الفهرس 
Formulation and Evaluation of Bioadhesive Buccal Discs of Fluvastatin SodiumOnly 14 pages are availabe for public view
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Abstract
Abstract
Purpose: The aim of this work was to formulate buccoadhesive discs of fluvastatin sodium (FVS) to be applied to the buccal mucosa, releasing the drug in a unidirectional manner, in order to improve the bioavailability of the drug and lower the dose-dependent adverse events.
Methods: The bioadhesive discs were prepared by direct compression using several bioadhesive polymers such as carbopol 934P, sodium carboxymethyl cellulose, sodium alginate, hydroxypropylmethyl cellulose, and guar gum. Ethyl cellulose was applied as the backing layer to achieve unidirectional release towards the mucosa. To improve drug release, microcrystalline cellulose or polyethylene glycol 6000 (PEG 6000) were added. Different permeation enhancers such as bile salts, surfactants, fatty acids, and dimethyl sulfoxide were tested to improve the permeability across buccal mucosa. Chicken pouch membrane was the used model membrane in drug permeation and bioadhesion strength and time studies. In-vivo relative bioavailability study was performed for the selected formulation on six healthy human volunteers using a commercial peroral product (Lescol®, Novartis) as a reference formulation. Plasma concentrations of fluvastatin were determined by liquid chromatography-mass spectrometry (LC-MS/MS).
Results: Sodium deoxycholate (SDC) was found to be the most effective permeation enhancer with an enhancement ratio (ER) of 1.74. Increasing the concentration of PEG 6000 in the formulation led to further enhancement in FVS permeation. The formulation of choice (F27) contained FVS, guar gum, and PEG 6000 in (0.5:1:1.5) ratios, in addition to SDC (at 4% of total medicated layer weight). The selected formula showed a drug release of 95.4% in 80 min, drug permeation of 75.6% in 4 h with permeation flux (Jss) of 3.837 mg cm-2 h-1, ex-vivo bioadhesion strength of 2.543 g, and bioadhesion time of 4.87 h. The mechanism of drug release was found to be anomalous non-Fickian transport according to Korsmeyer-Peppas model. In-vivo pharmacokinetic study on human volunteers showed that sustained release was achieved as indicated by the higher half value duration (HVD) which was 4.45 h for the buccal formulation compared to 1.44 h for the peroral formulation Lescol® (p=0.0012). The relative bioavailability was found to be 147.1% avoiding shooting blood levels with Cmax of 30.74 ng/ml and tmax of 2.33 h compared to 45.60 ng/ml and 1.17 h (p=0.0047 and p=0.0009), respectively. There was a positive correlation (r = 0.9617) between fractions permeated ex-vivo and fractions absorbed in-vivo.
Conclusion: There is a good potential of the prepared F27 buccoadhesive discs for systemic delivery circumventing the hepatic first pass metabolism as indicated by the enhanced bioavailability. Moreover, buccoadhesive discs of FVS provide the advantages of minimized elevated blood levels and sustained delivery in addition to a substantial reduction in dose and dose-related adverse events.
Keywords: Fluvastatin sodium, bioadhesive buccal discs, bioavailability, PEG 6000, sodium deoxycholate, LC-MS/MS.