Engineering orally disintegrating tablets for buccal delivery of cilostazol with enhanced dissolution and bioavailability: a novel dual porogenic approach, <i>in vitro</i> characterization, and <i>in vivo</i> evaluation in rats

Cilostazol (CTZ), is a BCS class II drug with limited bioavailability. In the current study, orally disintegrating tablets (ODTs) for buccal delivery of CTZ were prepared by two methods; lyophilization (Lyo-ODTs) and direct compression (DC-ODTs). All CTZ-ODTs were evaluated for <i>in vitro</i> disintegration time (DT) and wetting time (WT) tests, <i>in vitro</i> dissolution. Scanning electron microscopic (SEM) analysis was performed for the selected Lyo-ODT-7 and DC-ODT-2. Lyo-ODT-7 composed of aerosil^® 200 and PEG 4000 acquired the shortest DT (13.00 ± 0.14) and WT (33.00 ± 0.26) among the prepared ODTs. It also showed a 2.3 fold significantly enhanced dissolution profile at an early time point (5 min) that was maintained till 1 h, in simulated saliva fluid (pH ∼ 6.8), compared to Pletaal^® IR tablets (<i>p</i> &lt; 0.0001). SEM analysis revealed the remarkable porosity of Lyo-ODT-7, confirming its successfully enhanced disintegration and dissolution. Lyo-ODT-7 showed significantly enhanced pharmacokinetic parameters with a 3.5 and 3.6 fold increase in C_max (<i>p</i> = 0.0493) and AUC_0-24 (<i>p</i> = 0.0470), respectively compared to Pletaal^® IR tablets. The relative bioavailability of CTZ after buccal administration of Lyo-ODT-7 to rats was 364.45%, compared to the market oral IR tablets; Pletaal^®. The enhanced bioavailability imposes the successful oromucosal absorption of CTZ <i>via</i> buccal delivery of Lyo-ODT-7. Our study demonstrated that Lyo-ODT-7 could represent a favorable buccal dosage form for patients with intermittent claudication, suffering from dysphagia. It can also be used in cases of acute cerebral or myocardial infarction due to its significantly enhanced rate and extent of absorption. It is considered a promising approach for buccal delivery of BCS class II active pharmaceutical ingredients (APIs) suffering from solubility problems and hepatic first pass effect. ODTs containing CTZ were prepared via lyophilization and direct compression to produce Lyo-ODTs and DC-ODTs, respectively.Lyo-ODT-7 displayed the fastest DT, shortest WT and exhibited significantly enhanced in vitro dissolution at 5 minutes compared to Pletaal^® IR tablets (<i>p</i> &lt; 0.0001), at the buccal pH (6.8).SEM images of Lyo-ODT-7 elucidated its extremely porous structure with the appearance of wide pores having average pore diameter that is 2.27 fold significantly greater than the directly compressible ODT-2 (DC-ODT-2) (<i>p</i> = 0.0286).Lyo-ODT-7 also showed significantly enhanced C_max (<i>p</i> = 0.0493) and AUC_0-24 (<i>p</i> = 0.0470) that were 3.5 and 3.6 fold greater than Pletaal^® IR tablets, respectively with improved relative bioavailability ∼ 364.45%.A dual porogenic effect was achieved via implementing both lyophilization technique and a pore-former excipient, during pharmaceutical development of CTZ-loaded ODT (Lyo-ODT-7), and still mechanical properties were preserved.The implemented dual porogenic approach can aid in future development of successful buccal drug delivery systems with enhanced oromucosal absorption and improved bioavailability of BCS class II APIs. ODTs containing CTZ were prepared via lyophilization and direct compression to produce Lyo-ODTs and DC-ODTs, respectively. Lyo-ODT-7 displayed the fastest DT, shortest WT and exhibited significantly enhanced in vitro dissolution at 5 minutes compared to Pletaal^® IR tablets (<i>p</i> &lt; 0.0001), at the buccal pH (6.8). SEM images of Lyo-ODT-7 elucidated its extremely porous structure with the appearance of wide pores having average pore diameter that is 2.27 fold significantly greater than the directly compressible ODT-2 (DC-ODT-2) (<i>p</i> = 0.0286). Lyo-ODT-7 also showed significantly enhanced C_max (<i>p</i> = 0.0493) and AUC_0-24 (<i>p</i> = 0.0470) that were 3.5 and 3.6 fold greater than Pletaal^® IR tablets, respectively with improved relative bioavailability ∼ 364.45%. A dual porogenic effect was achieved via implementing both lyophilization technique and a pore-former excipient, during pharmaceutical development of CTZ-loaded ODT (Lyo-ODT-7), and still mechanical properties were preserved. The implemented dual porogenic approach can aid in future development of successful buccal drug delivery systems with enhanced oromucosal absorption and improved bioavailability of BCS class II APIs.

