A PHARMACEUTICAL STUDY ON SOME BIOADHESIVE DRUG DELIVERY SYSTEMS

Abstract

Formulation of mucoadhesive dosage forms is one of the formulation strategies available for improving drug absorption from dosage forms by improving residential time of the drug. Nasal delivery has a distinct advantage of protecting drug from hepatic first-pass metabolism. Salbutamol sulfate, a direct acting sympathomimetic; used for the treatment of acute and chronic asthma was chosen as the model drug in this thesis to prepare bioadhesive (mucoadhesive) dosage forms for nasal delivery since orally administered salbutamol or the swallowed portion of an inhaled dose undergoes first pass metabolism. The aim of this thesis was to formulate salbutamol sulfate in bioadhesive nasal delivery systems, intended to prolong the mucosal residence time, thus achieving higher absorption and bypassing hepatic metabolism. The work in this thesis was divided into three chapters:

Chapter One: Formulation and Evaluation of In-situ Gelling Systems.

Salbutamol sulfate (2%) in-situ gels were prepared in concentrations of GG; 0.2% (F.A), 0.4% (F.B) and 0.8% ( :q w/v respectively in deionised water with methyl paraben (0.05%) as preservative. While XG and SA in two concentrations of 0.1 and 0.3% were mixed with 0.4% in-situ gel formula (F.B) due to its good gelation and fluidity. The formulations were liquid at both room temperature and when refrigerated and all showed instantaneous gelation when contacted with simulated nasal fluid. All formulae exhibited pH range from 6.6 to 7.0 which is found to be within the reported nasal pH, therefore, they are expected to be non-irritant to the nasal mucosa. All formulae exhibited pseudo plastic behavior and incorporation of the drug caused a significant increase in the apparent viscosity as a result of hydrogen bonding between hydroxyl groups of drug with that of GG polymer which was confirmed by IR examination. Addition of 0.1 or 0.3% SA with GG 0.4% (F.B.l.i, F.B.l.ii) showed almost no change in viscosity. While addition of XG 0.1 or 0.3% with GG 0.4% (F.B.2.i, F.B.2.ii) had viscosity synergism may be due to molecular interaction ofGG with XG. In-vitro release study in simulated nasal fluid showed relatively fast release of SS under sink condition from all formulations and a 100% release was achieved after 2 hours. By increasing GG concentration, a lower drug release rate was shown in the first hour. Also addition of SA and XG to GG caused more sustained drug release in the first hour. Release kinetics of SS from the in-situ gels followed diffusion kinetic model. Microscopic results showed that F.B (0.4% GG), F.B.i; (0.4% GG: 0.1% SA) and F.B.2.i (0.4% GG: 0.1% XG) in-situ gels were safe without any mucosal irritation after repeated dose of 10 J..Ll once daily for 14 days. In-vitro mucoadhesion study has shown that in-situ gels can be retained on rabbit intestinal tissue hydrated with simulated nasal fluid with a flow rate of 0.8 ml/min for prolonged period of time in an order of0.8% >0.4% >0.2% GG. In-vivo mucoadhesiveness test was performed in rats and the results showed that in-situ gel formulation (0.4% F.B & 0.8% F.C) prolonged mucociliary transport time (MTT) from 5 min (control solution) to 16.5 and 19.5 minutes for 0.4% & 0.8% formulations respectively. An enhancement of the residence time and prolonged MTT were also