Development of nanoemulsion for efficient brain parenteral delivery of cefuroxime: designs, characterizations, and pharmacokinetics

Abstract

Background and aim: Drugs that are effective against diseases in the central nervous system and reach the brain via blood must pass through the blood-brain barrier (BBB), a unique interface that protects against potential harmful molecules. This presents a major challenge in neuro-drug delivery. This study attempts to fabricate the cefuroxime-loaded nanoemulsion (CLN) to increase drug penetration into the brain when parenterally administered.

Methods: The nanoemulsions were formulated using a high-pressure homogenization technique and were characterized for their physicochemical properties.

Results: The characterizations revealed a particle size of 100.32±0.75 nm, polydispersity index of 0.18±0.01, zeta potential of -46.9±1.39 mV, viscosity of 1.24±0.34 cps, and osmolality of 285.33±0.58 mOsm/kg, indicating that the nanoemulsion has compatibility for parenteral application. CLN was physicochemically stable within 6 months of storage at 4°C, and the transmission electron microscopy revealed that the CLN droplets were almost spherical in shape. The in vitro release of CLN profile followed a sustained release pattern. The pharmacokinetic profile of CLN showed a significantly higher C_max, area under the curve (AUC)_0-t , prolonged half-life, and lower total plasma clearance, indicating that the systemic concentration of cefuroxime was higher in CLN-treated rats as compared to cefuroxime-free treated rats. A similar profile was obtained for the biodistribution of cefuroxime in the brain, in which CLN showed a significantly higher C_max, AUC_0-t , prolonged half-life, and lower clearance as compared to free cefuroxime solution.

Conclusion: Overall, CLN showed excellent physicochemical properties, fulfilled the requirements for parenteral administration, and presented improved in vivo pharmacokinetic profile, which reflected its practical approach to enhance cefuroxime delivery to the brain.

Keywords: blood–brain barrier; cefuroxime; drug delivery; parenteral nanoemulsion; pharmacokinetics.

Figure 1

The molecular structure of cefuroxime.

Figure 2

Solubility of cefuroxime in different types of oils and oil mixtures. Note: Error bars denote standard deviation (n=3). Abbreviations: MCT, middle-chain triglyceride; PKOEs, palm kernel oil esters; PNO, pine nut oil; SEO, sesame oil; SBO, soybean oil; SSO, safflower seed oil; SUO, sunflower oil.

Figure 3

Solubility of cefuroxime in different types of surfactant solution. Note: Error bars denote standard deviation (n=3).

Figure 4

TEM photomicrographs of cefuroxime-loaded nanoemulsion after negative staining with uranyl acetate. Notes: (A) The image of oil droplet after 100× dilution. (B) The image of oil droplet after 50× dilution. The scale bars represent 100 nm. Abbreviation: TEM, transmission electron microscope.

Figure 5

Dose–response curve of CLN. Notes: The cytotoxicity effect of the formulation against hCMEC/D3 cell line as determined by MTT assay after 24 h exposure to cefuroxime standard solution, bcln, and CLN. Error bars indicate the standard deviation of three independent experiments. *Significant values (P<0.05) in comparison with free cefuroxime solution. Abbreviations: bcln, blank nanoemulsion; CLN, cefuroxime-loaded nanoemulsion; MTT, 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide.

Figure 6

In vitro release of CLN as a function of time compared to cefuroxime standard solution in phosphate buffer, pH 7.4. Notes: Drug release measurements were carried out in triplicate. Error bars denote standard deviation. *Significant values (P<0.05) in comparison with free cefuroxime solution. Abbreviation: CLN, cefuroxime-loaded nanoemulsion.

Figure 7

Droplet size of cefuroxime-loaded nanoemulsion under different storage conditions during 6 month stability test. Notes: All measurements were performed in triplicate. *Significant value (P<0.05) in comparison with the temperature of 4°C.

Figure 8

Plasma concentration against time profile after intraperitoneal administration of cefuroxime solution and CLN at the fixed dose of 20 mg/kg in rats. Notes: Each value represents the mean ± standard deviation (n=4). **Significant values (P<0.05) in comparison with cefuroxime solution. Abbreviation: CLN, cefuroxime-loaded nanoemulsion.

Figure 9

Brain concentration against time profile after intraperitoneal administration of cefuroxime solution and CLN at the fixed dose of 20 mg/kg in rats. Notes: Each value represents the mean ± standard deviation (n=4). **Significant values (P<0.01) in comparison with cefuroxime solution. Abbreviation: CLN, cefuroxime-loaded nanoemulsion.