Release Metformin Research Articles

Synthesis and Characterization of pH-Sensitive Genipin Cross-Linked Chitosan/Eudragit® L100 Hydrogel for Metformin Release Study Using Response Surface Methodology.

In this study, central composite design was utilized for the optimization of genipin cross-linked chitosan/Eudragit®-L 100 interpenetrating hydrogel network films fabricated through solvent evaporation technique. Hydrogel formulations were studied using response surface methodology; regression analysis and the surface plots were used to evaluate the effect of variables on T50% (the time for 50% of drug release) and dynamic swelling with optimum formulation selection. Initial burst release of drug was observed from the formulated hydrogels during the first 2 hours of dissolution at simulated gastric pH 1.2 and then slow release during the next 10 hours in the simulated intestinal fluid at pH 7.4. Different polymer ratios in formulation showed significant influence on T50% and dynamic swelling of hydrogel. The highest T50% was observed at 9.89 hour and dynamic swelling at 7.86 h. It was observed that by changing the polymer ratio with cross-linker, release rate of metformin could be modified. Cross-linker also affects drug release rate, i.e. the release rate is decreased with the increase in its concentration. The physical state of hydrogel was investigated by scanning electron microscope. It indicated the uniform distribution of drug in hydrogel matrix system. Moreover, the presence of hydrogen and ionic bonds between polymers and crosslinking agent formed interpenetrating hydrogel network, likely responsible for increased value of T50%, as confirmed by FTIR. Acute oral toxicity study was performed to investigate the toxic effect of crosslinking agent and polymer used in formulations.

Preparation and Evaluation of Natural Gum-Based Immediate Release Metformin Hydrochloride Tablet

Metformin hydrochloride is a first line BCS class III oral anti-diabetic drug used for the treatment of type 2 diabetes. The main goal of this study was to formulate, prepare and evaluate natural gum-based immediate release metformin hydrochloride tablet. Seven different formulations of compressed tablets were prepared following wet granulation process using different concentrations (10, 20, 30, 50, 60, 70, 80 and 90 mg) of Aegle marmelos gum as a binder. Aegle marmelos gum is a biodegradable natural gum which is economic, easily available and found useful as tablet binder for both conventional and novel dosage forms. Other excipients used in the formulation were microcrystalline cellulose (MCC), croscarmellose sodium (CCS), maize starch, colloidal silicon dioxide (CSD), sodium starch glycolate (SSG), magnesium stearate etc. In the present study, the compressed tablets were evaluated for weight variation, thickness, hardness, friability, disintegration time and dissolution. In vitro drug release study was carried out in phosphate buffer (pH 6.8) at 37 ± 0.5oC with 50 rpm using USP Dissolution Apparatus 2-Paddle method. The flowability of granules for all the batches was optimum which reflected in the bulk density and angle of repose. It can be concluded from this study that combination of Aegle marmelos as a binder with other excipients can be prospectively used in the preparation of metformin hydrochloride immediate release (IR) tablet.Bangladesh Pharmaceutical Journal 21(2): 101-108, 2018

Metformin-Loaded Hyaluronic Acid Nanostructure for Oral Delivery.

The objective of this study was to develop a nanodelivery system containing a mucoadhesive polymer hyaluronic acid (HA) for oral delivery. Metformin was used as a model drug. Blank and drug-loaded HA nanostructures were prepared by precipitation method and characterized for particle size (PS), zeta potential (ZP), physical stability (over 65days), surface morphology, moisture content, and physical state of the drug in the nanostructures. The cytotoxicity and hemolysis potential of the delivery system was assessed in Caco-2 cells and whole human blood, respectively. The in vitro release of metformin and its uptake in Caco-2 cells was evaluated using high-performance liquid chromatography. Ex vivo permeability of metformin was measured through goat intestinal membrane. The nanoparticles were physically stable and neutrally charged with an average PS of 114.53 ± 12.01nm. This nanodelivery system existed as nanofibers containing metformin in a crystalline state. This delivery system released the drug rapidly with > 50% of metformin released within 1h. Cellular uptake studies on Caco-2 cells indicated higher uptake of metformin from nanoparticle as compared to metformin in solution, up to first 45min. Ex vivo permeability studies on the other hand showed a higher metformin permeability from solution relative to that from nanoparticles through the goat intestinal membrane. Metformin nanoparticles were non-toxic at therapeutic concentrations in Caco-2 cells and showed no hemolytic effect to RBCs. This study indicates the preparation, characterization, as well as the potential use of HA nanostructures for oral delivery.

