Andrew K. Davey

Silica-lipid hybrid (SLH) microcapsules: a novel oral delivery system for poorly soluble drugs.

A silica-lipid hybrid (SLH) microcapsule system for oral delivery of poorly water-soluble drugs is reported for the first time. For the model drug celecoxib (CEL), SLH microcapsules composed of medium-chain triglycerides, lecithin and silica nanoparticles; with an internal porous matrix structure, were shown to offer several physicochemical and biopharmaceutical advantages in comparison with unmodified drug, lipid emulsion, dry emulsion and the commercial product, Celebrex. DSC and XRD analyses confirmed non-crystalline CEL in SLH microcapsules and verified medium term physical stability. Dissolution under sink conditions revealed a 2- to 5-fold increase in dissolution efficiencies (%DE) and significantly reduced t(50%) (> or =50-fold) for CEL formulated as SLH microcapsules. Orally dosed in vivo studies in rats demonstrated superior pharmacokinetics for SLH microcapsules. Specifically, the fasted-state bioavailability (F) was statistically higher (p<0.05) than for aqueous suspension, lipid solution, o/w emulsion and a maltodextrin-stabilised dry emulsion, and was greater than for Celebrex. SLHs showed the highest maximum plasma concentration (C(max)) among all tested formulations (p<0.05). Linear correlations were observed between %DE and the pharmacokinetic parameters (F and C(max)). It is postulated that SLH microcapsules improve CEL oral absorption via dissolution enhancement, potentially in conjunction with other unexplored mechanisms, hence offering the possibility of dose reduction for improved therapeutic efficacy and cost-effectiveness of poorly soluble drugs.

Dry Hybrid Lipid−Silica Microcapsules Engineered from Submicron Lipid Droplets and Nanoparticles as a Novel Delivery System for Poorly Soluble Drugs

We report on the fabrication and characterization of dry hybrid lipid-silica nanoparticle based microcapsules with an internal porous matrix structure for encapsulation of poorly soluble drugs, and their delivery properties (in vitro release and lipolysis and in vivo pharmacokinetics demonstrated for indomethacin as a model drug). Microcapsules were prepared by spray drying of Pickering o/w emulsions containing either negatively or positively charged lipophilic surfactant in the oil phase and hydrophilic silica nanoparticles in the aqueous phase. Effective microcapsule formation is critically dependent on the interfacial structure of the nanoparticle containing emulsions, which are in turn controlled by the surfactant charge and the nanoparticle to lipid ratio. Microcapsules (containing 50-85% oil) can be prepared with 10 times fewer silica nanoparticles when a droplet-nanoparticle charge neutralizing mechanism is operative. Cross-sectional SEM imaging has confirmed the internal porous matrix structure and identified pore sizes in the range 20-100 nm, which is in agreement with BET average pore diameters determined from gas adsorption experiments. Differential scanning calorimetry and X-ray diffraction analysis have confirmed that the model drug indomethacin remains in a noncrystalline form during storage under accelerated conditions (40 degrees C, 75% RH). Dissolution studies revealed a 2-5-fold increase in dissolution efficiency and significantly reduced the time taken to achieve 50% of drug dissolution values (> or =2- or 10-fold) for indomethacin formulated as microcapsules in comparison to o/w submicron emulsions and pure drug, respectively. Orally dosed in vivo studies in rats have confirmed superior pharmacokinetics for the microcapsules. Specifically, the fasted state absolute bioavailability (F) was statistically higher (93.07 +/- 5.09%) (p < 0.05) than for aqueous suspension (53.54 +/- 2.91%) and o/w submicron emulsion (64.57 +/- 2.11%). The microcapsules also showed the highest maximum plasma concentration (C(max)) among the investigated formulations (p < 0.05). In vitro lipolysis showed statistically higher (p < 0.05) fasted digestion (75.8% after 5 min) and drug solubilization (98% after 5 min) in digestive products for microcapsules than o/w emulsions. The hybrid lipid-silica microcapsules improve oral absorption by enhancing lipolysis and drug dissolution.

