Vildagliptin Research Articles

Vildagliptin: A New Hope for Diabetics

Vildagliptin: A New Hope for Diabetics

Development and validation of a reversed phase liquid chromatographic method for the determination of three Gliptins and Metformin in the presence of Metformin impurity (1-cyanoguanidine)

A simple and precise liquid chromatographic method has been developed and validated for the determination of either sitagliptin (STG), vildagliptin (VLG) or saxagliptin HCL (SXG) and metformin HCL (MET) in the presence of metformin degradation product, 1-cyanoguanidine (CGN). Chromatographic separation was achieved on a Symmetry ® cyanide column (150 mm × 4.6 mm, 5 μm). Isocratic elution using a mobile phase of potassium dihydrogen phosphate buffer (pH = 4.6) - acetonitrile (30:70, v : v ) at a flow rate of 1 mL/min with UV detection at 210 nm was performed. The LC method was used for the simultaneous determination of STG, VLG, SXG and MET in the ranges of 5-200, 5-200, 0.5-80.0 and 20-800 μg/mL, respectively. The results were statistically compared with the reference method for each drug using one-way analysis of variance (ANOVA). The method developed was satisfactorily applied to the analysis of the pharmaceutical formulations and proved to be specific and accurate for the quality control of the cited drugs in pharmaceutical dosage forms.

Development of Validated Stability Indicating Assay Method for Simultaneous Estimation of Metformin Hydrochloride and Vildagliptin by RP-HPLC

A simple, precise and stability-indicating HPLC method was developed and validated for the simultaneous determination of metformin hydrochloride (MET) and vildagliptin (VLG) in pharmaceutical dosage forms. The method involves use of easily available inexpensive laboratory reagents. The separation was achieved on Grace Cyano column (250 mm×4.6 mm) 5 µm with isocratic flow. The mobile phase was pumped at a flow rate of 1.0 mL/min, consisted of 25 mM ammonium bicarbonate buffer and acetonitrile (65:35, v/v). The UV detection was carried out at 207 nm. A linear response was observed over the concentration range of 25-125 µg/mL for MET and 50-250 µg/mL for VLG respectively. Limit of detection and limit of quantification for MET were 0.36 µg/mL and 1.22 µg/mL, and for VLG were 0.75 µg/mL and 2.51 µg/mL respectively. The method was successfully validated in accordance to ICH guidelines acceptance criteria for specificity, linearity, accuracy, precision, robustness, and system suitability. Individual drugs (MET and VLG) were exposed to thermal, photolytic, hydrolytic and oxidative stress conditions. The resultant stressed samples were analyzed by the proposed method. The method gave high resolution among the degradation products and the analytes. The peak purity of analyte peak in the stressed samples was confirmed by photo diode array detector. The proposed method was successfully applied for the quantitative analysis of MET and VLG in tablet dosage form, which will help to improve quality control and contribute to stability studies of pharmaceutical tablets containing these drugs.

A validated RP-HPLC method for simultaneous determination of Metformin HCl and Vildagliptin in pharmaceutical formulation

A selective and sensitive reverse phase high performance liquid chromatographic (RP-HPLC) method has been developed for the separation and quantification of metformin HCl (MET) and vildagliptin (VILD) in tablet dosage form. The determination was carried out using phenomenax C18 column (4.6150 mm) as a stationary phase and mobile phase comprised of phosphate buffer (pH6.0): methanol (65:35v/v). The pH of phosphate buffer is adjusted to 6.0 by using orthophosphoric acid. The flow rate was maintained at 1.0ml/min and the eluent was monitored at 255nm.The retention time of MET and VILD were 1.503 min and 5.530 min respectively. The method was validated in terms of linearity, precision, accuracy, ruggedness, specificity and robustness. The method was linear over the range 50-150 g/ml for both MET (r = 0.999) and VILD (0.998). For precision studies; RSD for MET and VILD were 0.24 and 0.14 respectively. The percentage recoveries for both drugs from their tablets were 100.16 and 99.98 respectively. Inter-day; intra-day RSD for both drugs were found be 0.27 and 0.26, 0.13 and 0.29 respectively.

