Puyathorn Napaphol, Tamdee Poomipat, Sirirak Jitnapa, Okonogi Siriporn, Phaechamud Thawatchai, Chantadee Takron
Programme of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand.
Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand.
Pharmaceutics. 2023 Sep 13;15(9):2315. doi: 10.3390/pharmaceutics15092315.
This research investigates the gel formation behaviour and drug-controlling performance of doxycycline-loaded ibuprofen-based in-situ forming gels (DH-loaded IBU-based ISGs) for potential applications in periodontal treatment. The investigation begins by exploring the physical properties and gel formation behaviour of the ISGs, with a particular focus on determining their sustained release capabilities. To gain a deeper understanding of the molecular interactions and dynamics within the ISGs, molecular dynamic (MD) simulations are employed. The effects of adding IBU and DH on reducing surface tension and water tolerance properties, thus affecting molecular properties. The phase transformation phenomenon is observed around the interface, where droplets of ISGs move out to the water phase, leading to the precipitation of IBU around the interface. The optimization of drug release profiles ensures sustained local drug release over seven days, with a burst release observed on the first day. Interestingly, different organic solvents show varying abilities to control DH release, with dimethyl sulfoxide (DMSO) demonstrating superior control compared to -Methyl-2-pyrrolidone (NMP). MD simulations using AMBER20 software provide valuable insights into the movement of individual molecules, as evidenced by root-mean-square deviation (RMSD) values. The addition of IBU to the system results in the retardation of IBU molecule movement, particularly evident in the DMSO series, with the diffusion constant value of DH reducing from 1.2452 to 0.3372 and in the NMP series from 0.3703 to 0.2245 after adding IBU. The RMSD values indicate a reduction in molecule fluctuation of DH, especially in the DMSO system, where it decreases from over 140 to 40 Å. Moreover, their radius of gyration is influenced by IBU, with the DMSO system showing lower values, suggesting an increase in molecular compactness. Notably, the DH-IBU configuration exhibits stable pairing through H-bonding, with a higher amount of H-bonding observed in the DMSO system, which is correlated with the drug retardation efficacy. These significant findings pave the way for the development of phase transformation mechanistic studies and offer new avenues for future design and optimization formulation in the ISG drug delivery systems field.
本研究调查了载有强力霉素的布洛芬基原位形成凝胶（载有DH的基于布洛芬的原位形成凝胶，DH-loaded IBU-based ISGs）在牙周治疗中的潜在应用的凝胶形成行为和药物控制性能。研究首先探索原位形成凝胶的物理性质和凝胶形成行为，特别关注确定其缓释能力。为了更深入地了解原位形成凝胶内的分子相互作用和动力学，采用了分子动力学（MD）模拟。添加布洛芬和强力霉素对降低表面张力和耐水性的影响，从而影响分子性质。在界面周围观察到相变现象，原位形成凝胶的液滴移动到水相中，导致布洛芬在界面周围沉淀。药物释放曲线的优化确保了药物在七天内持续局部释放，第一天观察到突释。有趣的是，不同的有机溶剂对强力霉素释放的控制能力不同，与N-甲基-2-吡咯烷酮（NMP）相比，二甲基亚砜（DMSO）表现出更好的控制能力。使用AMBER20软件进行的分子动力学模拟为单个分子的运动提供了有价值的见解，均方根偏差（RMSD）值证明了这一点。向系统中添加布洛芬导致布洛芬分子运动迟缓，在DMSO系列中尤为明显，添加布洛芬后强力霉素的扩散常数从1.2452降至0.3372，在NMP系列中从0.3703降至0.2245。均方根偏差值表明强力霉素分子波动减小，特别是在DMSO系统中，从超过140降至40 Å。此外，它们的回转半径受布洛芬影响，DMSO系统的值较低，表明分子紧凑性增加。值得注意的是（DH-IBU）构型通过氢键形成稳定配对，在DMSO系统中观察到更多的氢键，这与药物缓释效果相关。这些重要发现为相变机制研究的发展铺平了道路，并为原位形成凝胶药物递送系统领域的未来设计和优化配方提供了新途径。
