Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 1524 Av. Prof. Lineu Prestes, São Paulo-SP, 05508-000, Brazil.
AAPS PharmSciTech. 2022 Sep 19;23(7):260. doi: 10.1208/s12249-022-02411-9.
In this study, the addition of monoolein to phosphatidylcholine (PC), tricaprylin, and propylene glycol (PG) mixtures was studied to produce fluid precursor formulations (FIPs) that could transform into hexagonal phase (resistant to aqueous dilution) in vitro and in vivo. The overall goal was to obtain FIPs that could incorporate chemopreventive drugs for subcutaneous administration in the mammary tissue to inhibit the development and/or recurrence of breast cancer. Increasing PG content reduced FIP viscosity up to ~ 2.5-fold, while increases in PC (over monoolein) increased the formation of emulsified systems. The hexagonal phase was observed at 20% of water and higher, with the minimum amount of water necessary for this formation increasing with PG content. The selected FIP formed a depot in vivo after ~ 24 h of administration; its structure was compatible with the hexagonal phase and it remained in the mammary tissue for at least 30 days, prolonging the permanence of a fluorescent probe. In vitro, the release of the synthetic retinoid fenretinide was slow, with ~ 9% of the drug released in 72 h. Consistent with this slow release, fenretinide IC in breast cancer cells was ~ 100-fold higher in the selected FIP compared to its solution. The FIP reduced cell migration and presented higher cytotoxicity towards tumor compared to non-tumor cells. Given the limited number of options for pharmacological prevention of breast cancer development and recurrences, this formulation could potentially find applicability to reduce the frequency of administration and improve local concentrations of chemopreventive drugs.
在这项研究中，研究了将单油酸甘油酯加入到磷脂酰胆碱 (PC)、三辛酸甘油酯和丙二醇 (PG) 混合物中，以制备可在体外和体内转化为六方相（抵抗水稀释）的流体前体配方 (FIP)。总体目标是获得可用于皮下给药至乳腺组织以抑制乳腺癌发展和/或复发的 FIP，同时可将化学预防药物包裹其中。增加 PG 含量可将 FIP 的粘度降低至原来的 2.5 倍左右，而增加 PC（相对于单油酸甘油酯）则会增加乳化体系的形成。在 20%水及更高的水相中观察到六方相，而形成该相所需的最低水量随 PG 含量的增加而增加。所选 FIP 在给药后约 24 小时在体内形成一个储库；其结构与六方相相容，并且至少在 30 天内在乳腺组织中保持稳定，从而延长了荧光探针的持久性。体外，合成维甲酸 fenretinide 的释放缓慢，72 小时内约有 9%的药物释放。与这种缓慢释放一致，与溶液相比，fenretinide 在选定的 FIP 中对乳腺癌细胞的 IC 约高 100 倍。与非肿瘤细胞相比，FIP 可减少细胞迁移并表现出更高的肿瘤细胞毒性。鉴于用于预防乳腺癌发展和复发的药理学方法选择有限，这种制剂可能具有潜在的适用性，可减少给药频率并提高化学预防药物的局部浓度。
