COMPARATIVE BIOAVAILABILITY (BIOEQUIVALENCE) STUDY FOR FIXED DOSE COMBINATION TABLET CONTAINING AMLODIPINE, VALSARTAN, AND HYDROCHLOROTHIAZIDE USING A NEWLY DEVELOPED HPLC-MS/MS METHOD

Objective: The aim of the study was to evaluate the bioequivalence between a newly developed generic tablet containing fixed-dose combination of amlodipine besylate, valsartan and hydrochlorothiazide (10/160/25 mg), and the reference brand product Exforge HCT® tablet; using a newly developed HPLC-MS/MS method for simultaneous determination of these drugs in human plasma.Methods: The brand (reference) and the test (generic) products were administered to thirty-nine healthy subjects. A fasting, laboratory blind, single-dose, two-treatment, two-period, two-sequence, randomized crossover design was conducted with 14 d washout period between dosing. Serial blood samples were withdrawn from each subject immediately before dosing (zero time), and then at 0.33, 0.66, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 14, 16, 24, 48 and eventually at 72 h post dosing. Plasma samples were analyzed for simultaneous determination of amlodipine, valsartan and hydrochlorothiazide by a newly developed HPLC coupled with MS/MS detector. The linearity of the method was established for plasma concentration ranges of 0.2-12 ng/ml, 50-8000 ng/ml, and 2-250 ng/ml for amlodipine, valsartan, and hydrochlorothiazide, respectively.Results: Plasma concentration-time data of each individual were analyzed by non-compartmental method to measure the pharmacokinetics parameters; Cmax, Tmax, AUC0-t, AUC0-¥, lZ, T1/2. For amlodipine truncated AUC72hr was calculated. The 90% confidence interval for the pharmacokinetic parameters used for bioequivalence evaluation (Cmax and AUC) for amlodipine, valsartan, and hydrochlorothiazide were well within FDA acceptable ranges of 80-125%.Conclusion: It is concluded that the newly devolved generic product is bioequivalent with the brand product Exforge HCT® tablet. Thus, both products are clinically interchangeable.Keywords: Amlodipine, Valsartan, Hydrochlorothiazide, Pharmacokinetics, Bioequivalence, HPLC-MS/M

SAXAGLIPTIN LEVELS AND ITS PHARMACOKINETIC APPLICATION IN PRESENCE OF SUCRALOSE IN ANIMALS SERUM BY HPLC METHOD

Objective: It is to develop a simple, valid and rapid chromatographic method for quantification of saxagliptin in rats serum in order to study saxagliptin pharmacokinetics parameters in sucralose fed rats simultaneously to detect any interaction possibility between saxagliptin and sucralose in rats. Methods: In our developed method of analysis, mobile phase was consisted of phosphate buffer (pH =4) and methanol (70:30) v/v at flow rate of 1 ml/min with UV detection at 230 nm., C8 column of separation was used with the temperature of 40 °C using injection volume of 50 µl, samples run time was 10 min, and sildenafil citrate was used as internal standard. Saxagliptin was given to rats orally of (2g/kg) dose while sucralose was given with (11 mg/kg/day) dose.Results: A successful HPLC method was validated and developed to determine saxagliptin in rats serum, overall intra-day precision and accuracy were reasonable with coefficient of variation percentage CV % values range (o.14-4.03) and accuracy % range (99.5-104), while inter-day precision and accuracy showed accepted precision with CV% range (0.15-2.81) and accuracy % range (99.9-116). The coefficient of correlation was 0.99949 with reasonable sensitivity and selectivity. Combination effect of saxagliptin with sucralose on saxagliptin serum profile was demonstrated as strong statistical effect according to Cohen's d and significant P values too.Conclusion: A successful HPLC method was validated and developed to quantify saxagliptin in rats serum, combination effect of saxagliptin with sucralose over all time intervals of saxagliptin serum profile was demonstrated as strong statistical effect. Â

SAXAGLIPTIN LEVELS AND ITS PHARMACOKINETIC APPLICATION IN PRESENCE OF SUCRALOSE IN ANIMALS SERUM BY HPLC METHOD: A RESEARCH ARTICLE

