article · Pharmaceutics
Voxelotor is an antisickling agent, but its oral delivery is limited by poor aqueous solubility and low oral bioavailability. To address these issues, a self-nanoemulsifying drug delivery system was formulated. Researchers screened various oils, surfactants, and cosurfactants to determine their solubilisation capacity, using mixture design and desirability functions to optimise formulation attributes. The selected formulation exhibited a rapid self-emulsifying time of 32 seconds, a droplet size of 35 nanometres, and a zeta potential of -8 millivolts. In laboratory tests, the system achieved a 3.1-fold improvement in drug solubility compared to pure drug powder, with 88 percent of the drug remaining in the aqueous phase during in vitro lipolysis. Tests on Caco-2 cells demonstrated formulation safety at 0.9 milligrams per millilitre and improved cellular transport. In animal trials, the system produced a 1.7-fold increase in oral bioavailability in rats compared to a standard drug suspension.
Sickle cell therapies often face challenges reaching effective levels in the body due to poor absorption. By reformulating voxelotor into a nanoemulsion, this research demonstrates that the drug dissolves more effectively and absorbs better into the bloodstream. This approach could lead to more efficient dosing, potentially improving therapeutic outcomes for individuals who require antisickling treatments.
This work is an applied formulation study relevant to pharmaceutical developers seeking to improve oral delivery methods for poorly soluble antisickling therapies. Given that validation has only progressed to in vitro assays and small-animal pharmacokinetic testing in rats, the technology remains at an early, pre-clinical development stage that requires further formulation development and comprehensive clinical testing before commercial use is viable.
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Low aqueous solubility and poor oral bioavailability are limiting factors in the oral delivery of voxelotor, an antisickling agent. To overcome these limitations, a voxelotor self-nanoemulsifying drug delivery system was developed. Various oils, surfactants, and cosurfactants were screened for their solubilization potential for the drug. The area of nanoemulsification was identified using a ternary phase diagram. An experimental mixture design and a desirability function were applied to select SNEDDSs that contain a maximum amount of lipids and a minimum amount of surfactant, and that possess optimal emulsification properties (i.e., droplet sizes, polydispersity index (PDI), emulsification time, and transmittance percentage). The optimized SNEDDS formulation was evaluated for the self-emulsifying time (32 s), droplet size (35 nm), and zeta potential (-8 mV). In vitro dissolution studies indicated a 3.1-fold improvement in drug solubility from the optimized SNEDDS over pure drug powder. After 60 min of in vitro lipolysis, 88% of the voxelotor loaded in the SNEDDS remained in the aqueous phase. Cytotoxicity evaluation, using Caco-2 cells, indicated the safety of the formulation at 0.9 mg/mL. The transport of the voxelotor SNEDDS across Caco-2 monolayers was significantly enhanced compared to that of the free drug. Compared to the drug suspension, the developed SNEDDS enhanced the oral bioavailability (1.7-fold) of voxelotor in rats. The results suggest that further development of SNEDDSs for the oral delivery of voxelotor is needed.
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DOI: 10.3390/pharmaceutics13091388
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