Fabrication of Dissolving Microneedles with Thermal-Responsive Coating for NIR-Triggered Transdermal Delivery of Metformin on Diabetic Rats.

This study described near-infrared (NIR) light-responsive polymer-nanodot composite microneedles (MNs) used for on-demand transdermal drug delivery. Bismuth (Bi) nanodots stabilized by poly(vinylpyrrolidone) (PVP) as a photothermal conversion agent and metformin as an antidiabetic drug were introduced into the dissolving MNs coated with lauric acid (LA). When the MNs were irradiated with NIR light, light-to-heat transduction induced by the Bi nanodots caused the LA to melt. As a result, the polymer matrix was dissolved after absorbing the interstitial fluid, enabling the encapsulated metformin release from the MNs into skin tissue. Compared with subcutaneous injection of metformin, the administration using the Bi nanodots-induced NIR responsive MNs developed in the current research exhibited a remarkable hypoglycemic effect in vivo. This work indicates that the as-fabricated Bi nanodot-induced NIR responsive and LA-coated MNs have potential applications in diabetes treatment. Additionally, these artificial MNs also present a promising platform for delivering other therapeutic drugs.

DESIGN AND CHARACTERIZATION OF SUSTAINED RELEASE MATRIX TABLETS OF METFORMIN HYDROCHLORIDE USING COMBINATION OF HYDROPHILIC POLYMERS

Sustained release system is types of modified drug delivery system that can be used as an alternative to conventional system. Among different dosage forms, matrix tablets are widely accepted for oral sustained release Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. They are capable of reducing the dose intake, minimize the blood level oscillation dose related adverse effect and cost thus improves the patient compliance in the therapeutic management of diabetes. The Metformin hydrochloride matrix Sustained release tablets were prepared using different hydrophilic polymers in various proportions as release retarding agent to prolong the drug release and to improve the patience compliance. The tablets were evaluated for various tests like hardness, friability, disintegration and in-vitro dissolution studies. Keywords : Matrix Tablets, Metformin hydrochloride, Hardness, Friability, Disintegration and in-vitro dissolution studies

Development of an Injectable Slow-Release Metformin Formulation and Evaluation of Its Potential Antitumor Effects

Metformin is an antidiabetic drug which possesses antiproliferative activity in cancer cells when administered at high doses, due to its unfavorable pharmacokinetics. The aim of this work was to develop a pharmacological tool for the release of metformin in proximity of the tumor, allowing high local concentrations, and to demonstrate the in vivo antitumor efficacy after a prolonged metformin exposition. A 1.2% w/w metformin thermoresponsive parenteral formulation based on poloxamers P407 and P124, injectable at room temperature and undergoing a sol-gel transition at body temperature, has been developed and optimized for rheological, thermal and release control properties; the formulation is easily scalable, and proved to be stable during a 1-month storage at 5 °C. Using NOD/SCID mice pseudo-orthotopically grafted with MDA-MB-231/luc+ human breast cancer cells, we report that multiple administrations of 100 mg of the optimized metformin formulation close to the tumor site cause tissue accumulation of the drug at levels significantly higher than those observed in plasma, and enough to exert antiproliferative and pro-apoptotic activities. Our results demonstrate that this formulation is endowed with good stability, tolerability, thermal and rheological properties, representing a novel tool to be pursued in further investigations for adjuvant cancer treatment.

Characterization of poly-d-mannuronate and poly-l-guluronate block fractions from sodium alginate and preparation of hydrogels with poly(vinylalcohol)

Sodium salts of homopoly-d-mannuronic acid (MM) and of homopoly-l-guluronic acid (GG) from sodium alginates were characterized by NMR relaxometry. Determination of NMR spin-lattice and spin-spin relaxation times of water proton in homopolymeric block solutions and hydrogels indicated differences in homopolymeric blocks tertiary structure. Hydrogels of MM or GG blocks and poly(vinyl alcohol) (PVA) were prepared by freeze-thawing cycles method; their swelling properties and sensitivity to pH stimuli were assayed in control delivery of a model drug. MM/PVA hydrogels show better metformin release characteristics than GG/PVA hydrogels. It was found that release of the drug at pH 1.2 from hydrogels was minor to 5%. At the release equilibrium, 60 and 55% of the drug encapsulated were release from MM/PVA and GG/PVA hydrogels, respectively. Also, the release of metformin from hydrogels was studied by 1H NMR spectroscopy showing that 40 and 36% of drug were released after 4 h from MM/PVA and GG/PVA hydrogels, respectively.

