Preservative-free electrospun nanofibrous inserts for sustained delivery of ceftazidime; design, characterization and pharmacokinetic investigation in rabbit's eye

Abstract

Ocular drug delivery presents significant challenges, attributed to the various anatomical and physiological barriers, as well as the limitations associated with conventional ocular formulations including low bioavailability, necessitating frequent dosing. The objective of the essay was to design sustained release nanofibrous inserts loaded with ceftazidime (CAZ), an antibiotic effective against gram-negative and gram-positive microorganisms, for the treatment of ocular infections. These nanofibers were fabricated using the electrospinning technique, employing biodegradable polymers such as polyvinyl alcohol (PVA), polycaprolactone (PCL) and Eudragit® (EUD). The nanofibrous inserts exhibited adequate mechanical strength for ocular use with an average diameter < 250 nm. In the initial 12-h period, a burst drug release was observed, followed by a controlled release for 120 h. Cell viability test confirmed the non-toxicity and safety of the nanofibers. The in vivo study demonstrated that the inserts sustain a drug concentration exceeding the minimum inhibitory concentration (MIC) of Pseudomonas aeruginosa and Staphylococcus aureus for 4 and 5 days, respectively. The AUC_{0 - 120} for CAZ-PVA-PCL was reported 11,882.81 ± 80.5 μg·h/ml and for CAZ-PVA-EUD was 9649.39 ± 86.84 μg·h/ml. The nanofibrous inserts' extended drug release maintains effective antimicrobial concentrations, avoids the fluctuations of eye drops, and, by being preservative-free, eliminates cytotoxicity.

Keywords: Ceftazidime; Nanofibrous inserts; Ocular drug delivery; Ocular infection; Sustained delivery.

Graphical abstract

Fig. 1

Process of fabrication of ocular nanofibrous inserts.

Fig. 2

Measured surface contact angle for different formulations.

Fig. 3

The FTIR spectrum of CAZ, polymers, and prepared nanofibers.

Fig. 4

The DSC thermogram of CAZ, polymers, and the prepared nanofibers.

Fig. 5

The SEM image and mean diameter of designed ocular nanofibrous inserts.

Fig. 6

A: The HPLC peaks obtained at 1 h, 24 h and 120 h for different formulation during in vitro study and B: Comparison of the drug release percentage of ceftazidime in the time interval of 0 to 120 h from CAZ-PVA-EUD and CAZ-PVA-PCL nanofibers in in vitro conditions with pH = 7.4 and temperature of 37 °C.

Fig. 7

A: Cell viability percentage after treatment with different concentrations of ophthalmic formulation after a 24-h period using MTT method (n = 3). B: Antimicrobial activity of CAZ-PVA-PCL and CAZ-PVA-EUD ocular inserts against P. aeruginosa and S. aureus.

Fig. 8

a: Inserting the nanofibers in the cul-de-sac of the rabbit's eye. b: Observations of the rabbit's eye condition and the irritation ratings acquired through eye irritation assessments over a three-day period. c: The position of the nanofiber inserts at the end of the experiment after 72 h.

Fig. 9

A: The HPLC peaks obtained at different hours for the formulations during in vivo study, B: Ceftazidime release from in vivo studies in rabbit eyes over a time interval of 0 to 120 h, and C: over a time interval of 50 to 120 h.