Linagliptin Research Articles (Page 1)

The quality by design (QbD) approach was applied for optimizing the formulation of model antidiabetic drug Linagliptin (LIN) mucoadhesive microspheres (MS) through design of experiment (DoE). To Optimize LIN-MS a quality target product profile (QTPP) was established in which critical quality attributes (CQAs) such as MVD, % encapsulation efficiency (% EE) and t50 drug release were quantified. As critical material attributes (CMA) viz., Keltone (KE), Carbopol (CA) and Pectin (PC) were chosen and evaluated their effect on CQAs. Response surface design (RSM) viz., Central Composite Design (CCD) was studied to evaluate effects of CMA on stated CQAs within the design space. The main effect was observed with varied levels of KE, CA and PC on CQAs. Numerical optimization by point prediction method was applied to generate optimized formula with predicted response, later the experimental responses were validated and ratified within the design space. The results suggest QbD through DoE appears to be a useful approach for the rational design, optimization and characterization of LIN-MS.

The present study aims to develop and validate simple, cost effective Q-Absorbance Ratio Method for simultaneous quantification of Linagliptin (LIN) and Metformin HCl (MET). The proposed medium Acetonitrile: Methanol: Distilled Water at 1:1:1 (Solvent Blend) identified λmax 235nm for MET, 298nm for LIN and Isobestic point at 231.7nm for Q-Absorbance Ratio Method. The validation follows ICH Q2(R1) guidelines, demonstrating excellent linearity, accuracy, precision and sensitivity (LOD and LOQ) for LIN and MET. The developed method was successfully applied to a synthetic mixture and marketed formulation, showing % recovery within the acceptable limit with % RSD was less than 2.

The purpose of this study was to develop a reliable, rapid and sensitive method based on Ultra Violet spectroscopy (UV) for the determination of an anti-diabetic drug Linagliptin (LIN) in its pure form as well as in its pharmaceutical dosage forms. Different solvent blends were screened to select solvent blend which suits for the study. The solvent blend selected was comprising of Acetonitrile: Methanol: DW at 1:1:1 and same was used for the development, validation and quantification of LIN. The results show the linearity in the concentration range (1-50 µg/mL) with correlation coefficient R2 = 0.9999 with percent recovery (100 – 100.3 %) with RSD was less than 2%, LOD and LOQ 0.05657, 0.1714 µg/mL respectively. This method can show high quality and there is no significant interference with the excipients and in pharmaceutical forms. None of the studies showed the development of this method before.

A reverse phase high performance liquid chromatography (RP-HPLC) method has been developed and validated as a precise, accurate and cost-effective approach for the concurrent quantification of dapagliflozin propanediol monohydrate (DAPA), linagliptin (LINA) and metformin hydrochloride (METF). The greenness of the current approach was assessed using AGREE and GAPI tools. The Agilent Eclipse XBD C18 column (5 µm, 150 × 4.5 mm) and eluent consisting of buffer (pH adjusted to 3) and methanol (40:60 V/V) in isocratic condition, at 1.0 mL min-1 was finalized. The drugs were monitored at 215 nm. Linearity was attained encompassing the concentration range 2.5 - 7.5 µg mL-1, 1.25 - 3.75 µg mL-1 and 125 - 375 µg mL-1 for DAPA, LINA and METF, respectively. The precision results were within the acceptable limit of % relative standard deviation (% RSD) i.e. less than 2, and % recovery outcomes were found to be within the limit. This technique can be used routinely to quantify simultaneously METF, LINA and DAPA, in quality control laboratories. The developed method is environmental and operator-friendly.

