Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23 Uppsala, Sweden; Recipharm OT Chemistry AB, SE-754 50 Uppsala, Sweden.
College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
Int J Pharm. 2024 Dec 5;666:124738. doi: 10.1016/j.ijpharm.2024.124738. Epub 2024 Sep 21.
Multidrug formulations enhance patient compliance and extend the life cycle of pharmaceutical products. To overcome solubility challenges for multidrug combinations, amorphous formulations are commonly used. However, the excipients for creating amorphous formulations are often selected without an understanding of their effects on the bioavailability of the drugs. In this context, we investigated the impact of three types of excipients (polymers, surfactants and amino acids) on the supersaturation and thermodynamic activity of multidrug amorphous formulations. Additionally, we studied the particle size dynamics of the colloidal phase formed as a result of liquid-liquid phase separation. The amorphous solubility of two drugs, atazanavir and ritonavir, was determined in solutions containing predissolved excipients and the particle size dynamics of the colloidal particles was measured by dynamic light scattering. Dissolution experiments of atazanavir and ritonavir were conducted in predissolved sodium dodecyl sulfate (SDS), an anionic surfactant, and alanine solutions under non-sink conditions. Membrane transport of the drugs was evaluated using a MicroFLUX setup. The polymers had only minor effects on the amorphous solubility, but SDS significantly increased the solubilities of both drugs. In contrast, the other non-ionic surfactants and amino acids reduced the solubility of atazanavir but had no negative effect on ritonavir. Polymers were effective in maintaining supersaturation and preventing the coarsening of the colloidal particles. Conversely, alanine was neither able to inhibit the solution crystallization nor increase the flux of either drug. Despite the increase in the amorphous solubility of both drugs in SDS, flux was reduced. These results highlight the importance of properly selecting excipients for supersaturating amorphous formulations. The choice of excipient impacts the thermodynamic activity, the phase behaviour of the drugs and hence, the resulting absorption after oral intake.
多药物制剂可提高患者的依从性并延长药物产品的生命周期。为了克服多药物组合的溶解度挑战，通常使用无定形制剂。然而，用于制备无定形制剂的赋形剂通常是在不了解其对药物生物利用度影响的情况下选择的。在这种情况下，我们研究了三种赋形剂（聚合物、表面活性剂和氨基酸）对多药物无定形制剂的过饱和度和热力学活性的影响。此外，我们研究了由于液-液相分离而形成的胶体相的颗粒动力学。在含有预溶解赋形剂的溶液中测定了两种药物（阿扎那韦和利托那韦）的无定形溶解度，并通过动态光散射测量胶体颗粒的粒径动力学。在预溶解的十二烷基硫酸钠（SDS）阴离子表面活性剂和丙氨酸溶液中，在非溶出条件下进行了阿扎那韦和利托那韦的溶解实验。使用 MicroFLUX 装置评估了药物的膜转运。聚合物对无定形溶解度的影响较小，但 SDS 显著增加了两种药物的溶解度。相比之下，其他非离子表面活性剂和氨基酸降低了阿扎那韦的溶解度，但对利托那韦没有负面影响。聚合物在维持过饱和度和防止胶体颗粒粗化方面有效。相反，丙氨酸既不能抑制溶液结晶，也不能增加两种药物的通量。尽管 SDS 中两种药物的无定形溶解度增加，但通量降低。这些结果强调了为过饱和无定形制剂正确选择赋形剂的重要性。赋形剂的选择会影响热力学活性、药物的相行为，从而影响口服摄入后的吸收。
