Gliclazide Research Articles

Development of a gliclazide ionic liquid and its mesoporous silica particles: an effective formulation strategy to improve oral absorption properties.

Ionic liquid (IL) technology provides a useful platform to enhance the oral absorption of therapeutic agents. In the present work, gliclazide (GLI), a second-generation sulfonylurea drug was transformed into an IL with tetrabutylphosphonium. The physicochemical properties of this IL were systematically characterized by DSC, TGA, FT-IR, NMR, and HPLC. For the further preparation development, a solution stability test was conducted. GLI-based IL could improve the solution stability in a neutral environment. To assess oral potential, the solubility characteristics including equilibrium solubility, 24 h kinetic saturation solubilities and supersaturation profiles were first explored. Significant enhancement of solubilities, supersaturation ratio and duration of supersaturation was found for the synthesized IL. Computational methodology was utilized to better understand the improved solubility results. From the simulated results, [TBP][GLI] showed a longer time period when the distance between cation and anion was far above the baseline and a higher deviation degree, indicating less stable ion pairs of [TBP][GLI] in an aqueous environment and it being easy for the cation and anion to tear apart and form interactions with water molecules. The prepared [TBP][GLI] exhibited intestinal transportation ability and safety as evidenced by the in vitro gastrointestinal tract artificial membrane permeability assays (GIT-PAMPA) and cytotoxicity experiments with Caco-2 cells. A mesoporous carrier, AEROPERL® 300 Pharma, was chosen to load the IL and then encapsuled into enteric capsules. The prepared oral capsules containing GLI-based IL loaded mesoporous silica particles released fast and could realize 100% release within 60 min.

Pharmacodynamic assessment of gliclazide multiparticulate system: single-dose and multiple-dose studies

Background Conventional dosage forms of oral hypoglycemic drugs, including gliclazide (GLZ), may have a number of limitations, reducing their bioavailability. Thus, efforts are directed to design novel modified-release (MR) dosage forms for these drugs. The possible role of orally administered GLZ-MR multiparticulates in the treatment of hyperglycemia as well as improvement of impaired wound healing associated with type 2 diabetes mellitus was investigated.Objective This study aimed to evaluate the pharmacodynamics (PD) of GLZ-MR multiparticulate system against Diamicron MR tablets in nondiabetic (healthy) and streptozotocin-induced diabetic rats, by measuring blood glucose levels. For the first time, the hypothetical wound-healing capabilities of multiple doses of both treatments in diabetic rats were also studied by evaluating the wound diameter and histology.Materials and methods Novel cross-linked freeze-dried GLZ-alginate-gelatin beads were prepared. Two GLZ treatments at 4 mg/kg [test (T, MR beads) and reference (R, Diamicron MR 30 mg)] were administered to rats. A single-dose PD study was carried out on both healthy and diabetic rats, whereas the multiple-dose study was evaluated in diabetic rats. A single-dose pharmacokinetics (PK) study was conducted for assessment of the PK-PD relationship in healthy rats.Results and conclusion The single-dose study on nondiabetic rats showed that T beads exhibited a greater magnitude of blood glucose level reduction, with 1.5-fold increase in Cmax, compared with R. A direct linear relationship with high correlation was detected between GLZ glucose-lowering effect and its PK parameters, only for T beads. Multiple dosing of T beads was more efficient than R in managing hyperglycemia of wounded diabetic rats. T beads allowed almost complete wound closure, after multiple dosing for 17 days. The proposed GLZ beads could provide a promising therapeutic prospect for managing hyperglycemia as well as resolving impairment of wound healing associated with diabetes.

In Vitro Investigation of Binding Interactions between Albumin-Gliclazide Model and Typical Hypotensive Drugs.

Type 2 diabetes management usually requires polytherapy, which increases the risk of drug-to-drug interactions. Among the multiple diabetes comorbidities, hypertension is the most prevalent. This study aimed to investigate the binding interactions between the model protein, bovine albumin, and the hypoglycemic agent gliclazide (GLICL) in the presence of typical hypotensive drugs: quinapril hydrochloride (QUI), valsartan (VAL), furosemide (FUR), amlodipine besylate (AML), and atenolol (ATN). Spectroscopic techniques (fluorescence quenching, circular dichroism) and thermodynamic experiments were employed. The binding of the gliclazide to the albumin molecule was affected by the presence of an additional drug ligand, which was reflected by the reduced binding constant of the BSA–DRUG–GLICL system. This may indicate a possible GLICL displacement and its enhanced pharmacological effect, as manifested in clinical practice. The analysis of the thermodynamic parameters indicated the spontaneity of the reaction and emphasized the role of hydrogen bonding and van der Waals forces in these interactions. The secondary structure of the BSA remained almost unaffected.

