Optical diagnostics study of air flow and powder fluidisation in Nexthaler®--Part I: Studies with lactose placebo formulation.

Effective drug delivery to the lungs by a DPI device requires the air-stream through the device to have sufficient power to aerosolise the powder. Furthermore, sufficient turbulence must be induced, along with particle-wall and particle-particle collisions, in order to de-aggregate small drug particles from large carrier particles. As a result, the emitted and the fine particle doses produced by many commercially available DPI devices tend to be strongly affected by the natural inter-patient variability of the inhaled air flow. The Nexthaler® is a multi-dose breath-actuated dry-powder inhaler with minimum drug delivery-flow rate dependency and incorporating a dose protector. The actuation mechanism of the dose-protector ensures that the dose is only exposed to the inhaled air flow if the flow has sufficient power to cause complete aerosolisation. For this study, a proprietary lactose placebo powder blend was filled into "transparent" Nexthaler® to allow application of high-speed imaging and particle image velocimetry (PIV) techniques to successfully interrogate and reveal details of the powder entrainment and emission processes coupled with characterisation of the flow environment in the vicinity of the mouthpiece exit. The study showed that fluidisation of the bulk of the powder occurs very quickly (∼20ms) after withdrawal of the dose protector followed by powder emission from the device within ∼50ms thereafter. The bulk of the metered placebo dose was emitted within 100-200ms. The visualisation study also revealed that a very small fraction of powder fines is emitted whilst the dose protector still covers the dosing cup as the flow rate through the device accelerates. The PIV results show that the flow exiting the device is highly turbulent with a rotating flow structure, which forces the particles to follow internal paths having a high probability of wall impacts, suggesting that the flow environment inside the Nexthaler® DPI will be very beneficial for carrier-drug de-aggregation.

Didanosine polymorphism in a supercritical antisolvent process.

Solid-state properties of active ingredients are crucial in pharmaceutical development owing to their significant clinical and economical implications. In the present work we investigated the solid-state properties and the solubility in water of didanosine, DDI, re-crystallized from a dimethylsulfoxide solution using supercritical CO(2) as an antisolvent (SAS process) for comparison with the commercially available drug product. We also applied modern solid-state NMR (SS NMR) techniques, namely 2D (1)H DQ CRAMPS (Combined Rotation And Multiple Pulse Spectroscopy) and (1)H-(13)C on- and off-resonance CP (cross polarization) FSLG-HETCOR experiments, known for providing reliable information about (1)H-(1)H and (1)H-(13)C intra- and intermolecular proximities, in order to address polymorphism issues arising from the crystallization of a new form in the supercritical process. A new polymorph of didanosine was obtained from the supercritical antisolvent process and characterized by means of 1D and 2D multinuclear ((1)H, (13)C, (15)N) SS NMR. The particle size of the new crystal phase was reduced by varying the antisolvent density through a pressure increase. The structural differences between the commercial product and the SAS re-crystallized DDI are highlighted by X-ray diffractometry and well described by solid-state NMR. The carbon C6 (13)C chemical shift suggests that both commercial and re-crystallized didanosine samples are in the enol form. The analysis of homo- and heteronuclear proximities obtained by means of 2D NMR experiments shows that commercial and SAS re-crystallized DDI possess very similar molecular conformation and hydrogen bond network, but different packing. The new polymorph proved to be a metastable form at ambient conditions, showing higher solubility in water and lower stability to mechanical stress.

Supercritical extraction of carotenoids from Rosa canina L. hips and their formulation with beta-cyclodextrin.

The purpose of this research was to preliminary assess the suitability of a new method for the preparation of a solid formulation in form of powder composed by beta-cyclodextrin and the supercritical extract of Rosa canina hips. The method implies the extraction of carotenoids, in particular beta-carotene, from freeze dried fruits of R. canina with supercritical CO2 at 70 degrees C and 300 bar, in the presence of varying quantity of ethanol as entrainer. The obtained supercritical solution is then expanded at ambient conditions into an aqueous solution of beta-cyclodextrin to favour the interaction between beta-cyclodextrin and the lipophilic components of the extract. beta-carotene solubility (mole fraction) in supercritical CO2 or in supercritical CO2/ethanol mixtures were in the order of 1 10(-7). The beta-carotene extracted from R. canina fruits (nearly 10 microg/g of dry matrix), interacts almost quantitatively with beta-cyclodextrin affording a solid phase, which presents a low apparent solubility in water. Finally the interaction with beta-cyclodextrin results in a higher concentration of the beta-carotene trans- form relative to the cis- form in the extracted product when collected in an aqueous solution of beta-cyclodextrin with respect to the extract in n-hexane.

The influence of fasting on chicken liver metabolites, enzymes and mitochondrial respiration.

Chicken liver mitochondria were isolated in relatively pure form as indicated by electron microscopy and marker enzyme assay. The rate of respiration, respiratory control index and ADP/O ratios with several different substrates indicated that chicken liver mitochondria are more uncoupled than rat liver mitochondria. Chickens have ten-fold higher malate concentrations in liver than do rats, 2-oxoglutarate was also more abundant in chicken livers. Fasted birds had a five-fold increase in beta-hydroxybutyrate as compared with fed birds; whereas malate and lactate concentrations decreased. Fasted birds had increased levels of isocitrate dehydrogenase (NADP dependent) and lactate dehydrogenase in the cytosol, and increased malate dehydrogenase (NAD dependent), isocitrate dehydrogenase (NADP dependent) and malic enzyme activities in the mitochondria.