Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK.
Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, 70 Pembroke Place, Liverpool, L69 3GF, UK.
J Mater Chem B. 2021 Dec 15;9(48):9874-9884. doi: 10.1039/d1tb02297k.
A significant number of new chemical entities in the drug development pipeline are poorly soluble, therefore routes that facilitate effective administration is of considerable value. Lipid nanoparticles have proved an attractive approach for drug delivery; however, challenges that include optimising drug loading and understanding the impact of drug physiochemical parameters on nanoparticle properties have limited progression. In this work, we investigate the effect of modifying the log of a model drug on the formation and stability of lipid-based nanoparticles. A range of model drug analogues with systematically varying alkyl chains were produced using a lamivudine (nucleoside analog reverse transcriptase inhibitor) scaffold and processed into lipid nanoparticles by nanoprecipitation. Characterisation included evaluation of particle diameter, size distribution, drug loading and nanoformulation stability. A distinct correlation with the LaMer model of nucleation was observed and log appeared to strongly influence rates of nucleation. Model drugs with high log were uniform in particle size and distribution and offered enhanced stability. In addition, various model drug/lipid blends were produced and their physical properties were investigated using dynamic light scattering (DLS) and differential scanning calorimetry (DSC). Complex mixtures of lipids were shown to influence formulation crystallinity and strategies to form uniform and stable lipid based nanoparticles of high drug loading- through manipulation of log are discussed.
在药物开发管道中，大量的新化学实体的溶解度较差，因此，能够促进有效给药的途径具有相当大的价值。脂质纳米粒已被证明是一种有吸引力的药物传递方法；然而，包括优化药物载药量和理解药物物理化学参数对纳米颗粒性质的影响在内的挑战，限制了其进展。在这项工作中，我们研究了修饰模型药物的 logP 值对基于脂质的纳米颗粒的形成和稳定性的影响。使用拉米夫定（核苷类似物逆转录酶抑制剂）支架合成了一系列烷基链系统变化的模型药物类似物，并通过纳米沉淀将其加工成脂质纳米粒。特性包括粒径、粒径分布、药物载药量和纳米制剂稳定性的评估。观察到与 LaMer 成核模型的明显相关性，logP 值似乎强烈影响成核速率。具有高 logP 值的模型药物粒径和分布均匀，稳定性增强。此外，还制备了各种模型药物/脂质混合物，并使用动态光散射（DLS）和差示扫描量热法（DSC）研究了它们的物理性质。研究表明，复杂的脂质混合物会影响制剂的结晶度，并讨论了通过操纵 logP 值来形成均匀且稳定的高载药量基于脂质的纳米粒的策略。