Spectrophotometric and spectrofluorimetric methods for the determination of saxagliptin and vildagliptin in bulk and pharmaceutical preparations

New simple and sensitive spectrophotometric and spectrofluorimetric methods have been developed and validated for the determination of saxagliptin (SAX) and vildagliptin (VDG) in bulk and pharmaceutical preparations. The spectrophotometric methods were based on derivatization of the investigated drugs with two reagents: 1,2-naphthoquinone-4-sulfonic acid sodium salt (NQS) and 4-chloro-7-nitrobenzofurazan (NBD-Cl). For further increase in the sensitivity, the D1 spectra of the reactions products were also recorded. For NQS reaction, Beer’s law was obeyed over the ranges of 5–30 and 7–45μgmL−1 for the absorbance readings; and 3–32 and 5–50μgmL−1 for the derivative readings of SAX and VDG, respectively. For NBD-Cl reaction, Beer’s law was obeyed over the ranges of 3–20 and 4.5–35μgmL−1 for the absorbance readings; and 1.5–25 and 2.5–40μgmL−1 for the derivative readings of SAX and VDG, respectively. Spectrofluorimetric methods were developed based on the fact that the derivatized investigated drugs with NBD-Cl reagent are highly fluorescent products. The fluorescence concentration plots were linear over the ranges of 0.02–0.25 and 0.03–0.37μgmL−1 for SAX and VDG, respectively. The fluorescence measurement enabled the detection of SAX and VDG at concentrations of about 3 and 7ngmL−1, respectively. The proposed methods have been validated and successfully applied to the determination of the investigated drugs in their pharmaceutical preparations. The results obtained were statistically compared to those obtained from reference methods.

A simultaneous assay method using capillary zone electrophoresis for a fixed dose combination of vildagliptin and metformin hydrochloride in coated tablets

In the present study, a quick and reliable validated capillary zone electrophoresis (CZE) method was established for the simultaneous determination of vildagliptin (VLG) and metformin hydrochloride (MET) in pharmaceutical dosage form. Successful separation of the drugs by the CZE method was achieved in a fused silica capillary by applying a potential of 25 kV (positive polarity) and hydrodynamic injection by 50 mbar for 5 s. The selected running buffer consisted of 25 mM sodium tetraborate decahydrate solution (array pH 9.0) with UV/photodiode (PDA) detection at 207 nm and 250 nm for VLG and MET respectively. Specificity, linearity, precision, accuracy, limit of detection and limit of quantitation and robustness were established for VLG and MET in accordance with International Conference on Harmonization (ICH) guidelines. The specificity and stability-indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using PDA detection. Electrophoretic separation was obtained within 10 min and the method was linear in the range of 30–60 μg mL−1 and 300–600 μg mL−1 for VLG and MET, respectively (R2 > 0.9980). Precision of the method was reflected by RSD lower than 2.95% and accuracy results around 100% for both VLG and MET measurement. Moreover, the Plackett–Burman experimental design was used to evaluate robustness, producing results within the acceptable range.

Development and validation of RP-HPLC method for estimation of Vildagliptin from table dosage form

A new simple, specific, precise and accurate reversed-phase liquid chromatography method has been developed for the determination of Vildagliptin (VLG) in pharmaceutical dosage form. The separation was achieved on a Xterra® Waters C18 column (150mm×4.6mm, 5?m) using mobile phase consisting of a mixture of aqueous phase (1 ml of 25% ammonium hydroxide was dissolved in 1000 ml of water for chromatography, pH of the solution was adjusted to the value of 9.5 using a 50% solution of phosphoric acid) and organic phase (methanol) in the ratio of 60:40 v/v at a flow rate of 1.0 ml/min. Detection was carried out at 210nm. The retention time of Vildagliptin was found to be 6.3 min. The calibration curve was found linear between 5- 200?g/ml (r2 = 0.9997). Limit of detection and limit of quantitation were 1.47 and 4.90 ?g/mL, respectively. The percentage recoveries of Vildagliptin were found to be in the range of 99.11-100.62%. The method was validated in accordance with International Conference on Harmonization acceptance criteria for specificity, linearity, precision, accuracy, robustness and system suitability. The excipients did not interfere in the determination of VLG. The proposed method was successfully applied for the quantitative analysis of VLG in tablet dosage form, which will help to improve quality control. DOI: http://dx.doi.org/10.3329/ijpls.v1i1.12947 International Journal of Pharmaceutical and Life Sciences Vol.1(1) 2012

Attenuation of Renovascular Damage in Zucker Diabetic Fatty Rat by NWT-03, an Egg Protein Hydrolysate with ACE- and DPP4-Inhibitory Activity

BackgroundDipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme (ACE) are important target enzymes in glycemic control and renovascular protection. Here, we studied the effect of NWT-03, an egg protein hydrolysate with DPP4- and ACE-inhibitory activity, on renovascular damage in Zucker diabetic fatty (ZDF) rats. Comparisons were made to rats treated with vildagliptin (VIL), included as a positive control for the effect of DPP4 inhibition.MethodsZDF rats received NWT-03 (1 g/kg/day) or VIL (3 mg/kg/day) from 10 to 25 weeks of age. Metabolic and renal functions were assessed; the kidney was removed for histological analysis of glomerulosclerosis and expression of pro-inflammatory/fibrotic markers (RT-PCR and Western blotting); and the aorta was removed for studies of endothelium-dependent relaxation (EDR).FindingsHyperinsulinemic ZDF rats typically developed signs of type-2 diabetes and renovascular damage, as evidenced by albuminuria, glomerulosclerosis, and impaired EDR. Neither NWT-03 nor VIL improved metabolic parameters; for VIL, this was despite a 5-fold increase in glucagon-like peptide (GLP)-1 levels. NWT-03 and VIL both reduced renal interleukin (Il)-1β/Il-13 mRNA expression and glomerulosclerosis. However, only NWT-03 additionally decreased renal tumor necrosis factor (TNF)-α mRNA and P22phox protein expression, reduced albuminuria, and restored aortic EDR. Indomethacin added to the organ bath instantly improved aortic EDR, indicating a role for cyclooxygenase (COX)-derived contractile prostanoids in opposing relaxation in ZDF rats. This indomethacin effect was reduced by NWT-03, but not by VIL, and coincided with decreased renal COX-1/2 protein expression.Conclusion and InterpretationLong-term supplementation with the egg protein hydrolysate NWT-03 attenuated renovascular damage in this preclinical rat model of type 2 diabetes. A comparison to the DPP4-inhibitor VIL suggests that the effects of NWT-03 were related to both ACE- and DPP4-inhibitory properties. The development of protein hydrolysates with a multiple-targeting strategy may be of benefit to functional food formulations.

Quantitative Model of the Relationship Between Dipeptidyl Peptidase‐4 (DPP‐4) Inhibition and Response: Meta‐Analysis of Alogliptin, Saxagliptin, Sitagliptin, and Vildagliptin Efficacy Results

Dipeptidyl peptidase-4 (DPP-4) inhibition is a well- characterized treatment for type 2 diabetes mellitus (T2DM). The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). Publicly available data involving late-stage or marketed DPP-4 inhibitors were leveraged for the analysis. Nonlinear mixed-effects modeling was performed to describe the relationship between DPP-4 inhibition and mean response over time. Plots of the relationship between metrics of DPP-4 inhibition (ie, weighted average inhibition [WAI], time above 80% inhibition, and trough inhibition) and response after 12 weeks of daily dosing were evaluated. The WAI was most closely related to outcome, although other metrics performed well. A model was constructed that included fixed effects for placebo and drug and random effects for intertrial variability and residual error. The relationship between WAI and outcome was nonlinear, with an increasing response up to 98% WAI. Response to DPP-4 inhibitors could be described with a single drug effect. The WAI appears to be a useful index of DPP-4 inhibition related to HbA1c. Biomarker to response relationships informed by model-based meta-analysis can be leveraged to support study designs including optimization of dose, duration of therapy, and patient population.

Comparison of glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mettilus

Increased understanding of the role of incretin hormones in maintaining glucose homeostasis has enabled the development of pharmacotherapies that target deficient incretin activity in type 2 diabetes mellitus.lncretin-based therapies could be classified into 2 categories with different mechanisms of action:glucagon-like peptide 1 ( GLP-1 ) receptor agonists ( e.g.liraglutide,exenatide twice daily,and exenatide once weekly),and the dipeptidyl peptidase 4 ( DPP-4 ) inhibitors ( e.g.sitagliptin,linagliptin,saxagliptin,and vildagliptin),which inhibit the breakdown of endogenous GLP-1.Both categories share some specific characteristics,such as glucose-dependent insulin stimulation and low incidence of hypoglycemia.But there are also different profiles in efficacy between these 2 classes.This article reviews the pharmacokinetics and clinical aspects of efficacy and safety of these 2 classes of incretin-based therapies and elucidates their roles in treating type 2 diabetes mellitus. Key words: Incretins; Diabetes mellitus, type 2; Glucagon-like peptide 1 receptor agonist; Dipeptidylpeptidase 4 inhibitor

