Utility of thiocarbamoyl moiety in synthesis of some new sulphur containing heterocyclic compounds and evaluation of their antimicrobial activity

The reaction of N,N'-(1,4-phenylene)bis(2-cyanoacetamide) (1) with phenyl isothiocyanate gave thiocarbamoyl derivative 3, which reacted with α-halocarbonyl compounds in a mixture of ethanol:N,N-dimethylformamide in the presence of triethylamineto afford thiazoles 4, 7, 10 and thiophene12 derivatives. While, when the same reaction was refluxed in a mixture of ethanol:N,N-dimethylformamide only afforded the acyclic compounds 5, 6, 8, 9 and 11, which when refluxed in N,N-dimethylformamide in presence of triethylamine gave the corresponding above thiazole and thiophene derivatives. Moreover, the reaction of compound 3 with dihalo compounds afforded cyclic dithio derivatives 13a, 13b and 14. The newly synthesized compounds were characterized by analytical, spectral data and evaluation of their antimicrobial activities of 4, 7, 14 and 15 have a high antimicrobial activity

Effect of Gastric Fluid Volume on the in Vitro Dissolution and in Vivo Absorption of BCS Class II Drugs: A Case Study with Nifedipine

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (Cmax, tmax, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250 mL) on Cmax, tmax, or AUC0-6 of orally administered nifedipine IR capsules (10 mg). However, administration of large water volumes resulted in lower variability in nifedipine Cmax (47 vs. 70% for 250 and 50 mL, respectively). Administration of large water volumes with nifedipine 10 mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended

Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats

The study aims to compare, through histological and biochemical studies, the effects of quercetin, melatonin and their combination in regulation of immuno-inflammatory mediators and heat shock protein expressions in sodium nitrite induced hypoxia in rat lungs. The results revealed that NaNO2 injection caused a significant decrease in Hb in rats, while serum levels of TNF-α, IL-6 and CRP, VEGF and HSP70 were elevated compared to the control group. Administration of melatonin, quercetin or their combination before NaNO2 injection markedly reduced these parameters. Histopathological examination of the lung tissue supported these biochemical findings. The study suggests that melatonin and/or quercetin are responsible for lung tissue protection in hypoxia by downregulation of immuno-inflammatory mediators and heat shock protein expressions. Pre-treatment of hypoxic animals with a combination of melatonin and quercetin was effective in modulating most of the studied parameters to near-normal levels

LC-MS analysis to determine the biodistribution of a polymer coated ilomastat ocular implant

Ilomastat is a matrix metalloproteinase inhibitor (MMPi) that has shown the potential to inhibit scarring (fibrosis) by mediating healing after injury or surgery. A long lasting ocular implantable pharmaceutical formulation of ilomastat is being developed to mediate the healing process to prevent scarring after glaucoma filtration surgery. The ilomastat implant was coated with water permeable and biocompatible phosphoryl choline polymer (PC1059) displayed extended slow release of ilomastat in vitro and in vivo. The ocular distribution of ilomastat from the implant in rabbits at day 30 post surgery was determined by the extraction of ilomastat and its internal standard marimastat from the ocular tissues, plasma, aqueous humour and vitreous fluid followed by capillary-flow liquid chromatography (cap-LC), the column effluent was directed into a triple quadrupole mass spectrometer operating in product scan mode. The lower limits of quantification (LLOQs) were 0.3 pg/μL for ocular fluids and plasma, and 3 pg/mg for ocular tissues. The extraction recoveries were 90-95% for ilomastat and its internal standard from ocular tissues. Ilomastat was found in ocular fluids and tissues at day 30 after surgery. The level of ilomastat was 18 times higher in the aqueous humour than vitreous humour. The concentration ranking of ilomastat in the ocular tissues was sclera > bleb conjunctiva > conjunctiva (rest of the eye) > cornea. Mass spectrometry analysis to confirm the presence of ilomastat in the ocular tissues and fluids at day 30 post-surgery establishes the extended release of ilomastat can be achieved in vivo, which is crucial information for optimisation of the ilomastat coated implant

Probing physiological media composition and polymer- plasticizer interactions on dissolution of pH-responsive systems

