Pioglitazone HCl Research Articles

Development and characterization of pioglitazone loaded liposphere for the effective treatment of diabetes mellitus type 2

Lipospheres which represent novel drug delivery vehicles are water-insoluble lipid spheres forming a solid hydrophobic core, with a layer of phospholipids embedded on the surface of the core. Drugs or other biologically active agents may be contained in the hydrophobic core, adhered to the phospholipids, or a combination thereof. Lipid based carrier system (lipospheres) was adopted to eliminate the toxic effects associated with the use of polymers as carrier and entrapment of high amount of poorly bioavailable lipophilic compound. Due to its poor aqueous solubility of Pioglitazone HCl, was selected as drug candidate to develop lipospheres employing the melt dispersion technique. The Pioglitazone HCl - loaded lipospheres were found to be an effective natural carrier in terms of discrete particle size, encapsulation efficiency, and satisfactory in vitro release characteristics. In the presence of cetyl alcohol, the incorporated phospholipid could combine with drug by hydrophilic and hydrophobic interactions, consequently improved the drug entrapment efficiency and produced the sustained release rate.

AN ENHANCEMENT OF SOLUBILITY OF PIOGLITAZONE HYDROCHLORIDE USING LIQUISOLID TECHNIQUE

The new mathematical model was developed by studying angle of slide using N, N-dimethyl acetamide, non-volatile liquid vehicle and prepared liquisolid tablets, in which the different concentrations of non-volatile liquid adsorbed over carrier and coating material separately. Both DSC and FT-IR study showed better compatibility and stability. The optimized formulation showed higher drug release during in-vitro and in-vivo study against conventional and marketed preparation. The present work concludes that N, N-dimethyl acetamide enhanced the solubility of pioglitazone HCl with higher dissolution rate through liquisolid technique.

New and selective HPTLC-Densitometric method for determination of pioglitazone hydrochloride

New sensitive and selective HPTLC-densitometric method has been developed for the determination of pioglitazone hydrochloride. The proposed method depends on the interaction of the drug with ophthaldehyde (as spray reagent) and densitometric measurement (using UVP scanner) of the intensity of the produced pink color. Separation was achieved on HPTLC silica gel 60 aluminum sheets with chloroform-methanol (10:1 v/v) as mobile phase, and the R F value was 0.51 ± 0.01. The linearity of the method was studied in the range of 200–3000 ng per spot. Agood correlation coefficient (0.998) was obtained between the drug concentration and the corresponding optical intensities of the produced color. Limits of detection and quantification were found 65.06 and 197.16 ng per spot, respectively. The proposed method was applied successfully for the determination of pioglitazone HCl in pure form and in pharmaceutical dosage forms.

A Validated RP-HPLC Method for Simultaneous Estimation of Antidiabetic Drugs Pioglitazone HCl and Glimepiride

A simple, fast and economic reversed phase high performance liquid chromatographic (RP-HPLC) method has been developed and validated for simultaneous and quantitative analyses of pioglitazone HCl and glimepiride in pharmaceutical dosage forms. The method was developed using the mobile phase comprising of potassium dihydrogen phosphate buffer (KH2PO4) at pH 3.4 and acetonitrile in the ratio of 40:60 (v/v) over C-18 bonded silica column (250 x 4.6 mm, 5 um, Phenomenex Inc.) at ambient temperature. The flow rate was at 0.8 min/min and the eluent was monitored by UV detection at 235 nm. The recoveries were found to be >97% for pioglitazone and >99% for glimepiride, demonstrative of accuracy of the protocol. Inter-day and intra-day precision of the new method were less than the maximum allowable limit (RSD% ? 2.0) according to ICH, USP and FDA guidelines. The method showed linear response with correlation coefficient (r2) values of 0.9991 for pioglitazone and 0.9999 for glimepiride. Therefore, the method was found to be accurate, reproducible, sensitive and less time consuming and can be successfully applied for the assay of pioglitazone and glimepiride in combined formulations. DOI: http://dx.doi.org/10.3329/bpj.v16i1.14497 Bangladesh Pharmaceutical Journal 16(1): 69-75, 2013

Clinical Proof-of-Concept Study With MSDC-0160, a Prototype mTOT-Modulating Insulin Sensitizer