Objective: It is to develop a simple, valid and rapid chromatographic method for quantification of saxagliptin in rats serum in order to study saxagliptin pharmacokinetic parameters in sucralose fed rats simultaneously to detect any interaction possibility between saxagliptin and sucralose in rats. Methods: In our developed method of analysis, mobile phase consisted of phosphate buffer (pH =4) and methanol (70:30) v/v at flow rate of 1 ml/min with UV detection at 230 nm., C8 column of separation was used with temperature of 40 C ° using injection volume of 50 µl, samples run time was 10 min, and sildenafil citrate was used as internal standard. saxagliptin was given to rats orally of (2g/kg) dose while sucralose was given with (11 mg/kg/day) dose.Results: A successful HPLC method was validated and developed to determine saxagliptin in rats serum, overall intra-day precision and accuracy were reasonable with coefficient of variation percentage CV % values range (o.14-4.03) and accuracy % range (99.5-104), while inter-day precision and accuracy showed accepted precision with CV% range (0.15-2.81) and accuracy % range (99.9-116). The coefficient of correlation was 0.99949 with reasonable sensitivity and selectivity. Combination effect of saxagliptin with sucralose on saxagliptin serum profile was demonstrated as strong statistical effect according to Cohen's d and significant P values too.Conclusion: A successful HPLC method was validated and developed to quantify saxagliptin in rats serum, combination effect of saxagliptin with sucralose over all time intervals of saxagliptin serum profile was demonstrated as strong statistical effect

LIQUORICE BEVERAGE EFFECT ON THE PHARMACOKINETIC PARAMETERS OF ATORVASTATIN, SIMVASTATIN, AND LOVASTATIN BY LIQUID CHROMATOGRAPHY-MASS SPECTROSCOPY/MASS SPECTROSCOPY

ABSTRACTObjective: The objective of this study is to examine the effects of pre-consumption of freshly prepared liquorice beverage (4 ml/kg) on thepharmacokinetic (PK) parameters of (80 mg/kg) oral dose of atorvastatin, simvastatin, and lovastatin in healthy rats plasma.Methods: A simple, rapid, and applicable analytical method was developed for the determination of each statin in rats' plasma. This method usesliquid chromatography-mass spectroscopy/mass spectroscopy. The mobile phase composed of methanol and formic acid in water and glimepiride asan internal standard. 108 rats were used in this study. Liquorice juice was given, and then each of the statins was given to test groups and liquoriceonly to the control groups, and then plasma samples were withdrawn on specific time schedule then PK analysis was performed.Results: The analytical method showed acceptable linearity, recovery, precision, and accuracy. Administration of liquorice resulted in a significantincrease in maximum concentration in plasma (C) of the three statins, also the area under plasma level-time curves (area under curve) was increasedsignificantly. Moreover, the bioavailability of the drugs. On the other hand, the elimination of the three drugs showed no great changes, which suggestsan interaction between liquorice and the transporting system of statins on the gut and biliary wall.maxConclusion: Consumption of liquorice results in increase bioavailability of atorvastatin, simvastatin, and lovastatin.Keywords: Liquorice, Atorvastatin, Liquid chromatography-mass spectroscopy/mass spectroscopy, Simvastatin, Lovastatin, Pharmacokineticparameters

