Loratadine bioavailability via buccal transferosomal gel: formulation, statistical optimization, in vitro/in vivo characterization, and pharmacokinetics in human volunteers
Loratadine bioavailability via buccal transferosomal gel: formulation, statistical optimization, in vitro/in vivo characterization, and pharmacokinetics in human volunteers
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DOI：
10.1080/10717544.2017.1321061
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发表时间：
2017-05-08
期刊：
影响因子：
6
通讯作者：
Elkarmalawy, Marwa H.
中科院分区：
文献类型：
--
作者：
Elkomy, Mohammed H.;El Menshawe, Shahira F.;Elkarmalawy, Marwa H.
氯雷他定（LTD）是一种抗组胺药，溶解度有限，口服生物利用度差（由于广泛的首过代谢），口服吸收差异很大。本研究旨在开发和统计学优化用于经颊递送LTD的传递体凝胶。通过常规薄膜水合法制备携带LTD的传递体，并使用序贯质量设计方法进行优化，该方法涉及用于筛选的Placket-Burman设计，然后是用于优化Tween-80/Span-60/Span-80混合物的约束单纯形质心设计。转移体的特征在于包封率，粒径和形状。将优化的转移体掺入粘膜粘附凝胶中。该凝胶的特点是流变学，离体渗透通过鸡袋颊粘膜，在体外释放，和粘膜粘附。在健康志愿者中研究了LTD制剂单次10 mg给药后的药代动力学行为。通过使用准等比例的表面活性剂混合物，获得了以亚微米尺寸（380 nm）、球形形状和足够的负载量（60%）为特征的最佳转移体。在渗透量、释放百分比和粘膜粘附时间方面，证明转移体凝胶上级对照、无转移体凝胶。转移体凝胶的生物利用度与Claritin口服片剂相当。然而，当使用口腔凝胶时，C-max和AUC的个体间变异性分别降低了76%和90%。体外释放度与体内口腔吸收分数呈良好的线性相关（R-2 >0.97）。综上所述，本研究开发了一种新型LTD口腔给药系统。然而，需要进一步的临床研究来评估其治疗效果和实用性。
Loratadine (LTD) is an antihistaminic drug that suffers limited solubility, poor oral bioavailability (owing to extensive first-pass metabolism), and highly variable oral absorption. This study was undertaken to develop and statistically optimize transfersomal gel for transbuccal delivery of LTD. Transfersomes bearing LTD were prepared by conventional thin film hydration method and optimized using sequential Quality-by-Design approach that involved Placket-Burman design for screening followed by constrained simplex-centroid design for optimization of a Tween-80/Span-60/Span-80 mixture. The transferosomes were characterized for entrapment efficiency, particle size, and shape. Optimized transferosomes were incorporated in a mucoadhesive gel. The gel was characterized for rheology, ex vivo permeation across chicken pouch buccal mucosa, in vitro release, and mucoadhesion. Pharmacokinetic behavior of LTD formulations was investigated in healthy volunteers following administration of a single 10-mg dose. Optimal transferosomes characterized by submicron size (380 nm), spherical shape and adequate loading capacity (60%) were obtained by using quasi-equal ratio surfactant mixture. In terms of amount permeated, percentage released, and mucoadhesion time, the transferosomal gel proved superior to control, transferosome-free gel. Bioavailability of the transferosomal gel was comparable to Claritin (R) oral tablets. However, inter-individual variability in C-max and AUC was reduced by 76 and 90%, respectively, when the buccal gel was used. Linear Correlation of in vitro release with in vivo buccal absorption fractions was established with excellent correlation coefficient (R-2 >0.97). In summary, a novel buccal delivery system for LTD was developed. However, further clinical investigation is warranted to evaluate its therapeutic effectiveness and utility.