Development and validation of a reversed-phase column liquid chromatographic method for simultaneous determination of two novel gliptins in their binary mixtures with Metformin

A new, simple, accurate, and precise liquid chromatographic method has been developed and validated for the determination of two novel dipeptidylpeptidase-4 (DPP-4) inhibitors; namely vildagliptin (VLG) and saxagliptin HCl (SXG) simultaneously in their binary mixtures with metformin HCl (MET). Chromatographic separation was achieved on an Inertsil® CN-3 column (250 mm x 4.6 mm, 5 µm). Isocratic elution using a mobile phase of potassium dihydrogen phosphate buffer pH (4.6) - acetonitrile (15:85, v:v) at a flow rate of 1 mL/min with UV detection at 208 nm was performed. The liquid chromatographic method was used for the simultaneous determination of either VLG, SXG and MET in the range of 5-200, 0.5-20 and 50-2000 μg/mL, respectively. The methods developed were satisfactorily applied to the analysis of the pharmaceutical formulations and proved to be specific and accurate for the quality control of the cited drugs in pharmaceutical dosage forms.

Glucagon-like Peptide 1 and Type 2 Diabetes: Targets and New Therapies

Glucagon-like peptide 1 (GLP-1) is an incretin hormone which is released from gut. It stimulates insulin secretion, suppresses glucagon secretion and the combined effects on insulin and glucagon secretion result in inhibition of hepatic glucose production, which importantly contributes to the glucose lowering effect of the hormone. It seems GLP-1 can be used in treatment of diabetic patient but because of its rapid elimination by DPP-4, is not suitable for clinical use. Therefore two strategies have been used to exploit the beneficial actions of the hormone (i) development of more stable activators of the GLP-1 receptor so-called GLP-1 mimetics like exenatide, Liraglutide and (ii) inhibitors of DPP-4 like sitagliptin, vildagliptin and saxagliptin. These components can be used in monotherapy or in combination with metformin, insulin, sulphonylurea. The pathophysiological bases of these therapeutics are reviewed in this article.

Stability-Indicating RP-LC Method for the Determination of Vildagliptin and Mass Spectrometry Detection for a Main Degradation Product

A simple, precise and stability-indicating reversed-phase liquid chromatography method was developed and validated for the determination of vildagliptin (VLG) in pharmaceutical dosage form. The chromatographic separation was obtained within 6 min and was linear in the range of 20-80 µg/mL (r(2) = 0.9999). Limit of detection and limit of quantitation were 0.63 and 2.82 µg/mL, respectively. The method was validated in accordance with International Conference on Harmonization acceptance criteria for specificity, linearity, precision, accuracy, robustness and system suitability. Stress studies were carried out and no interference of the degradation products was observed. The excipients did not interfere in the determination of VLG. Furthermore, the main degradation product obtained from the stress studies (thermal, oxidative and alkaline hydrolysis) was evaluated for mass spectrometry and its molecular structure was predicted. The proposed method was successfully applied for the quantitative analysis of VLG in tablet dosage form, which will help to improve quality control and contribute to stability studies of pharmaceutical tablets containing this drug.

Efficacy and safety of vildagliptin and metformin combination therapy in type 2 diabetes

Vildagliptin,a dipeptidyl peptidase-4 (DPP-4) inhibitor,is always used in combination with metformin.Data from multiple clinical trials showed that vildagliptin and metformin combination therapy can improve HbA1c,fasting blood glucose,and postprandial blood glucose without weight gain,good gastrointestinal (GI)tolerance,and no increase in the incidence of hypoglycemia.Vildagliptin increases plasma levels of glucagon-like peptide-1 ( GLP-1 ).When glucose levels are above normal fasting levels,enhanced GLP-1 levels stimulate insulin secretion.Mefformin has been shown to increase insulin sensitivity and inhibit hepatic glucose production.The effect of vildagliptin to increase plasma levels of intact GLP-1 was enhanced in patients receiving concomitant metformin. Key words: Dipeptidyl peptidase-4 inhibitor; Glucagon-like peptide-1 ; Vildagliptin; Diabetes mellitus; type 2