Pharmacoscintigraphic evaluation and antidiabetic efficacy of gliclazide-loaded 99mTc-labelled mucoadhesive microspheres

BackgroundThe current study was carried out to evaluate the possible application of Musa balbisiana starch in formulation of mucoadhesive microsphere for oral delivery of gliclazide (GLZ). The study objective was to improve the oral bioavailability along with prolongation of its duration of action for a better glycaemic control. Ionic gelation technique was employed in formulating the dosage form. Optimization of the batches was carried out by response surface methodology using 32 full factorial designs. The microsphere prepared was characterized for several parameters along with its in vitro release study. The gastrointestinal transit of the optimized batch of prepared microspheres after oral administration was studied in rabbits by using the gamma scintigraphy technique utilizing 99mTc as the labelling agent in the presence of stannous chloride. Also, the optimized batch was studied for its pharmacokinetic parameters. Moreover, the antidiabetic efficacy of the prepared microsphere was evaluated in rats by using the streptozotocin (STZ)-induced diabetic model.ResultsThe factorial design experiment resulted in an optimum formulation coded as F8. The compatible nature of the drug and excipient was revealed from FTIR, DSC and IST studies. The scanning electron micrographs also showed the occurrence of spherical microspheres having a smooth surface. The in vitro release study provided an evidence of an initial burst effect that was followed by a prolong release phase. The pharmacokinetic parameters justified the ability of the prepared dosage form in sustaining the drug release with a 2.7-fold enhancement in drug bioavailability. The images obtained during the gamma scintigraphy study suggested the gastro-retentive nature of the dosage form with the gastro-retentive ability for more than 4 h. Also, the pharmacodynamics study carried out in diabetic rat model confirmed about the better efficacy of the dosage form in lowering the elevated blood glucose level.ConclusionThe overall study data provide valuable information about the potential of this banana starch in formulation of a mucoadhesive dosage form that can be used for enhancement of bioavailability of drug-like gliclazide which in turn can provide a beneficial effect in the management of diabetes.

Evaluation of the effectiveness and tolerability of gliclazide modified release 60 mg in patients with type 2 diabetes observing fasting during Ramadan in Pakistan: An analysis from the global DIA-RAMADAN study

AimTo assess safety and effectiveness of gliclazide MR 60 mg in people with controlled or suboptimal controlled T2DM treated with breakable gliclazide MR 60 mg formulation. MethodThis study data has been extracted from an international, observational study conducted in nine Asian and Middle Eastern countries. Total 220 patients with T2DM were recruited from Pakistan. The primary endpoint was the proportion of patients reporting at least 1 symptomatic HE, whereas secondary endpoints were changes in glycosylated haemoglobin (HbA1c) %, fasting plasma glucose (FPG) mg/dL, and body weight (kg) and proportion of patients reporting any HE (confirmed or severe), between inclusion visit (V0) and end of the study visit (V1). ResultsDuring Ramadan, 3.6% (n = 8/220) patients had experienced at least one symptomatic HEs. A significant (p-value < 0.001) reduction was observed in HbA1c: (mean [SD]) (−0.4 [0.9] %), and body weight (−0.7 [4.8] kg). Thirteen adverse events (AEs) unrelated to gliclazide MR were reported during the study pre-Ramadan and post-Ramadan periods. ConclusionThis study shows safety and effectiveness profile of gliclazide MR 60 mg by emphasizing on the low risk of HEs, effective glycaemic control and body weight reduction in T2DM patients, who are inclined to fasting during Ramadan.