Pharmacokinetic Equivalence of the High Dose Strength Fixed-Dose Combination Tablet of Gemigliptin/Metformin Sustained Release (SR) and Individual Component Gemigliptin and Metformin XR Tablets in Healthy Subjects.

BackgroundIn type 2 diabetes mellitus therapy, fixed-dose combination (FDC) can offer not only benefits in glucose control via the combined use of agents, but also increase patient compliance. The aim of this study was to assess the pharmacokinetic equivalence of the high dose of the FDC tablet (gemigliptin/metformin sustained release [SR] 50/1,000 mg) and a corresponding co-administered dose of individual tablets.MethodsThis study was randomized, open-label, single dose, two treatments, two-period, crossover study, which included 24 healthy subjects. Subjects received the FDC or individual tablets of gemigliptin (50 mg) and metformin XR (1,000 mg) in each period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) of the FDC tablet and co-administration of individual tablet for both gemigliptin and metformin were calculated.ResultsThe GMRs (FDC tablets/co-administration; 90% CIs) for Cmax and AUClast of gemigliptin were 1.079 (0.986–1.180) and 1.047 (1.014–1.080), respectively. For metformin, the GMRs for Cmax, and AUClast were 1.038 (0.995–1.083) and 1.041 (0.997–1.088), respectively. The 90% CIs for GMRs of Cmax and AUClast for gemigliptin and metformin fell entirely within bounds of 0.800–1.250. Both administration of FDC tablet and co-administration of individual tablets were well tolerated.ConclusionFDC tablet exhibited pharmacokinetic equivalence and comparable safety and tolerability to co-administration of corresponding doses of gemigliptin and metformin XR as individual tablets.Trial RegistrationClinicalTrials.gov Identifier: NCT02056600

Biorelevant drug release of Metformin dosage forms using complementary in vitro tools

Drug release from immediate release (IR) and extended release (ER) metformin products was investigated using the Dow Chemical Company’s FloVitroTM biorelevant dissolution instrument. This was complemented by using the Sirius SDi2 (Surface Dissolution Imaging) platform to investigate mechanistic differences accounting for drug release. Level A IVIVC was demonstrated for metformin IR dosage forms, using FloVitroTM, whilst ER tablets demonstrated lower Cmax and Tmax using the same method. The SDi2 showed disintegration as the main release mechanism for IR tablets, whilst swelling and drug diffusion was observed for ER tablets. FloVitroTM and SDi2 technologies can be used to compare behaviour of formulations during dosage form selection

Sugar-Coated Nanobullet: Growth Inhibition of Cancer Cells Induced by Metformin-Loaded Glyconanoparticles.

Metformin, a widely used drug for treating type-2 diabetes, has now been discovered to reduce cancer cell proliferation. However, further efforts are needed to design effective metformin delivery vehicles, instead of bare metformin. Herein we report a highly efficient transport nanostructure based on core-shell glyconanoparticles (GNPs), with gold as the core and dextran as the shell interspersed with metformin molecules. The dextran shell facilitates the entry of GNPs into living cells, which allows the subsequent release of metformin. Using MCF-7 breast cancer cells as an example, significant cell growth inhibition was observed after treatment of metformin-containing GNPs (MGNPs). Compared with bare metformin or bare GNPs, MGNPs show a stronger capacity for cell growth inhibition with good biocompatibility. Furthermore, inactivation of mitochondria and activation of p53 protein are observed during MGNP treatment, which provides evidence for metformin-induced cell apoptosis pathways. This work provides a new therapeutic tool for the treatment of cancer.

Evaluation of two novel plant gums for bioadhesive microsphere and sustained-release formulations of metformin hydrochloride.

The biological half life of metformin requires multiple doses which are associated with poor patient compliance. This justifies the need for a dosage form with reduced dosing frequency. Gums from Enterolobium cyclocarpum and Cedrela odorata trees were evaluated in formulating bioadhesive microspheres containing metformin hydrochloride, for sustained drug release. Hydroxylpropylmethyl cellulose (HPMC) was the standard. Microspheres were produced from formulations of API and either cedrela gum (FC), enterolobium gum (FE) or HPMC (FH), using a W/O solvent extraction technique. The microspheres were characterized using a particle size analyzer, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffractometer (PXRD), drug entrapment, in vitro release and mucoadhesion studies. The data was analyzed using ANOVA and t-test at p = 0.05. FT-IR spectroscopy indicated no alteration in the functional groups of metformin. A yield of 92-98% microspheres was obtained from all the formulations which had a particle size range of 72-84 μm. SEM revealed cylindrical to near-spherical particles with rough surfaces. The drug release profile showed a burst over the first 30 min followed by a steady release for about 5 h and a slow release for 5 days. Formulations containing the gums sustained the release of API for almost the same time as HPMC formulations; the ranking order was FE > FH > FC (p > 0.05). All the formulations exhibited good concentration-dependent mucoadhesive properties. The gums were suitable for formulation of mucoadhesive microspheres for sustained release of metformin. The formulations showed good release properties in an alkaline pH.

