Trelagliptin Research Articles

Spectrophotometric Method Development and Validation for the Estimation of Trelagliptin Succinate in Bulk and Pharmaceutical Dosage Form

A Simple, precise and sensitive ultraviolet spectrophotometric method was developed for the estimation of Trelagliptin succinate in bulk and pharmaceutical dosage form, method was run through LABINDIA UV-Visible spectrophotometer-3200 with solvent of acetonitrile was used. In this method working wavelength was selected at 276 nm. The developed method was validated as per the international conference on harmonization (ICH Q2(R1)) guidelines. The drug was obeying Beer-Lambert’s law revealed good correlation in the concentration range of 10 - 60 µg/ml with correlation coefficient (r2) of 0.9993. The validity of the proposed method was assessed by applying the standard addition technique where the percentage recovery of the added standard was found to be 99.97 % for Trelagliptin succinate. The absorbance was found to be 0.0365 - 0.0506 with %RSD for both inter-day precision & intraday precision. The limit of detection and quantification were calculated and was found to be 0.0563 µg/mL and 0.1689 µg/mL respectively. The developed method was successfully applied to the determination of Trelagliptin in commercially available dosage form with percentage assay of 98.52. The proposed method is recommended for routine analysis of Trelagliptin in bulk and dosage forms in quality control testing laboratories. Since it is rapid, simple, accurate and sensitive.

TRELAGLIPTIN'S REAL WORLD EFFICACY AMONG TYPE 2 DIABETES PATIENTS IN CAMBODIA (TRELA -REAL STUDY)

Background: Trelagliptin is the rst once-weekly oral therapy for type 2 diabetes in Cambodia. The afrmation of its efcacy and safety in Cambodian Type 2 Diabetes patients is to be established for extending the clinical benet of this unique oral anti-diabetic agent in this population Objective: To conrm the effect of Trelagliptin (TRELA), a selective once weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, on glycemic control in the management of Type 2 Diabetes Mellitus (T2DM) in real-world practice settings in Cambodia Methods: An open-label, multicentric prospective, observational single-arm study was conducted across Phnom Penh and three other provinces in Cambodia which will include Siem Reap, Kampong Cham, and Battambang in outpatient settings. One hundred and fty patients with Type 2 Diabetes were enrolled after seeking informed consent. Trelagliptin 100 mg one tablet per week was administered to patients with type 2 diabetes who showed poor glycemic control (HbA1c ≥6.5% ) on diet/exercise therapy alone or diet/exercise therapy plus other oral antidiabetic agents or insulin. The study primary endpoint(s) included changes in glycated hemoglobin (HbA1c) from baseline at the end of three months, and at the end of six months of the study. The secondary endpoints included patient satisfaction and investigator assessment at the end of treatment (6 months) to once weekly treatment to Trelagliptin. Result: Treatment with Trelagliptin 100 mg/week led to a mean change in HbA1c 0.86% (from 8.76 ± 2.02 to 7.9 ± 1.60, p < 0.05, CI 95) at the end of 3 months. At the end of 6 months, the mean change in HbA1c was 1.26% (from 8.76 ± 2.02 to 7.5 ± 1.34), p<0.05, CI 95) (p-value signicant) Patient satisfaction and preference with once-weekly trelagliptin treatment was reported in 97.04 % (n=131) patients. As per the investigator's assessment, 77.04 % (n=104) of the patients reported a “good” response to Trelagliptin treatment at the end of the study over a period of 6 months. In 14.07 % (n=19) patients investigators reported that “excellent” response was achieved. Whereas 5.19% (n=7) and 3.7% (n=5) patients reported average and poor responses, respectively. Trelagliptin treatment once a week was demonstrated to be clinically efcacious as monotherapy and in combination with other anti-hyperglycemic agents. Trelagliptin treatment was found to be efcacious in treatment naïve and treatment-experienced patients. The clinical benets of Trelagliptin were consistent across age groups, body mass index (BMIs), and associated co-morbidities like hypertension. Trelagliptin was well tolerated and was safely used in addition to Metformin, Sulfonylureas, Thiazolidinediones, SGLT2-inhibitors & Insulin treatment. The glucose-lowering effect of Trelagliptin was comparable to other DPP4 inhibitors (gliptins), and other classes of oral anti-diabetic medications with the additional advantage of once-a-week dosing treatment regime. Conclusion: Treatment with once-a-week trelagliptin as initial monotherapy and in combination therapy with other anti-hyperglycemic agents for glucose control in Type 2 Diabetes was efcacious and well-tolerated. Trelagliptin 100 mg once a week treatment achieved treatment satisfaction in most patients and reported “good” investigator response in majority of type 2 diabetes patients. Trelagliptin 100 mg once-a-week treatment is a useful consideration in the management of type 2 diabetes patients