Objective: In this study, a low-cost, sensitive and practical electroanalytical method was developed and validated for the determination of Linagliptin (LNG), a therapeutic agent used in the treatment of Diabetes Mellitus, one of the most common chronic diseases worldwide, characterized by high blood glucose levels and directly affecting millions of people. Material and Method: Electroanalytical studies were completed using screen-printed carbon electrodes in pH: 8 Britton - Robinson buffer solution. Mechanistic studies were carried out by cyclic voltammetry technique. Adsorptive stripping differential pulse voltammetry technique was used for the electrochemical determination of LNG. Result and Discussion: The developed method exhibited linearity in the range of 0.1 - 7.5 µM and the limit of detection value was calculated as 37 nM. The developed method was applied for the determination of LNG from urine and a recovery value of 100.02% was obtained.

Zirconium nanoparticles decorated chitosan@hematoxylin/pencil graphite as a novel voltammetric sensor for monitoring of linagliptin/dapagliflozin co-therapy.

A fluorescence quenching strategy was conceptualized to establish an environmentally compatible analytical system for trace-level detection of Linagliptin (LGP), an anti-diabetic pharmaceutical compound. This research delineates a biochemical sensing mechanism relying on an electrostatic coupling between LGP and Erythrosine B (EB), a biologically certified fluorophore, within optimized acidic parameters. The molecular association induced a concentration-dependent reduction in EB's intrinsic emission intensity at λem 554nm, attributed to the generation of a non-luminescent LGP-EB supramolecular assembly. Methodical optimization of operational parameters governing the recognition process-including pH modulation, stoichiometric ratios, and temporal stability-yielded a linear response across 0.30-2.50µg/mL, with detection and quantification capacities reaching 0.0286µg/mL and 0.0943µg/mL, respectively. Validation studies confirmed adherence to International Council for Harmonization (ICH) criteria, exhibiting ≤ 1.9% relative standard deviation in precision assessments and 98.9-100.8% recovery rates in spiked samples. The technique's efficacy was verified across multiple matrices, encompassing raw drug substances, pharmaceutical formulations, and simulated biological media. Ecological compatibility was rigorously evaluated through modern sustainability metrics aligned with green analytical chemistry principles. Implementation of the White Analytical Chemistry (WAC) protocol via the RGB 12 algorithm designated the methodology as "environmentally considerate," reflecting minimal reagent consumption and energy requirements. Concurrent analysis using the BAGI (Biocompatible Analytical Greenness Index) tool produced exceptional scores in ecological safety and methodological adaptability, confirming its proficiency in harmonizing analytical precision with sustainable practices. This dual-focused approach addresses critical needs in pharmaceutical quality control while advancing eco-responsible analytical methodologies.

This study presents a novel electrochemical sensor for simultaneously determining of co-formulated antidiabetic drugs, dapagliflozin (DPG) and linagliptin (LNG) via a carbon paste electrode modified with carbon dots (CDs) prepared from a renewable green source. The carbon dots, derived from avocado peels, were electrodeposited onto the carbon paste to enhance the kinetics of electron transport and the electroactive surface area. Optimization of the electrodeposition parameters is achieved with a limit of detection 3.24 μM, and 2.7 μM, within a range from 1.0 × 10−5 to 0.36 × 10−3 M and 1.0 × 10−5 to 0.2 × 10−3 M for LNG and DPG, respectively. The study highlights the environmental sustainability of a voltammetric electrode, evaluated through green analytical tools like Analytical greenness (AGREE). This approach underscores the potential of green-sourced carbon dots in advancing electroanalytical methods in the field of pharmaceutical analysis.

Aim Linagliptin (LGP) has poor oral bioavailability due to P-gp efflux and first-pass metabolism. This study aimed to develop LGP-loaded novasomes (LGP-NVS) for intranasal brain delivery. Methods LGP-NVS were prepared via thin film hydration and optimised using a Box-Behnken design, varying cholesterol, stearic acid, and span-80 levels. Fifteen formulations were evaluated for particle size, entrapment efficiency, zeta potential, and drug release. The optimised formula underwent further surface, compatibility, permeability, and stability studies. Results The optimised formula showed high entrapment (84.22% ± 1.68%), small particle size (239.35 ± 15.20 nm), plausible zeta potential (−30.25 ± 1.23 mV), polydispersity index (0.32 ± 0.058), and controlled release (66.85 ± 2.25% after 8 h). Transmission electron microscopy demonstrated uniform size. Stability was maintained over three months. Ex-vivo permeation studies showed 1.39-fold higher permeation through camel nasal mucosa compared to drug solution. Conclusion Intranasal LGP-NVS might be an auspicious therapeutic avenue for the combat of Alzheimer’s disease.