Bioequivalence of the Highest Dose Strength Fixed-Dose Combination Tablet Of Gemigliptin/Metformin Sustained Release (SR) and Individual Component Gemigliptin and Metformin XR Tablets in Healthy Subjects

Bioequivalence of the Highest Dose Strength Fixed-Dose Combination Tablet Of Gemigliptin/Metformin Sustained Release (SR) and Individual Component Gemigliptin and Metformin XR Tablets in Healthy Subjects

Diabetes medication pharmacology

Diabetes medication pharmacology

Controlled release of metformin from chitosan–based nanocomposite films containing mesoporous MCM-41 nanoparticles as novel drug delivery systems

Biocompatible nanocomposite films based on blended chitosan and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (BP) polymers containing metformin (MET) drug and MCM-41 or MCM-41-APS (APS=aminopropylsilane) nanoparticles (NPs) were designed and fabricated in order to prepare novel drug delivery systems which are useful for controlled drug release purposes. The total pore volume and mesopore volume of MCM-41 were measured equal to 1.08 and 1.05 cm3/g but those of MCM-41-APS were 0.54 and 0.26 cm3/g indicating smaller values for the APS functionalized material. The film thickness was the highest for CS-BP-G-10%MET (70μm) but it was the smallest for the CS-BP-G-4%MCM-41 (49μm). For all of the films, the swelling percent was the highest in acidic medium but it was decreased in PBS and the least water uptake occurred in the alkaline environment. The lowest and the highest water uptake was observed for the films incorporated with 4%MCM-41NPs and 4%MCM-41-APS-10%MET, respectively. The SEM micrographs of the films after three days water uptake in pH=4 medium exhibited that all of the films were stable against cracking and/or tearing. It was found that increasing the MCM-41 or MCM-41-APS amount within the films decreased the elongation at break but enhanced the tensile stress. The release of the MET was sharply increased within ∼22–24h (burst release) but after that the drug release was slowly enhanced during 15days (sustained release). Finally, it was concluded that the film 4% MCM-41-APS-10%MET NPs was the most promising drug delivery system because it had improved hydrophilicity, hydrolytic stability, biocompatibility, mechanical and drug release properties.

DESIGN AND INVITRO CHARACTERIZATION OF METFORMIN LOADED RESEALED ERYTHROCYTES

Objective: Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes. The objective of the present study was to retard the release of metformin using carrier erythrocyte for getting a parenteral slow release depot formulation.Methods: The study retards the release of metformin by encapsulating in carier erythrocyte. Endocytosis is the method used for the encapsulation of the drug metormin.Results: The optimized formulation shows 98.34% of drug release within 12 days. From the invitro release data zero order kinetic graph shows the best fit graph. % cell recovered was found to be 73-78% and it suggests that the loading technique was less destructive.Conclusion: The optimized formulation is a perfect carrier for the parenteral slow release depot of metformin.Keywords: Resealed erythrocytes, cross linking, cell recovery, endocytosis, slow release depot formulation

Slow Release Metformin Effect in Weight Loss and Total Calorie Intake in Obese Volunteers

Obesity can cause serious problems that will lead to poor quality of life, increased morbidity and mortality rate. Slow-release metformin will work longer in the body with a single dose everyday be an alternative drug for weight loss. The purpose of this study was to compare the effectiveness of slow-release metformin compared to metformin regular to body weight and calorie intake in volunteers with obesity. The study was conducted on 16 volunteers who were divided into two groups in pairs. Volunteers will be measured weight and calorie intake with a 24-hour food recall method, data was taken at the time before the intervention, the end of week 1st, 2nd, 3rd, and 4th. The result obtained weight loss better in the group receiving slow-release metformin by 5.08% compared to the group receiving regular metformin by 2,60%, but there was no significant difference between the groups in terms of calorie intake during the study. The conclusion of this study is a slow-release metformin is greater in weight loss than regular metformin, but does not affect the amount of calorie intake.Keywords: Metformin, slow-release, weight loss, calorie intake, obesity

In vitro dissolution studies on commercial brands containing immediate release pioglitazone and metformin hydrochloride extended release tablets

<i>In vitro</i> dissolution studies on commercial brands containing immediate release pioglitazone and metformin hydrochloride extended release tablets

Effect of Metformin-sustained Release Therapy on Low-density Lipoprotein Size and Adiponectin in the South Indian Women with Polycystic Ovary Syndrome.

