Development of a gastroretentive controlled release metformin delivery system.

摘要

Metformin hydrochloride is an orally administered biguanide that has been widely used in the treatment and management of non-insulin dependent diabetes mellitus (NIDDM). A controlled-release (CR) formulation of metformin may reduce GI side effects (abdominal discomfort, nausea, and diarrhea), reduce the dosing frequency, prolong therapeutic effect, and improve patient compliance. CR-metformin formulation is also supported by the first-pass pharmacodynamic effect; where the drug produces an augmented pharmacological effect by improving the glucose lowering effect of metformin with sustained exposure of presystemic sites (liver and small intestine) to the drug. Metformin is also a good candidate for gastroretentive drug delivery as its absorption is limited to upper GIT.;A single unit controlled-release gas-generating gastroretentive metformin tablet was formulated. The gas-generating agents, a mixture of citric acid and sodium bicarbonate, generated carbon dioxide once the tablet was placed in an HCl/KCl buffer (pH 2.2). The gas-generation helped the tablets to float on top of the dissolution vessel contents. The addition of microcrystalline cellulose and magnesium stearate helped the tablets to hydrate in a controlled manner, float and become buoyant. Hydroxyethylcellulose (HEC) was considered as a good polymer base that is able to float in a short period of time in the designed formulation and control the release of metformin over the period of 10 hours.;Evaluation of the different gastroretentive formulations was necessary to control the dosage form and ensure batch-to-batch uniformity. The gastroretentive performance was evaluated through measuring the buoyancy and floating lag times. The release of the drug was assessed using USP 20 apparatus II (paddle) modified with the insertion of mesh. The swelling and erosion behavior was investigated by the textural analysis of the swollen tablets using a TA.XT2i texture analyzer.;The developed CR-gastroretentive metformin formulation, containing 200mg HEC and 200mg HPMC, was found to be a swellable controlled system, swelling played a more dominant role than erosion. The drug release was affected to a larger extent by the diffusional process rather than relaxational/erosional process. Neither stirring speed nor pH values were considered to have an effect on buoyancy and drug release.