Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials.

Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from the European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-NDC assay. The IGH::CCND1 fusion was identified in 94% of patients, clonal IGH-V-(D)-J rearrangements in all, and 79% had ≥1 somatic gene mutation.

The effect of mechanical dry coating with magnesium stearate on flowability and compactibility of plastically deforming microcrystalline cellulose powders.

Mechanofusion is a dry coating method that can be used to improve the flowability of cohesive powder by coating host particles with a lubricant, for example magnesium stearate (MgSt). It has been shown previously that fragmenting material can under some circumstances be mechanofused with MgSt without impairing compactibility of the powder and without reducing the dissolution rate of the resulting tablets. However, the effects on material with viscoelastic behaviour, known to be sensitive for the negative effects of MgSt, is not known.

Single-step Coprocessing of Cohesive Powder via Mechanical Dry Coating for Direct Tablet Compression.

This study aims at testing the feasibility of a single-step coating process to produce a powder formulation of active and inactive ingredients for direct compression. A cohesive ibuprofen powder was coprocessed with a coating material, a binder (polyvinylpyrrolidone K25), and a superdisintegrant (crospovidone). Magnesium stearate (MgSt), l-leucine, and silica were selected as coating materials (1% w/w).

The influence of lung surfactant liquid crystalline nanostructures on respiratory drug delivery.

The respiratory route increasingly has been used for both local and systemic drug delivery. Although drug is absorbed rapidly after respiratory delivery, the role of lung surfactant in drug delivery is not well understood. The human lung contains only around 15mL of surface lining fluid spread over ∼100m surface.

Insights into Spray Development from Metered-Dose Inhalers Through Quantitative X-ray Radiography.

Purpose: Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques.

Methods: We present a technique for obtaining quantitative measurements of spray density in pMDI sprays.

Surface Energy Determined by Inverse Gas Chromatography as a Tool to Investigate Particulate Interactions in Dry Powder Inhalers.

Dry powder inhalers (DPIs) usually contain drug particles <6 µm which agglomerate and/ or adhere on the surfaces of large carriers particles. The detachment of drug particles from carriers and de-agglomeration of drug particles into primary particles is essential for drug deposition in the deep lung. These processes are influenced by the surface energy of particles.

Influence of coating material on the flowability and dissolution of dry-coated fine ibuprofen powders.

This study investigates the effects of a variety of coating materials on the flowability and dissolution of dry-coated cohesive ibuprofen powders, with the ultimate aim to use these in oral dosage forms. A mechanofusion approach was employed to apply a 1% (w/w) dry coating onto ibuprofen powder with coating materials including magnesium stearate (MgSt), L-leucine, sodium stearyl fumarate (SSF) and silica-R972. No significant difference in particle size or shape was measured following mechanofusion with any material.

Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate.

Intensive dry powder coating (mechanofusion) with tablet lubricants has previously been shown to give substantial powder flow improvement. This study explores whether the mechanofusion of magnesium stearate (MgSt), on a fine drug powder can substantially improve flow, without preventing the powder from being directly compacted into tablets. A fine ibuprofen powder, which is both cohesive and possesses a low-melting point, was dry coated via mechanofusion with between 0.

Improving the de-agglomeration and dissolution of a poorly water soluble drug by decreasing the agglomerate strength of the cohesive powder.

Influence of ternary, poorly water-soluble components on the agglomerate strength of cohesive indomethacin mixtures during dissolution was studied to explore the relationship between agglomerate strength and extent of de-agglomeration and dissolution of indomethacin (Ind). Dissolution profiles of Ind from 20% Ind-lactose binary mixtures, and ternary mixtures containing additional dibasic calcium phosphate (1% or 10%; DCP), calcium sulphate (10%) and talc (10%) were determined. Agglomerate strength distributions were estimated by Monte Carlo simulation of particle size, work of cohesion and packing fraction distributions.

Effect of surface coating with magnesium stearate via mechanical dry powder coating approach on the aerosol performance of micronized drug powders from dry powder inhalers.

The objective of this study was to investigate the effect of particle surface coating with magnesium stearate on the aerosolization of dry powder inhaler formulations. Micronized salbutamol sulphate as a model drug was dry coated with magnesium stearate using a mechanofusion technique. The coating quality was characterized by X-ray photoelectron spectroscopy.

Characterising surface energy of pharmaceutical powders by inverse gas chromatography at finite dilution.

Objectives: The objectives of this project were the use of surface energy distributions in: distinguishing the effects of magnesium stearate on the surface energy of lactose processed by two methods: mixing in a Turbula and mechanofusion; characterising surface energy of materials before and after micronisation; and understanding surface energy changes of micronised lactose before and after storage at high relative humidity (RH).

Methods: Heptane, octane and nonane were used to determine nonpolar surface energy, and dichloromethane and ethyl acetate were used to determine polar surface energy in inverse gas chromatography at finite dilution.

Key Findings: The total surface energy of lactose decreased more after mechanofusion with magnesium stearate than mixing in Turbula.

Powder strength distributions for understanding de-agglomeration of lactose powders.

Purpose: The purpose was to calculate distributions of powder strength of a cohesive bed to explain the de-agglomeration of lactose.

