Mechanistic phase transition and computerized modeling of solvent exchange-based in situ forming matrix systems for treatment of oral cavity infectious diseases

Abstract

In situ matrix-forming systems possess a unique capability for spontaneous transformation into a solid matrix upon administration to the target site. This approach offers less invasive and prolonged drug release at the local site. The transformation of liquid formulations into a solid matrix after delivery is attributed to solvent exchange-induced mechanisms. This thesis focuses on in situ forming matrices (ISMs), with particular emphasis on the small molecule including borneol (BOR) and ibuprofen (IBU) as matrix formers. The selected ISM formulation maintains a matrix concentration of 40% w/w. These ISMs were characterized by low viscosity (< 20 cP) and high injectability (< 3 N). They also exhibited excellent spreadability and wettability with a low surface tension (< 45 mN/m) and low contact angle (< 25˚), respectively. The BOR-based ISM, when incorporated with lincomycin HCl (LH), demonstrated an exceptionally low water tolerance value (8.29%) and exhibited statistically significant antimicrobial activity at LH loadings of 5% (NBL5) and 7.5% (NBL7.5) against Staphylococcus aureus ATCC 25923 and Porphyromonas gingivalis ATCC 33277, enabling precise drug release over 8 days. In the case of 5% doxycycline hyclate (DH) loaded IBU-based ISMs (DID40 and DIN40), a unique phase transformation is observed, characterized by IBU droplet movement before transitioning to a solid matrix. The tortuous structure of the IBU matrix effectively retarded drug release over a week (% drug release on the seventh day were 35.17 ± 2.23% for DID40 and 53.19 ± 2.66% for DIN40). Furthermore, these formulations displayed a strongly statistically significant antimicrobial activity against periodontitis pathogens like P. gingivalis ATCC 33277 and Aggregatibacter actinomycetemcomitans ATCC 29522. Additionally, the DH-loaded IBU-based ISMs demonstrated superior anti-inflammatory activity compared to the control. To gain a deeper understanding of the mechanistic phase transition attributed to solvent exchange at the molecular level, molecular dynamics (MD) simulations using the Amber20 software were conducted. These simulations unveiled profound insights into the molecular mechanisms governing solvent exchange. In LH-loaded BOR-based ISMs, an increase in BOR content reduced the mobility and fluctuation of LH molecules, as indicated by a decrease in diffusion constant (from 0.56 to 0.21) and root mean square deviation (RMSD) values (from around 50 to 35 Å), respectively. The MD simulation revealed that solvent exchange process was interfered by BOR, as evidenced by a decreased in the diffusion coefficient and RMSD of both organic solvents and water molecules within the simulation box. In IBU-based ISMs, DH's diffusion constant decreased from 1.2452 to 0.3372, and in the NMP series, it decreased from 0.3703 to 0.2245. The RMSD values of DH also decreased from over 140 to 40 Å following the addition of IBU. This indicated that IBU retarded the mobility of both solvent and drug molecules. Additionally, intermolecular H-bonding interactions between the hydroxyl group of IBU and DH were observed in the final state of the simulation.This comprehensive investigation shed light on the multifaceted nature of solvent exchange-based ISM systems and their potential in addressing oral cavity infectious diseases. It leveraged state-of-the-art molecular dynamics simulations to unravel the intricacies of their phase transformation phenomena.

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