FORMULATION AND EVALUATION OF METFORMIN HYDROCHLORIDE AND GLICLAZIDE SUSTAINED RELEASE BILAYER TABLETS: A COMBINATION THERAPY IN MANAGEMENT OF DIABETES

Objective: The main objective of the present investigation is to develop a sustained-release (SR) formulation to optimize the postprandial elevation of glucose level in type 2 Diabetic subjects using combination therapy. In the present research work, bilayer sustained release formulation of metformin hydrochloride (MFH) and gliclazide (GLZ), based on monolithic-matrix technology was developed and evaluated. Methods: The formulations of metformin hydrochloride layer and gliclazide layer that contain polyox WSR coagulant and different viscosity grades of hydroxyl propyl methylcellulose (HPMC) as sustained-release matrix were prepared by direct compression and wet granulation method respectively. The bilayer tablets were prepared after carrying out the optimization of metformin layer and evaluated for various pre-compression and post-compression parameters. For the best formulation selected on basis of in vitro evaluation of tablets, Fourier-transform infrared spectroscopy (FT-IR) studies and comparison of in vitro dissolution profile of developed formulation with the innovator were performed. Results: Metformin hydrochloride and gliclazide showed sustained release of drug by diffusion mechanism and followed first-order kinetics. The best formulation of metformin hydrochloride (M7) and gliclazide (G8) show 99.93% and 99.65% of drug release in 24 h respectively. The similarity factor (f2) was 79.95 for metformin hydrochloride and 73.62 for gliclazide when compared with the innovator. Conclusion: The monolith diffusion-controlled bilayer tablets of metformin hydrochloride and gliclazide offer improved patient compliance and convenience with better postprandial hyperglycemic control with once-a-day dosing. The sustained release of the drug up to 24 h regulate antidiabetic activity round the clock with minimal side effects.

LC-MS/MS determination of glimepiride in human plasma with a high recovery at picogram scale: Pharmacokinetic study after oral administration

Abstract Although glimepiride (GLM) is the first-line treatment of Type II diabetes, low extraction recovery is still a significant limitation in previous plasma analysis methods. An optimized solid-phase extraction method of GLM in human plasma with excellent extraction recovery, 100 ± 0.06%, was achieved using liquid chromatography-electrospray ionization tandem mass spectrometry and Gliclazide (GLZ) as an internal standard. GLM was extracted from 100 µL plasma sample using Sep-Pak® vac 1cc (100 mg) C18 column and methylene chloride: methanol (2: 1, v/v) as eluant. Both GLM and GLZ were monitored by a triple quad mass spectrometer applying positive multiple reaction monitoring mode (+MRM). The protonated precursor ions and product ions of GLM and GLZ were m/z 491(352), and m/z 324 (127), respectively. The detection and measurement of low levels of GLM in human plasma reached to picogram range (limit of detection (LOD) = 60 pg/mL, limit of quantification (LOQ) = 200 pg/mL). The method was validated in terms of selectivity, linearity, recovery, accuracy, and precision. The method was successfully applied to the pharmacokinetic study of GLM following oral administration of 1 mg GLM tablets to 12 healthy volunteers.

Cocrystallization of gliclazide with improved physicochemical properties

BackgroundCocrystallization is one of the crystal engineering strategies used to alter the physicochemical properties of drugs that are poorly water-soluble. Gliclazide (GLZ), an antidiabetic drug, belongs to Biopharmaceutical Classification System class-II (low solubility and high permeability) and has low bioavailability, resulting in poor therapeutic effects in patients. Therefore, to impart better solubility and bioavailability of GLZ, the study was carried out by preparing GLZ cocrystals using liquid-assisted grinding method with three coformers [3,5-dinitrosalicylic acid (DNS), 2,6-pyridine dicarboxylic acid (PDA), and L-proline (LPN)], and these were characterized using Differential Scanning Colorimetry (DSC), Powder X-ray diffraction (PXRD), Fourier Transform Infra-red spectroscopy (FTIR), and Raman spectral studies. Further, Scanning electron microscopy (SEM) analysis, accelerated stability, solubility, in vitro dissolution studies, and in vivo pharmacokinetic studies were performed in male Wistar rats.ResultsDSC and PXRD analysis confirmed the formation of the GLZ cocrystals. Hydrogen bonding between pure GLZ and its coformers was demonstrated based on FTIR and Raman analysis. SEM data showed morphological images for GLZ cocrystals differed from those of pure GLZ. In comparison with pure GLZ, these GLZ cocrystals have greatly improved solubility, in vitro dissolution, and in vivo profiles. Among the three, GLZ–DNS cocrystals outperformed the pure drug in terms of solubility (6.3 times), degradation (1.5 times), and relative bioavailability (1.8 times).ConclusionHence, cocrystallization of GLZ leads to improved physicochemical properties of poorly soluble drug gliclazide.