西洛他唑（Cilostazol, CTZ）属于生物药剂学分类系统（BCS）II类药物，生物利用度有限。本研究采用两种方法制备了用于CTZ口腔黏膜递送的口腔速溶片（orally disintegrating tablets, ODTs）：冷冻干燥法（lyophilization, Lyo-ODTs）与直接压片法（direct compression, DC-ODTs）。对所有CTZ载药ODTs开展了体外崩解时限（DT）、润湿时间（WT）测定以及体外溶出度评价。针对筛选得到的Lyo-ODT-7与DC-ODT-2，开展了扫描电子显微镜（SEM）分析。由Aerosil®200与聚乙二醇4000（PEG 4000）制备的Lyo-ODT-7，在所制备的所有ODTs中展现出最短的崩解时限（13.00±0.14）与润湿时间（33.00±0.26）。与市售Pletaal®速释片相比，该制剂在pH约6.8的模拟唾液中，于早期时间点（5分钟）的溶出曲线提升了2.3倍，且该优势可维持至1小时（p<0.0001）。扫描电子显微镜分析结果显示Lyo-ODT-7具有显著的多孔结构，证实其崩解与溶出性能得到有效提升。与Pletaal®速释片相比，Lyo-ODT-7的药代动力学参数显著优化：峰浓度（Cmax）与0~24小时血药浓度-时间曲线下面积（AUC0-24）分别提升3.5倍与3.6倍（p=0.0493，p=0.0470）。以市售口服速释片Pletaal®为参比，大鼠经口腔黏膜递送Lyo-ODT-7后，CTZ的相对生物利用度可达364.45%。该结果证实Lyo-ODT-7可通过口腔黏膜途径实现CTZ的高效吸收。本研究表明，Lyo-ODT-7可作为间歇性跛行合并吞咽困难患者的优选口腔黏膜给药制剂；同时，由于其吸收速率与吸收程度均显著提升，该制剂也可用于急性脑梗死或心肌梗死的救治。该策略为存在溶解度问题与肝脏首过效应的BCS II类活性药物成分（active pharmaceutical ingredients, APIs）的口腔黏膜递送提供了一种极具前景的解决方案。采用冷冻干燥法与直接压片法分别制备了CTZ载药ODTs，即Lyo-ODTs与DC-ODTs。Lyo-ODT-7展现出最快的崩解时限与最短的润湿时间，在口腔黏膜pH（6.8）条件下，其5分钟时的体外溶出度显著优于Pletaal®速释片（p<0.0001）。Lyo-ODT-7的扫描电子显微镜图像显示其具有高度多孔的结构，其平均孔径较直接压片制备的DC-ODT-2显著高出2.27倍（p=0.0286）。与Pletaal®速释片相比，Lyo-ODT-7的Cmax与AUC0-24分别提升3.5倍与3.6倍（p=0.0493，p=0.0470），相对生物利用度提升至约364.45%。在CTZ载药ODTs（Lyo-ODT-7）的药学开发过程中，联合使用冷冻干燥技术与致孔辅料实现了双重致孔效应，同时保留了制剂的机械性能。该双重致孔策略可为未来开发具有高效口腔黏膜吸收与优化生物利用度的BCS II类API口腔给药系统提供参考。采用冷冻干燥法与直接压片法分别制备了CTZ载药ODTs，即Lyo-ODTs与DC-ODTs。Lyo-ODT-7展现出最快的崩解时限与最短的润湿时间，在口腔黏膜pH（6.8）条件下，其5分钟时的体外溶出度显著优于Pletaal®速释片（p<0.0001）。Lyo-ODT-7的扫描电子显微镜图像显示其具有高度多孔的结构，其平均孔径较直接压片制备的DC-ODT-2显著高出2.27倍（p=0.0286）。与Pletaal®速释片相比，Lyo-ODT-7的Cmax与AUC0-24分别提升3.5倍与3.6倍（p=0.0493，p=0.0470），相对生物利用度提升至约364.45%。在CTZ载药ODTs（Lyo-ODT-7）的药学开发过程中，联合使用冷冻干燥技术与致孔辅料实现了双重致孔效应，同时保留了制剂的机械性能。该双重致孔策略可为未来开发具有高效口腔黏膜吸收与优化生物利用度的BCS II类API口腔给药系统提供参考。

搜集汇总

背景与挑战

背景概述

该数据集研究了一种用于西洛他唑颊黏膜递送的口腔崩解片，采用冻干和直接压片两种方法制备，其中冻干法制备的Lyo-ODT-7表现出最优性能，崩解和润湿时间最短，溶解速度显著提升，SEM分析揭示其多孔结构。体内评估显示，Lyo-ODT-7能大幅提高西洛他唑的生物利用度，相对生物利用度达364.45%，表明双重造孔方法有效增强了颊黏膜吸收，适用于BCS II类药物的递送系统开发。