Peng Rui, Müllertz Anette, Bannow Jacob, Rades Thomas
Department of Pharmacy, Faculty of Health and Medical Science, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Department of Pharmacy, Faculty of Health and Medical Science, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; Bioneer: FARMA, Department of Pharmacy, University of Copenhagen, Universitetsparken 4, 2100 Copenhagen, Denmark.
Eur J Pharm Biopharm. 2025 Nov;216:114862. doi: 10.1016/j.ejpb.2025.114862. Epub 2025 Sep 11.
Supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) have emerged as a promising approach to increase the drug load of hydrophobic molecules, compared to conventional SNEDDS (con-SNEDDS). This study aimed to explore the relationship between equilibrium solubility (S) and the maximum supersaturation concentration (CS) in SNEDDS preconcentrates for three model drugs: carvedilol (CVL), ritonavir (RTV) and nilotinib (NTB). The emulsion droplet size of con-SNEDDS (90 % of S) and super-SNEDDS (90 % of CS), and the influence of polyvinylpyrrolidone-vinyl acetate copolymers 64 (PVP/VA 64) was assessed, as well as the relationship between physical stability and viscosity of super-SNEDDS in the presence of PVP/VA 64. A Design of Experiment (DoE) approach was applied to optimize SNEDDS compositions. The results showed linear correlations between S and CS across all three model drugs, leading to a consistent (but drug dependent) maximum degree of supersaturation (DS) (CVL = 2.49, RTV = 4.56, NTB = 2.54) within the DoE design space. Dissolving 4 % (w/w) PVP/VA 64 in the SNEDDS preconcentrates did not influence the described correlations or DS. Emulsion droplet size remained unchanged upon drug loading to 90 % of S (con-SNEDDS) compared to drug-free SNEDDS. Further loading to 90 % of CS (super-SNEDDS) also resulted in negligible size changes in emulsions with initial droplet sizes below 60 nm, whereas those above 60 nm exhibited pronounced droplet size increase, following a quadratic relationship compared with their initial con-SNEDDS droplet size. Incorporation of PVP/VA 64 enhanced both the physical stability and viscosity of super-SNEDDS; however, only a weak correlation was observed between these two parameters, suggesting that viscosity alone did not govern the stabilization of super-SNEDDS. In summary, within the design space, DS is drug-dependent, but independent of SNEDDS composition or polymer addition; droplet size of super-SNEDDS is dependent on both drug and SNEDDS composition, but is unaffected by polymer; in contrast, physical stability is jointly influenced by drug properties, SNEDDS composition, and polymer addition.
与传统自纳米乳化药物递送系统（con-SNEDDS）相比，过饱和自纳米乳化药物递送系统（super-SNEDDS）已成为一种增加疏水分子载药量的有前景的方法。本研究旨在探讨三种模型药物（卡维地洛（CVL）、利托那韦（RTV）和尼洛替尼（NTB））在SNEDDS预浓缩物中的平衡溶解度（S）与最大过饱和浓度（CS）之间的关系。评估了con-SNEDDS（S的90%）和super-SNEDDS（CS的90%）的乳液滴粒径，以及聚乙烯吡咯烷酮-醋酸乙烯酯共聚物64（PVP/VA 64）的影响，以及在PVP/VA 64存在下super-SNEDDS的物理稳定性与粘度之间的关系。采用实验设计（DoE）方法优化SNEDDS组成。结果表明，所有三种模型药物的S与CS之间均呈线性相关，在DoE设计空间内导致一致的（但依赖于药物）最大过饱和度（DS）（CVL = 2.49，RTV = 4.56，NTB = 2.54）。在SNEDDS预浓缩物中溶解4%（w/w）的PVP/VA 64不会影响所述相关性或DS。与不含药物的SNEDDS相比，将药物负载至S的90%（con-SNEDDS）时乳液滴粒径保持不变。进一步负载至CS的90%（super-SNEDDS）时，初始滴粒径低于60 nm的乳液滴粒径变化也可忽略不计，而初始滴粒径高于60 nm的乳液滴粒径则显著增加，与它们初始的con-SNEDDS滴粒径呈二次关系。加入PVP/VA 64可增强super-SNEDDS的物理稳定性和粘度；然而，这两个参数之间仅观察到弱相关性，表明仅粘度并不能控制super-SNEDDS的稳定性。总之，在设计空间内，DS依赖于药物，但与SNEDDS组成或聚合物添加无关；super-SNEDDS的滴粒径依赖于药物和SNEDDS组成，但不受聚合物影响；相反，物理稳定性受药物性质、SNEDDS组成和聚合物添加的共同影响。
