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

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

Utility of Sulphones in Heterocyclic Synthesis: Synthesis of Some Pyridine, Chromene and Thiophene Derivatives

Phenylsulfonylacetonitrile (1) when reacted with α,β-unsaturated nitriles (2a,b) and/or 2-hydroxynaphthaldehyde yields pyridine derivatives (3a,b) and / or the iminochromene derivative (4) respectively. The behavior of (1) towards some a-halogenated compounds has been investigated

Physiological bicarbonate buffers: stabilisation and use as dissolution media for modified release systems.

Bicarbonate media are reflective of the ionic composition and buffer capacity of small intestinal luminal fluids. Here we investigate methods to stabilise bicarbonate buffers which can be readily applied to USP-II dissolution apparatus. The in vitro drug release behaviour of three enteric coated mesalazine (mesalamine) products is investigated. Asacol 400 mg and Asacol 800 mg (Asacol HD) and the new generation, high dose (1200 mg) delayed and sustained release formulation, Mezavant (Lialda), are compared in pH 7.4 Krebs bicarbonate and phosphate buffers. Bicarbonate stabilisation was achieved by: continuous sparging of the medium with 5% CO(2)(g), application of a layer of liquid paraffin above the medium, or a specially designed in-house seal device that prevents CO(2)(g) loss. Each of the products displayed a delayed onset of drug release in physiological bicarbonate media compared to phosphate buffer. Moreover, Mezavant displayed a zero-order, sustained release profile in phosphate buffer; in bicarbonate media, however, this slow drug release was no longer apparent and a profile similar to that of Asacol 400 mg was observed. These similar release patterns of Asacol 400 mg and Mezavant displayed in bicarbonate media are in agreement with their pharmacokinetic profiles in humans. Bicarbonate media provide a better prediction of the in vivo behaviour of the mesalazine preparations investigated