Nakane S, Kakumoto M, Yukimatsu K, Chien Y W
Pharmaceuticals Development Center, Toyobo Co., Ltd., Shiga, Japan.
Pharm Dev Technol. 1996 Oct;1(3):251-9. doi: 10.3109/10837459609022593.
Several transmucosal therapeutic systems (TmTs) were developed to study the enhanced/controlled delivery of luteinizing hormone-releasing hormone (LHRH) through oral mucosae for prolonged periods. TmTs is a track field-shaped bilayer mucoadhesive device consisting of fast-release and sustained-release layers. In vivo evaluations were performed in beagle dogs, and pharmacokinetic profiles were monitored to characterize the transmucosal permeation kinetics of LHRH delivered by the various TmTs formulations containing a stabilizer, cetylpyridinium chloride, and a permeation enhancer, such as bile salts, to enhance the stability and permeability of LHRH. The plasma LHRH concentrations were observed to reach the plateau level within 30 min and were maintained for 2 hr following application of TmTs, in contrast to a rapid elimination profile observed after IV administration. Addition of 5% bile salt into the fast-release layer was observed to produce an enhancement in the absorption rate, higher plateau plasma levels, and greater systemic bioavailability. Addition of pH modifiers was noted to affect the bile salt enhanced transmucosal delivery of LHRH. To prolong the plasma LHRH level, several loading doses of LHRH were incorporated into the sustained-release layer. The plasma levels were sustained and the area under the curve (AUC) values were found to be linearly dependent upon the combined loading doses of LHRH in the fast-release and sustained-release layers. Mucosal irritation was also measured, using buccal mucosa, and results were observed to be low and reversible for the single application. The results indicated that TmTs is relatively safe and capable of achieving enhanced and controlled transmucosal delivery of peptide drugs.
为了研究促黄体生成激素释放激素（LHRH）通过口腔黏膜实现长期增强/控释，开发了几种经黏膜治疗系统（TmTs）。TmTs是一种跑道形状的双层黏膜黏附装置，由速释层和缓释层组成。在比格犬身上进行了体内评估，并监测药代动力学特征，以表征含有稳定剂十六烷基氯化吡啶和渗透促进剂（如胆盐）的各种TmTs制剂所递送的LHRH的经黏膜渗透动力学，从而提高LHRH的稳定性和渗透性。与静脉注射后观察到的快速消除情况相反，应用TmTs后，血浆LHRH浓度在30分钟内达到平台期水平，并维持2小时。在速释层中添加5%胆盐可提高吸收速率、提高血浆平台水平并提高全身生物利用度。注意到添加pH调节剂会影响胆盐增强的LHRH经黏膜递送。为了延长血浆LHRH水平，在缓释层中加入了几个剂量的LHRH。血浆水平得以维持，且发现曲线下面积（AUC）值与速释层和缓释层中LHRH的联合负荷剂量呈线性相关。还使用颊黏膜测量了黏膜刺激性，单次应用的结果显示刺激性较低且可逆。结果表明，TmTs相对安全，能够实现肽类药物的增强和控释经黏膜递送。
