基于脂质的制剂(LbFs)已在药物应用中取得了成功;然而,在将整个剂量的药物溶解到限定的液体体积中仍然存在挑战.在这项研究中,在LbF中采用温度诱导的过饱和方法来解决药物负荷和药物负担问题.过饱和LbFs(super-LbF)采用温度诱导过饱和法制备,其中药物负载高于其平衡溶解度。Further,使用两种模型药物研究了药物的物理化学和热特性对药物负载的影响及其与表观过饱和度(aDS)的相关性,伊布替尼和恩扎鲁他胺.在物理稳定性方面对所有制备的LbFs进行了评估,色散,和溶解能力,以及药代动力学评估。在2-2.5的较高aDS值长期储存时,在脂质溶液中观察到药物重结晶。此外,高通量脂解研究表明,由于制剂溶剂化能力的下降和随后产生的原位过饱和,所有LbF中的药物浓度显著降低(无论药物负载如何)。Further,体内结果证明常规LbF和super-LbF的药代动力学参数相当.热力学亚稳态的短持续时间限制了潜在的吸收益处。然而,Ibr和Enz的super-LbFs表现出优越的外形,与各自的结晶悬浮液相比,药物暴露增加了1.7倍和5.2倍。总之,这项研究强调了LbF中温度诱导的过饱和对增强药物负载的潜力,并强调了药物特性之间的复杂相互作用,配方特征,和体内性能。
Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug\'s physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.