Development of gliclazide ionic liquid and the transdermal patches: An effective and noninvasive sustained release formulation to achieve hypoglycemic effects

Ionic liquids (IL) technology provides a useful platform to achieve the topical delivery of therapeutic agents, because of its capability to improve skin permeability. While the majority of the researches aimed to achieve local action by topical IL delivery, systemic action of therapeutic agents by local topical application has rarely been reported. In the present work, Gliclazide (GLI), a second-generation sulfonylurea drug was transformed into an IL with tributyl(tetradecyl)phosphonium for the first time. The physicochemical properties of this IL were systematically characterized by DSC, TGA, FT-IR, NMR, and HPLC. The transdermal patch based on this IL was further prepared using DURO-TAK®87-4098. The fabricated gliclazide based ionic liquid [P6,6,6,14][GLI] transdermal patch displayed satisfactory in vitro and in vivo performance. The [P6,6,6,14][GLI] patch released 88.17% of the loaded drug within a 3-day period in the in vitro dissolution test, confirming its sustained release property. Meanwhile, GLI effectively permeated through the artificial skin from [P6,6,6,14][GLI] transdermal patch in the in vitro skin permeation test, with the permeation rate and lag time of 16.571 ± 0.328 μg/cm2/h and 3.027 ± 0.154 h respectively. The [P6,6,6,14][GLI] transdermal patch showed favorable PK profile in rat as compared with GLI oral suspension. The relative bioavailability of GLI reached 92.06% of GLI oral suspension, while the Cmax was significantly reduced. Most importantly, [P6,6,6,14][GLI] transdermal patch demonstrated superior hypoglycemic effect to the oral suspension both in the fasted and fed condition, confirming the feasibility of systemic action by local topical delivery of IL. In addition, the [P6,6,6,14][GLI] transdermal patch caused no skin irritation based on histopathological analysis.

Safety and Tolerability of Sodium Glucose Co-transporter -2 Inhibitors (SGLT2i) During Ramadan Fasting

Background: Diabetic management during Ramadan fasting is a significant clinical challenge. Sodium glucose co-transporter -2 inhibitors (SGLT2i) are new class of antidiabetic medications known for low frequency of associated hypoglycemia. The present study aimed to evaluate efficacy, safety and tolerability of SGLT2i in diabetic patients practicing Ramadan fasting. Patients and methods: The study included 94 patients. They comprised 51 patients who received metformin and sulfonylureas (SU): glimepiride (1-6 mg/d) or gliclazide MR (60-120mg/d) and 43 patients who received metformin and SGLT2i: empagliflozin (25 mg), dapagliflozin (10 mg) or canagliflozin (300 mg). The study outcome parameters were frequency of hypoglycemia episodes, volume depletion episodes, number of days with early breaking of fasting and missed fasting days. Results: It was found that patients in SGLTi group experiences significantly fewer symptomatic (9.3 % versus 35.3 %, p=0.003) and documented (7.0 % versus 25.5 %, p=0.017) hypoglycemic episodes as compared to the SU group. However, there were no significant differences between the studied groups regarding the frequency of patients with volume depletion episodes (5.9 % versus 16.3 %, p= 0.1). Moreover, there were no significant differences between groups regarding the frequency of patients with early breaking of fasting (11.8 % versus 9.3 %, p=0.7) or missed fasting (3.9 % versus 2.3 %, p=0.66). None of the studied patients discontinued the prescribed medications. Conclusions: SGLT2i combined with metformin for diabetic patients during Ramadan fasting are effective, safe and well-tolerated with the advantage of reduced hypoglycemic events.

353-P: Safety and Tolerability of Sodium-Glucose Cotransporter 2 Inhibitors during Ramadan Fasting

