Fabrication and statistical optimization of surface engineered PLGA nanoparticles for naso-brain delivery of ropinirole hydrochloride: in-vitro–ex-vivo studies

Abstract

Ropinirole hydrochloride (RPN), a nonergot dopamine D₂-agonist used in the management of Parkinson’s disease, has poor oral bioavailability (52%) due to extensive hepatic metabolism. The intent of present research work was aimed at design and statistical optimization of RPN-loaded poly (lactic-co-glycolic acid) (PLGA)-based biodegradable nanoparticles (NPs) surface modified using natural emulsifier, vitamin E (d-α-tocopheryl polyethylene glycol 1000 succinate [TPGS]) for direct nose-to-brain delivery in order to avoid hepatic first-pass metabolism, and improve therapeutic efficacy with sustained drug release. RPN-NPs were prepared by modified nanoprecipitation technique and optimized using 2³ factorial design of experiment. The effect of polymer and emulsifier concentration was evaluated on particle size and entrapment efficiency (EE%). Formulation PL₆ was considered as desirable with highest EE% (72.3 ± 6.1%), PS (279.4 ± 1.8 nm), zeta potential (−29.4 ± 2.6 mV), and cumulative drug diffusion of 96.43 ± 3.1% in 24 h. The ANOVA results for the dependent variables demonstrated that the model was significant (p value < 0.05) for response variables. Histopathological study of optimized batch (PL₆) demonstrated good retention of NPs with no severe signs of damage on the integrity of nasal mucosa. Differential scanning calorimetry revealed the absence of any chemical interaction between RPN, PLGA, and TPGS while SEM study confirmed spherical shape of optimized NPs. Accelerated stability studies of freeze-dried optimized batch demonstrated negligible change in the average PS and EE% after storage at 25 ± 2 °C/60 ± 5% (relative humidity (RH) for the period of three months. The promising results of optimized batch suggested practicability of investigated system for enhancement of bioavailability and brain targeting of CNS acting drugs like RPN.

Keywords:

• brain targeting
• surface modification
• vitamin E TPGS
• hepatic metabolism
• biodegradable polymer
• naso-brain delivery

Acknowledgments

The authors are thankful to Wockhardt Pharmaceutical (Aurangabad, India), Purac Biomaterials (Netherland) for providing Ropinirole hydrochloride and PLGA, respectively. The facilities provided by the management and principal of H.R. Patel Institute of Pharmaceutical Education And Research, cannot be left unacknowledged.