Mechanistic underpinning formation of non-solvent induced phase inversion-based borneol in situ forming matrix for treatment of oral cavity infectious diseases

Abstract

The mechanistic phase inversion, characterized by its ability to transform from a liquid to a solid-like matrix upon contact with an aqueous solution, has gained popularity as a simplified mechanism for in situ forming matrix (ISM). In this study, borneol was chosen as a matrix-forming agent for non-solvent induced phase inversion-based ISMs due to its safety and low aqueous solubility. The primary objective of this research is to conduct a comprehensive investigation into the mechanistic phase inversion and the development of antimicrobial-loaded borneol-based ISMs for the treatment of oral cavity diseases. The assessment included physicochemical testing, matrix morphology analysis, drug release, and antimicrobial activity. A 40% w/w borneol-based ISM was developed successfully for clotrimazole-loaded spray for oropharyngeal candidiasis treatment. Additionally, a vancomycin HCl-loaded 40% w/w borneol-based ISM (VDB) was formulated for periodontitis treatment, characterized by low viscosity (6.18 cP), favorable wettability, and solid-like borneol matrix formation. Moreover, VDB had achieved a 14-day release profile through Fickian diffusion, and dimethyl sulfoxide (DMSO) was confirmed as the suitable solvent without affecting the crystallization change of the borneol precipitate. Additionally, the 40%w/w borneol-based ISM with doxycycline hyclate (DH) and 5%w/w triacetin extended drug release via Fickian diffusion and effectively targeted periodontitis pathogens. In this research, the application of UV-visible imaging provided real-time insights into the mechanisms of phase inversion, DH release, and matrix formation. Borneol significantly retarded solvent diffusion and DH release. Initially, rate of solvent diffusion (0.030-0.048 molar/hour) and DH diffusion (0.22-0.27 mg/mL/hour) were high but gradually constant after 10 hours. Additionally, molecular dynamics (MD) modeling contributed valuable insights into the initial phase inversion processes that occurred on a millisecond scale upon contact between ISM and aqueous solutions. The drug diffusion constant of borneol-based ISM was significantly lower than that of borneol-free ISM (0.32 vs. 0.52 m2/s), underscoring the pivotal role of borneol in retarding DH release. Therefore, the mechanistic underpinnings of phase inversion bridged the gap between formulation development and analytical fields, offering direct visualization of dynamic processes previously challenging to monitor during the early stages of phase inversion. Understanding the mechanistic underpinning of phase inversion not only contributes to the ability to anticipate drug release patterns but also offers valuable insights for shaping the trajectory of future ISM formulations.

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