Background: Diabetic management during Ramadan fasting is a significant clinical challenge. Sodium glucose co-transporter -2 (SGLT-2) inhibitors are new class of antidiabetic medications known for low frequency of associated hypoglycemia. The present study aimed to evaluate efficacy, safety and tolerability of SGLT-2 inhibitors in diabetic patients practicing Ramadan fasting. Patients and Methods: The study included 94 patients. They comprised 51 patients who received metformin and sulfonylureas: Glimepiride (1mg-6mg/d) or Gliclazide MR (60-120mg/d) and 43 patients who received SGLT2 inhibitors: Empagliflozin (25 mg), Dapagliflozin (10 mg) or Canagliflozin (300 mg). The study outcome parameters were frequency of hypoglycemia episodes, volume depletion episodes, number of days with early breaking of fasting and missed fasting days. Results: It was found that patients in SGLTI group experiences significantly fewer symptomatic (9.3 % versus 35.3 %, p=0.003) and documented (7.0 % versus 25.5 %, p=0.017) hypoglycemic episodes as compared to the SU group. However, there were no significant differences between the studied groups regarding the frequency of patients with volume depletion episodes (5.9 % versus 16.3 %, p= 0.1). Moreover, there were no significant differences between groups regarding the frequency of patients with early breaking of fasting (11.8 % versus 9.3 %, p=0.7) or missed fasting (3.9 % versus 2.3 %, p=0.66). None of the studied patients discontinued the prescribed medications. Conclusions: SGLT-2 inhibitors combined with metformin for diabetic patients during Ramadan fasting are effective, safe and well-tolerated with the advantage of reduced hypoglycemic events. Disclosure E. M. A. Eid: None. A. Hussein: None. H. A. Ghazi: None.

Clinical Effectiveness and Safety of Gliclazide MR and Linagliptin Combination in the Management of Patients With T2DM and Chronic Kidney Disease (CKD) Switched From Glimepiride - a Real-World, Retrospective, Observational Study

Background: Type 2 diabetes (T2DM) patients are at high risk of developing to CKD and progressing to adverse outcomes vs Nondiabetics. The aim was to evaluate the effectiveness and safety of gliclazide MR switched from glimepiride in combination with linagliptin considering their associated potential benefits in albuminuria reduction and delaying progression of adverse renal outcomes in T2DM patients with kidney disease as shown in previous data. Methodology: The medical study database of the author’s hospital identified T2DM patients with stage 1–3 CKD with mean eGFR of 50.4 ± 8.56 ml/min/1.73 m2 and were inadequately controlled with glimepiride (mean dose 3.24mg) for the last 3 months. These patients were switched to gliclazide MR with appropriate equivalent dose while DPP-4 inhibitors like linagliptin (5 mg OD) (79%), sitagliptin (14%), vildagliptin (7%), were continued as background therapy. About 59.35% of subjects were on glimepiride 2 mg, 21.93% subjects on glimepiride 3 mg and 18.7% on glimepiride 4 mg. The gliclazide dose was up titrated by 30 mg every 15 days to achieve a target post-prandial glucose (PPG) ≤180 mg/dL. The average dose of gliclazide MR during the study was 44 mg; approximately two-thirds of patients 61% were on 60 mg, 22% on 90mg, and 7% on 30 mg. Patients were counselled to recognize the symptoms and record the hypoglycemic episodes. The statistical analysis included the analysis of changes in glycemic control, risk of hypoglycemia & renal function parameters. The patients were followed up for 24 weeks duration. Results: A total 218 eligible patients (110 female & 108 male) with CKD (stages 1–3) were included. The mean age, body weight, baseline HbA1c, FPG, PPG levels, mean eGFR, and UACR (urine albumin creatinine ratio) were 62.94 ± 8.72 years, 67.9 ± 9.33 kg, 8.51 ±0.81%, 148.53 ± 16.72, 202 ± 18.45 mg/dL, 50.49 ± 8.56 ml/min/1.73 m2 and 154.34 mg/g respectively. Gliclazide MR was initiated substituting glimepiride with appropriate dosing determined by the physician. Two subjects discontinued the therapy due to intolerability. At 24 weeks follow up, HbA1c, FPG, PPG level was reduced by -0.63, -10.33, -30.04%, respectively (p< 0.001). There was a significant reduction in events of overall hypoglycemia (22.25%). Improvement in renal function with respect to eGFR level (+1.77 ml/min/1.73 m2) and albuminuria reduction (-45.56 mg/g) were also observed in patients. Conclusion: This study demonstrates the clinical effectiveness and safety of gliclazide MR with the combination of DPP-4is like linagliptin as an alternate option to glimepiride in diabetes patients with chronic kidney disease.

Alleviation of cisplatin-induced hepatotoxicity by gliclazide: Involvement of oxidative stress and caspase-3 activity.

