Gastroretentive Cosolvent-Based In Situ Gel as a Promising Approach for Simultaneous Extended Delivery and Enhanced Bioavailability of Mitiglinide Calcium.

Ion cross-linking in situ gels are novel liquid sustained-release drug delivery systems. These systems are unsuitable for poorly water-soluble drugs such as the novel antidiabetic drug mitiglinide calcium (MTG). Thus, our goal was to assess the possibility of using cosolvency approach in formulating gastroretentive in situ gel of the short half-life MTG to simultaneously enhance its bioavailability and sustain its release. MTG in situ gel formulations were developed using propylene glycol as a cosolvent to dissolve MTG in the polymer solution, followed by characterization of viscosity, gel strength, floating ability, and in vitro MTG release and phramacokinetics evaluation. The optimized formulation (composition: 1% gellan gum, 0.75% sodium alginate, 0.75% calcium carbonate, and 7.5% propylene glycol) exhibited reasonable viscosity but on introduction into simulated gastric fluid, it formed firm gel that floated within seconds over the surface and remained buoyant for 24 h. The formula exhibited in vivo sustained release manner of MTG over 24 h and improved the bioavailability of the drug. Thus, cosolvency presents a promising approach to deliver hydrophobic drugs in sustained-release liquid formulations. These formulations will improve diabetic patients' compliance by eliminating the necessity of frequent dosing with a better disease management.

Gastroretentive Microsponge as a Promising Tool for Prolonging the Release of Mitiglinide Calcium in Type-2 Diabetes Mellitus: Optimization and Pharmacokinetics Study.

Diabetes mellitus is one of the leading causes of death due to the persistent hyperglycemia that leads to potential complications. Lack of patients' adherence to their prescribed medication regimens, due to the requirement of frequent dosing, leads to failure of 40-50% of patients to manage their disease. Thus, microsponges of the novel short half-life mitiglinide calcium (MTG) were formulated using Quasi-emulsion solvent diffusion method, employing Eudragit RS100, ethyl cellulose, and polyvinyl alcohol, then characterized in terms of production yield, entrapment efficiency, particle size, in vitro buoyancy, in vitro drug release, and in vivo pharmacokinetics in rabbits. Optimization was done using response surface methodology; the optimized formulation was investigated by FTIR, DSC, and SEM. Results revealed that the optimized MTG microsponge was successfully formulated with high production yield (61.61% ± 0.6), entrapment efficiency (77.7% ±1.37), and particle size of 192.76 µm and it remained buoyant over simulated gastric fluid for 24 h with high percentage of in vitro buoyancy (91.01% ± 2.5). Moreover, it sustained the in vitro drug release with cumulative % release of 83.74 ± 1.5 after 24 h. This microsponge was highly porous in nature with interconnected pores where MTG was entrapped with good compatibility as confirmed by SEM, DSC, and FTIR analysis; Pharmacokinetic studies showed improvement in Cmax and AUC0-∞ (1.92- and 20.68-fold, respectively) with marked prolongation in MRT and t1/2 (7.22- and 7.97-fold, respectively) than the marketed tablet. Thus, it is a promising approach to improve diabetic patients' compliance by eliminating the necessity of frequent dosing thus attaining better diabetes control.

Study on Three Principal Degraded Impurities of Mitiglinide Calcium / 中国药房

OBJECTIVE:To isolate and purify three principal degraded impurities of mitiglinide calcium (impurity A,B,C) and identify their structures,establish HPLC method for content determination of impurity A,B,C. METHODS:Mitiglinide calci-um was used as raw material and reacted with acid;3 impurities were then separated by HPLC and their structures were elucidated by IR,MS,1H NMR,13C NMR,LC-ESI-MS and ORD. 3 impurities of 3 batches of mitiglinide calcium were determined,and the determination was performed on Agilent Extend-C18 column with mobile phase consisted of 0.01 mol/L sodium acetate solution-ace-tonitrile-triethylamine(60:40:0.1,pH=3.0)at the flow rate of 1.0 ml/min. The detection wavelength was set at 210 nm and sam-ple size was 20 μl. The response tests of 3 impurities and mitiglinide calcium were conducted. RESULTS:After treated with acid, impurity A,B,C had been obtained,and their purity were 99.05%,98.87%,99.98%,respectively after isolation and purifica-tion;after identifying the structure, 3 impurities were S-2-bezylsuccinic acid, S-2-bezylsuccinic acid-4-methyl ester, methyl (2S)-2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl) propionate;methodological study of content determination of impurities were all up to the requirement. The linear range of impurity A,B,C were 0.387 5-3.875,0.395-3.95 and 0.392 5-3.925 μg/ml(all r were 1.000 0). The response value of impurity A,B,C and mitiglinide calcium were 2.316 1,2.636 1,2.617 8 and 2.620 4,re-spectively. CONCLUSIONS:The structures of 3 principal degraded impurities of mitiglinide calcium have been identified and con-firmed;the content of them can be determined by HPLC main component self-comparison method.

Effect of mitiglinide calcium on fasting plasma fibroblast growth factor-21 level in patients with newly diagnosed type 2 diabetes mellitus / 中华内分泌代谢杂志

Eighty-two newly-diagnosed type 2 diabetic patients with poor glycemic control were treated by mitiglinide calcium for 16 weeks.Plasma fibroblast growth factor-21 ( FGF-21 ) level were evaluated.The relationship of plasma FGF-21 levels with body mass index,body fat,waist-to-hip ratio,lipid,blood glucose,HbA1c,and free fatty-acid were analyzed.Plasma FGF-21 was decreased significantly by treatment with mitiglinide calcium in type 2 diabetic patients,and it may play a role in the pathogenesis of type 2 diabetes mellitus.