Silica nanoparticles to control the lipase-mediated digestion of lipid-based oral delivery systems

We investigate the role of hydrophilic fumed silica in controlling the digestion kinetics of lipid emulsions, hence further exploring the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by silica-lipid hybrid (SLH) microcapsules. An in vitro lipolysis model was used to quantify the lipase-mediated digestion kinetics of a series of lipid vehicles formulated with caprylic/capric triglycerides: lipid solution, submicrometer lipid emulsions (in the presence and absence of silica), and SLH microcapsules. The importance of emulsification on lipid digestibility is evidenced by the significantly higher initial digestion rate constants for SLH microcapsules and lipid emulsions (>15-fold) in comparison with that of the lipid solution. Silica particles exerted an inhibitory effect on the digestion of submicrometer lipid emulsions regardless of their initial location, i.e., aqueous or lipid phases. This inhibitory effect, however, was not observed for SLH microcapsules. This highlights the importance of the matrix structure and porosity of the hybrid microcapsule system in enhancing lipid digestibility as compared to submicrometer lipid emulsions stabilized by silica. For each studied formulation, the digestion kinetics is well correlated to the corresponding in vivo plasma concentrations of a model drug, celecoxib, via multiple-point correlations (R(2) > 0.97). This supports the use of the lipid digestion model for predicting the in vivo outcome of an orally dosed lipid formulation. SLH microcapsules offer the potential to enhance the oral absorption of poorly soluble drugs via increased lipid digestibility in conjunction with improved drug dissolution/dispersion.

An oral delivery system for indomethicin engineered from cationic lipid emulsions and silica nanoparticles

We report on a porous silica-lipid hybrid microcapsule (SLH) oral delivery system for indomethacin fabricated from Pickering emulsion templates, where the drug forms an electrostatic complex with cationic lipid present in the oil phase. Dry SLH microcapsules prepared either by spray drying (approximately 1-5 microm) or phase coacervation (20-50 microm) exhibit a specific internal porous matrix structure with pore diameters in the range of 20 to 100 nm. Dissolution studies under sink conditions and in the presence of electrolytes revealed a decreased extent of dissolution; this confirms the lipophilic nature the drug-lipid complex and its location in the oil phase. Orally dosed in-vivo studies in rats showed complete drug absorption and statistically higher fasted state bioavailability (F) (p<0.05) in comparison to aqueous suspensions and o/w submicron emulsions of indomethacin. It is postulated that the SLH microcapsules improve oral absorption via complete solubilisation of drug-lipid electrostatic complexes during enzymatic lipolysis in the GI track.

Cellular Effects of Pyocyanin, a Secreted Virulence Factor of Pseudomonas aeruginosa

Pyocyanin has recently emerged as an important virulence factor produced by Pseudomonas aeruginosa. The redox-active tricyclic zwitterion has been shown to have a number of potential effects on various organ systems in vitro, including the respiratory, cardiovascular, urological, and central nervous systems. It has been shown that a large number of the effects to these systems are via the formation of reactive oxygen species. The limitations of studies are, to date, focused on the localized effect of the release of pyocyanin (PCN). It has been postulated that, given its chemical properties, PCN is able to readily cross biological membranes, however studies have yet to be undertaken to evaluate this effect. This review highlights the possible manifestations of PCN exposure; however, most studies to date are in vitro. Further high quality in vivo studies are needed to fully assess the physiological manifestations of PCN exposure on the various body systems.

Molecular Mechanisms Underlying the Effects of Statins in the Central Nervous System

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins’ effects on the central nervous system (CNS), particularly on cognition and neurological disorders such as stroke and multiple sclerosis, have received increasing attention in recent years, both within the scientific community and in the media. Current understanding of statins’ effects is limited by a lack of mechanism-based studies, as well as the assumption that all statins have the same pharmacological effect in the central nervous system. This review aims to provide an updated discussion on the molecular mechanisms contributing to statins’ possible effects on cognitive function, neurodegenerative disease, and various neurological disorders such as stroke, epilepsy, depression and CNS cancers. Additionally, the pharmacokinetic differences between statins and how these may result in statin-specific neurological effects are also discussed.

Maternal undernutrition reduces P-glycoprotein in guinea pig placenta and developing brain in late gestation.

Poor nutrition is a major cause of fetal growth restriction which increases neonatal morbidity and mortality, as well as the risk of adult onset diseases. The objective of the study was to determine the effect of maternal undernutrition on P-glycoprotein (P-gp) expression in the placenta and the brain of both the mother and the fetus. Maternal undernutrition in guinea pigs caused placental restriction, and thus decreased fetal weight. Pups in the maternal undernutrition (UN) group had fewer capillaries in the placenta and more capillaries in the brain of the fetus. Placental, maternal and fetal brain MDR1 mRNA expression was the same in the Control and UN groups. Maternal undernutrition resulted in a significant decrease in P-gp protein expression in the placenta and fetal brain, but not the maternal brain. These findings indicate that maternal undernutrition may impact on fetal exposure to drugs administered to the mother during pregnancy due to changes in placental transfer.

Effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism

1. The objective of this study was to investigate the effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism. 2. After oral administration of diammonium glycyrrhizinate (50 mg kg−1), the peak plasma concentration (Cmax), area under the plasma concentration–time curve from zero to time τ (AUC0–τ), and absolute bioavailability of aconitine (0.2 mg kg−1) significantly increased 1.64-, 1.63- and 1.85-fold, respectively, but there was no significant change in half life (t1/2) or clearance (CL). In the other two routes of administration via the tail vein and hepatic portal vein, diammonium glycyrrhizinate (15 mg kg−1) did not affect any of the pharmacokinetic parameters of aconitine (0.02 mg kg−1). Thus, diammonium glycyrrhizinate can enhance the absorption of aconitine, leading to higher oral bioavailability and plasma levels, but it does not influence its elimination. 3. Moreover, an in vitro everted gut sac model and Ussing chamber model were used to investigate the potential mechanism. Results from bidirectional transport and inhibition studies demonstrated that P-glycoprotein was the main efflux transporter involved in the absorption of aconitine in rats. The absorption enhancement effect of diammonium glycyrrhizinate should be mainly attributed to inhibiting the activity of P-glycoprotein rather than to the influence on the paracellular or transcellular transport.

Antihyperglycemic Effects of Baicalin on Streptozotocin – Nicotinamide induced Diabetic Rats

The aim of the study was to investigate the effects of baicalin on blood glucose, insulin and cytokine levels. Rat diabetes was induced by intraperitoneal (i.p.) injection of nicotinamide and streptozotocin. Diabetic rats were dosed with i.p. baicalin or oral metformin daily for 8 days. Blood glucose, insulin and hepatic glycogen were determined using conventional methods. The activity of hepatic hexokinase was determined using a coupled assay with glucose‐6‐phosphate dehydrogenase. Serum levels of interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α) and adiponectin were measured by enzyme‐linked immunosorbent assay. Administration of baicalin at 50 or 100 mg/kg significantly decreased plasma glucose levels in a dose dependent manner. The serum insulin level was not increased by baicalin treatment. Administration of baicalin at a high dose (100 mg/kg) resulted in a significant increase of liver glycogen content and a reduction of serum TNF‐α. The activity of hepatic hexokinase was significantly increased after dosing baicalin at 25, 50 or 10 mg/kg. Administration of baicalin (50 or 10 mg/kg) or metformin (10 mg/kg) significantly alleviated the morphological injury to the pancreas caused by STZ. The possible mechanisms contributing to the hypoglycemic effect include increasing the hepatic glycogen content and glycolysis, and reducing the serum levels of TNF‐α. Copyright

The Neuroprotective Effects of Isosteviol against Focal Cerebral Ischemia Injury Induced by Middle Cerebral Artery Occlusion in Rats

Occlusion of a cerebral artery impairs blood flow leading to neuronal death. Reperfusion of the tissue is associated with inflammation, increased reactive oxygen species, necrosis and apoptosis. Hence, damage to the brain will continue even after the blood flow is restored. Isosteviol has been demonstrated to have protective effects against ischemia-reperfusion (IR) injury in the rat heart and the current study was undertaken to determine whether it is also effective in preventing IR injury in the brain. Rats were divided into six groups: a sham-operation control group and 5 IR groups that were pre-treated with either isosteviol 5 mg.kg (-1), 10 mg.kg (-1), 20 mg.kg (-1), nimodipine 5 mg.kg (-1), or saline. Cerebral ischemia was induced for 2 hours. Twenty-two hours after re-perfusion the rats were assessed for neurobehavioral deficit, infarct volume, histological changes, and malondialdehyde, superoxide dismutase (SOD), Bcl-2 and NF-kappaB levels in brain tissue. Pre-treatment with isosteviol reduced infarct volume, ameliorated cell death and infiltration of neutrocytes, improved neuro-locomotor activity, increased SOD activity, induced Bcl-2, suppressed lipid superoxidation and the expression of NF-kappaB, and therefore retarded necrosis and apoptosis of neurons and inflammation. These positive effects were dose-dependent with an isosteviol dose of 20 mg.kg (-1), thus being as effective as nimodipine.