Khorami Keyoomars, Farahani Sam Darestani, Müllertz Anette, Rades Thomas
Department of Pharmacy, Faculty of Health and Medical Science, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Pharmaceutics. 2024 Dec 16;16(12):1602. doi: 10.3390/pharmaceutics16121602.
: This study aims to broaden the knowledge on co-amorphous phospholipid systems (CAPSs) by exploring the formation of CAPSs with a broader range of poorly water-soluble drugs, celecoxib (CCX), furosemide (FUR), nilotinib (NIL), and ritonavir (RIT), combined with amphiphilic phospholipids (PLs), including soybean phosphatidylcholine (SPC), hydrogenated phosphatidylcholine (HPC), and mono-acyl phosphatidylcholine (MAPC). : The CAPSs were initially prepared at equimolar drug-to-phospholipid (PL) ratios by mechano-chemical activation-based, melt-based, and solvent-based preparation methods, i.e., ball milling (BM), quench cooling (QC), and solvent evaporation (SE), respectively. The solid state of the product was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), and differential scanning calorimetry (DSC). The long-term physical stability of the CAPSs was investigated at room temperature under dry conditions (0% RH) and at 75% RH. The dissolution behavior of the CCX CAPS and RIT CAPS was studied. : Our findings indicate that SE consistently prepared CAPSs for CCX-PLs, FUR-PLs, and RIT-PLs, whereas the QC method could only form CAPSs for RIT-PLs, CCX-SPC, and CCX-MAPC. In contrast, the BM method failed to produce CAPSs, but all drugs alone could be fully amorphized. While the stability of each drug varied depending on the PLs used, the SE CAPS consistently demonstrated the highest stability by a significant margin. Initially, a 1:1 molar ratio was used for screening all systems, though the optimal molar ratio for drug stability remained uncertain. To address this, various molar ratios were investigated to determine the ratio yielding the highest amorphous drug stability. Our results indicate that all systems remained physically stable at a 1.5:1 ratio and with excess of PL. Furthermore, the CAPS formed by the SE significantly improves the dissolution behavior of CCX and RIT, whereas the PLs provide a slight precipitation inhibition for supersaturated CCX and RIT. : These findings support the use of a 1:1 molar ratio in screening processes and suggest that CAPSs can be effectively prepared with relatively high drug loads compared to traditional drug-polymer systems. Furthermore, the study highlights the critical role of drug selection, the preparation method, and the PL type in developing stable and effective CAPSs.
本研究旨在通过探索与更广泛的难溶性药物（塞来昔布（CCX）、呋塞米（FUR）、尼洛替尼（NIL）和利托那韦（RIT））结合两亲性磷脂（PLs），包括大豆磷脂酰胆碱（SPC）、氢化磷脂酰胆碱（HPC）和单酰基磷脂酰胆碱（MAPC），形成共无定形磷脂体系（CAPSs），以拓宽对其的认识。CAPSs最初通过基于机械化学活化、熔融和溶剂的制备方法，即分别通过球磨（BM）、骤冷（QC）和溶剂蒸发（SE），以等摩尔药物与磷脂（PL）比例制备。通过X射线粉末衍射（XRPD）、偏光显微镜（PLM）和差示扫描量热法（DSC）对产物的固态进行表征。在室温下干燥条件（0%相对湿度）和75%相对湿度下研究了CAPSs的长期物理稳定性。研究了CCX CAPS和RIT CAPS的溶解行为。我们的研究结果表明，SE能始终如一地制备CCX-PLs、FUR-PLs和RIT-PLs的CAPSs，而QC方法只能形成RIT-PLs、CCX-SPC和CCX-MAPC的CAPSs。相比之下，BM方法未能制备出CAPSs，但所有单独的药物都能完全无定形化。虽然每种药物的稳定性因所用的PLs而异，但SE CAPS始终以显著优势表现出最高的稳定性。最初，使用1:1摩尔比筛选所有体系，尽管药物稳定性的最佳摩尔比仍不确定。为了解决这个问题，研究了各种摩尔比以确定产生最高无定形药物稳定性的比例。我们的结果表明，所有体系在1.5:1的比例和PL过量的情况下保持物理稳定。此外，通过SE形成的CAPS显著改善了CCX和RIT的溶解行为，而PLs对过饱和的CCX和RIT提供了轻微的沉淀抑制作用。这些研究结果支持在筛选过程中使用1:1摩尔比，并表明与传统药物-聚合物体系相比，CAPSs可以有效地以相对较高的药物负载量制备。此外，该研究突出了药物选择、制备方法和PL类型在开发稳定有效的CAPSs中的关键作用。
