Effect of berberine on in vitro metabolism of sulfonylureas: A herb-drug interactions study.

Patients with type 2 diabetes may co-ingest herbal and prescription medicines to control their blood sugar levels. Competitive binding of drug and herb may mutually affect their metabolism. This can alter the level of drug and its kinetics in the body, potentially causing toxicities or loss of efficacy. Understanding how the metabolism of sulfonylureas like glyburide and gliclazide can be affected by the presence of berberine and vice versa can provide valuable information on the possible risk of toxicities caused by co-ingestion of drugs. METHODS: Berberine and sulfonylureas (glyburide and gliclazide) were co-incubated with rat liver microsomes in the presence of a NADPH-regenerating system. The metabolites of berberine and sulfonylureas were analysed using liquid chromatography with high-resolution mass spectrometry in the positive ion mode. The role of individual isozymes in the metabolism of berberine, glyburide and gliclazide was investigated by using specific inhibitors. RESULTS: In vitro metabolism of berberine led to the formation of demethyleneberberine (B1a) and its isomer B1b through demethylenation. Berberrubine (B2a) and its isomer B2b were formed through demethylation. The isozymes CYP3A and CYP2D were found to be involved in the metabolism of berberine. In vitro metabolism of glyburide and gliclazide led to the formation of hydroxylated metabolites. The isozymes CYP3A and CYP2C were found to be involved in the metabolism of glyburide. Gliclazide was metabolised by CYP2C. In vitro co-incubation of glyburide or gliclazide with berberine showed that each drug's metabolism was compromised as they share a common isozyme. A strong negative linear correlation of glyburide or gliclazide metabolite levels and the concentration of berberine confirmed the effect of berberine on the metabolism of sulfonylureas. CONCLUSIONS: The metabolism of sulfonylureas and berberine was affected when these compounds were co-incubated with each other. This may be attributable to competitive binding of the herb and drug to the catalytic sites of the same isozymes.

Updates on Managing Type 2 Diabetes Mellitus with Natural Products: Towards Antidiabetic Drug Development.

Over the years, natural products have shown success as antidiabetics in in vitro, in vivo studies and clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs, and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

Characterization of gliclazide release from Isabgol husk hydrogel beads by validated HPLC method.

Isabgol husk, a medicinally important natural polysaccharide was applied for fabrication of hydrogel beads by ionic gelation method to incorporate gliclazide. Different strengths of Isabgol husk and sodium alginate were utilized for assessing the process variables on formulation performance. Aqueous solution of calcium chloride in 2, 5 and 8% w/v strength was used as cross-linker for polymeric blends of Isabgol husk and sodium alginate. The formulations were characterized for various parameters such as particle size, swelling index, entrapment efficiency, in vitro release, and release kinetics. The quantification of gliclazide throughout the study was performed by HPLC method which was validated according to ICH guidelines for system suitability, linearity, accuracy, sensitivity, precession, robustness, and ruggedness. The surface morphology of beads was observed by scanning electron microscopy. The formed beads were brown, free flowing, spherical, and irregular in structure. The size in different formulations varied from 752.83 +/- 0.630 to 838.62 +/- 0.741 microm. The beads remained for 2-3 h in alkaline phosphate buffer (pH 7.4), after that they showed disintegration. The formulations released up to 95% of loaded gliclazide in phosphate buffer (pH 7.4) within 8 h. No significant difference was observed in parameters studied such as particle size, entrapment efficiency and swelling index for hydrogel beads during accelerated stability study (p > 0.05). The regression equation developed by HPLC method was linear (r5 > 0.9990) over the range 2.5 to 10 microg/mL. The limit of detection (LOD) and limit of quantification (LOQ) were 0.037619 microg/mL and 0.113997 microg/mL, respectively. The observed values for number of theoretical plates (N > or = 2000), tailing factor (T < or = 2), asymmetry factor (AF < or = 1), and relative standard deviation (RSD < or = 1%) of applied method showed the reliability for gliclazide estimation in Isabgol husk hydrogel beads.

Gastrointestinal transition and anti-diabetic effect of Isabgol husk microparticles containing gliclazide.

Isabgol husk with sodium alginate was formulated into gliclazide loaded microparticles which were characterized for particle size, swelling index, entrapment efficiency, in vitro release, release kinetics, stability, hypoglycemic effect, surface morphology, and gastrointestinal transition. The particle size in different formulations varied from 752.83 ± 0.630 to 872.03 ± 0.293 µm. It was analyzed by dissolution study that up to 98% of loaded gliclazide was released in simulated intestinal fluid (SIF, pH 7.4) within 8h. The formulations containing sodium alginate and Isabgol husk-sodium alginate showed bioequivalency with marketed sustained release tablets (Glizid MR 60(®)) in terms of release pattern. The drug maintained its integrity in terms of functional groups after fabrication in formulations as observed by FTIR analysis. The hypoglycemic effect of gliclazide loaded Isabgol husk-sodium alginate microparticles was found to be 37 ± 6.356% in terms of changes of blood glucose level from base glucose level (100%) in diabetic condition after 24h of oral administration and it was more than marketed conventional tablets (95.5 ± 3.286%). The retention of microparticles was observed in small intestine up to 10h during whole body X-ray imaging. The study revealed that microparticles composing of Isabgol husk may have the potential for regulating blood glucose level in diabetic animals with controlled release of gliclazide.