Methods: De-agglomeration profiles of Lactohale 300(®) (L300) and micronized lactose (ML) were constructed by particle sizing aerosolised plumes dispersed at air flow rates of 30-180 l/min. The work of cohesion distribution was determined by inverse gas chromatography.

Dissolution of a poorly water-soluble drug dry coated with magnesium and sodium stearate.

The purpose of this research was to investigate the influence of dry coating micronized cohesive powders of a poorly water-soluble drug, indomethacin with force control agents, on its dissolution performance. A dry mechanical fusion method (mechanofusion) was used to coat indomethacin powders with magnesium stearate (0.25%,1%,5%) and sodium stearate (5%).

Counter-intuitive enhancement in the dissolution of indomethacin with the incorporation of cohesive poorly water-soluble inorganic salt additives.

The objective of this work was to investigate the influence of various micronized poorly water-soluble inorganic materials on the dissolution and de-agglomeration behaviour of a micronized, poorly water-soluble model drug, indomethacin, from lactose interactive mixtures. Dissolution of indomethacin was studied using the USP paddle method and the data were modelled with multi-exponential equations using a nonlinear least squares algorithm in order to obtain key parameter estimates. The dispersion of indomethacin mixtures was measured by laser diffraction.

Use of surface energy distributions by inverse gas chromatography to understand mechanofusion processing and functionality of lactose coated with magnesium stearate.

The purpose was to employ a new finite dilution approach to determine total surface energy distributions of mechanofused powders by inverse gas chromatography (IGC) to contribute to the understanding of their improved flow properties and to help optimise the magnesium stearate (MgSt) coating. Pharmatose 450M was mechanofused with between 0.1 and 8% (w/w) of MgSt.

Understanding improved dissolution of indomethacin through the use of cohesive poorly water-soluble aluminium hydroxide: effects of concentration and particle size distribution.

The objective of this study was to explore the effects of concentration and particle size distribution of an added poorly water-soluble inorganic salt, aluminium hydroxide, on the dissolution of a poorly water-soluble drug, indomethacin (IMC), from lactose interactive mixtures. Dissolution was studied using the United States Pharmacopeia paddle method in buffer pH 5.0 and the data most aptly fitted a bi-exponential dissolution model which represented dissolution occurring from dispersed and agglomerated particles.

Investigation of the extent of surface coating via mechanofusion with varying additive levels and the influences on bulk powder flow properties.

The objective of this study was to investigate if the coating extent created by a mechanofusion process corresponded with observed changes in bulk powder properties. A fine lactose powder (approximate median diameter 20 μm) was dry coated with magnesium stearate using from 0.1 to 5% (w/w) content.

Characterization of the surface properties of a model pharmaceutical fine powder modified with a pharmaceutical lubricant to improve flow via a mechanical dry coating approach.

The aim of this study is to investigate the changes in physical and chemical surface properties of a fine lactose powder, which has been processed by a mechanical dry coating approach. A commercially available milled lactose monohydrate powder (median diameter around 20 μm) was dry coated with a pharmaceutical lubricant, magnesium stearate (MgSt). Substantial changes in bulk behavior have been shown previously and the purpose of the current work was to understand the relationship between these bulk changes and physico-chemical changes in the surface.

Determination of the polar and total surface energy distributions of particulates by inverse gas chromatography.

This Letter reports a technique of measuring polar surface energy distributions of lactose using inverse gas chromatography (IGC). The significance of this study is that the total surface energy distributions can now be characterized by combining the already known dispersive surface energy distribution with polar surface energy distribution determined in this study. The polar surface energy was calculated from the specific free energies for surface interactions with a monopolar basic probe, ethyl acetate, and a monopolar acidic probe, dichloromethane.

Improving aerosolization of drug powders by reducing powder intrinsic cohesion via a mechanical dry coating approach.

The aim of this study was to investigate the effect of coating on the aerosolization of three model micronized powders. Three model powder materials (salbutamol sulphate, salmeterol xinafoate, triamcinolone acetonide) were chosen not only for their different chemical properties but also for their different physical properties such as shape and size distribution. Each powder was coated with 5% (w/w) magnesium stearate using two different dry mechanofusion approaches.

Understanding the influence of powder flowability, fluidization and de-agglomeration characteristics on the aerosolization of pharmaceutical model powders.

The aim of this study was to investigate the influence of the intrinsic inter-particulate cohesion of model pharmaceutical powders on their aerosolization from a dry powder inhaler. Two cohesive poly-disperse lactose powders with median particle sizes of around 4 and 20 microm were examined. The results showed that after dry coating with magnesium stearate, their flowability, fluidization and de-agglomeration behaviours could be substantially improved, as indicated by powder rheometry, shear testing and laser diffraction aerosol testing.

Improving powder flow properties of a cohesive lactose monohydrate powder by intensive mechanical dry coating.

The objective of this study was to improve the cohesive lactose powder flowability. A cohesive lactose monohydrate powder was processed in either a tumbling blender or an intensive mechanical processor with either magnesium stearate or fumed silica. No substantial changes in particle size were detected by laser diffraction following either treatment.