Hot-melt extruded in situ gelling systems (MeltDrops Technology): Formulation development, in silico modelling and in vivo studies

In situ gelling systems (ISGS) can prolong retention time and bioavailability of ophthalmic solutions. The complexity and cost of ISGS avert their industrial scale-up and clinical implementation. In this study, we demonstrate novel application of hot-melt extrusion (HME) technology for continuous manufacturing of ISGS (MeltDrops Technology). Timolol maleate (TIM) and dorzolamide hydrochloride (DRZ) loaded MeltDrops were successfully developed using HME for glaucoma management, thereby resolving issues with batch manufacturing of ISGS, prolonging retention time thus improving bioavailability. The MeltDrops technology involves one-step, i.e., passing all the ingredients through an extruder at a screw speed between 20–50 rpm and barrel temperature of 80 °C. The comparative evaluation of MeltDrops and batch-processed ISGS demonstrated that MeltDrops exhibited better physical and chemical content uniformity.

The extrusion temperature and screw speed were critical factors influencing content uniformity and properties of the MeltDrops. MeltDrops showed sustained drug release for >12 hours in vitro (TIM= 83.07%; DRZ = 60.43%, 12hours) versus marketed eyedrops. The developed MeltDrops followed Peppas-Sahlin model, combining Fickian diffusion and swelling processes. The in vivo study in New Zealand rabbits revealed superior effectiveness and safety of the MeltDrops as compared to the marketed eyedrops. Herein we conclude, MeltDrops would serve as a cutting-edge platform technology that can be used to manufacture various ISGS with one-step processability, cost-effectiveness, and improved product quality, which are otherwise processed by batch manufacturing that involves numerous complex processing steps.

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Materials

TIM and DRZ were kindly donated by Cipla Pvt. Ltd. (Mumbai, India). Kolliphor® 407 (Poloxamer 407, P407), and Kolliphor® 188 (Poloxamer 188, P188) were kindly donated by BASF India Ltd. (Thane, India). Metolose® SR 90SH-100000SR (100000 mPas) was kindly donated by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Carbopol® 940 NF was kindly donated by Lubrizol India Pvt. Ltd. Benzalkonium chloride and sodium chloride was procured from S.D. fine chemical Ltd. (Mumbai, India) and Somu Organo Chem Pvt.

Srushti M. Tambe, Divya D. Jain, Chetan Hasmukh Mehta, T. Ashwini, Usha Yogendra Nayak, Purnima D. Amin, Hot-melt extruded in situ gelling systems (MeltDrops Technology): Formulation development, in silico modelling and in vivo studies, European Journal of Pharmaceutics and Biopharmaceutics, 2023, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2023.05.008.

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