Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel.
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel.
J Pharm Sci. 2020 Sep;109(9):2729-2734. doi: 10.1016/j.xphs.2020.05.017. Epub 2020 Jun 1.
Apomorphine (APO), a potent treatment for Parkinson's disease, is only administered parenterally either as intermittent injections or as an infusion. This is due to extensive hepatic "first pass" metabolism. Prolonged delivery through buccal mucosa may be potential substitute for parenteral infusions. To investigate this concept of buccal mucosal delivery, permeability ex vivo studies were performed through excised porcine buccal mucosa by utilizing Ussing diffusion chamber. Permeability rates were assessed for APO from simulated saliva medium at pH 7.4 as well as with utilization of different permeability modifying methods. Lowering the pH to 5.9 decreased permeability rate six-fold, while addition of ethanol : propylene glycol solution elevated it four-fold. Addition of nano-scale lipospheres to the donor compartment delayed the accumulation of APO at the receiver side, prolongating the lag-time from one to approx. three hours. These findings were strengthened by results obtained with co-administration of permeability markers (standards) atenolol and metoprolol. Simulation of the obtained permeability rates to in vivo setup in human showed therapeutically relevant plasma levels when using the outcomes of the current study. These findings verify the novel concept of APO prolonged release buccal administration as a noninvasive substitute for parenteral infusions in treating Parkinson's disease.
阿扑吗啡（APO）是一种治疗帕金森病的有效药物，只能通过间歇性注射或输注的方式进行给药。这是由于其在肝脏中会经历广泛的“首过”代谢。通过颊黏膜进行长时间的输送可能是替代肠外输注的潜在方法。为了研究颊黏膜给药的这一概念，我们通过利用 Ussing 扩散室，对取自猪颊黏膜的离体组织进行了体外渗透实验。我们评估了 APO 从模拟唾液介质（pH 值为 7.4）中的渗透速率，以及使用不同的渗透修饰方法的渗透速率。将 pH 值降低到 5.9 会使渗透速率降低六倍，而添加乙醇：丙二醇溶液则会将其提高四倍。将纳米级脂质体添加到供体腔室中会延迟 APO 在受体侧的积累，将滞后时间从 1 小时延长至约 3 小时。这些发现得到了与渗透标记物（标准品）阿替洛尔和美托洛尔共同给药获得的结果的支持。将获得的渗透速率模拟到人体的体内设置中，结果表明，当使用本研究的结果时，可获得具有治疗相关性的血浆水平。这些发现验证了 APO 颊黏膜缓释给药的新概念，即作为治疗帕金森病的肠外输注的非侵入性替代方法。