It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator–activated receptor-γ (PPAR-γ)-dependent side effects. In this phase IIb clinical trial, 258 patients with type 2 diabetes completed a 12-week protocol with 50, 100, or 150 mg of MSDC-0160 (an mTOT modulator), 45 mg pioglitazone HCl (a PPAR-γ agonist), or a placebo. The two active treatments lowered fasting glucose levels to the same extent. The decreases in glycated hemoglobin (HbA1c) observed with the two higher doses of MSDC-0160 were not different from those associated with pioglitazone. By contrast, fluid retention as evidenced by reduction in hematocrit, red blood cells, and total hemoglobin was 50% less in the MSDC-0160–treated groups. There was also a smaller increase in high-molecular-weight (HMW) adiponectin with MSDC-0160 than with pioglitazone (P < 0.0001), suggesting that MSDC-0160 produces less expansion of white adipose tissue. Thus, mTOT modulators may have glucose-lowering effects similar to those of pioglitazone but without the adverse effects associated with PPAR-γ agonists.

Antioxidant and anti-inflammatory effects of Urtica pilulifera extracts in type2 diabetic rats

Ethnopharmacological relevance"Urtica pilulifera has been traditionally used in Egyptian system as an herbal remedy to be a diuretic, antiasthmatic, anti-inflammatory, hypoglycemic, hemostatic, antidandruff and astringent" Aim of the studyTo evaluate the potential effects of ethyl acetate (EA), chloroform (CHLOR) and hexane (HEXA) extracts of Urtica piluliferaas oral anti-diabetic agents as well as to evaluate their possible anti-oxidant and anti-inflammatory effects in type2 diabetic rat model. Material and methodsType2 diabetes was induced by a high fat diet and low dose streptozotocin (STZ). Diabetic adult male albino rats were allocated into groups and treated according to the following schedule; Pioglitazone HCL (PIO), EA, CHLOR and HEXA extracts of Urtica pilulifera at two doses of 250 and 500mg/kg were used. In addition, a normal control group and a diabetic control one were used for comparison. Blood glucose, insulin resistance, antioxidant enzymes, 8-hydroxy-2-deoxyguanosine (8-OHdG) as well as C-reactive protein and tumor necrosis factor-α levels were evaluated. ResultsEA and CHLOR extracts of Urtica pilulifera exhibited a significant hypoglycemia associated with antioxidant and anti-inflammatory effects in diabetic rats; however, HEXA extract showed no beneficial effect. These activities are responsible, at least partly, for improvements that have been seen in hyperglycemia and insulin resistance of diabetic rats. ConclusionOur results encourage the traditional use of Urtica pilulifera extract as an antioxidant and anti-inflammatory agent as an additional therapy of diabetes.

A Pilot Trial of Pioglitazone HCl and Tretinoin in ALS: Cerebrospinal Fluid Biomarkers to Monitor Drug Efficacy and Predict Rate of Disease Progression

Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30 mg/d and tretinoin 10 mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs) were performed to measure cerebrospinal fluid (CSF) biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of −1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of −.86 (P = .18). Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline.

Formulation and evaluation of bilayer tablet by using melt granulation technique for treatment of diabetes mellitus.

The objective of present study was to prepare and characterize Bilayer tablet formulation containing Metformin HCl in extended release matrix form and Pioglitazone HCl in immediate release form for the treatment of diabetes mellitus. Different formulations containing Metformin HCl were manufactured using 32 factorial designs. Influence of hydrophilic carrier, hydrophobic polymer on drug release was studied. Immediate release layer of Pioglitazone was optimized using different super disintegrants. All formulations were evaluated for percentage drug release. Optimization results indicated that release rate of Metformin is directly proportional to the levels of Eudragit S 100 and PEG 6000. Results confirmed that Bilayer tablet formulation containing extended release of Metformin HCl and immediate release of Pioglitazone HCl could be developed by using melt granulation technique.

SIMULTANEOUS ESTIMATION OF PIOGLITAZONE, GLIMEPIRIDE AND GLIMEPIRIDE IMPURITIES IN COMBINATION DRUG PRODUCT BY A VALIDATED STABILITY- INDICATING RP-HPLC METHOD

A new, single, stability indicating RP-HPLC method has been developed and validated for the simultaneous estimation of pioglitazone, glimepiride and glimepiride impurities i.e., related compound B and related compound C from combination drug product containing pioglitazone, glimepiride and metformin HCl. The chromatographic separation was achieved on a cyano stationary phase (250 x 4.6mm, 5.0 microns particles) with simple mobile phase combination delivered in gradient mode at a flow rate of 0.8mL min -1 at 230nm. In the developed method, the critical close eluting compound of glimepiride related compound B and related compound C was found more than 6.5 resolutions. This method is capable to detect glimepiride related compound B and related compound C at a level below 0.005% with respect to glimepiride sample concentration of 0.1mg mL-1 for a 25 µL injection volume. The proposed method was validated according to the ICH guidelines and proved suitable for routine and stability analysis of these drugs in pharmaceutical preparations.

