Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM, Université de Liège, 4000 Liège, Belgium; Laboratory of Drug Development, Center of Training, Research and Expertise in Pharmaceutical Sciences (CFOREM), Doctoral School of Sciences and Health, Université Joseph KI-ZERBO, 03 BP 7021 Ouagadougou 03, Burkina Faso; Institut Supérieur des Sciences de la Santé (INSSA), Université Nazi Boni, 01 BP 1091 Bobo-Dioulasso 01, Burkina Faso.
Laboratory of Drug Development, Center of Training, Research and Expertise in Pharmaceutical Sciences (CFOREM), Doctoral School of Sciences and Health, Université Joseph KI-ZERBO, 03 BP 7021 Ouagadougou 03, Burkina Faso.
Eur J Pharm Biopharm. 2024 Nov;204:114513. doi: 10.1016/j.ejpb.2024.114513. Epub 2024 Sep 21.
High solubility in water and physiological fluids is an indispensable requirement for the pharmacological efficacy of an active pharmaceutical ingredient. Indeed, it is well established that pharmaceutical substances exhibiting limited solubility in water are inclined towards diminished and inconsistent absorption following oral administration, consequently resulting in variability in therapeutic outcomes. The current advancements in combinatorial chemistry and pharmaceutical design have facilitated the creation of drug candidates characterized by increased lipophilicity, elevated molecular size, and reduced aqueous solubility. Undoubtedly, the issue of poorly water-soluble medications has been progressively escalating over recent years. Indeed, 40% of the top 200 oral medications marketed in the United States, 33% of drugs listed in the US pharmacopoeia, 75% of compounds under development and 90% of new chemical entities are insufficiently water-soluble compounds. In order to address this obstacle, formulation scientists employ a variety of approaches, encompassing both physical and chemical methods such as prodrug synthesis, salt formation, solid dispersions formation, hydrotropic substances utilization, solubilizing agents incorporation, cosolvent addition, polymorphism exploration, cocrystal creation, cyclodextrins complexation, lipid formulations, particle size reduction and nanoformulation techniques. Despite the utilization of these diverse approaches, the primary reason for the failure in new drug development persists as the poor aqueous solubility of pharmaceutical compounds. This paper, therefore, delves into the foundational principles that underpin the implementation of various formulation strategies, along with a discussion on the respective advantages and drawbacks associated with each approach. Additionally, a discourse is provided regarding methodological frameworks for making informed decisions on selecting an appropriate formulation strategy to effectively tackle the key challenges posed during the development of a poorly water-soluble drug candidate.
高水溶性和在生理流体中的高溶解性是药物活性成分发挥药效的必要条件。事实上，人们已经充分认识到，在水中溶解度有限的药物在口服后往往会吸收不良且不一致，从而导致治疗效果的变异性。目前组合化学和药物设计的进步促进了具有更高脂溶性、更大分子尺寸和更低水溶解度的药物候选物的创造。毫无疑问，近年来水溶性差的药物问题一直在逐渐加剧。事实上，美国市场上销售的前 200 种口服药物中有 40%、美国药典中列出的药物有 33%、处于开发阶段的药物有 75%、新化学实体有 90%是水溶性差的化合物。为了解决这个问题，制剂科学家采用了各种方法，包括物理和化学方法，如前药合成、盐形成、固体分散体形成、增溶物质利用、增溶剂加入、共溶剂添加、多晶型探索、共晶形成、环糊精络合、脂质制剂、粒径减小和纳米制剂技术。尽管使用了这些不同的方法，但新药开发失败的主要原因仍然是药物化合物的水溶性差。因此，本文深入探讨了实施各种制剂策略的基础原理，并讨论了每种方法的优缺点。此外，还讨论了在选择适当的制剂策略方面做出明智决策的方法框架，以有效地解决水溶性差的药物候选物开发过程中面临的关键挑战。
