Optimization of Bromocriptine-Mesylate-Loaded Polycaprolactone Nanoparticles Coated with Chitosan for Nose-to-Brain Delivery: In Vitro and In Vivo Studies

Abstract

Bromocriptine mesylate (BM), primarily ergocryptine, is a dopamine agonist derived from ergot alkaloids. This study aimed to formulate chitosan (CS)-coated poly ε-caprolactone nanoparticles (PCL NPs) loaded with BM for direct targeting to the brain via the nasal route. PCL NPs were optimized using response surface methodology and a Box–Behnken factorial design. Independent formulation parameters for nanoparticle attributes, including PCL payload (A), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) concentration (B), and sonication time (C), were investigated. The dependent variables were nanoparticle size (Y1), zeta potential (Y2), entrapment efficiency (EE; Y3), and drug release rate (Y4). The optimal formulation for BM-PCL NPs was determined to be 50 mg PCL load, 0.0865% TPGS concentration, and 8 min sonication time, resulting in nanoparticles with a size of 296 ± 2.9 nm having a zeta potential of −16.2 ± 3.8 mV, an EE of 90.7 ± 1.9%, and a zero-order release rate of 2.6 ± 1.3%/min. The optimized BM-PCL NPs were then coated with CS at varying concentrations (0.25, 0.5, and 1%) to enhance their effect. The CS-PCL NPs exhibited different particle sizes and zeta potentials depending on the CS concentration used. The highest EE (88%) and drug load (DL; 5.5%) were observed for the optimized BM-CS-PCL NPs coated with 0.25% CS. The BM-CS-PCL NPs displayed a biphasic release pattern, with an initial rapid drug release lasting for 2 h, followed by a sustained release for up to 48 h. The 0.25% CS-coated BM-CS-PCL NPs showed a high level of permeation across the goat nasal mucosa, with reasonable mucoadhesive strength. These findings suggested that the optimized 0.25% CS-coated BM-CS-PCL NPs hold promise for successful nasal delivery, thereby improving the therapeutic efficacy of BM.

Microfluidic-Assisted Formulation of ε-Polycaprolactone Nanoparticles and Evaluation of Their Properties and In Vitro Cell Uptake

“…The Z-potential is a valuable parameter for predicting colloidal dispersions' storage stability, as reported by Thode et al [71]. When the zeta potential exhibits high negative values, it indicates the presence of electrostatic repulsion between particles, which prevents aggregation and stabilizes the nanoparticulate dispersion [18,45,72]. Moreover, negatively charged NPs have low toxicity to cells [73].…”

“…The zeta potential values ranged from −14.6 to −21.0 mV across all formulations, and the method of formulation and variation in polymer concentration did not impact these values. As a result, it can be inferred that the NPs will remain physically stable [45].…”

Research progress in brain-targeted nasal drug delivery

“…Although this process is a protective mechanism for maintaining optimal respiratory system functionality, it can also shorten the contact time between a drug and the nasal mucosa, directly affecting the efficiency of drug absorption through the nose, as a drug molecule typically remains within the nasal cavity for a period of approximately 20–30 min after administration ( Du et al, 2023 ). To counteract the effects of this clearance mechanism, it is usually possible to extend the drug adhesion time and increase drug absorption by selecting appropriate dosage forms, using bioadhesive materials, or modifying the surface of drug carriers, such as nanoparticles ( Badran et al, 2023 ), liposomes ( Kannavou et al, 2023 ), and microemulsions ( Pailla et al, 2022 ) with specific ligands.…”