Abstract
An optimized formulation of a sustained release tablet of Gliclazide was developed. The use of Doptimal design with a polynomial statistical model to analyze dissolution data reduced the number of laboratory tests required to obtain an optimal dosage form. The final formulation contained 22 mg of Methocel®E15LV, 16.5 mg Methocel®E15 and 10.0 mg of Dibasic Calcium Phosphate per 30 mg Gliclazide sustained release tablet. Dissolution studies performed on tablets from 5000 tablet test batches released greater than 90 percent of loaded drug in eight hours. Drug release from the optimized tablets followed a pattern more closely similar to zero-order than other mechanisms of drug release tested. Storage of tablets in accelerated and ambient conditions for 6 and 12 months respectively did not alter any of the physico-chemical properties, drug release or the drug release rate compared to initial observations and dissolution data of the prepared tablets. The addition of potassium phosphate and monosodium phosphate to the tablet reduced the effect pH has on Gliclazide dissolution compared to the commercially available product.
Highlights
Gliclazide 1-(3-azabicyclo (3.3.0)oct-3-yl)-3-p-tolylsulphonylurea is an oral hypoglycemic agent used to treat non-insulin-dependent diabetes mellitus
The effects of the independent parameters [X1, X2 and X3 represent the amount of the excipients Methocel®K15M (10 - 20 mg), Methocel® E15LV (10 - 30 mg) and dicalcium phosphate (DCP) (10 - 50 mg) added, respectively] on response variables (Y1, Y2, Y4, Y6 and Y8 that are the percentages of gliclazide released from tablets at 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours, respectively) were analyzed as follows
Where X1, X2 and X3 were amounts of Methocel®K15M, Methocel®E15LV and DCP, respectively; bi was statistically significant when p-value 0.05; Yi is the percentage of Gliclazide release at time = i hour
Summary
Gliclazide 1-(3-azabicyclo (3.3.0)oct-3-yl)-3-p-tolylsulphonylurea is an oral hypoglycemic agent used to treat non-insulin-dependent diabetes mellitus. After a single 80 mg dose of gliclazide (Diamicron®) immediate release tablet to 16 healthy volunteers, gliclazide peak plasma concentrations of 5.40 ± 1.03 μg/l were attained in about 3.5 ± 0.9 hours. After a single dose of 30 mg gliclazide modified release tablet, Diamicron®MR, to 12 volunteers, mean absolute concentrations of gliclazide ranged between 79% to 110% (average 97%) compared to IV (AUCIV was 17.8 ± 4.8 μg∙hr/ml) showing complete absorption. Gliclazide plasma concentrations declined monoexponentially from peak concentrations, Cmax and were measurable up to 36 - 72 hours after oral dosing of the modified release gliclazide tablets In addition, no significant differences were observed in AUC, tmax, t1/2, and Cmax after administration of the 30 mg MR gliclazide tablet under fasted and fed conditions. The release of gliclazide over a 24-hour period has been shown to parallel the circadian glycemic profile of type 2 diabetes
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