Gao Xiuqing, Wu Lei, Tsai Robert Y L, Ma Jing, Liu Xiaohua, Chow Diana S-L, Liang Dong, Xie Huan
Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
Department of Pharmcological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
Pharmaceutics. 2021 Apr 17;13(4):574. doi: 10.3390/pharmaceutics13040574.
Mycophenolic acid (MPA) is commonly used for organ rejection prophylaxis via oral administration in the clinic. Recent studies have shown that MPA also has anticancer activities. To explore new therapeutic options for oral precancerous/cancerous lesions, MPA was designed to release topically on the dorsal tongue surface via a mucoadhesive patch. The objective of this study was to establish the pharmacokinetic (PK) and tongue tissue distribution of mucoadhesive MPA patch formulation after supralingual administration in rats and also compare the PK differences between oral, intravenous, and supralingual administration of MPA. Blood samples were collected from Sprague Dawley rats before and after a single intravenous bolus injection, a single oral dose, or a mucoadhesive patch administration on the dorsal tongue surface for 4 h, all with a dose of 0.5 mg/kg of MPA. Plots of MPA plasma concentration versus time were obtained. As multiple peaks were found in all three curves, the enterohepatic recycling (EHR) model in the Phoenix software was adapted to describe their PK parameters with an individual PK analysis method. The mean half-lives of intravenous and oral administrations were 10.5 h and 7.4 h, respectively. The estimated bioavailability after oral and supralingual administration was 72.4% and 7.6%, respectively. There was a 0.5 h lag-time presented after supralingual administration. The results suggest that the systemic plasma MPA concentrations were much lower in rats receiving supralingual administration compared to those receiving doses from the other two routes, and the amount of MPA accumulated in the tongue after patch application showed a sustained drug release pattern. Studies on the dynamic of drug retention in the tongue after supralingual administration showed that ~3.8% of the dose was accumulated inside of tongue right after the patch removal, ~0.11% of the dose remained after 20 h, and ~20.6% of MPA was not released from the patches 4 h after application. The data demonstrate that supralingual application of an MPA patch can deliver a high amount of drug at the site of administration with little systemic circulation exposure, hence lowering the potential gastrointestinal side effects associated with oral administration. Thus, supralingual administration is a potential alternative route for treating oral lesions.
霉酚酸（MPA）在临床上通常通过口服用于预防器官排斥反应。最近的研究表明，MPA还具有抗癌活性。为了探索口腔癌前/癌性病变的新治疗选择，设计了一种通过粘膜粘附贴片使MPA在舌背表面局部释放的方法。本研究的目的是建立大鼠舌下给药后粘膜粘附MPA贴片制剂的药代动力学（PK）和舌组织分布，并比较MPA口服、静脉注射和舌下给药之间的PK差异。在单次静脉推注、单次口服剂量或在舌背表面给予粘膜粘附贴片4小时之前和之后，从Sprague Dawley大鼠采集血样，所有剂量均为0.5mg/kg的MPA。获得了MPA血浆浓度与时间的曲线。由于在所有三条曲线中均发现多个峰，因此采用Phoenix软件中的肠肝循环（EHR）模型，通过个体PK分析方法描述其PK参数。静脉注射和口服给药的平均半衰期分别为10.5小时和7.4小时。口服和舌下给药后的估计生物利用度分别为72.4%和7.6%。舌下给药后出现0.5小时的滞后时间。结果表明，与接受其他两种给药途径的大鼠相比，接受舌下给药的大鼠全身血浆MPA浓度要低得多，贴片应用后舌中积累的MPA量呈现出持续的药物释放模式。舌下给药后舌中药物保留动态的研究表明，贴片去除后约3.8%的剂量积聚在舌内，20小时后约0.11%的剂量残留，给药后4小时约20.6%的MPA未从贴片中释放。数据表明，MPA贴片的舌下应用可以在给药部位递送大量药物，而全身循环暴露很少，从而降低了与口服给药相关的潜在胃肠道副作用。因此，舌下给药是治疗口腔病变的一种潜在替代途径。
