefGoogle Scholar
  5. 5.
    Larramendy C, Taravini IRE, Saborido MD, Ferrario JE, Murer MG, Gershanik OS. Cabergoline and pramipexole fail to modify already established dyskinesias in an animal model of parkinsonism. Behav Brain Res. 2008;194:44–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Olanow CW. The scientific basis for the current treatment of Parkinson’s disease. Annu Rev Med. 2004;55:41–60.PubMedCrossRefGoogle Scholar
  7. 7.
    Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;2(8):577–88.PubMedCrossRefGoogle Scholar
  8. 8.
    Nyholm D, Nilsson RAI, Dizdar N, Constantinescu R, Holmberg B, Jansson R, et al. Duodenal levodopa infusion monotherapy vs. oral polypharmacy in advanced Parkinson disease. Neurology. 2005;64:216–23.PubMedCrossRefGoogle Scholar
  9. 9.
    Chen L, Togasaki DM, Langston JW, Di Monte DA, Quik M. Enhanced striatal opioid receptor-mediated G-protein activation in L-DOPA treated dyskinetic monkeys. Neuroscience. 2005;132:409–20.PubMedCrossRefGoogle Scholar
  10. 10.
    Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med. 2000;342:1484–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Nutt JG, Obeso JA, Stocchi F. Continuous dopamine-receptor stimulation in advanced Parkinson’s disease. Trends Neurosci. 2000;23:S109–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Olanow CW, Schapira AHV, Rascol O. Continuous dopamine-receptor stimulation in early Parkinson’s disease. Trends Neurosci. 2000;23:S117–26.PubMedCrossRefGoogle Scholar
  13. 13.
    Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol. 2006;5:677–87.PubMedCrossRefGoogle Scholar
  14. 14.
    Nutt JG. Continuous dopaminergic stimulation: is it the answer to the motor complications of levodopa? Mov Disord. 2007;22:1–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Steiger M. Constant dopaminergic stimulation by transdermal delivery of dopaminergic drugs: a new treatment paradigm in Parkinson’s disease. Eur J Neurol. 2008;15:6–15.PubMedGoogle Scholar
  16. 16.
    Pearce RK, Banerji T, Jenner P, Marsden CD. De novo administration of ropinirole and bromocriptine induces less dyskinesia than L-dopa in the MPTP treated marmoset. Mov Disord. 1998;13:234–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Maratos EC, Jackson MJ, Pearce RK, Cannizzaro C, Jenner P. Both short and long-acting D-1/D-2 dopamine agonists induce less dyskinesia than L-DOPA in the MPTP-lesioned common marmoset (Callithrix jacchus). Exp Neurol. 2003;179:90–102.PubMedCrossRefGoogle Scholar
  18. 18.
    Bibbiani F, Costantini LC, Patel R, Chase TN. Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates. Exp Neurol. 2005;192:73–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Antonini A, Isaias IU, Canesi M, Zibetti M, Mancini F, Manfredi L, et al. Duodenal levodopa infusion for advanced Parkinson’s disease: 12-month treatment outcome. Mov Disord. 2007;22:1145–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Katzenschlager R, Hughes A, Evans A, Manson AJ, Hoffman M, Swinn L, et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: a prospective study using single-dose challenges. Mov Disord. 2005;20:151–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Sujith OK, Lane C. Review: therapeutic options for continuous dopaminergic stimulation in Parkinson’s disease. Ther Adv Neurol Disord. 2009;2:105–13.PubMedCrossRefGoogle Scholar
  22. 22.
    Jenner P. A novel dopamine agonist for the transdermal treatment of Parkinson’s disease. Neurology. 2005;65:S3–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Rotigotine. (accessed 03/05/12)
  24. 24.
    Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease. JAMA. 2000;284:231–8.CrossRefGoogle Scholar
  25. 25.
    Zhang LP. Long acting sustained-release formulation containing dopamine receptor agonist and the preparation method thereof. U.S. Publication 2008/0260846, 2008.Google Scholar
  26. 26.
    Kehr J, Hu XJ, Yoshitake T, Scheller D. Determination of the dopamine agonist rotigotine in microdialysates from the rat brain by microbore column liquid chromatography with electrochemical detection. J Chromatogr B. 2007;845:109–13.CrossRefGoogle Scholar
  27. 27.
    Przedborski S, Levivier M, Jiang H. Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience. 1995;67:631–47.PubMedCrossRefGoogle Scholar
  28. 28.
    Truong L, Allbutt H, Kassiou M, Henderson JM. Developing a preclinical model of Parkinson’s disease: a study of behaviour in rats with graded 6-OHDA lesions. Behav Brain Res. 2006;169:1–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Cannazza G, Di Stefano A, Mosciatti B, Braghiroli D, Baraldi M, Pinnen F, et al. Detection of levodopa, dopamine and its metabolites in rat striatum dialysates following peripheral administration of L-DOPA prodrugs by mean of HPLC-EC. J Pharm Biomed Anal. 2005;36:1079–84.PubMedCrossRefGoogle Scholar
  30. 30.
    Lundblad M, Andersson M, Winkler C, Kirik D, Wierup N, Cenci MA. Pharmacological validation of behavioral measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci. 2002;15:120–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Stockwell KA, Virley DJ, Perren M, Iravani MM, Jackson MJ, Rose S, et al. Continuous delivery of ropinirole reverses motor deficits without dyskinesia induction in MPTP-treated common marmosets. Exp Neurol. 2008;211:172–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Kehr J, Hu XJ, Goiny M, Scheller DK. Continuous delivery of rotigotine decreases extracellular dopamine suggesting continuous receptor stimulation. J Neural Transm. 2007;114:1027–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Hammarlund-Udenaes M, Paalzow LK, de Lange EC. Drug equilibration across the blood–brain barrier-pharmacokinetic considerations based on the microdialysis method. Pharm Res. 1997;14:128–34.PubMedCrossRefGoogle Scholar
  34. 34.
    Zubair M, Jackson MJ, Tayarani-Binazir K, Stockwell KA, Smith LA, Rose S, et al. The administration of entacapone prevents L-dopa-induced dyskinesia when added to dopamine agonist therapy in MPTP-treated primates. Exp Neurol. 2007;208:177–84.PubMedCrossRefGoogle Scholar
  35. 35.
    Grace AA. The tonic/phasic model of dopamine system regulation: its relevance for understanding how stimulant abuse can alter basal ganglia function. Drug Alcohol Depend. 1995;37:111–29.PubMedCrossRefGoogle Scholar
  36. 36.
    Schmidt WJ, Lebsanft H, Heindl M, Gerlach M, Gruenblatt E, Riederer P, et al. Continuous versus pulsatile administration of rotigotine in 6-OHDA-lesioned rats: contralateral rotations and abnormal involuntary movements. J Neural Transm. 2008;115:1385–92.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Aiping Wang
    • 1
    • 2
  • Lexi Wang
    • 1
  • Kaoxiang Sun
    • 2
    • 3
  • Wanhui Liu
    • 2
    • 3
  • Chunjie Sha
    • 3
  • Youxin Li
    • 1
    • 3
  1. 1.College of Life ScienceJilin UniversityChangchunChina
  2. 2.School of PharmacyYantai UniversityYantaiChina
  3. 3.State Key Laboratory of Long-acting & Targeting Drug Delivery SystemYantaiChina

Personalised recommendations