Re-purposing of linagliptin for enhanced wound healing and skin rejuvenation via chitosan- modified PLGA nanoplatforms.

Diabetic kidney disease (DKD) is a leading cause of end stage kidney disease. Elevated salt sensitivity by epithelial sodium channel (ENaC) overexpression may be a residual risk factor for DKD. We found that combination therapy of linagliptin (LINA) to empagliflozin (EMPA), but not EMPA alone decreased phosphorylated Nedd4-2 (p-Nedd4-2) and ENaC levels in DKD rats in association with the increased urinary sodium excretion (USE). More extensive renoprotective effects were observed by the combination therapy of LINA and EMPA in deoxycorticosterone and high salt-treated mice. Acute injection experiments showed time-lagged administration of LINA to EMPA increased USE, and its effect sustained until 3 h. High salt and high glucose increased p-Nedd4-2 and ENaC levels in cultured distal tubules, which was inhibited by LINA or glucagon like peptide-1 (GLP-1), but there were no additive effects of LINA on GLP-1, the latter of which was blocked by GLP-1 receptor agonist. USE was higher and ENaC expression was lower in DKD patients received SGLT2is and DPP4is than those without. Our present findings suggest that addition of LINA to EMPA decreases p-Nedd4-2 and ENaC levels via the activation of GLP-1-receptor axis, which could ameliorate salt sensitivity and help prevent kidney injury in DKD.

Interest is increasing in using novel diabetic medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a porcine model of chronic coronary ischemia. Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement over the left circumflex coronary artery at age 11 weeks. Two weeks thereafter, swine received either vehicle without drug (n= 9) or LIN 2.5 mg (n= 8). Following the elapse of 5 weeks of treatment, swine underwent terminal harvest. LIN significantly increased stroke volume, ejection fraction, cardiac output, and ischemic myocardial perfusion, while decreasing Tau (all P< .05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor-β (all P < .05). Apoptosis, measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining, was significantly reduced, and accompanied by decreases in apoptosis-inducing factor, BCL2-associated agonist of cell death, caspase-9, and cleaved caspase-9 (all P < .05). Additionally, there were significant increases in phosphoinositide 3-kinase, phospho-protein kinase B, 5' adenosine monophosphate-activated protein kinase, phospho-5' adenosine monophosphate-activated protein kinase, and endothelial nitric oxide synthase, and significant reductions in collagen 18 and angiostatin (all P < .05). LIN significantly improved left ventricular function, cellular survival, and attenuated adverse remodeling, all likely secondary to augmented perfusion ischemic myocardial perfusion. Given that this increased perfusion occurred independently of changes in vascular density, treatment likely resulted in enhanced microvascular reactivity. These benefits warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease. SIGNIFICANCE STATEMENT: Linagliptin significantly improved cardiac cellular survival, left ventricular function, and attenuated adverse myocardial remodeling in a clinically relevant, large animal model of chronic ischemic cardiomyopathy. This warrants further investigation of linagliptin to fully understand its therapeutic potential.

Linagliptin: A comprehensive profile.