Development of novel gastroretentive drug delivery system of gliclazide: hollow beads.

AIM: The current communication deals with the development of hollow floating beads of gliclazide. The primary effect of this drug is to potentiate glucose-stimulated insulin release from pancreatic islet-ß-cells by induction of a decrease in potassium efflux from these cells. Because of the poor aqueous solubility, its absorption is limited. Thus, an attempt was made to improve its release profile. METHODS: The hollow drug-loaded alginate beads in combination with low methoxyl pectin and hydroxypropylmethylcellulose (HPMC) were prepared by a simple ionotropic gelation method. The beads were evaluated for particle size and morphology using optical microscopy and scanning electron microscopy (SEM), respectively. Mucoadhesion test was done using goat stomach mucosal membrane. Release characteristics of the gliclazide-loaded hollow beads were studied in 0.1 N HCl (pH 1.2) and phosphate buffer (pH 5.8). RESULTS: The developed beads were spherical in shape with hollow internal structure and had a particle size in the range of 0.730 ± 0.05 to 0.890 ± 0.03 mm. The incorporation efficiency of alginate -pectin beads was higher than alginate -HPMC beads. The Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction analysis showed stable character of drug in the drug-loaded hollow beads and revealed the absence of any drug -polymer interactions. The beads remained buoyant for more than 12 h. The drug release from beads followed Fickian diffusion with swelling. CONCLUSION: The preliminary results of this study suggest that the developed beads containing gliclazide could enhance drug entrapment efficiency, reduce the initial burst release and modulate the drug release.

Development of novel gastroretentive floating particulate drug delivery system of gliclazide.

The objective of present project was to improve the dissolution profile of gliclazide by developing floating alginate beads using various biodegradable polymers like gelatin, pectin and hydroxypropylmethylcellulose (HPMC). The floating beads were prepared by a simple ionotropic gelatin method using calcium carbonate as gas generating agent. The developed beads were characterized by Fourier transform infrared spectroscopy analysis, differential scanning calorimetry, X-ray diffraction analysis and scanning electron microscopy (SEM). The prepared beads showed good in vitro floatation, which was dependent on the concentration of gas-forming agent. SEM photomicrographs confirmed that the developed beads were spherical in shape and had particle size in the range of 730 to 890 µm. The incorporation efficiency was found to be in the range of 59.96 to 85.1%. The cumulative percent drug release from the beads after 10 h dissolution study at pH 1.2 and pH 5.8 was in the range of 33 to 46% and 82 to 95% respectively. The concentration of the gas generating agent was found to influence the release rate. The mechanism of drug release was Fickian diffusion with swelling. The in vivo sub-acute hypoglycemic study in high fat diet induced diabetic C57BL/6J mice demonstrated significant (p < 0.05) hypoglycemic effect over a period of 12 h and 24 h, respectively, with HPMC and pectin beads. A significant (p & 0.05) reduction in fasting and non-fasting blood glucose levels, reduction in fasting plasma insulin level and a significant improvement in glucose tolerance were observed in animals treated with formulations. The developed beads were suitable carriers for improving the systemic absorption of gliclazide and maintaining reduced blood glucose levels.

Formulation and evaluation of Ficus glomerata mucilage sustained release matrix tablets of gliclazide.

The main aim of present investigation was to develop sustained release matrix tablets of Gliclazide using fruit mucilage from the plant Ficus glomerata. Varying ratios of drug and polymer viz. 1:0.25, 1:0.5, 1:0.75, 1:1.0 and 1:1.25 were selected for the study. The flow properties of powdered mucilage and physical properties of matrix tablets were performed. The swelling behavior and release rate characteristics were studied. The in vitro drug release data was analyzed by zero order, first order, Higuchi plot, Peppas plot and Hixon-Crowell Models. It was observed that as the proportion of mucilage increased the release of drug from the matrix tablets was retarded. Stability studies were conducted at 40±2ºC and RH 75±5% for 3 months indicates that Gliclazide was stable in the matrix tablets. The Differential Scanning Calorimetric (DSC) and Fourier Transform Infrared (FTIR) study revealed that there was no negative chemical interaction between drug and the mucilage used. From the dissolution study, it was concluded that dried Ficus glomerata mucilage can be used as an excipient for making sustained release matrix tablets.

Design and development of gliclazide-loaded chitosan microparticles for oral sustained drug delivery: in-vitro/in-vivo evaluation.