Inclusion parameters of pioglitazone hydrochloride and glipizide with β-cyclodextrin and its methyl derivative: calorimetric and

Solution calorimetry, a direct method to determine the thermodynamic parameters was used to investigate the inclusion phenomenon (stability constant, K; complexation enthalpy, ΔHo) of two poorly soluble oral hypoglycemic agents, pioglitazone hydrochloride (pioglitazone HCl) and glipizide with ß- cyclodextrin (ß-CD) and its methyl derivative (methyl-ß-CD). The inclusion complexes prepared by kneading were characterized in the solid state by differential scanning calorimetry and X-ray powder diffraction. The host-guest geometry and stoichiometry for the complexes indicated by proton NMR studies was confirmed by solution calorimetry. In case of pioglitazone HCl, two types of 1:1 complexes co-existing in solution have been revealed as pyridine ring as well as thiazoledione ring can be included in the cavity of cyclodextrin. The value of K1 and K2 determined using two class binding model utilizing non-linear least square regression was found to be 1940 M-1 and 1478 M-1 at pH 8 for complex with ß-CD. Glipizide, a bigger molecule showed 1:2 complex with ß-CD with a stability constant of 1880 M-1 at pH 8 with ß-CD. The magnitude of equilibrium constants decreased at pH 4 which is attributed to the presence of ionized species for both the drug molecules at lower pH. The inclusion of the drugs in the cyclodextrin cavity is an exothermic process accompanied by small negative value of ΔGo and positive value of ΔSo. The magnitude of equilibrium constant increased with the use of methyl-ß-CD for both drugs indicating their better complexing ability. This supports the enhanced solubility and dissolution rates observed with methyl-ß-CD.© 2010 International Formulae Group. All rights reserved.Keywords: Pioglitazone, glipizide, encapsulation, solubility, calorimetry, equilibrium constant.

Effect of method of preparation on pioglitazone HCl-β-cyclodextrin inclusion complexes

Pioglitazone HCl is an antidiabetic agent with poor aqueous solubility. Inclusion complexes of pioglitazone HCl were prepared with β-cyclodextrin using various methods (physical mixing, kneading method, co-precipitation). The main aim of the present invention is to study the effect of the method of preparation on the dissolution profiles of pioglitazone HCl-β-Cyclodextrin inclusion complexes. The phase solubility profile of pioglitazone HCl with β-cyclodextrin was classified as AL-type and stability constant with 1:1 molar ratio was 115.45, calculated from the phase solubility diagram. Formation of the inclusion complex between pioglitazone HCl and β-cyclodextrin was confirmed by the Fourier Transform Infrared (FT- IR) spectroscopy. The dissolution profile of inclusion complexes were determined and compared with those of pioglitazone HCl alone and its physical mixtures.The dissolution rate of the pioglitazone HCl-β-cyclodextrin inclusion complex prepared by the co-precipitation method was six times higher when compared with the pure drug. The method of complexation of pioglitazone HCl in β-CD increased the dissolution rate of the drug in the following order: Coppt > KM > PM >Drug.

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액토스TM정(염산 피오글리타존 15 mg)에 대한 피로스TM정의 생물학적 동등성

The purpose of the present study was to evaluate the bioequivalence of two pioglitazone HCl tablets, , tablets (Lilly Korea. Ltd., Korea) as a reference drug and , tablets (Reyon Pharm. Co., Ltd., Korea) as test drug, according to the guideline of Korea Food and Drug Administration (KFDA). Twenty-four healthy male Korean volunteers received one tablet containing pioglitazone HCl 15 mg in a crossover study. There was a one-week washout period between the doses. Plasma concentrations of pioglitazone were monitored for over a period of 36 hr after administration by using a high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under the plasma concentration-time curve from time zero to 36 hr (), maximum plasma drug concentration () and time to reach () were complied from the plasma concentration-time data. Analysis of variance (ANOVA) test was utilized for the statistical analysis of the parameters using logarithmically transformed and . The 90% confidence intervals of the ratio and the ratio for /. were log 0.8753-log 1.1286 and log 0.8669-log 1.1734, respectively. These values were within the acceptable bioequivalence intervals of log 0.80-log 1.25, recommended by KFDA. In all of these results, we concluded that the . tablet was bioequivalent to the . tablet, based on the rate and extent of absorption.

