Otake Hiroko, Fumihiko Ogata, Nakazawa Yosuke, Misra Manju, Tsubaki Masanobu, Kawasaki Naohito, Nagai Noriaki
Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, Japan.
Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
PLoS One. 2025 Jun 10;20(6):e0326051. doi: 10.1371/journal.pone.0326051. eCollection 2025.
Top-down approaches efficiently convert hydrophobic drugs into nanoparticles, and the selection of appropriate additives is critical for successful nanoparticle formulation. Methylcellulose is an additive capable of reducing the drug particle size to less than 200 nm using the wet bead milling method, a breakdown method, and a dermal gel containing indomethacin (IMC) nanocrystal formulated with methylcellulose, which achieved high skin absorption. In this study, we focused on gum arabic (GA) as an alternative additive to methylcellulose and demonstrated whether formulations (carbopol gels) containing IMC nanocrystals with GA for dermal application (IMC-NP@GCgel) enhanced the local and systemic absorption of IMC. The particle size was significantly reduced by bead milling with GA, and the mean particle size of the IMC-NP@GCgel was 40-200 nm. The drug release and skin permeability from IMC-NP@GCgel was higher than those from carbopol gels containing the IMC microcrystals (mean particle size was 15.6 µm, IMC-MP@GCgel). In addition, IMC levels in the skin tissue of rats treated with the IMC-NP@GCgel were higher than those of rats treated with the IMC-MP@GCgel. However, the plasma IMC levels did not differ between the IMC-MP@GCgel- and IMC-NP@GCgel-treated rats. We successfully designed IMC nanocrystals using GA instead of methylcellulose. Moreover, we found that the addition of GA supported the absorption of IMC nanocrystals and enhanced the skin retention of the drug without increasing plasma IMC levels. These results provide useful information for the development of dermal formulations based on nanocrystals.
自上而下的方法能够有效地将疏水性药物转化为纳米颗粒，而选择合适的添加剂对于成功制备纳米颗粒至关重要。甲基纤维素是一种添加剂，使用湿珠磨法（一种破碎方法）可将药物粒径减小至小于200nm，并且用甲基纤维素配制的含吲哚美辛（IMC）纳米晶体的皮肤凝胶实现了高皮肤吸收。在本研究中，我们重点关注阿拉伯胶（GA）作为甲基纤维素的替代添加剂，并证明含GA的用于皮肤应用的IMC纳米晶体的制剂（卡波姆凝胶，IMC-NP@GCgel）是否能增强IMC的局部和全身吸收。用GA进行珠磨可显著降低粒径，IMC-NP@GCgel的平均粒径为40-200nm。IMC-NP@GCgel的药物释放和皮肤渗透性高于含IMC微晶的卡波姆凝胶（平均粒径为15.6µm，IMC-MP@GCgel）。此外，用IMC-NP@GCgel处理的大鼠皮肤组织中的IMC水平高于用IMC-MP@GCgel处理的大鼠。然而，IMC-MP@GCgel和IMC-NP@GCgel处理的大鼠之间血浆IMC水平没有差异。我们成功地使用GA而非甲基纤维素设计了IMC纳米晶体。此外，我们发现添加GA有助于IMC纳米晶体的吸收，并增强药物在皮肤中的滞留，而不会增加血浆IMC水平。这些结果为基于纳米晶体的皮肤制剂开发提供了有用信息。