Micellar liquid chromatography (MLC) has proven beneficial efficiency and ecological impact for routine quality control activities. In the proposed study, cyrene was investigated for the first time, together with other green additives, as a novel safe organic solvent in reversed-phase MLC. Quality-by-design (QbD) approach screened their effect on the separation performance. Six antidiabetic drugs from different classes, namely, metformin (MTF), empagliflozin (EMP), ertugliflozin (ERT), linagliptin (LNT), sitagliptin (SIT), and gliclazide (GCZ) were utilized to assess some newly approved antidiabetic drugs and combinations. An organic solvent-free mobile phase consisting of (0.01M Brij-35, 0.09M sodium dodecyl sulfate, and 0.01M ammonium acetate, pH 5.0) separated the studied drugs using an RP-C18 core-shell column. The flow rate was set at 1.2mL/min, and analytes were detected using a photodiode array detector at 245, 270, and 225nm. System suitability parameters demonstrated MLC capability to eliminate organic solvents without compromising separation efficiency. The method was validated across a concentration range of 2.0-30.0µg/mL for EMP, ERT, and LNT, 20.0-120.0µg/mL for GCZ and SIT, and 100.0-600.0µg/mL for MTF. The method successfully determined analytes in different single and multicomponent tablets. Greenness assessment was performed using MoGAPI and AGREE metrics.

Linagliptin (LNG) exhibits poor bioavailability and numerous side effects, significantly limiting its use. Transdermal drug delivery systems (TDDS) offer a potential solution to overcome the first-pass effect and gastrointestinal reactions associated with oral formulations. The aim of this study was to develop LNG microparticle gels to enhance drug bioavailability and mitigate side effects. Linagliptin hyaluronic acid (LNG-HA) microparticles were prepared by spray drying method and their formulation was optimized via a one-factor method. The solubility and release were investigated using the slurry method. LNG-HA microparticle gels were prepared and optimised using in vitro transdermal permeation assay. The hypoglycaemic effect of the LNG-HA microparticle gel was examined on diabetic mice. The results indicated that the LNG-HA microparticle encapsulation rate was 84.46%. Carbomer was selected as the gel matrix for the microparticle gels. Compared to the oral API, the microparticle gel formulation demonstrated a distinct biphasic release pattern. In the first 30 minutes, only 43.56% of the drug was released, followed by a gradual release. This indicates that the formulation achieved a slow-release effect from a dual reservoir system. Furthermore, pharmacodynamic studies revealed a sustained hypoglycemic effect lasting for 48 hours with the LNG microparticle gel formulation. These findings signify that the LNG microparticle gel holds significant clinical value for providing sustained release and justifies its practical application.

Introduction: Interest is increasing in using novel diabetic medications, such as GLP-1 receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a swine model of chronic myocardial ischemia (CMI). Goals: Study the effect of DPP-4 inhibitor LIN in a clinically relevant swine model of CMI to gain insight into potential therapies for patients with myocardial ischemia. Methods: Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement on the left coronary circumflex (LCx) at age 11 weeks. Two weeks later, swine received either vehicle without drug (CON, n=9, F=4, M=5) or LIN 2.5 mg (n=8, F=5, M=3). After 5 weeks of treatment, swine underwent terminal harvest. Results: LIN significantly increased cardiac output, stroke volume, ischemic myocardial perfusion at rest, ischemic myocardial perfusion while pacing at 150 beats per minute, and ejection fraction, while decreasing tau (all p&lt;0.05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor beta (all p&lt;0.05). Apoptosis, measured by TUNEL, was significantly reduced, along with decreases in apoptosis-inducing factor, Caspase-9, BAD, and cleaved Caspase-9 (all p&lt;0.05). Additionally, there were significant increases in PI3K, phospho-AKT, AMPK, phospho-AMPK, and ENOS, and a significant reduction in collagen 18 and angiostatin (all p&lt;0.05). There were no significant changes in heart rate, arteriolar density, capillary density, or total oxidative stress. Conclusion: LIN significantly improved myocardial function and perfusion, likely due to reduced fibrosis and apoptosis. The increased perfusion, independent of vascular density, suggests enhanced vascular reactivity. These benefits in a high-fidelity large animal model of CMI warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease.