Investigation of Pharmacokinetic Parameters of Trelagliptin in Egyptian Volunteers Using Sensitive LC-MS/MS: A Comparative Study with a Japanese Population.

Trelagliptin (TLN) is a novel once-weekly antidiabetic drug that enhanced the patient compliance in type 2 diabetes. TLN analysis and bioanalysis literature review showed many methods for TLN assay either in dosage form or as biological fluids (pharmacokinetic parameters), but all those methods did not consider the full details dealing with biological assay of TLN. Studies that included information about pharmacokinetic parameters did not mention the used analytical procedures for those determinations and parameters. Although some LC-MS/MS and UPLC-UV methods were reported for TLN bioassay in rats' plasma, they used direct precipitation techniques, and the current described procedure showed lower LLOQ than all the reported methods in spite of that working on human plasma is more complicated than on rats' plasma. In this study, LC-MS/MS bioanalysis of TLN in human plasma (4–1000 nM) was employed successfully with LLOQ of 4 nM which is lower than all reported methods in rats' plasma followed by a preliminary pharmacokinetic study. Alogliptin was used as internal standard (IS) because of its structure similarity to TLN. Pharmacokinetic parameters of TLN were investigated in Egyptian volunteers, and they had been compared to Japanese. Liquid-liquid extraction showed more sensitive results than direct precipitation. The proposed method was successfully applied to a pharmacokinetic study conducted on Egyptian volunteers. No dose modification is required upon comparing the pharmacokinetic parameters of the current study and previous studies on non-Egyptian volunteers.

Trelagliptin succinate: DPP-4 inhibitor to improve insulin resistance in adipocytes

Trelagliptin inhibits the enzyme dipeptidyl-4 (DPP-4) to treat type 2 diabetes and it may possess the potential to improve insulin resistance. However, the molecular mechanism is not known. In this study, the effect of trelagliptin succinate in improving insulin resistance was investigated. The differentiation system of 3T3-L1 mouse preadipocytes was used to determine the content of adipokines and the content of GLUT4 in the outer membrane. The expression of AKT, P-AKT, IRS-1 and P-IRS-1 in differentiated 3T3-L1 adipocytes was determined by western blotting. Our results demonstrated that trelagliptin succinate increased the expression of AKT, P-AKT, IRS-1 and P-IRS-1 in the PI-3K/AKT insulin signaling pathway. These events promote the trans-membrane function of GLUT4 and concomitant glucose intake in adipocytes. In addition, the secretion of free fatty acids and resistin were decreased. In conclusion, our study suggested that trelagliptin succinate improved insulin resistance in adipocytes via regulation of PI-3K/AKT/GLUT4 insulin signaling pathway.

Analysis and bio-analysis of omarigliptin, trelagliptin and alogliptin: Applied to biological samples and degradation kinetic study