AimsCisplatin (CP), as an effective alkylating agent, is widely used in cancer treatment, while hepatotoxicity is one of its side effects. Gliclazide (GLZ), as an oral hypoglycemic drug, has antioxidant and anti‐inflammatory properties. This study was designed to investigate the protective effect of GLZ against CP‐induced hepatotoxicity in mice.MethodsIn this experimental study, 64 adult male mice randomly were allocated into eight groups (8 mice/group). Control, GLZ (5, 10, and 25 mg/kg, orally), CP (10 mg/kg, single dose, intraperitoneally), and CP+GLZ (in three doses). GLZ was administrated for 10 consecutive days. CP was injected on the 7th day of the study. At the end of the experiment, hepatotoxicity was evaluated by serum and tissue biochemical, histopathological, and immunohistochemical assessments.ResultsThe data were revealed that CP increased oxidative stress (increased MDA and reduced GSH), liver damage enzymes (ALT, AST, and ALP), and immunoreactivity of caspase‐3 in liver tissue of CP‐injected mice. Also, CP induced histopathological changes such as eosinophilic of hepatocytes, dilatation of sinusoids, congestion, and proliferation of Kupffer cells. GLZ administration significantly ameliorated serum functional enzyme and hepatic oxidative stress markers in CP‐injected mice. In addition, the histological and immunohistochemical alterations were ameliorated in GLZ‐treated mice. Of the three doses, 10 and 25 mg/kg were more effective.ConclusionsIn conclusion, GLZ with its antioxidant, anti‐inflammatory, and anti‐apoptotic activities, can be suggested as a promising drug in the treatment of CP‐induced hepatotoxicity.

Formulation, Pharmacokinetics evaluation, and IVIVC Assessment of Gliclazide Multiparticulates in Rat Model.

In vitro and in vivo studies of gliclazide (GLZ)-loaded freeze-dried alginate-gelatin (AL-GL) beads were carried out, aiming to modify its oral bioavailability. Crosslinked freeze-dried GLZ AL-GL beads (particle size: 1.5- and 3.0-mm) were prepared. In vitro evaluation of GLZ AL-GL beads included SEM, DSC, FT-IR, and release rate study in gradient media. In vivo study was single-dose (4 mg/kg), randomized, parallel-group design, two-treatment (T: test GLZ AL-GL beads and R: reference product Diamicron® 30-mg MR tablet) conducted in 96 healthy rats. Each group was subdivided into 2 sub-groups (G1 and G2) having different blood sampling schemes for up to 72 h. Assessment of level A in-vitro-in-vivo correlation (IVIVC) model was carried out. AL-GL beads successfully increased GLZ release rate compared to R. GLZ percent released (Q4h) was 109.34, 86.85, and 43.43% for 1.5-mm and 3.0-mm beads and R, respectively. DSC analysis confirmed the interaction of AL-GL via crosslinking. No chemical interaction of GLZ has occurred as proved by FT-IR. Relative bioavailability (T/R) for AUC0-∞ was 132.45% for G1 and 146.16% for G2. No significant differences between T and R in the primary pharmacokinetic parameters were determined. Tmax values were found to be earlier in the case of G1 than those of G2. A secondary absorption peak of GLZ was clearly detected in the case of R while its sharpness was minimized in T. High IVIVC was established, and hence, the proposed in vitro release model perfectly correlated with the in vivo study. The current study design might be a platform to enable panoramic view for GLZ variability in vivo.

Modulating Gliclazide Release and Bioavailability Utilizing Multiparticulate Drug Delivery Systems

To formulate multiparticulate controlled-release alginate-gelatin (AL-GL) beads in order to modify gliclazide (GLZ) release rate. AL-GL beads were prepared using different glutaraldehyde concentrations and dried using either air or freeze-drying method. For comparison, calcium alginate beads (AL-beads) were prepared at different temperatures. Drug incorporation efficiency, beads swelling%, drug release rate, and kinetics in gradient conditions (USP Apparatus-4) were studied. Selected AL-GL beads, as a test formulation (T), were in-vivo compared with Diamicron® 80 mg conventional tablet (R). AL-beads curing temperature was inversely proportional to GLZ incorporation efficiency and directly proportional to beads swelling%. GLZ release from AL-beads was slow in 0.1 N HCl and very fast in pH 7.4. In case of AL-GL beads, GLZ incorporation efficiency and swelling% were inversely proportional to glutaraldehyde concentration. AL-GL beads showed zero-order release of GLZ for up to 11 h. Scanning electron microscope (SEM) images of the freeze-dried beads showed a highly porous surface. Differential scanning calorimetry (DSC) and Fourier transform infra-red (FT-IR) studies indicated an interaction between alginate and gelatin due to crosslinking, while FT-IR indicated the absence of chemical interaction with GLZ. The relative bioavailability (T/R) was 97.57, 138.34, and 143.53%, for Cmax, AUC0–72, and AUC0–∞, respectively. Tmax of T was significantly higher than R. AL-GL beads could represent promising delivery systems for modulating GLZ release rate and minimizing the variation in its absorption.