DETERMINATION OF HYDROLYSIS PARAMETERS OF YOHIMBINE HCl AT NEUTRAL AND SLIGHTLY ACIDIC MEDIUM

Objectives: In the process of investigating various new drug delivery systems of yohimbine HCl (Yoh), it was necessary to study some of the physical chemical properties of the drug including its stability at neutral, acidic and slightly acidic conditions.Methods: A validated HPLC method was developed and employed for analysis of Yoh containing solutions. The mobile phase composed of 60% menthol: 40% NaOAc (%v/v), and Gemi C18 column, 5 µm particle size was used as a stationary phase. The degradation product was found to be yohimbinic acid (YA). The retention times for Yoh and YA were 5 and 3 minutes, respectively. This study investigated the kinetics of hydrolysis of Yoh at pH 6.0 and 7.0 at temperatures from 50 °C to 80 °C.Results: The reaction followed first order kinetics and the activation energy ∆E of the reaction at pH 6 and pH 7 was found to be 16.2 and 16.8 Kcal. mole-1, respectively. While the values of A were found to be 41.8 and 44.1 Kcal. mole-1 at pH 6 and 7, respectively. The pseudo first order rate constants (K) at pH 6 and 7 were calculated as 2.76 Ñ… 10 -3 h-1 and 3.42 Ñ… 10 -3 h-1, respectively.Conclusion: Such results indicate high stability of the drug at these pH values. At highly acidic medium the reaction was found to be extremely slow indicating the absence of acid catalysis on the hydrolysis of Yoh. Thus, the yohimbine ester group resists hydrolysis in highly acidic conditions.Â

Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets

Fused deposition modelling (FDM) 3D printing has shown the most immediate potential for on-demand dose personalisation to suit particular patient's needs. However, FDM 3D printing often involves employing a relatively large molecular weight thermoplastic polymer and results in extended release pattern. It is therefore essential to fast-track drug release from the 3D printed objects. This work employed an innovative design approach of tablets with unique built-in gaps (Gaplets) with the aim of accelerating drug release. The novel tablet design is composed of 9 repeating units (blocks) connected with 3 bridges to allow the generation of 8 gaps. The impact of size of the block, the number of bridges and the spacing between different blocks were investigated. Increasing the inter-block spaces reduced mechanical resistance of the unit, however, tablets continued to meet pharmacopeial standards for tablet's friability. Upon introduction into gastric medium, 1 mm spaces tablet broke into mini-structures within 4 min and met the USP criteria of immediate release products (86.7% drug release at 30 min). Real-time ultraviolet (UV) imaging indicated that the cellulosic matrix has expanded due to swelling of HPC upon introduction to dissolution medium. This was followed by a steady erosion of the polymeric matrix at a rate of 8 μm/min. The design approach was more efficient than formulation approach of adding disintegrants to accelerate tablet disintegration and drug release. This work provides a unique example where computer-aided design was instrumental at modifying the performance of solid dosage forms. Such an example may serve as a foundation for a new generation of dosage forms with complicated geometric structures to achieve functionality that are usually reached by formulation approach. [Abstract copyright: Copyright © 2017. Published by Elsevier B.V.

Genetic analysis : therapeutic drug monitoring of metformin and glimepiride on diabetic patients’ plasma including genetic polymorphism

Diabetes is a widespread disease that needs to be controlled. Therapeutic monitoring of drugs is very helpful in maintaining desirable doses. To study a correlation between the blood level of metformin (to a lesser extent, glimepiride) and genotyping (mainly the SULT1A1 genotype). Determine drug levels using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) tool. A validated LC-MS/MS method was developed to determine metformin and glimepiride levels in human plasma. DNA extraction was performed using Jena Bioscience’s Blood DNA preparation, in which a column kit was used to extract DNA for genetic polymorphism. The investigation was carried out using both medications in type 2 diabetes patients alongside the genetic polymorphism. One hundred and six patients were assessed. The prevalence of homozygosity for SULT1A1 and wild-type CYP2D6 * 4 were 72.6% and 73.6%, respectively. After adjustment for daily intake of metformin, three patients out of five with the highest levels of metformin had no homozygosity (SULT1A1 genotype). Statistically, variables that demonstrated an insignificant correlation with the level of metformin were body mass index (rs (87) = 0.32, P = 0.011) and age (rs (87) =0.26, P = 0.017). The homozygous (SULT1A1 genotype) correlation was moderate (rs (87) =0.21, P = 0.052). According to the findings, patients with the wt/wt CYP2D6 genotype had considerably greater levels of endoxifen than those with the v/v CYP2D6 genotype. The study’s results reported a probable correlation between the blood level of metformin (to a lesser extent, glimepiride) and genotyping (mainly the SULT1A1 genotype). Genotype-guided drug therapy may provide a novel contribution to maximize drug efficacy and/or minimize toxicity