A simple liquid chromatographic method was developed for the bio-assay of omarigliptin (OMR), trelagliptin (TRE) and alogliptin (ALO) in rat plasma using Hypersil Gold C18 column with UV detection as an economic alternative for the reported LC-MS methods in the literature. Isocratic elution based on simple mobile phase (acetonitrile:phosphate buffer, 50:50, v/v) was applied with UV detection at 240 nm for OMR and at 274 nm for TRE and ALO because of their structure similarity except for one fluorine atom. Liquid-liquid extraction technique was used for plasma sample preparations using diethyl ether as the best extracting solvent according to log-P of the drugs & applying vacuum evaporation before the reconstitution with the mobile phase. The method was validated according to FDA guidelines. The proposed method was applied to biological samples (n = 3) after oral administration to rats. Further applications were completed using the same LC method including assay of TRE and ALO in human plasma and study of stress degradation for OMR in bulk as a stability indicating assay. Factorial design was applied to test the method robustness using Box Behnken design with three factors and one replicate. First order kinetic plot of acid degradation of OMR at 60 °C, 70 °C & 80 °C showed kinetic plots of the natural logarithm (Ln) of OMR remaining percent versus time for each temperature. Arrhenius plot was used in the kinetic study and half-life (t1/2), shelf life (t90), degradation rate constant (K25), Activation energy (Ea) & Arrhenius frequency factor (A) were calculated. A minor comparative study was also applied to show the difference between UPLC, UHPLC & HPLC for the assay of OMR. All of these applications were performed with the minimal possible cost as the major privilege of the presented economic work over the reported expensive LC-MS bio-analytical methods.

Clinical Trial of Trelagliptin Succinate Tablets in the Treatment of Type 2 Diabetes

Clinical Trial of Trelagliptin Succinate Tablets in the Treatment of Type 2 Diabetes

Binding behavior of trelagliptin and human serum albumin: Molecular docking, dynamical simulation, and multi-spectroscopy

This study aims to investigate the interaction mechanism of a hypoglycemic agent, trelagliptin (TLP), and human serum albumin (HSA) through computer simulation and assisted spectroscopy methods. Computer simulation including molecular docking and molecular dynamics analysis was conducted under physiological conditions. Molecular docking results indicate that TLP bound to HSA at site I, and the binding behavior was mainly governed by hydrophobic force. Competitive experiments further verified the theoretical conclusion from molecular docking. Molecular dynamics simulation revealed that TLP indeed stably bound to site I of HSA in the hydrophobic subdomain IIA. Moreover, TLP presented a certain effect on the structural compactness of HSA. In molecular dynamics simulation, hydrogen bonds appeared, which suggested the reliability and stability of the combination. The binding energy of the stable phase is around −250 kJ/mol. Fluorescence quenching studies and time-resolved fluorescence analysis indicated that the evident fluorescence quenching phenomenon of HSA could be due to TLP binding initiated by static quenching mechanism. The binding constants (Ka) of the complex were found to be around 104 via fluorescence data, and the calculated thermodynamic parameters indicated that hydrophobic force played major role in the binding of TLP to HSA. Synchronous fluorescence and three-dimensional fluorescence results demonstrated that TLP slightly disturbed the microenvironment of amino residues. Circular dichroism spectra showed that TLP affected the secondary structure of HSA. The theoretical and experimental results showed excellent agreement.

Different Spectrophotometric Methods for Simultaneous Determination of Trelagliptin and Its Acid Degradation Product.

New spectrophotometric and chemometric methods were carried out for the simultaneous assay of trelagliptin (TRG) and its acid degradation product (TAD) and applied successfully as a stability indicating assay to recently approved Zafatek® tablets. TAD was monitored using TLC to ensure complete degradation. Furthermore, HPLC was used to confirm dealing with one major acid degradation product. The proposed methods were developed by manipulating zero-order, first-derivative, and ratio spectra of TRG and TAD using simultaneous equation, first-derivative, and mean-centering methods, respectively. Using Spectra Manager II and Minitab v.14 software, the absorbance at 274 nm–260.4 nm, amplitudes at 260.4 nm–274.0 nm, and mean-centered values at 287.6 nm–257.2 nm were measured against methanol as a blank for TRG and TAD, respectively. Linearity and the other validation parameters were acceptable at concentration ranges of 5–50 μg/mL and 2.5–25 μg/mL for TRG and TAD, respectively. Using one-way analysis of variance (ANOVA), the optimized methods were compared and proved to be accurate for the simultaneous assay of TRG and TAD.

