Ultra-thin film tribology of elastomeric seals in pressurised metered dose inhalers

Within pressurised Metered Dose Inhalers (pMDIs) the contact between the valve components and elastomeric seals is of major significance, representing the main contributory factor to the overall system frictional characteristics. Therefore, the seal performance is extremely important and must be optimised to meet the contradictory requirements of preventing leakage and allowing smooth actuation. The environmentally driven trend to HFA formulations as opposed to CFC based ones has deteriorated this problem due to poor lubrication conditions and it has, consequently, increased the frictional losses during the pMDI actuation (hysteresis cycle). Research has been conducted into the key areas of the inhaler mechanism. As such, the contact pressure distribution and resulting reactions have been investigated, with emphasis on the correct treatment of the elastomer (seal) characteristics. The modelling of the device has been conducted within the environment of the multibody dynamics commercial software ADAMS, where a virtual prototype has been built using solid CAD geometries of the valve components. An equation was extrapolated to describe the relation between the characteristics of the ultra thin film contact conditions (sliding velocity, surface geometry, film thickness and reaction force) encountered within the inhaler valve and integrated into the virtual prototype allowing the calculation of friction within the conjuncture (due to viscous shear and adhesion). The latter allowed the analysis and optimisation of key device parameters, such as seal geometry, lubricant properties etc. It has been concluded that the dominant mechanism of friction is adhesion, while boundary lubrication is the prevailing lubrication regime due to the poor surface roughness to film thickness ratio. The multibody dynamics model represents a novel multi physics approach to study the behaviour of pMDIs, including rigid body inertial dynamics, general elasticity, surface interactions (such as adhesion), hydrodynamics and intermolecular surface interactions (such as Van der Waals forces). Good agreement has been obtained against experimental results at component and device level

Thin film tribology of pharmaceutical elastomeric seals

The primary purpose of valve seals in inhalation and other drug dispensing devices is to inhibit leakage of highly volatile formulation from pressurised canisters. This requirement often conflicts with smooth operation of valves because of poor lubrication of seals. The repercussions of this can be variability in dispensed dose as well as loss of prime and gradual wear of seals. Although a good volume of literature is available for general purpose o-ring seals, the characteristic behaviour of those used in pharmaceutical devices deviate from this significantly. The paper studies tribology of such seals, subjected to global fitment and canister pressure deformation and localised conjunctional elastohydrodynamic pressures. It is shown that ideally smooth seals would operate under iso-viscous elastic (soft EHL) regime of lubrication. However, the predicted ultra-thin films are insufficient to ensure fluid film lubrication because of rough micro-scale nature of elastomeric seal surface and poor lubricity of the usual bio-compatible formulations. The paper also shows that siliconisation of elastomeric contacting surface only marginally improves its tribological performance

Tribology of rough ultra-film contacts in drug delivery devices

Elastomeric seals are extensively used in an assortment of drug delivery devices, such as syringes and pressurized metered dose inhalers. Although tribology of rubber seals and o-rings is reasonably well understood in engineering applications, the drug mixtures and formulations do not enjoy the required rheology to ensure coherent hydrodynamic action. In fact formation of uninterrupted hydrodynamic films is not actually sought in drug delivery devices, which often contain mixtures that are volatile when exposed to the environment. Furthermore, while engineering devices are often driven to overcome friction, many drug delivery systems are actuated manually and frequently by frail individuals. Therefore, the tribological problem is quite complex with many biological and environmental constraints. This paper highlights a parametric friction model for combined adhesive friction due to asperity interactions and non-Newtonian viscous action of the formulation. The model predicts the hysteretic behaviour of elastomeric seal contacts and conforms reasonably well to the experimental measurements of the same through actuation and release of inhaler valves

Obesity-Related Upregulation of Monocyte Chemotactic Factors in Adipocytes : Involvement of Nuclear Factor-κB and c-Jun NH2-Terminal Kinase Pathways

OBJECTIVE—We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity

Impact of asymmetries on fuel performance in inertial confinement fusion

Low-mode asymmetries prevent effective compression, confinement, and heating of the fuel in inertial confinement fusion (ICF) implosions, and their control is essential to achieving ignition. Ion temperatures (Tion) in ICF experiments are inferred from the broadening of primary neutron spectra. Directional motion (flow) of the fuel at burn also impacts broadening and will lead to artificially inflated "Tion" values. Flow due to low-mode asymmetries is expected to give rise to line-of-sight variations in measured Tion. We report on intentionally asymmetrically driven experiments at the OMEGA laser facility designed to test the ability to accurately predict and measure line-of-sight differences in apparent Tion due to low-mode asymmetry-seeded flows. Contrasted to chimera and xrage simulations, the measurements demonstrate how all asymmetry seeds have to be considered to fully capture the flow field in an implosion. In particular, flow induced by the stalk that holds the target is found to interfere with the seeded asymmetry. A substantial stalk-seeded asymmetry in the areal density of the implosion is also observed

