(T0930-12-67) Glimepiride Releases from Laboratory Compounded and Two Commercial Tablets Using a Proposed Three Stage In Vitro Dissolution Study

Purpose: Glimepiride is used in patients with non-insulin-dependent diabetes mellitus. Pancreatin normally produced in the pancreas is a mixture of digestive enzymes (amylase, protease and lipase) to help breaking down food to convert into energy. Patients suffer from pancreatic secretion deficiency, such as surgical pancreatectomy, pancreatitis and cystic fibrosis are treated with commercial supplements. The trypsin in pancreatin hydrolyzes proteins into oligopeptides; amylase hydrolyzes starches into oligosaccharides and the disaccharide maltose; and lipase hydrolyzes triglycerides into fatty acids and glycerol. The in vitro dissolution studies described in the majority compendium monographs do not include digestive enzymes in the medium. We previously reported glimepiride as practice insoluble in water (AAPS Poster 2021). In this study we asked whether the lipase within pancreatin affects highly lipophilic drugs administered by mouth using glimepiride as a model drug. We compounded tablets using a commercial sweetened flavor powder, mango (PCCA) and compare with brand name tablets and tablets USP (a generic product). Glimepiride USP powder was also used as a control group.

Methods: Glimepiride of 2 mg and 4 mg plus 10% combined with the sweetened flavor powder mango to compress into 100-mg tablets. Three-stage in vitro dissolution conducted using Apparatus 2 at 37.0±0.5°C, 75 rpm were (a) 750 mL of 0.1 N HCl for 4 h, (b) addition of 200 mL of 0.20M tribasic sodium phosphate to make into 950 mL Buffer Stage 1 (pH 6.4) for 4 h, and (c) addition of 0.10N NaOH to make into 1000 mL Buffer Stage 2 (pH 7.4) for another 16 h. Pancreatin of 10.88 g was either added or not added in the beginning of Buffer Stage 1. Nine samples were taken at 2, 4, 6, 8, 9, 22 and 24 h. HPLC analysis followed the compendium monograph method. All experiments performed triplicates.

Results: Despite that glimepiride standard curve is linear between 0.004 and 1.0 mg/mL, the standard samples made from Glimepiride USP powder ranged from 0.004 to 0.1 mg/mL were plotted against area under the curve using LC at 228 nm and graphed to allow the drug release properties to be determined for the studied tablets by interpolation on the graph. No chromatographic peak was found in 2 mg glimepiride powder group until 24 h dissolution. The 4 mg powder dissolved in the medium were detectable in 22 h and 24 h (30.5% vs. 30.8% without pancreatin, while 29.8% vs. 25.9% with pancreatin respectively). For the 2 mg tablets without pancreatin added in Buffer Stage 1, the release from lab compounded tablets at 22 h and 24 h were 87.5% vs.93.0%; from brand name tablets were 119.3% and 111.1%; and from Tablets USP were 119.8% vs. 123.9% respectively. For the 2 mg tablets with pancreatin added in Buffer Stage 1, the releases at 22 h and 24 h were 63.6% vs. 53.4% for the lab formulated group, from brand name tablets were 120.5% vs. 109.9%, and from the tablets USP group were 106.7% vs. 76.7% respectively. For the 4 mg tablets without pancreatin added in Buffer Stage 1, the release from lab compounded tablets at 22 h and 24 h were 65.0% vs. 91.7%; from the brand name tablets were 96.1% and 102.9%; and from the tablets USP were 101.1% vs. 104.8%. For the 4 mg tablets with pancreatin added in Buffer Stage 1, the release from lab compounded tablets at 22 h and 24 h were 115.9% vs. 101.4%, from the brand name tablets were 101.7% and 85.9%, and from the tablets USP group were 97.3 vs. 90.5% respectively. The t-test showed 2 mg lab compounded tablets and tablets USP were significantly decreased in percent of release at 24 h when the medium contained pancreatin in comparison with no pancreatin (p < 0.015, and p < 0.04 separately, Figures 1 a&b). The mean releases of 4 mg lab compounded, brand name and tablets USP at 24 h (Figures 2 a&b) also lower in the pancreatin group than the without pancreatin group. But the t-test p value did not support the significance due to the higher standard deviations values in the pancreatin groups.

Conclusion: The lipase in pancreatin is known to hydrolyze triglycerides into fatty acids and glycerol. Glimepiride is a highly lipophilic drug. This in vitro investigation found glimepiride percent release from the lower strength glimepiride (2 mg) was significantly reduced from 22 h to 24 h, while the the amount of pancreatin added in Buffer Stage 1 medium impacted 4 mg tablets less. The data also showed that the 2 mg tablets made from commercial sweetened flavor powder, mango simplified formulation work and increase glimepiride solubility, but have not yet reached those of the commercial tablet groups (Figures 1a and 2a) due to the various excipients used. Other excipient(s) will need to be added to the lab compounded tablets.

References: U.S. Pharmacopeial Convention USP43-NF38. Maryland: Pharmacopeia, 2022, p. 2109, 2111, 2802, 2805, 6945.

Acknowledgements: Authors will like to express their appreciation for the financial support from SOP-B, MCPHS University.


Figure 1 The three-stage in vitro release profiles of three 2-mg tablets. They were laboratory compounded, brand name, and tablets USP in (a) dissolution medium contained no pancreatin, and (b) pancreatin being added in the beginning of Buffer Stage 1.


Figure 2 The three-stage in vitro release profiles of three 4-mg tablets. They were laboratory compounded, brand name, and tablets USP in (a) dissolution medium contained no pancreatin, and (b) pancreatin being added in the beginning of Buffer Stage 1.