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

Abstract

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 in vitro disintegration time (DT) and wetting time (WT) tests, in vitro 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 (p < 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 (p = 0.0493) and AUC_0-24 (p = 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 via 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.HIGHLIGHTSODTs 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 (p < 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) (p = 0.0286).Lyo-ODT-7 also showed significantly enhanced C_max (p = 0.0493) and AUC_0-24 (p = 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.