Tanaka Akiko, Furubayashi Tomoyuki, Enomura Yuki, Hori Tomoki, Shimomura Rina, Maeda Chiaki, Kimura Shunsuke, Inoue Daisuke, Kusamori Kosuke, Katsumi Hidemasa, Sakane Toshiyasu, Yamamoto Akira
Department of Biopharmaceutics, Kyoto Pharmaceutical University.
Biol Pharm Bull. 2017;40(2):212-219. doi: 10.1248/bpb.b16-00787.
The effect of changes in the mucosal fluid volume on the nasal drug absorption of powder formulations was evaluated using warfarin (WF), piroxicam (PXC), and norfloxacin (NFX) as model drugs. Lactose and sodium chloride (NaCl), which are water soluble and small-sized chemicals that increase osmotic pressure after dissolution, were used as excipients to change the mucosal fluid volume. The in vitro study using a Madin-Darby canine kidney (MDCK) cell monolayer indicated that lactose and NaCl, sprayed over the surface of air interface monolayers, increased the fluid volume on the monolayer surface and enhanced the transepithelial transport of the model drugs. The in vivo animal study indicated that the nasal absorption of PXC is enhanced by lactose and NaCl after nasal administration of the powder formulations. This is likely due to the enhanced dissolution of PXC on fluid-rich nasal mucosa and an increase in the effective surface area for drug permeation, which lead to better nasal absorption. However, both excipients failed to increase the nasal absorption of WF and NFX. To clarify the mechanism of the drug-dependent effect of lactose and NaCl, the nasal residence of the formulation was examined using FD70 as a non-absorbable marker. The nasal clearance of FD70 was enhanced by lactose and NaCl, leading to a decrease in the nasal drug absorption. Lactose and NaCl caused no damage to the nasal tissue. These results indicate that the addition of water-soluble excipients such as lactose to powder formulations can enhance the nasal absorption of highly permeable but poorly soluble drugs.
以华法林（WF）、吡罗昔康（PXC）和诺氟沙星（NFX）作为模型药物，评估了粘膜液体积变化对粉末制剂鼻腔药物吸收的影响。乳糖和氯化钠（NaCl）是水溶性的小尺寸化学物质，溶解后会增加渗透压，用作改变粘膜液体积的辅料。使用Madin-Darby犬肾（MDCK）细胞单层进行的体外研究表明，喷洒在空气界面单层表面的乳糖和NaCl增加了单层表面的液体体积，并增强了模型药物的跨上皮转运。体内动物研究表明，鼻腔给予粉末制剂后，乳糖和NaCl可增强PXC的鼻腔吸收。这可能是由于PXC在富含液体的鼻粘膜上的溶解增强以及药物渗透有效表面积增加，从而导致更好的鼻腔吸收。然而，两种辅料均未能增加WF和NFX的鼻腔吸收。为了阐明乳糖和NaCl的药物依赖性作用机制，使用FD70作为非吸收性标记物检查了制剂的鼻腔滞留情况。乳糖和NaCl增强了FD70的鼻腔清除率，导致鼻腔药物吸收减少。乳糖和NaCl未对鼻组织造成损伤。这些结果表明，在粉末制剂中添加乳糖等水溶性辅料可增强高渗透性但难溶性药物的鼻腔吸收。