The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss-Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiability. Through PBPK-CGNM analysis using reported autoradiography data ([14C]-LNG) in wild-type and Dpp-4-deficient rats, DPP-4-specific distributions of LNG in various tissues were clearly differentiated from nonspecific parts. By fitting to human plasma concentrations and urinary and fecal excretions of LNG after intravenous and oral administrations, multiple unknown PBPK parameters were simultaneously estimated by the CGNM. Notably, the amount of tDPP-4 and the reabsorption clearance for LNG-DPP-4 complexes were identifiable, indicating their critical role in explaining the complex nonlinear pharmacokinetics of LNG. Compared with previous PBPK analyses, the CGNM allowed us to incorporate greater model complexity (e.g., consideration of tDPP-4 expressions and invitro binding kinetics), ultimately resulting in a more accurate reproduction of LNG's TMDD. In conclusion, by considering LNG as a high-affinity probe for DPP-4, comprehensive PBPK-CGNM analyses suggested a dynamic whole-body distribution of DPP-4, including its involvement in the renal reabsorption of LNG.

To augment oral bioavailability, linagliptin (LGP) loaded solid lipid nanoparticles (SLNs) have been formed using the solvent evaporation technique of emulsification. Utilizing the Box Behken design (BBD), examining the relation between independent and dependent variables was possible. Particle size (PS), entrapment efficiency (EE), and in-vitro drug release (DR) studies were considered response factors, whereas the various concentrations of lipid carrier, surfactant, and co-surfactant were considered process variables for optimization. The design expert program was used to obtain the optimized batch. At 24 hours, it was discovered that the optimized batch expected responses for PS, %EE, and %DR were 105.83 nm, 81.19, and 96.69%, respectively. The observed PS, %EE, and %DR responses of the optimized batch at 24 hours were determined to be 101.36 nm, 80.56, and 96.31%, respectively. There is no interaction seen in the basic physical mixing of drug and polymer, according to the FTIR spectra of pure drugs, polymers, and drug and polymer mixtures. The optimized formulation’s average size was found to be 138 nm by the particle size analysis. Similarly, a value of 0.255 was found by the polydispersity index (PDI). This suggests that the SLN in the formulation has a homogeneous size dispersion. With a zeta value of -32.8 mV, stability is indicated. Linagliptin was effectively developed as a drug with a 24-hour sustained release. Wistar rats were used in the in-vivo evaluation of linagliptin SLN formulations. The drug bioavailability increased five times (a highly significant fivefold increase) in LGP-loaded SLNs (AUC0-t ≈ 134.5 μg*h/mL) compared to raw LGP (AUC0-t = 27.23 μg*h/mL).

Diabetic wound healing including diabetic foot ulcers is a major clinical challenge, which could bring an increased level of mortality and morbidity. However, conventional wound dressings exhibit limited healing efficacy due to their lack of active modulation for the healing process. Here, a near-infrared (NIR) stimuli-responsive composite hydrogel dressing with the synergistic effect of both mechanical contraction and epithelial-mesenchymal transition (EMT) was developed to facilitate cell migration and vascularization for diabetic wound healing. In the methacrylated gelatin-based composite hydrogel, N-isopropylacrylamide and polydopamine nanoparticles were incorporated to endow the composite hydrogel with thermosensitive and photothermal properties. Linagliptin (LIN) was loaded into the composite hydrogel, and the drug release rate could be controlled by NIR laser irradiation. NIR-triggered on-demand active contraction of wound area and LIN release for biological stimulation were potentially realized in this responsive system due to the thermally induced sol-gel transition of the composite hydrogel. The release of loaded LIN could effectively promote cell migration by activating EMT and enhancing angiogenesis. In the full-thickness skin defect model, the LIN-loaded composite hydrogel with NIR laser irradiation had the highest wound closure rate as compared with the pure hydrogel and LIN-loaded hydrogel groups. Therefore, this composite hydrogel can serve as an excellent platform for promoting wound healing and will find more practical value in clinical treatment.

Miniaturized green capillary electrophoresis system for the simultaneous analysis of Linagliptin and cefiximein in plasma