Flow-Injection Chemiluminometric Determination of Pioglitazone HCl by Its Sensitizing Effect on the Cerium-Sulfite Reaction

A flow injection chemiluminescent (FI-CL) method was developed for the determination of pioglitazone HCl. It is based on the sensitizing effect of the drug on the oxidation reaction of sulfite with cerium(IV). The different experimental parameters affecting the chemiluminescence intensity, such as concentration of reagents and some physical parameters of the manifold, were carefully studied and incorporated into the procedure. The method permits the determination of 0.05 - 3.0 microg ml(-1) of pioglitazone HCl with correlation coefficient r = 0.9999. The lower limit of detection (LOD) is 0.01 microg ml(-1) (S/N = 2) and the lower limit of quantitation (LOQ) is 0.05 microg ml(-1). The proposed method was compared with other reported methods and was found to be equally accurate and precise. It was successfully applied to the determination of the drug in pharmaceutical preparations and in biological fluids.

A Validated Adsorptive Stripping Voltammetric Determination of Antidiabetic Agent Pioglitazone HCl in Tablets and Biological Fluids

Square-wave adsorptive cathodic stripping voltammetry was used to determine pioglitazone HCl in Britton Robinson buffer of pH5. The adsorptive cathodic peak was observed at -1.5 V vs. Ag/AgCl. The peak response was characterized with respect to pH, supporting electrolyte, frequency, scan increment, pulse-amplitude, accumulation potential and pre-concentration time. Under optimal conditions, the peak current is proportional to the concentration of pioglitazone HCl, and a linear calibration graphs were obtained within the concentration levels of 10-8 and 10-4 M following different accumulation time periods (0-300 s). The obtained results were analyzed and the statistical parameters were calculated. The detection limit is 8.08 × 10-9 M (3.17 ng ml-1) using 300 s pre-concentration time, whereas the quantitative limit is 2.45 × 10-8 M (9.63 ng ml-1). The proposed method was applied to assay the drug in pharmaceutical formulations and biological fluids. The pharmacokinetic parameters of drug in human plasma were estimated as: Cmax=785.8 ng ml-1, tmax=1.5 h, Ke=0.125 h-1 and t1/2 = 8 h which are favorably compared with those reported in literature.

Simultaneous Spectrophotometric Estimation and Validation of Three Component Tablet Formulation Containing Pioglitazone Hydrochloride, Metformin Hydrochloride and Glibenclamide

Simultaneous estimation of active ingredients in multicomponent pharmaceutical products normally requires the use of separation techniques, such as HPLC, HPTLC, or GC, followed by their quantitation. Presented here are two spectrophotometric methods that do not require prior separation for simultaneous estimation of three drugs—pioglitazone HCl, metformin HCl, and glibenclamid—in a tablet formulation. Shimadzu UV 1700, capable of multicomponent analysis, was used for quantitation. In method I, absorbance of the sample solution was measured at 285 nm and 300 nm for the estimation of pioglitazone HCl and glibenclaimide, and at 237 nm for estimation of metformin hydrochloride, respectively. Method II is based on a multiwavelength spectroscopic method. Recording the absorbances of standard solutions at 237 nm, 268 nm, 280 nm, and 300 nm were processed by means of statistical calculations and results of the sample solution were obtained. All three drugs obey Beer's law in the concentration ranges used for the methods. The result of the analysis for both methods were tested and validated for various parameters according to ICH guidelines. The utility of the developed methods has been demonstrated by an analysis of commercial formulation containing all the three drugs.