OBJECTIVES: The objective of this study was to prepare gliclazide-chitosan microparticles with tripolyphosphate by ionic crosslinking. METHODS: Chitosan microparticles were produced by emulsification and ionotropic gelation. The effects of process variables including chitosan concentration, pH of tripolyphosphate solution, glutaraldehyde volume and release modifier agent such as pectin added to the tripolyphosphate crosslinking solution were evaluated. The microparticles were examined with scanning electron microscopy, infrared spectroscopy and differential scanning colorimetry. The serum glucose lowering effect of gliclazide microparticles was studied in streptozotocin-diabetic rabbits compared with the effect of pure gliclazide powder and gliclazide commercial tablets. KEY FINDINGS: The particle sizes of tripolyphosphate-chitosan microparticles were over the range 675-887 µm and the loading efficiency of drug was greater than 94.0%. In-vivo testing of the gliclazide-chitosan microparticles in diabetic rabbits demonstrated a significant antidiabetic effect of gliclazide-chitosan microparticles after 8 h that lasted for 18 h compared with gliclazide powder, which produced a maximum hypoglycaemic effect after 4 h. CONCLUSIONS: The results suggests that gliclazide-chitosan microparticles are a valuable system for the sustained delivery of gliclazide.

Design and development of gliclazide mucoadhesive microcapsules: in vitro and in vivo evaluation.

In this study an attempt was made to prepare mucoadhesive microcapsules of gliclazide using various mucoadhesive polymers designed for oral controlled release. Gliclazide microcapsules were prepared using sodium alginate and mucoadhesive polymer such as sodium carboxymethyl cellulose (sodium CMC), carbopol 934P or hydroxy propylmethyl cellulose (HPMC) by orifice-ionic gelation method. The microcapsules were evaluated for surface morphology and particle shape by scanning electron microscope. Microcapsules were also evaluated for their microencapsulation efficiency, in vitro wash-off mucoadhesion test, in vitro drug release and in vivo study. The microcapsules were discrete, spherical and free flowing. The microencapsulation efficiency was in the range of 65-80% and microcapsules exhibited good mucoadhesive property in the in vitro wash off test. The percentage of microcapsules adhering to tissue at pH 7.4 after 6 h varied from 12-32%, whereas the percentage of microcapsules adhering to tissue at pH 1.2 after 6 h varied from 35-68%. The drug release was also found to be slow and extended for more than 16 h. In vivo testing of the mucoadhesive microcapsules in diabetic albino rats demonstrated significant antidiabetic effect of gliclazide. The hypoglycemic effect obtained by mucoadhesive microcapsules was for more than 16 h whereas gliclazide produced an antidiabetic effect for only 10 h suggesting that mucoadhesive microcapsules are a valuable system for the long term delivery of gliclazide.

Preparation and in vitro/in vivo evaluation of gliclazide loaded Eudragit nanoparticles as a sustained release carriers.

The aim of this study was to formulate and optimize gliclazide-loaded Eudragit nanoparticles (Eudragit L100 and Eudragit RS) as a sustained release carrier with enhanced efficacy. Eudragit L 100 nanoparticles (ELNP) were prepared by controlled precipitation method whereas Eudragit RSPO nanoparticles (ERSNP) were prepared by solvent evaporation method. The influence of various formulation factors (stirring speed, drug:polymer ratio, homogenization, and addition of surfactants) on particle size, drug loading, and encapsulation efficiency were investigated. The developed Eudragit nanoparticles (L100 and RS) showed high drug loading and encapsulation efficiencies with nanosize. Mean particle size altered by changing the drug:polymer ratio and stirring speed. Addition of surfactants showed a promise to increase drug loading, encapsulation efficiency, and decreased particle size of ELNP as well as ERSNP. Dissolution study revealed sustained release of gliclazide from Eudragit L100 as well as Eudragit RSPO NP. SEM study revealed spherical morphology of the developed Eudragit (L100 and RS) NP. FT-IR and DSC studies showed no interaction of gliclazide with polymers. Stability studies revealed that the gliclazide-loaded nanoparticles were stable at the end of 6 months. Developed Eudragit NPs revealed a decreased t(min) (ELNP), and enhanced bioavailability and sustained activity (ELNP and ERSNP) and hence superior activity as compared to plain gliclazide in streptozotocin induced diabetic rat model and glucose-loaded diabetic rat model. The developed Eudragit (L100 and RSPO) NP could reduce dose frequency, decrease side effects, and improve patient compliance.

[Effect of oral antidiabetic agents on fructose biosynthesis]. / Viianie protivodiabeticheskikh sredtstv dlia priema vnutr' na obrazovanie fruktozamina.

The oral antidiabetic drugs (glyformin, glyclaside, glycvidon, glybenclamide) at a concentration of 10-196 mM affect the synthesis of fructosamine in an incubation medium containing 40 mM of glucose and 5% of human serum albumin. All these drugs decrease the fructosamine yield measured in the medium on the 4th day of incubation at 37-198 degrees C, while the effect of glycvidon is pronounced even on the 7th day. The introduction of glyformin, glycvidon, and glybenclamide at an amount close to the maximum daily dose over a period of one month reduces the level of fructosamine in the blood of rats with experimental diabetes mellitus, while not affecting the level of glucose in the blood of test animals. Thus, the oral antidiabetic drugs reduce the level of fructosamine--an agent known to modify the protein structure, thus favoring the development of complications in the course of diabetes under permanent hyperglycemia conditions.