Vildagliptin treatment for type 2 diabetic patients in clinical practice

Vildagliptin is a potent and specific inhibitor of dipeptidyl peptidase 4,which has been implicated to enhance and prolong the physiological actions of incretion hormones including glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide.Vildagliptin is an orally administered drug and has been licensed for the treatment of type 2 diabetes mellitus.Vildagliptin monotherapy or in combination with other drugs can effectively lower glycosylated haemoglobin levels to a great extent.In addition,vildagliptin acts in a glucose-dependent manner,explaining its low risk of hypoglycemia.This drug has been proved well tolerated with few gastrointestinal side effects or oedema.Therefore vildagliptin is a promising new option for type 2 diabetic patients,and these patients would achieve better glycemic control and fewer complications in the long run. Key words: Vildagliptin ; Dipeptidyl peptidase-4 ; Diabetes mellitus,type 2 ;

Liquid Chromatographic Methods for the Determination of Vildagliptin in the Presence of its Synthetic Intermediate and theSimultaneous Determination of Pioglitazone Hydrochloride and Metformin Hydrochloride

Two reversed-phase liquid chromatographic (RP-LC) methodsare described for the determination of two binary mixtures of hypoglycemic agents. In the first method,vildagliptin (VDG) was determined inthe presence of 3-amino-1-adamantanol(AAD),a synthetic intermediate and impurity of VDG.In the second method, pioglitazone hydrochloride (PGZ) and metformin hydrochloride (MET) weresimultaneously determined in their binary mixture.Chromatographic separation in the two methods was achieved on a Symmetry® Waters C18 column (150mm×4.6mm, 5μm).In the first mixture, isocratic elution using a mobile phase of potassium dihydrogen phosphate buffer pH (4.6) -acetonitrile-methanol(30:50:20,v/v/v) at a flow rate of 1 mL min-1 with UV detection at 220 nm was performed. In the second method, isocratic elution based on potassium dihydrogen phosphate buffer pH (4.6)-acetonitrile (60:40, v/v) at a flow rate of 1 mL min-1 with UV detection at 210 nm was performed. Linearity, accuracy and precision were found to be acceptable over the concentration ranges of 5-200 μgmL-1,0.5-3 μgmL-1 and 10-150 μgmL-1 for VDG, PGZ and MET, respectively. The optimized methodswere validated and proved to be specific, robust, precise and accurate for the quality control of the drugs in theirpharmaceutical preparations.

New drugs: Vildagliptin

New drugs: Vildagliptin

Comparison of vildagliptin and acarbose monotherapy in patients with type 2 diabetes: a 24-week, multi-center, double-blind, double-dummy, active-controlled, randomized trial

Objective To compare the efficacy and tolerability of monotherapy with vildagliptin and acarbose in patients with type 2 diabetes (T2DM). Methods Drug-naive T2DM patients were treated by vildagliptin(100 mg daily, given as two equally-divided doses, n=399)or acarbose (up to 300 mg daily, given as three equally-divided doses, n=202) for 24 weeks in this multi-center, randomized, double-blind, double-dummy, parallel-arm and active-controlled study. Results Vildagliptin and acarbose decreased HbA1Cto a similar extent during 24-week treatment. The adjusted mean change from baseline to endpoint in HbA1C was-1.44% in patients receiving vildagliptin and-1.36%in those receiving acarbose, meeting the statistical criterion for non-inferiority (upper limit of 95% confidence interval for between-treatment difference ≤0.4%). There was no significant difference in responder rates between groups(P>0.05). Fasting plasma glucose(FPG) tended to decrease more with acarbose (-1.52 mmol/L)than with vildagliptin(-1. 25 mmol/L), not meeting the statistical criterion for non-inferiority (upper limit of 95% confidence interval for between-treatment difference >0.6 mmol/L). Body weight did not change in vildagliptin-treated patients(-0.5 kg)but decreased in acarbose-treated patients (-1. 8 kg, P<0.01). The proportion of patients experiencing any adverse event was 33. 6% vs 50. 0% in patients receiving vildagliptin or aearbose, respeetively. Adverse gastrointestinal events were significantly more frequent with acarbose(24. 8%)than with vildagliptin (11.3%, P<0.01). No hypoglycemia was reported in either treatment group. Conclusion Vildagliptin is effective and well tolerated in patients with T2DM, demonstrating similar HbA1C reduction as aearbose, but with less adverse gastrointestinal event. Key words: Dipeptidyl peptidase-Ⅳ ; HbA1C ; Glucagon-like peptide-1 ; Incretin hormones

Vildagliptin equals acarbose for monotherapy in T2DM

Vildagliptin equals acarbose for monotherapy in T2DM

Vildagliptin + antihypertensives: pharmacokinetics unchanged

Vildagliptin + antihypertensives: pharmacokinetics unchanged