Formulation design and optimization of cationic-charged liposomes of brimonidine tartrate for effective ocular drug delivery by design of experiment (DoE) approach

Abstract

Objective: The present study was aimed to design and optimize brimonidine tartrate (BRT) loaded cationic-charged liposome formulation with enhanced trans-corneal drug permeation, prolonged corneal residence, and sustained drug release for effective ocular delivery.

Methods: Design of experiment (DoE) based formulation optimization was done by three-factor, three-level Box-Behnken design selecting lipid, cholesterol, and drug content as independent variables and particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and cumulative % drug release (CDR) as response variables. The optimized formulation consisting of 79.2 mM lipid, 36.2 mM cholesterol, and 15.8 mg/mL drug was prepared by thin film hydration-sonication method using EPCS:DOTAP (1:1) as lipid component and characterized for all desired critical quality attributes (CQAs), drug release kinetics, TEM, DSC, XRD analysis, ex vivo trans-corneal drug permeation, and physical stability studies.

Results: The optimized liposome formulation exhibited experimentally observed responses close to predicted values having 150.4 nm (PS), 0.203 (PDI), 30.62 mV (ZP), and 55.17% (EE). The observed CDR (%) was 36.15% at 1 h and 91.13% at 12 h exhibiting sustained drug release profile and followed Higuchi drug release kinetics. The TEM, DSC, and XRD studies revealed spherical, nanosized, small unilamellar vesicles effectively entrapping BRT in liposomes. The ex vivo permeation study across goat cornea recorded apparent permeability (P_app) 1.011 ± 0.07 cm.min^-1 and steady-state flux (J_ss) 17.63 ± 1.22 µg.cm^-2.min^-1 showing >2-fold enhanced drug permeation as compared to BRT solution.

Conclusion: The developed liposomal formulation possessed all recommended CQAs in optimal range with enhanced trans-corneal drug permeation and remained physically stable in 3 months stability study.

Keywords: Box–Behnken design (BBD) optimization; Brimonidine tartrate; cationic charged liposome; design of experiment (DoE); drug release kinetics of liposome; formulation optimization of liposome; ocular drug delivery; trans-corneal drug permeation.