Objectives:The aim of the study is to compare surrogate markers of cardiovascular disease (CVD) risk, such as adiponectin (APN) levels and low-density lipoprotein (LDL) size, before and after sustained release metformin (Met-SR) therapy in women with polycystic ovarian syndrome (PCOS).Methods:Sixty women with PCOS and sixty age-matched controls in the age group 18–45 years were recruited after obtaining informed consent. Women with PCOS were initiated on Met-SR 1 g orally, which was increased to 1.5 g after 2 weeks and continued up to 24 weeks. Demographic data along with family history of type 2 diabetes mellitus, PCOS, and CVD were collected. Lipid profile plasma APN levels and LDL size were measured before and after therapy in the PCOS group. Data analysis was performed using the GraphPad Prism-5 software.Results:Women with PCOS had greater dyslipidemia, lower APN level and LDL size, and increased lipid accumulating product index as compared to controls. After 6 months of Met-SR therapy, women with PCOS demonstrated significant increase in plasma APN levels and LDL size and significant decrease in weight, waist-hip ratio (WHR), waist circumference (WC), and blood pressure (BP). A significant decrease was observed in body mass index (BMI) in the overweight and obese PCOS subgroups.Conclusion:Met-SR increases LDL size, APN concentration and decreases weight, WC, WHR, and BP in patients with PCOS. Met-SR may have salutary effects on LDL particle size through effects on APN levels in women with PCOS.

Study on release of naproxen and metformin encapsulated in biopolymer-inorganic mesoporous matrices as controlled drug-delivery systems

In this study, a new methodology was applied for controlling the release of different drugs by encapsulating them in organic-inorganic hybrids via sol-gel technique. The assembled organic-inorganic hybrids had diverse BET surface area, porosity, and high heat resistance. The synthesized organic-inorganic hybrids were based on zirconium(IV) propoxide, and tetraethyl orthosilicate as precursor of inorganic network, and chitosan or N-triethylchitosan as organic or biopolymer components. In these hybrid composites, drug and biopolymer were coated with a mesoporous inorganic material. FT-IR, FE-SEM, DSC, BET, XRD techniques, and Zeta potential analysis used for investigating the formation of metformin/chitosan@ZrO2 and sodium naproxen/N-triethylchitosan@SiO2 hybrid composites. Then for investigating the role of sol-gel process, the release of metformin and sodium naproxen in the prepared hybrid composites was investigated as model drugs. Compare to drug/biopolymer composite, incorporation of ZrO2 or SiO2 coating enhanced the drug entrapment appreciably, and naturally reduced the rate of drug release. For example, the metformin/chitosan composite without ZrO2 coating released the whole drug in less than10 h in pH 7.4 when the composite coated with ZrO2 released the entrapped drug after 25 h.

Studies on Formulation and Evaluation of Ethyl Cellulose Based Extended Release Metformin Hydrochloride Matrix Tablets

Monolithic matrix tablets of metformin hydrochloride were formulated as extended release tablets by employing ethyl cellulose polymer and the extended release characterization of the formulated tablets was investigated. Extended release matrix tablets containing 500 mg metformin hydrochloride were developed by changing concentration of drug : polymer (EC) in the ratio of 5:1, 5:2, 5:3 and 5:4 by direct compression. Formulations were optimized based on the acceptable tablet properties invitro and invivo drug release. The resulting formulations produced robust tablets with optimum hardness, weight variation, drug content and low friability. The result of invitro and invivo drug release studies indicated that formulation (drug:polymer =5:3), is the most successful of the study and exhibited constant and extended release of metformin hydrochloride 99-100.5% release at the end of 10 h compared with reference standard. Further, the formulation F3 was subjected to exposure at room and accelerated condition to stability studies. A decrease in release of the drug was observed on increasing polymer ratio at certain level. Before tablet compression, the resulting formulation blends were evaluated for angle of repose, bulk density, % porosity, % compressibility index and drug polymer compatibility study of drug and excipients. The t25, t50 and t90 drug release values was calculated from selected formulation F3 on every month of stability studies and comparision of both room and accelerated condition by statistical t-test, there is no difference between storage temperature. The formulation F3 was showed similar invitro and invivo drug release when compared to marketed sustained release tablet (F5M).