(W1030-01-01) Formulation Development and In Vitro-Ex Vivo Characterization of Hot-Melt Extruded Ciprofloxacin Hydrochloride Ocular Inserts for Topical Ocular Applications

Purpose: The aim of this study was to develop, characterize, and evaluate a bioadhesive, hot-melt extruded (HME), extended-release ocular inserts containing ciprofloxacin hydrochloride (CIP-HCL) for better therapeutic outcomes during the management of bacterial keratitis (BK).

Methods: The inserts were fabricated with FDA approved, biocompatible, biodegradable, bioadhesive polymers– Klucel™ hydroxypropylcellulose (HPC, 140,000 Dalton) and polyethylene oxide (PEO)–and plasticizers–polyethylene glycol 4000 (PEG 4000) and sorbitol–that were tuned in different ratios utilizing a design of experiment approach (Optimal mixture design) for optimization. The physical mixtures were extruded through a co-rotating twin-screw extruder (Haake Minilab ThermoFisher Scientific^®), and the extruded film was cut with dimensions of 4 mm × 2 mm × 1 mm to obtain the ocular inserts. The inserts were evaluated for appearance, weight variation, surface pH, uniformity of thickness, drug content, swelling index, thermal analysis (Figure 1) (DSC; differential scanning calorimetry), drug–excipient compatibility (FTIR; Fourier transform infrared spectroscopy), moisture loss and absorption, mechanical characteristics (texture analyzer), surface morphology (SEM; Scanning electron microscope), mucoadhesive strength (texture analyzer), in vitro release, antimicrobial efficacy (Pseudomonas aeruginosa), ex-vivo transcorneal permeation (vertical Franz diffusion apparatus), and stability at room temperature over three months.

Results: The results revealed an inverse relationship between HPC concentration and CIP-HCL release from the prepared inserts, and an extended-release profile covering 24 h (Figure 2). The optimized inserts were stable over three-months storage at room temperature with respect to drug content, thermal behavior, pH, and release profile. There was no change in integrity under highly humid or dry environmental conditions based on visual examination. The developed CIP-HCL-HME inserts also demonstrated adequate mucoadhesive strength. In addition, SEM micrographs showed a smooth surface of the prepared insert. Furthermore, there was no bacterial growth in any of the release samples during the release experiment (0.5 h to 24 h), indicating that MIC against Pseudomonas aeruginosa was achieved across all release time points. Moreover, the ex vivo transcorneal permeation studies through excised rabbit corneas revealed that the developed CIP-HCL-HME inserts prolonged the transcorneal flux of the drug compared to the commercial eyedrops (Vigamox^®) and the immediate-release inserts.

Conclusion: The obtained results revealed that the preparation of ocular inserts containing CIP-HCL using an HME approach was successful, robust, and reproducible. Moreover, the prepared ocular inserts could reduce the frequency of administration to once a day thereby increasing patient compliance. Thus, the developed CIP-HCL ophthalmic formulation could exhibit prolonged antibacterial activity, which could provide better therapeutic outcomes in the treatment of BK.

References: 1. Thakkar, R.; Komanduri, N.; Dudhipala, N.; Tripathi, S.; Repka, M.A.; Majumdar, S. Development and Optimization of Hot-Melt Extruded Moxifloxacin Hydrochloride Inserts, for Ocular Applications, Using the Design of Experiments. International Journal of Pharmaceutics 2021, 603, 120676, doi:10.1016/j.ijpharm.2021.120676.
2. Youssef, A.A.A.; Cai, C.; Dudhipala, N.; Majumdar, S. Design of Topical Ocular Ciprofloxacin Nanoemulsion for the Management of Bacterial Keratitis. Pharmaceuticals (Basel) 2021, 14, 210, doi:10.3390/ph14030210.

Acknowledgements: The authors declare no conflict of interest.


Figure 1. Overlay of DSC thermograms to evaluate thermal characteristics of the pure materials, physical mixtures (PM), and Ciprofloxacin hydrochloride-polymer compatibility for the extruded ocular inserts.


Figure 2. In vitro release profiles of extruded Ciprofloxacin hydrochloride (CIP-HCL-HME) ocular inser