Bioadhesive Controlled Metronidazole Release Matrix Based on Chitosan and Xanthan Gum

Metronidazole, a common antibacterial drug, was incorporated into a hydrophilic polymer matrix composed of chitosan xanthan gum mixture. Hydrogel formation of this binary chitosan-xanthan gum combination was tested for its ability to control the release of metronidazole as a drug model. This preparation (MZ-CR) was characterized by in vitro, ex vivo bioadhesion and in vivo bioavailability study. For comparison purposes a commercial extended release formulation of metronidazole (CMZ) was used as a reference. The in vitro drug-release profiles of metronidazole preparation and CMZ were similar in 0.1 M HCl and phosphate buffer pH 6.8. Moreover, metronidazole preparation and CMZ showed a similar detachment force to sheep stomach mucosa, while the bioadhesion of the metronidazole preparation was higher three times than CMZ to sheep duodenum. The results of in vivo study indicated that the absorption of metronidazole from the preparation was faster than that of CMZ. Also, MZ-CR leads to higher metronidazole Cmax and AUC relative to that of the CMZ. This increase in bioavailability might be explained by the bioadhesion of the preparation at the upper part of the small intestine that could result in an increase in the overall intestinal transit time. As a conclusion, formulating chitosan-xanthan gum mixture as a hydrophilic polymer matrix resulted in a superior pharmacokinetic parameters translated by better rate and extent of absorption of metronidazole

Plasma concentrations of 25-hydroxyvitamin D among Jordanians: Effect of biological and habitual factors on vitamin D status

<p>Abstract</p> <p>Background</p> <p>Vitamin D is cutaneously synthesized following sun exposure (vitamin D₃) as well as it is derived from dietary intake (vitamin D₃and D₂). Vitamin D₂and D₃are metabolized in the liver to 25-hydroxyvitamin D (25(OH)D). This metabolite is considered the functional indicator of vitamin D stores in humans. Since Jordan latitude is 31°N, cutaneous synthesis of vitamin D₃should be sufficient all year round. However, many indications reveal that it is not the case. Thus, this study was conducted to determine the 25(OH)D status among Jordanians.</p> <p>Methods</p> <p>Three hundred healthy volunteers were enrolled in a cross sectional study; 201 females and 99 males. 25(OH)D and calcium concentrations were measured by enzyme linked immunosorbent assay and spectroscopy techniques, respectively. All participants filled a study questionnaire that covered age, sex, height, weight, diet, and dress style for females. Females were divided according to their dress style: Western style, Hijab (all body parts are covered except the face and hands), and Niqab (all body parts are covered including face and hands).</p> <p>Results</p> <p>The average plasma 25(OH)D levels in males and females were 44.5 ± 10.0 nmol/l and 31.1 ± 12.0 nmol/l, respectively. However, when female 25(OH)D levels were categorized according to dress styles, the averages became 40.3, 31.3 and 28.5 nmol/l for the Western style, Hijab and Niqab groups, respectively. These 25(OH)D levels were significantly less than those of males (p < 0.05, 0.001, 0.001, respectively). In addition, the plasma 25(OH)D levels of the Western style group was significantly higher than those of Hijab and Niqab groups (p < 0.001). Furthermore, dairy consumption in males was a positive significant factor in vitamin D status. Even though calcium concentrations were within the reference range, the Hijab and Niqab-dressed females have significantly less plasma calcium levels than males (p < 0.01).</p> <p>Conclusions</p> <p>Very low plasma 25(OH)D levels in females wearing Hijab or Niqab are highly attributed to low sunlight or UVB exposure. In addition, most of males (76%) and Western style dressed females (90%) have 25(OH)D concentrations below the international recommended values (50 nmol/l), suggesting that although sun exposure should be enough, other factors do play a role in these low concentrations. These findings emphasize the importance of vitamin D supplementation especially among conservatively dressed females, and determining if single nucleotide polymorphisms of the genes involved in vitamin D metabolism do exist among Jordanians.</p