This study explored the in vitro dissolution of pH-responsive methacrylic acid methylmethacrylate copolymer coated dosage forms, in particular Eudragit S coated 5- aminosalicylic acid (5-ASA) tablets for ileo-colonic delivery. Ionic parameters that influence the in vitro dissolution were identified as ionic strength, pKa of the buffer and its concentration. Physiological bicarbonate buffers (Hanks and Krebs) were explored as potential dissolution media as they are more representative of the ionic and buffer composition of small intestinal fluids. In comparison to compendia! phosphate buffers, they were found to provide a better reflection of the in vivo disintegration times of these ileo-colonic tablets as reported in the literature. Jejunal fluids were obtained from human volunteers and Hanks buffer provided a very good reflection of buffer capacity and solubility of 5-ASA in these fluids. The dissolution of acrylic film coatings was found to be influenced by the plasticizer component of the formulation. A small library of plasticizers was screened with the objective of determining parameters that correlate to dissolution of polymer free films. Free film dissolution was measured using two-compartment permeation cells. Dielectric properties of the films were studied by TSDC (thermally stimulated depolarisation currents). Secondary relaxations were deconvoluted and identified. Glass transition temperature (Tg) (indicator of segmental mobility) was measured using TSDC, differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). Plasticizer structure and solubility were identified as determining factors in dissoiution of acrylic free films. Low temperature TSDC spectra showed a relationship of the total secondary relaxation area and relaxation area of the carboxylic acid functional group of the polymer with dissolution time. No correlation was found amongst the glass transition temperatures obtained by TSDC, DSC and DMA with dissolution time of the films. Although the Tg trend was similar for the films, Tg values obtained by TSDC were lower than those observed by DMA and DSC. Immediate release 5-ASA and prednisolone tablets were coated with the different Eudragit SI plasticizer formulations. The formulations with the extreme dissolution profiles gave rise to similar trends for the coated tablets and free films however the formulations with intermediate dissolution onset times displayed different trends in the two states. These differences were reasoned to be due to drug and excipients in the core interacting with the coat. These findings will contribute to a mechanistic approach in formulation development.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Drug Physicochemical Properties and Capsule Fill Determine Extent of Premature Gastric Release from Enteric Capsules

Intrinsically, enteric capsule shells offer several advantages compared to coating of dosage forms with enteric polymers. We undertook a systematic investigation to elucidate capsule-fill parameters that may result in premature gastric drug release from Vcaps® Enteric capsules (Lonza CHI, Morristown, NJ, USA). Four model drugs with different ionization and solubility profiles were investigated: acetaminophen, ketoprofen, trimethoprim and atenolol. Different fill loads, diluents and drug-to-diluent ratios were explored. Enteric capsules were filled with drug or drug and diluent powder mix and underwent USP II dissolution testing using mini-vessels and paddles. Capsules were tested in pH 2 (0.01 M HCl) or pH 4.5 (3.2 × 10−5 M HCl) 200 mL acid media to simulate normal, fasted or hypochlorhydric gastric pH, respectively. Acetaminophen, trimethoprim and atenolol displayed premature gastric drug release from enteric capsules. The extent of premature release was dependent on drug solubility, ionization profile and capsule-fill level. At 100 mg drug-fill level, acetaminophen, trimethoprim and atenolol gave rise to 10.6, 12.2 and 83.1% drug release, respectively, in normal, fasted, gastric fluids. Diffusion layer pH of trimethoprim and atenolol in pH 2 media was determined to be pH 6.3 and 10.3, respectively. Upon increasing capsule-fill load using microcrystalline cellulose as a diluent, a significant reduction in premature gastric release was observed. However, including mannitol as a diluent was only effective at decreasing premature drug release at a low drug-to-diluent ratio. Systematic in vitro screening of enteric capsule fills needs to be conducted to ensure that drug product performance is not compromised

Flaxseed and quercetin improve anti-inflammatory cytokine level and insulin sensitivity in animal model of metabolic syndrome, the fructose-fed rats

The purpose of this study is to assess the beneficial effect of quercetin, flaxseed and/or in combination as synergetic in an animal model of metabolic syndrome (MtS), high fructose (HF)-fed rats. Fifty male Sprague–Dawley rats, 3-month old and weighing between 110 and 120 g were randomly divided into 2 groups. Rats were given drinking water (−ve control rats) or 10% fructose in drinking water (HF; fructose-fed rats) with standard chow for 8 weeks. After 4 weeks of fructose feeding, HF-fed rats were further divided into matched 4 subgroups. Different groups of animals (n − 10, each group) were administered; 10% HF (5 mg/kg, +ve control), flaxseed (F; 50 mg/kg), quercetin (Q; 50 mg/kg), flaxseed + quercetin, (FQ; 25 mg/kg of each), respectively. All ingredients were given orally once daily and subsequent 4 weeks. Serum glucose, insulin, lipids profile, leptin, and adiponectin were estimated. After 4 weeks of feeding, a significant increase in blood glucose level was observed in HF fed rats compared to normal rats, but this increase was significantly decreased after administration of F, Q and FQ. The raised serum insulin level in HF fed rats was significantly decreased after administration of F and FQ groups. Significantly higher concentrations of triacylglycerols (TG), total cholesterol and low density lipoprotein cholesterol (LDL-C) were observed in HF fed rats and these increases were lower after administration of F, Q and FQ. There was a significant increase in serum high density lipoprotein cholesterol (HDL-C) in the FQ group. The increased serum leptin level was decreased significantly in F, Q and FQ groups. Whereas the reduction of serum adiponectin level in HF fed rats was increased in F, Q and FQ groups. These data suggested that protective effect of flaxseed and quercetin consumption as functional foods could reduce risk for people with decreased insulin sensitivity and increased oxidative stress, such as those with the metabolic syndrome or type 2 diabetes