Suitability of various chromatographic and spectroscopic techniques for analysis and kinetic degradation study of trelagliptin

Multifaceted comparative analytical methods for trelagliptin (TRL) were investigated, applied to ZAFATEK tablets and HPLC-UV was selected for a degradation kinetic study. UPLC-MS/MS (Method I), UPLC-UV (Method II), HPLC-UV (Method III), UHPLC-UV (Method IV) and direct UV (Method V) methods were developed. Methods (I-V) showed satisfactory results using TRL concentration ranges of 50–800 ng/mL, 2.5–80 μg/mL, 5–100 μg/mL, 5–100 μg/mL and 5–50 μg/mL, respectively. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 358.176 to 134.127 for TRL and m/z 340.18 to 116.08 for alogliptin (IS) were employed utilizing positive mode Electrospray Ionization (ESI). The degradation kinetic study (Method VI) was carried out using 1 N HCl based on three different temperatures (70 °C, 80 °C and 90 °C). Through the optimized method-3, a good chromatographic separation of TRL from its major degradation product was achieved. Arrhenius plot was used in the kinetic study and the apparent 1st order degradation rate constant (K), t1/2, t90, and the activation energies were calculated for each temperature and at 25 °C. The optimized UPLC-MS/MS method is suitable for further TRL assay either in biological fluids or in the presence of impurities.

Development of a validated HPLC method for the quantitative determination of trelagliptin succinate and its related substances in pharmaceutical dosage forms

Trelagliptin succinate is a dipeptidyl peptidase IV (DPP-4) inhibitor which is used as a new long-acting drug for once-weekly treatment of type 2 diabetes mellitus (DM). In the present study, a rapid, sensitive and accurate high-performance liquid chromatography (HPLC) method was developed and validated for separation and determination of trelagliptin succinate and its eight potential process-related impurities. The chromatographic separation was achieved on a Waters Xselect CSH™ C18 (250mm×4.6mm, 5.0μm) column. The mobile phases comprised of 0.05% trifluoroacetic acid in water as well as acetonitrile containing 0.05% trifluoroacetic acid. The compounds of interest were monitored at 224nm and 275nm. The stability-indicating capability of this method was evaluated by performing stress test studies. Trelagliptin succinate was found to degrade significantly in acid, base, oxidative and thermal stress conditions and only stable in photolytic degradation condition. The degradation products were well resolved from the main peak and its impurities. In addition, the major degradation impurities formed under acid, base, oxidative and thermal stress conditions were characterized by ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap). The method was validated to fulfill International Conference on Harmonisation (ICH) requirements and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The developed method in this study could be applied for routine quality control analysis of trelagliptin succinate tablets, since there is no official monograph.

Synthesis of Trelagliptin Succinate

An improved process for the synthesis of antidiabetic drug trelagliptin succinate through unprotected (R)-3-aminopiperidine was described. The impurity profile with different conditions of the key substitution was illustrated, and then the best reaction condition was identified. The optimizations also included the bromination of 4-fluoro-2-methylbenzonitrile so that the process became efficient and concise.

X-ray powder diffraction data for trelagliptin succinate, C18H20FN5O2•C4H6O4

Experimental X-ray powder diffraction data, unit-cell parameters, and space group for trelagliptin succinate, C18H20FN5O2•C4H6O4, are reported [a = 18.481(6), b = 8.120(4), c = 7.903(4) Å, α = 89.972(0)°, β = 97.722(4)°, γ = 90.120(0)°, unit-cell volume V = 1175.37 Å3, Z = 2, and space-group P1]. All measured lines were indexed and are consistent with the P1 space group. No detectable impurity was observed.

Identification, characterization and HPLC quantification of process-related impurities in Trelagliptin succinate bulk drug: Six identified as new compounds

A sensitive, selective and stability indicating reversed-phase LC method was developed for the determination of process related impurities of Trelagliptin succinate in bulk drug. Six impurities were identified by LC–MS. Further, their structures were characterized and confirmed utilizing LC–MS/MS, IR and NMR spectral data. The most probable mechanisms for the formation of these impurities were also discussed. To the best of our knowledge, six structures among these impurities are new compounds and have not been reported previously. The superior separation was achieved on an InertSustain C18 (250mm×4.6mm, 5μm) column in a gradient mixture of acetonitrile and 20mmol potassium dihydrogen phosphate with 0.25% triethylamine (pH adjusted to 3.5 with phosphate acid). The method was validated as per regulatory guidelines to demonstrate system suitability, specificity, sensitivity, linearity, robustness, and stability.