Rotigotine Loaded Microspheres To Achieve Continuous Dpaminergic Stimulation In The Treatment Of Psrkinson's Sease

Parkinson's disease (PD) is a progressive neurodegenerative disorder leading toexpression of motor symptoms characterized by resting tremor, muscular rigidity andbradykinesia. Levodopa (L-DOPA) is highly effective in reversing the motorsymptoms of PD. However, long-term treatment with L-DOPA results in thedevelopment of disabling and troublesome motor complications called dyskinesias, amovement disorder usually designated as L-DOPA induced dyskinesias (LID). It ishard to control and limits the utility of L-DOPA. Substantial evidence hasaccumulated indicating that LID in PD is associated with non-physiological orpulsatile stimulation of striatal dopamine receptors. Therefore, the concept ofcontinuous dopaminergic stimulation (CDS) has been developed and has receivedconsiderable attention for treatment of PD. There are a variety of methods that canachieve CDS treatment in PD. Although these methods can reduce, improve and evenreverse the motor complications, many of these methods either have inadequatetherapeutic benefit or are difficult to operate with poor compliance. Therefore, it iscrucial to develop a more convenient and practical means of achieving CDS andapplying to the most of the PD patient groups.To achieve continuous dopaminergic stimulation for the treatment of PD rotigotinewas entrapped into biodegradable poly (lactic-co-glycolic acid) (PLGA) microspheresby an oil-in-water emulsion/solvent evaporation method. Several rotigotine loadedmicrospheres were prepared and their characteristics (size, drug encapsulationefficiency and drug release profiles) were evaluated. We found that palmitic acid caneffectively reduce the burst release of drug and a smooth release within 14 days wasachieved by blends of polymer. The effects of processing parameters, such as polymers concentration, PVA concentration, the ratio of oil to water, and thehomogenization rate on the characteristics of microspheres were also investigated.The drug loading of rotigotine loaded microspheres achieved by the optimized processwas 26.9% and the encapsulation efficiency was 89.7%. The in vitro drug releasesustained for 14 days.The pharmacokinetics of rotigotine loaded microspheres in both blood and brain (bymicrodialysis) in rat was investigated. The plasma concentration of rotigotine reachedCmaxof 6.38±0.80 ng/mL at 48-72h after the administration of rotigotine loadedmicrospheres. It can be detected on 16th day after administration and the eliminationwas slow. The brain extracellular drug concentration monitored by microdialysisshowed that rotigotine can be detected in the dialysate in the first 1 h after theadministration and a peak concentration of 8.16±0.95 ng/mL (corrected by in vivorecovery) was obtained on day 8 and a constant and stable level of extracellularrotigotine was maintained at 3.94±2.06 ng/mL. The results suggested that rotigotineloaded microspheres can provide a continuous stimulation on the dopamine receptors.The major pharmacodynamics of rotigotine loaded microspheres was evaluated on6-OHDA-lesioned rats. A significant increase in rotation activity of PD rats suggestedthat rotigotine loaded microspheres can produce stable and steady efficacy in the PDrats and the efficacy lasted for about 14 days. The results of continuous observationfor 24h on the 8th day showed that the efficacy was constant and stable within 24h.The results indicated that rotigotine loaded microspheres can provide CDS for thetreatment of PD.Although RoMS could be effective in the therapy of early PD, L-DOPA was still aninevitable supplementation for most patients with PD. Therefore, in this study weinvestigated both the therapeutic benefit and inducibility of AIMs of continuousrotigotine administration combination with L-DOPA on 6-OHDA-leisioned rats. Wefound that: 1) There is no significant difference of the therapeutic benefit between theconcomitant treatment of continuous (or pulsatile) rotigotine and L-DOPA andmono-treatment with L-DOPA (p>0.05). 2) Pulsatile L-DOPA induced marked AIMs, while the concomitant treatment of rotigotine microspheres and L-DOPA cansignificantly decrease the inducibility of dyskinesia whether dyskinesia was alreadyestablished or not comparing to mono L-DOPA treatment. However, the concomitanttreatment of pulsatile rotigotine and L-DOPA induced marked AIMs too. The resultssuggest that L-DOPA in combination with continuous stimulation of dopaminergicreceptors by rotigotine has lower propensity to induce dyskinesia in this experimentalmodel. In conclusion, this study highlights the potential advantages that rotigotineloaded microspheres could be used especially in combination with L-DOPA in mid tolate stage PD to reduce dyskinesia development whether dyskinesia has beenpreviously established or not.In situ forming implant (ISFI) was studied to obtain longer sustained-releaseformulation for rotigotine. The results showed that ISFI could provide a sustaineddrug release for 4 weeks.In conclusion, rotigotine loaded microspheres can provide a continuous delivery ofrotigotine with small fluctuations of drug levels in plasma and brain striatum duringdosing intervals in rats and can also produce stable and steady efficacy in the PD ratswhich lasts for about 14 days, those results enabled rotigotine loaded microspheres tobe a potent alternative of CDS in the treatment of early PD. Rotigotine loadedmicrospheres and pulsatile L-DOPA combination treatment could reduce thedyskinesia development and the intensity of the established dyskinesia and maintaintherapeutic efficacy compared to pulsatile L-DOPA monotherapy. The resultsindicated the potential advantage of the combination treatment on the mild andadvanced PD.