Panbachi Shaida, Beranek Josef, Kuentz Martin
University of Basel, Department of Pharmaceutical Sciences, Klingelbergstrasse 50, 4056 Basel, Switzerland; Zentiva, k.s., U Kabelovny 130, 102 00 Praha 10, Czech Republic; University of Applied Sciences and Arts Northwest. Switzerland, School of Life Sciences, Institute of Pharma Technology, Hofackerstr. 30, CH-4132 Muttenz, Switzerland.
Zentiva, k.s., U Kabelovny 130, 102 00 Praha 10, Czech Republic.
Int J Pharm. 2025 Feb 25;671:125279. doi: 10.1016/j.ijpharm.2025.125279. Epub 2025 Jan 26.
In recent years, deep eutectic solvents (DESs) with their outstanding solubilization properties have emerged as strong candidates for oral enabling formulations of poorly soluble drugs. This study explores the use of drug-based therapeutic DESs (THEDESs) to solubilize a poorly soluble compound with the aim of providing a fixed-dose combination of two complementary therapeutic agents. Specifically, potential anticancer effects of ibuprofen (IBU) are harnessed in a novel type of THEDES to dissolve higher amounts of abiraterone acetate (AbAc), an antitumor agent. Four IBU-based combinations were studied: 1:4 M ratio with octanoic acid (OctA), 1:5 with nonanoic acid (NonA), 1:3 with decanoic acid (DeA) or 1:2 with dodecanoic acid (DoA). Fatty acids of different chain lengths were analyzed and discussed considering surface charge densities obtained via quantum chemistry. The THEDESs listed could apparently dissolve AbAc amounts up to 1311.0 ± 125.4 mg/g in IBU:OctA THEDES, 1151.7 ± 22.2 mg/g in IBU:NonA, 1160.4 ± 33.5 mg/g in IBU:DeA, and 231.3 ± 10.7 mg/g in IBU:DoA. In vitro dissolution of the simultaneously released drugs reached 37.8 ± 9.0 % to 64.2 ± 1.0 % for IBU and 5.0 ± 3.3 % to 19.4 ± 0.1 % for AbAc. This increased to between 60.4 ± 2.8 % and 79.4 ± 5.0 % of released IBU, and 23.6 ± 1.0 % to 57.3 ± 5.8 % of released AbAc, with 20 % (w/w) Tween 80 added to the formulations. This showed the significant potential of drug-containing THEDESs as solubilizing agents for poorly soluble drugs, in the form of fixed-dose combinations of synergistic APIs.
近年来，具有出色增溶性能的低共熔溶剂（DESs）已成为难溶性药物口服制剂的有力候选者。本研究探索使用基于药物的治疗性低共熔溶剂（THEDESs）来增溶一种难溶性化合物，目的是提供两种互补治疗剂的固定剂量组合。具体而言，在一种新型的THEDES中利用布洛芬（IBU）的潜在抗癌作用来溶解更高量的抗肿瘤药物醋酸阿比特龙（AbAc）。研究了四种基于IBU的组合：与辛酸（OctA）的摩尔比为1:4、与壬酸（NonA）的摩尔比为1:5、与癸酸（DeA）的摩尔比为1:3或与十二烷酸（DoA）的摩尔比为1:2。考虑通过量子化学获得的表面电荷密度，对不同链长的脂肪酸进行了分析和讨论。所列的THEDESs在IBU:OctA THEDES中显然可溶解高达1311.0±125.4mg/g的AbAc，在IBU:NonA中为1151.7±22.2mg/g，在IBU:DeA中为1160.4±33.5mg/g，在IBU:DoA中为231.3±10.7mg/g。同时释放药物的体外溶出度对于IBU达到37.8±9.0%至64.2±1.0%，对于AbAc达到5.0±3.3%至19.4±0.1%。在制剂中添加20%（w/w）吐温80后，这一比例分别提高到释放的IBU的60.4±2.8%至79.4±5.0%，以及释放的AbAc的23.6±1.0%至57.3±5.8%。这表明含药物的THEDESs作为难溶性药物的增溶剂具有巨大潜力，可制成协同活性成分的固定剂量组合形式。