PH-Sensitive Nanoparticles Developed and Optimized Using Factorial Design for Oral Delivery of Gliclazide

Background Gliclazide is an oral hypoglycaemic agent used for the treatment of non-insulin dependent diabetes mellitus T2DM. Gliclazide has low solubility in the stomach and poor oral absorption and bioavailability. The pH-dependent solubility of gliclazide influences the intra- and inter-subject variability.PurposeThe purpose of this study was to develop, optimize and evaluate pH-sensitive nanoparticles (NPs) based on Eudragit® S100 polymer for oral delivery of gliclazide (GLZ) in an attempt to improve its absorption and bioavailability and to reduce its intra- and inter-subject variability.MethodsNanoprecipitation technique was used for preparation of GLZ NPs. A 33 full factorial design was applied to study the effect of independent variables (polymer concentration, volume of the organic phase and stabilizer’s concentration) on the mean particle size, zeta potential and the incorporation efficiency of GLZ NPs. The developed optimal formulation was evaluated using various methods including X-ray diffraction (XRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM), drug dissolution and glucose stimulated insulin section test.ResultsThe analysis of the results revealed transformation of GLZ from crystalline to unstructured form and the absence of any chemical interactions between GLZ and the polymer. The in vitro drug release was dependent on the dissolution behaviour of the polymer. The glucose-stimulated insulin section test showed that incorporation of GLZ into NPs has potentiated its effect on insulin secretion in β cells in presence of 10 mM glucose.ConclusionOur study suggests that the optimized NPs have a potential to improve the oral absorption of GLZ.Graphical abstract

Novel Swellable/Expandable Gastroretentive Floating Films of Gliclazide Folded in Capsule Shell for the Effective Management of Diabetes Mellitus: Formulation Development, Optimization and In Vitro Evaluation

Background: Gliclazide (GLZ) belongs to the second-generation of sulphonylureas; it is a drug of choice for the management of type II DM. It belongs to BCS Class II. The major site of drug absorption for GLZ is the stomach; it displays variation in the drug absorption rate and bioavailability due to the shorter gastric retention time. The floating mechanism gets affected when the gastric fluid level is not sufficiently higher, which ultimately obstructs the floating behavior, which is the major limitation of reported formulations. This limitation can be overcome by folding the film into the capsule shell dissolved in the gastric fluid and the film swells/expands to dimensions higher than pylorus sphincter (12mm), thus preventing its evacuation. Objective: The study aims to explore the floating mechanism in the design of films along with a tendency to expand by swelling and unfolding by utilizing a mixture of hydrophilic and hydrophobic polymer to achieve the controlled drug delivery and prolonged gastric retention of drug. Methods: The gastroretentive floating films were formulated by the solvent casting technique using 32 full factorial designs and subjected to in vitro evaluation parameters, drug-excipient compatibility, Xray diffraction and accelerated stability study. Results: The pre-formulation study established the purity and identification of a drug. FTIR study confirmed no drug excipient interaction. F3, F6, and F9 were optimized based on in vitro floating characteristics, swelling/expanding ability, and unfolding time. All developed formulations were unfolded within 14-22 min after capsule disintegration. The F3 was selected as the final formulation as its ability to control the release of the drug for 24 hrs followed by zero-order kinetics having super case 2 transport. XRD confirmed the amorphousness of the drug within the formulation. The stability study results revealed that the formulation was quite stable at extreme storage conditions. Conclusion: The developed novel formulation has good potential for the effective management and treatment of diabetes mellitus.

