Optimized Encapsulation of the FLAP/PGES-1 Inhibitor BRP-187 in PVA-Stabilized PLGA Nanoparticles Using Microfluidics

Abstract

The dual inhibitor of the 5-lipoxygenase-activating protein (FLAP) and the microsomal prostaglandin E2 synthase-1 (mPGES-1), named BRP-187, represents a promising drug candidate due to its improved anti-inflammatory efficacy along with potentially reduced side effects in comparison to non-steroidal anti-inflammatory drugs (NSAIDs). However, BRP-187 is an acidic lipophilic drug and reveals only poor water solubility along with a strong tendency for plasma protein binding. Therefore, encapsulation in polymeric nanoparticles is a promising approach to enable its therapeutic use. With the aim to optimize the encapsulation of BRP-187 into poly(lactic-co-glycolic acid) (PLGA) nanoparticles, a single-phase herringbone microfluidic mixer was used for the particle preparation. Various formulation parameters, such as total flow rates, flow rate ratio, the concentration of the poly(vinyl alcohol) (PVA) as a surfactant, initial polymer concentration, as well as presence of a co-solvent on the final particle size distribution and drug loading, were screened for best particle characteristics and highest drug loading capacities. While the size of the particles remained in the targeted region between 121 and 259 nm with low polydispersities (0.05 to 0.2), large differences were found in the BRP-187 loading capacities (LC = 0.5 to 7.29%) and drug crystal formation during the various formulations.

Gentiopicroside PLGA Nanospheres: Fabrication, in vitro Characterization, Antimicrobial Action, and in vivo Effect for Enhancing Wound Healing in Diabetic Rats

“…Incorporation of the optimized type and concentration of surfactant is the magic key trade to controlling the stability of the drug-loaded nanosystem, protecting the drug from fast degradation, and keeping the integrity of PLGA matrix. 46 Among versatile types of surfactant used in NSs preparation, it is clear that PVA is widely used with a significant impact on the stability and physical features of drug-loaded nanoparticles including nanospheres and/or nanocapsules. 18 , 46 , 47 GPS has hydrophobic nature with limited aqueous solubility.…”

“… 46 Among versatile types of surfactant used in NSs preparation, it is clear that PVA is widely used with a significant impact on the stability and physical features of drug-loaded nanoparticles including nanospheres and/or nanocapsules. 18 , 46 , 47 GPS has hydrophobic nature with limited aqueous solubility. 26 Increasing PVA concentration in the external aqueous phase supports GPS molecules to be tightly incorporated into PLGA core and minimum diffusion out to the external phase leading to higher entrapment efficiency ( Table 3 ).…”

“…Different literature showed that the effect of PVA on release profile is basically concentration-dependent. 47 , 48 GPS is tightly incorporated with inner PLGA core and insoluble in an aqueous phase containing lower concentrations of PVA, below that is required for micellar formation and/or solubilizing GPS, 46 resulting in suppressing the initial burst of GPS out to release medium parallel with neglected effect on the total % cumulative release after three days. 47 , 48 Typical spheres of GPS-loaded PLGA nanoformulations demonstrated by transmission electron micrographs ensure that emulsion solvent evaporation method utilizing probe sonication could be considered an accessible and optimum technique could produce core /shell nanosystem.…”

Microfluidics Technology for the Design and Formulation of Nanomedicines

“…MFs has been used to optimize the loading capacity of PNP. For example, Behnke et al [165], have investigated different MF parameters including FRR, TFR, initial polymer concen-tration, the concentration of the PVA as a surfactant, and their effect on the improvement of encapsulation efficiency. By using PLGA to encapsulate an anti-inflammatory drug candidate (dual inhibitor of the 5-lipoxygenase-activating protein (FLAP) and the microsomal prostaglandin E2 synthase-1 (mPGES-1)), which are named BRP-18.…”

“…The highest drug loading (7.3%) was observed for the formulation of PLGA with c = 15 mg mL and 10% BRP-187 (w/w PLGA) with 0.3% (w/w) PVA. Changing the manufacturing method from bulk method to microfluidic increase the (LC) significantly and simplified the whole procedure [165].…”