Characteristics of new composite- and classical potentiometric sensors for the determination of pioglitazone in some pharmaceutical formulations

The construction and electrochemical response characteristics of poly(vinyl chloride) membrane sensors for pioglitazone HCl (PG) are described. The sensing membranes incorporate ion association complexes of pioglitazone cation and sodium tetraphenylborate (NaTPB) (sensor 1) or phosphomolybdic acid (PMA) (sensor 2) or phosphotungstic acid (PTA) (sensor 3) as electroactive materials. The sensors display a fast, stable and near-Nernstian response over a relative wide pioglitazone concentration range (1 × 10 −2 to 10 −6 M), with cationic slopes of 55.0 ± 0.5, 58.0 ± 0.5 and 53.0 ± 0.5 mV per concentration decade over a pH range of 1.0–5.0. The sensors show good discrimination of pioglitazone from several inorganic and organic compounds. The direct determination of 2.5–3900.0 μg/ml of pioglitazone show an average recovery of 98.5, 99.0 and 98.4% and a mean relative standard deviation of 1.6, 1.5 and 1.7% at 100.0 μg/ml for sensors 1, 2 and 3, respectively. The proposed sensors have been applied for direct determination of pioglitazone in some pharmaceutical preparations. The results obtained by determination of pioglitazone in tablets using the proposed sensors are comparable favorably with those obtained using the HPLC method. The sensors have been used as indicator electrodes for potentiometric titration of pioglitazone.

The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus

To evaluate the glycemic control, lipid effects, and safety of pioglitazone in patients with type 2 diabetes mellitus. Patients (n = 197) with type 2 diabetes mellitus, a hemoglobin A1c (HbA1c) > or = 8.0%, fasting plasma glucose (FPG) > 7.7 mmol/l (140 mg/dl), and C-peptide > 0.331 nmol/l (1 ng/ml) were enrolled in this 23-week multi-center (27 sites), double-blind clinical trial and randomized to receive either a placebo or pioglitazone HCl 30 mg (pioglitazone), administered once daily, as monotherapy. Patients were required to discontinue all anti-diabetic medications 6 weeks before receiving study treatment. Efficacy parameters included HbA1c fasting plasma glucose (FPG), serum C-peptide, insulin, triglycerides (Tg), and cholesterol (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C]). Adverse event rates, serum chemistry, and physical examinations were recorded. Compared with placebo, pioglitazone significantly (P= 0.0001) reduced HbA1c (-1.37% points), FPG (-3.19 mmol/l; -57.5 mg/dl), fasting C-peptide (-0.076+/-0.022 nmol/l), and fasting insulin (-11.88+/-4.70 pmol/l). Pioglitazone significantly (P < 0.001) decreased insulin resistance (HOMA-IR; -12.4+/-7.46%) and improved beta-cell function (Homeostasis Model Assessment (HOMA-BCF); +47.7+/-11.58%). Compared with placebo, fasting serum Tg concentrations decreased (-16.6%; P = 0.0178) and HDL-C concentrations increased (+12.6%; P= 0.0065) with pioglitazone as monotherapy. Total cholesterol and LDL-C changes were not different from placebo. The overall adverse event profile of pioglitazone was similar to that of placebo, with no evidence of drug-induced elevations of serum alanine transaminase (ALT) concentrations or hepatotoxicity. Pioglitazone improved insulin resistance and glycemic control, as well as Tg and HDL-C - which suggests that pioglitazone may reduce cardiovascular risk for patients with type 2 diabetes.

Pioglitazone: A Review of Japanese Clinical Studies

SummaryPioglitazone, a new thiazolidinedione agent, has been shown to increase insulin sensitivity in clinical trials. Pioglitazone HCl was rapidly absorbed within one hour, achieved peak concentrations at 2–3 h, and was eliminated from serum at 24–36 h. Pioglitazone demonstrated dose-dependent pharmacokinetics. Food did not significantly affect the pharmacokinetic profile of pioglitazone. The pharmacokinetic profile of sulfonylurea agents was not significantly altered by concurrent administration with pioglitazone. Pharmacokinetic studies in healthy volunteers and in patients with type 2 diabetes indicated that pioglitazone may be administered once daily. In patients with type 2 diabetes, pioglitazone as monotherapy and in combination with sulfonylureas or an α-glucosidase inhibitor significantly reduced fasting blood glucose, HbA1c, triglycerides, and free fatty acids, and significantly increased HDL-cholesterol. Pioglitazone demonstrated either minor increases or decreases in cholesterol with no adverse effect on LDL-cholesterol. No patients experienced jaundice or ALT elevations > three times the upper limit of normal. Adverse events were mild and transient; all subjects returned to their baseline health status or laboratory tests upon withdrawal from, or completion of, the studies. Based upon these preliminary studies, full-scale clinical investigations were conducted in Japan, the United States, and Europe. As a result, in many countries pioglitazone has gained approval for use in patients with type 2 diabetes.