Development and Validation of a Rapid Analytical Method for the Simultaneous Quantification of Metabolic Syndrome Drugs by HPLC-DAD Chromatography

Worldwide, 25% of the population suffers from metabolic syndrome (MetS). The treatment of patients with MetS regularly includes drugs prescribed simultaneously to treat several disorders that manifest at the same time, such as hypercholesterolemia, arterial hypertension, and diabetes. To the authors’ best knowledge, there is no previous published analytical method for the simultaneous quantification of drugs used in the treatment of these diseases. In the present study, a rapid high-performance liquid chromatography with a diode-array detector HPLC-DAD methodology was developed for simultaneous quantification of carvedilol (CVD), telmisartan (TEL), bezafibrate (BZT), gliclazide (GZD), and glimepiride (GMP) in bulk and pharmaceutical form. The chromatographic separation of the five pharmaceuticals was achieved on a Hypersil GOLD C18 Selectivity (5 µm, 150 × 4.60 mm2) using a mobile phase of acetonitrile (50%) and 0.02 M KH2PO4, pH 3 (50%) at a flow rate of 1 mL/min and at 25 °C. The total separation time was 9 min. The analytical method was validated following the International Conference on Harmonization guidelines. A reproducible method was obtained with acceptable limits of detection (LOD) and quantification (LOQ) for CVD (0.012 and 0.035 μg mL−1), TEL (0.103 and 0.313 μg mL−1), BZT (0.025 and 0.076 μg mL−1), GZD (0.039 and 0.117 μg mL−1), and GMP (0.064 and 0.127 μg mL−1). The validated method allowed the determination of these drugs in commercial pharmaceutical products both individually and simultaneously. The present method was found to be suitable for simultaneous quantification of the five drugs that are most commonly used in the simultaneous treatment of the metabolic syndrome.

Current data on the effectiveness of gliclazide and molecular mechanisms of action of the drug

With the growing prevalence of type 2 diabetes mellitus (T2DM) the possibility of treating it with available drugs is one of the main issues. Although glycemic control and reduction of micro- and macrovascular outcomes remain important aspects of treatment, the main limiting factors are the availability and cost of oral hypoglycemic agents. Although newer agents, such as sodium -glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists, potentially being valuable for patients with insulin resistance and cardiovascular complications, they are relatively expensive and have limited availability. Second-generation sulfonylureas effectively reduce glycated hemoglobin and contribute to the prevention of micro- and macrovascular complications of T2DM The review substantiates the role of Gliclazide MR as a more affordable drug for the treatment of T2DM, the safety of which has been confirmed by many studies; cardio-and nephroprotective effects are shown, as well as mechanisms for influencing в-cells of the pancreas and extrapancreatic effects through activation of phospholipase C and the G-protein-сoupled-receptors (GPCR) are analyzed. The latest data on the assessment of adverse events of Gliclazide MR are presented in comparison with both other sulfonylureas and glucose-lowering drugs of other classes.

Investigating the beneficial effect of aliskiren in attenuating neuropathic pain in diabetic Sprague-Dawley rats.

ObjectivesWorldwide, diabetic neuropathy (DN) is a major complication of diabetes mellitus. The direct renin inhibitor aliskiren is recognized as a treatment for cardiovascular disease in diabetic patients, but little is known about its potential benefits in cases of diabetic neuropathy. Accordingly, we investigated the effects of aliskiren (ALIS) and gliclazide (GLZ) and their combination therapy on peripheral neuropathy in streptozotocin‐induced diabetic rats.MethodsIn total, 112 adult Sprague‐Dawley rats were used for this study. Diabetes was induced using streptozotocin (STZ), whereas the control group was treated with an equal volume of citrate buffer. The diabetic rats were divided randomly into six groups according to the proposed treatment regime: diabetic control (DC), gliclazide (GLZ), aliskiren (ALIS), ramipril (RAM), (GLZ + ALIS) and (GLZ + RAM). Behavioural responses to thermal (hot‐plate) and mechanical (tail‐pinch) pain were evaluated. After eight weeks of daily treatments, the animals were fasted and sacrificed. The blood samples were collected, with the serum separated and subjected to various biochemical and enzyme analyses so as to assess the effect of the treatments on diabetic peripheral neuropathy.ResultsAfter 8 weeks, aliskiren alone and in combination with gliclazide therapy had a significant effect (P < .001) in reducing blood glucose levels and showed increased hot‐plate and tail‐flick latencies compared with the diabetic control group. The threshold of mechanical hyperalgesia was also significantly elevated (P < .001).Conclusions/InterpretationsThese data suggest that either aliskerin alone or in combination with gliclazide can protect against the development and progression of diabetic neuropathy.