The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice

<p>Abstract</p> <p>Background</p> <p>Sidestream smoke is closely associated with airway inflammation and hyperreactivity. The present study was designed to investigate if the Raf-1 inhibitor GW5074 and the anti-inflammatory drug dexamethasone suppress airway hyperreactivity in a mouse model of sidestream smoke exposure.</p> <p>Methods</p> <p>Mice were repeatedly exposed to smoke from four cigarettes each day for four weeks. After the first week of the smoke exposure, the mice received either dexamethasone intraperitoneally every other day or GW5074 intraperitoneally every day for three weeks. The tone of the tracheal ring segments was recorded with a myograph system and concentration-response curves were obtained by cumulative administration of agonists. Histopathology was examined by light microscopy.</p> <p>Results</p> <p>Four weeks of exposure to cigarette smoke significantly increased the mouse airway contractile response to carbachol, endothelin-1 and potassium. Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected. In addition, the smoke-induced infiltration of inflammatory cells and mucous gland hypertrophy were attenuated by the administration of GW5074 or dexamethasone.</p> <p>Conclusion</p> <p>Sidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.</p

The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice

© 2008 Lei et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Effects of Helicobacter suis γ-glutamyl transpeptidase on lymphocytes: modulation by glutamine and glutathione supplementation and outer membrane vesicles as a putative delivery route of the enzyme

Helicobacter (H.) suis colonizes the stomach of the majority of pigs as well as a minority of humans worldwide. Infection causes chronic inflammation in the stomach of the host, however without an effective clearance of the bacteria. Currently, no information is available about possible mechanisms H. suis utilizes to interfere with the host immune response. This study describes the effect on various lymphocytes of the γ-glutamyl transpeptidase (GGT) from H. suis. Compared to whole cell lysate from wild-type H. suis, lysate from a H. suis ggt mutant strain showed a decrease of the capacity to inhibit Jurkat T cell proliferation. Incubation of Jurkat T cells with recombinantly expressed H. suis GGT resulted in an impaired proliferation, and cell death was shown to be involved. A similar but more pronounced inhibitory effect was also seen on primary murine CD4+ T cells, CD8+ T cells, and CD19+ B cells. Supplementation with known GGT substrates was able to modulate the observed effects. Glutamine restored normal proliferation of the cells, whereas supplementation with reduced glutathione strengthened the H. suis GGT-mediated inhibition of proliferation. H. suis GGT treatment abolished secretion of IL-4 and IL-17 by CD4+ T cells, without affecting secretion of IFN-γ. Finally, H. suis outer membrane vesicles (OMV) were identified as a possible delivery route of H. suis GGT to lymphocytes residing in the deeper mucosal layers. Thus far, this study is the first to report that the effects on lymphocytes of this enzyme, not only important for H. suis metabolism but also for that of other Helicobacter species, depend on the degradation of two specific substrates: glutamine and reduced glutatione. This will provide new insights into the pathogenic mechanisms of H. suis infection in particular and infection with gastric helicobacters in general

Shark Tooth Weapons from the 19th Century Reflect Shifting Baselines in Central Pacific Predator Assemblies

The reefs surrounding the Gilbert Islands (Republic of Kiribati, Central Pacific), like many throughout the world, have undergone a period of rapid and intensive environmental perturbation over the past 100 years. A byproduct of this perturbation has been a reduction of the number of shark species present in their waters, even though sharks play an important in the economy and culture of the Gilbertese. Here we examine how shark communities changed over time periods that predate the written record in order to understand the magnitude of ecosystem changes in the Central Pacific. Using a novel data source, the shark tooth weapons of the Gilbertese Islanders housed in natural history museums, we show that two species of shark, the Spot-tail (Carcharhinus sorrah) and the Dusky (C. obscurus), were present in the islands during the last half of the 19th century but not reported in any historical literature or contemporary ichthyological surveys of the region. Given the importance of these species to the ecology of the Gilbert Island reefs and to the culture of the Gilbertese people, documenting these shifts in baseline fauna represents an important step toward restoring the vivid splendor of both ecological and cultural diversity