Kelsall Kristen N, Foroughi Leila M, Frank Derek S, Schenck Luke, LaBuda Anthony, Matzger Adam J
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
Macromolecular Science and Engineering Program, University of Michigan, Ann Arbor, Michigan 48109, United States.
Mol Pharm. 2023 Mar 6;20(3):1779-1787. doi: 10.1021/acs.molpharmaceut.2c00970. Epub 2023 Jan 31.
Crystalline drugs with low solubility have the potential to benefit from delivery in the amorphous form. The polymers used in amorphous solid dispersions (ASDs) influence their maximum drug loading, solubility, dissolution rate, and physical stability. Herein, the influence of hydrophobicity of crosslinked polyethylenimine (PEI) is investigated for the delivery of the BCS class II nonsteroidal anti-inflammatory drug flufenamic acid (ffa). Several synthetic variables for crosslinking PEI with terephthaloyl chloride were manipulated: solvent, crosslinking density, reactant concentration, solution viscosity, reaction temperature, and molecular weight of the hyperbranched polymer. Benzoyl chloride was employed to cap amine groups to increase the hydrophobicity of the crosslinked materials. Amorphous deprotonated ffa was present in all ASDs; however, the increased hydrophobicity and reduced basicity from benzoyl functionalization led to a combination of amorphous deprotonated ffa and amorphous neutral ffa in the materials at high drug loadings (50 and 60 wt %). All ASDs demonstrated enhanced drug delivery in acidic media compared to crystalline ffa. Physical stability testing showed no evidence of crystallization after 29 weeks under various relative humidity conditions. These findings motivate the broadening of polymer classes employed in ASD formation to include polymers with very high functional group concentrations to enable loadings not readily achieved with existing polymers.
低溶解度的结晶药物有可能从无定形形式的给药中获益。用于无定形固体分散体（ASD）的聚合物会影响其最大载药量、溶解度、溶解速率和物理稳定性。在此，研究了交联聚乙烯亚胺（PEI）的疏水性对BCS II类非甾体抗炎药氟芬那酸（ffa）给药的影响。对用对苯二甲酰氯交联PEI的几个合成变量进行了调控：溶剂、交联密度、反应物浓度、溶液粘度、反应温度和超支化聚合物的分子量。使用苯甲酰氯封端胺基以增加交联材料的疏水性。所有ASD中均存在无定形去质子化ffa；然而，苯甲酰官能化导致的疏水性增加和碱性降低，在高载药量（50%和60%重量）下，材料中出现了无定形去质子化ffa和无定形中性ffa的组合。与结晶ffa相比，所有ASD在酸性介质中均表现出增强的药物递送。物理稳定性测试表明，在各种相对湿度条件下29周后没有结晶迹象。这些发现促使扩大用于形成ASD的聚合物类别，以包括具有非常高官能团浓度的聚合物，从而实现现有聚合物难以达到的载药量。
