(T1030-03-13) Design and Optimization of Ciprofloxacin Hydrochloride Biodegradable 3D Printed Ocular Inserts: Full Factorial Design In Vitro and Ex Vivo Evaluations

Purpose: The current study was aimed to explore the feasibility of coupling hot-melt extrusion (HME) with fused deposition modeling three-dimensional printing (FDM-3DP) technology for developing customized sustained-release ciprofloxacin hydrochloride (CIP-HCL) printed inserts for ocular applications. Both technologies can facilitate the fabrication of tailored, patient-centered, and complex-shaped ocular dosage forms.

Methods: The CIP-HCL ocular inserts were fabricated by coupling high-throughput, solvent-free, and continuous HME with FDM-3DP. Insert fabrication utilized biocompatible, biodegradable, bioadhesive Klucel™ hydroxypropyl cellulose polymer, by FDM-3DP technique using a design of experiment approach to achieve a tailored release profile. The physical mixtures were extruded into filaments through a co-rotating twin-screw extruder (Haake Minilab ThermoFisher Scientific^®). The extruded filaments were evaluated for printability and other mechanical properties by applying a 3-point bend test using a TA-XT2i texture analyzer. A fused filament fabrication 3D printer (Prusa i3 3D desktop printer, Prusa Research, Prague, Czech Republic) was used to print the oval-shape inserts, and Cura© software (version 15.04; Ultimaker, Geldermalsen, Netherlands) was employed for the 3DP process to adjust printing parameters. The printing temperature was set at 180°C, whereas the bed temperature was 40°C, and the inserts were printed at a speed of 10 mm/s. The physical appearance, weight variations, surface pH, uniformity of thickness, drug content, thermal properties, drug-excipient compatibility, surface morphology, in vitro release (Figure 1), antibacterial activity, and ex-vivo transcorneal permeation were evaluated for n=3 printed inserts. Furthermore, a stability study of the printed inserts was conducted over 3 months at room temperature.

Results: An inverse relationship was noted between insert thickness, infill density, and drug release rate. The optimized formulation demonstrated an extended-release profile over 24 h, no physical or chemical incompatibility (Figure 2), excellent mucoadhesive strength, smooth surface, and lack of bacterial growth (Pseudomonas aeruginosa). In addition, SEM micrographs showed a smooth surface of the prepared insert. The designed inserts were stable at room temperature considering drug content, thermal behavior, and release profile over three months. Moreover, the ex vivo transcorneal permeation studies through excised rabbit corneas revealed that the developed CIP-HCL-3DP inserts prolonged the transcorneal flux of the drug compared to the commercial eyedrops (Ciprofloxacin Ophthalmic Hydrochloride solution, 0.3% as a base, Leading Pharma LLC, NJ, USA; Lot # 018B041) and the immediate-release printed inserts.

Conclusion: The flexible printed inserts allow placement of inserts to achieve the desired dosages of CIP-HCL ensuring patient compliance. For ocular delivery of CIP-HCL, these FDM-3DP polymeric inserts afford a longer-lasting effect than solution/topical eye drops. The fabricated insert could reduce administration frequency to once-daily dosing, affording a promising topical delivery platform with prolonged antibacterial activity and superior therapeutic outcomes for managing ocular bacterial infections.

References: 1- Awad, A., Trenfield, S.J., Gaisford, S., Basit, A.W., 2018. 3D printed medicines: A new branch of digital healthcare. International Journal of Pharmaceutics 548, 586–596. https://doi.org/10.1016/j.ijpharm.2018.07.024
2- Youssef, A., Dudhipala, N., Majumdar, S., 2020. Ciprofloxacin Loaded Nanostructured Lipid Carriers Incorporated into In-Situ Gels to Improve Management of Bacterial Endophthalmitis. Pharmaceutics 12, 572. https://doi.org/10.3390/pharmaceutics12060572

(A) In vitro release profiles of ciprofloxacin hydrochloride from CIP-3DP-SR inserts (8 runs), (B) In vitro release profile of ciprofloxacin hydrochloride from CIP-3DP-IR vs. the optimized design of CIP-3DP-SR inserts, (C) Effect of insert thickness on CIP-HCL release from CIP-3DP-SR inserts, and (D) Effect of infill density on CIP-HCL release from CIP-3DP-SR inserts (n=3). Abbreviations: CIP, ciprofloxacin; IR, immediate release; SR, sustained release.



Figure 2. FTIR spectra for (A) Ciprofloxacin hydrochloride, (B) HPC JXF, (C) PEO N10, (D) PEG 4000, (E) Sorbitol, (F) PM of CIP-3DP-IR, (G) Extruded filaments of CIP-3DP-IR, (H) CIP-3DP-IR inserts, (I) PM of CIP-3DP-SR insert, (J) Extruded filaments of CIP-3DP-SR, and (K) CIP-3DP-IR inserts.