Libo Wu

Core-shell Particles for the Dispersion of Small Polar Drugs and Biomolecules in Hydrofluoroalkane Propellants

PurposeDemonstrate the applicability of a novel particle-based technology for the development of suspensions of small polar drugs and biomolecules in hydrofluoroalkane (HFA) propellants for pressurized metered-dose inhalers (pMDIs).Materials and MethodsEmulsification diffusion was used to prepare core–shell particles. The shell consisted of oligo(lactide) grafts attached onto a short chitosan backbone. The active drug was arrested within the particle core. Colloidal Probe Microscopy (CPM) was used to determine the cohesive forces between particles in a model HFA propellant. The aerosol characteristics of the formulations were determined using an Anderson Cascade Impactor (ACI). Cytotoxicity studies were performed on lung epithelial and alveolar type II cells.ResultsCPM results indicate that particle cohesive forces in liquid HFA are significantly screened in the presence of the polymeric shell and correlate well with the physical stability of suspensions in propellant HFA. The proposed formulation showed little or no cytotoxic effects on both Calu-3 and A549 cells.ConclusionsCore–shell particles with a shell containing the lactide moiety as the HFA-phile showed excellent dispersion stability and aerosol characteristics in HFA-based pMDIs. This is a general strategy that can be used for developing novel suspension pMDIs of both small polar drugs and large therapeutic molecules.

Molecular order in Langmuir-Blodgett monolayers of metal-ligand surfactants probed by sum frequency generation.

Molecular organization of Langmuir-Blodgett (LB) monolayers of novel copper-containing metal-ligand surfactants was characterized by the surface-selective vibrational sum frequency generation (SFG) spectroscopy. The orientational and conformational order inferred from the SFG peak amplitudes and line shapes were correlated with the two-dimensional phases of the monolayers observed in the compression isotherms. The octadecyl-pyridin-2-ylmethyl-amine (L(PyC18)) ligand by itself shows good amphiphilic properties, as indicated by the high monolayer collapse pressure at the air/water interface, but its LB films transferred onto fused silica exhibit a high degree of trans-gauche conformational disorder in the alkyl tails. Coordination of copper(II) ions to the chelating head group enhances the molecular alignment and reduces the fraction of gauche defects of the alkyl chains. Monolayers of single-tail (L(PyC18)Cu(II)Cl(2)) and double-tail [(L(PyC18))(2)Cu(II)]Cl(2) metallosurfactants show distinctly different behavior of their molecular organization as a function of the area per molecule. Our observations suggest metal-ligand interactions as a pathway to induce molecular order in LB monolayer films.

Interfacial Behavior and Film Patterning of Redox‐Active Cationic Copper(II)‐Containing Surfactants

Herein, we describe the synthesis and characterization of a novel series of single-tail amphiphiles LPyCn (Py=pyridine, Cn=C18, C16, C14, C10) and their copper(II)-containing complexes, which are of relevance for patterned films. The N-(pyridine-2-ylmethyl)alkyl-1-amine ligands and their complexes [CuIICl2(LPyC18)] (1), [CuIICl2(LPyC16)] (2), [CuIICl2(LPyC14)] (3), [CuIIBr2(LPyC18)] (4), [CuIIBr2(LPyC16)] (5), and [CuIIBr2(LPyC10)] (6) were synthesized, isolated, and characterized by means of mass spectrometry, IR and NMR spectroscopies, and elemental analysis. Complexes 1, 2, 3, and 6 had their molecular structure solved by X-ray diffraction methods, which showed that the local geometry around the metal center is distorted square planar. With the aim of using these species as precursors for redox-responsive films, an assessment of their electrochemical properties involved cyclic voltammetry in different solvents, with different supporting electrolytes and scan rates. Density functional theory calculations of relevant species in bulk and at interfaces were used to evaluate their electronic structure and dipole moments. The morphology and order of the resulting films at the air/water interface were studied by isothermal compression and Brewster angle microscopy. Biphasic patterned Langmuir films were observed for all complexes except 3 and 6, and dependence on the chain length and the nature of the halogen coligand determine the characteristics of the isotherms and their intricate topology. Complexes 3 and 6, which have shorter chain lengths, failed to exhibit organization. These results exemplify the first comprehensive study of the behavior of single-tail metallosurfactants, which are likely to lead to high-end technological applications based on their patterned films.

Solvation in hydrofluoroalkanes: how can ethanol help?

Objectives  The goal of this work was to evaluate the ability of ethanol mixed with hydrofluoroalkanes (HFAs) to improve solvation of moieties of relevance to pressurized metered‐dose inhalers (pMDIs).

Ethoxylated copolymer surfactants for the HFA134a–water interface: interfacial activity, aggregate microstructure and biomolecule uptake

In this work we examine the aggregation behavior of ethoxylated copolymer surfactants in 1,1,1,2-tetrafluoroethane in the presence of water, and the ability of such aggregates to uptake a model biomolecule. Our approach consists of developing a rational framework for understanding the behavior of interfacially active species at the HFA134a-water (HFA134a|W) interface using a combination of in situ high-pressure tensiometry, spectroscopy, and small-angle neutron scattering (SANS). The optimum hydrophilic-to-HFA-philic balance (HFB) for the ethylene oxide-propylene oxide-ethylene oxide (EOnPO∼43EOn, where subscripts indicate the number of repeat units) surfactant series at the HFA134a|W interface was determined at 298 K and saturation pressure of the propellant (under pressure). The selection of promising candidates for the reverse aggregate formation studies was based on the tension vs. HFB scan. Tensiometric information revealed that EO3PO43EO3 occupies a very large area per molecule at the HFA134a|W interface, which represents a general trend for compressible solvents that are small and also able to interact with water more favorably than alkane solvents. The water solubilization capacity of the EO3PO43EO3 surfactant was investigated in situ by UV-vis spectroscopy, with a suitable solvatochromic probe. At a surfactant concentration above the determined critical aggregation concentration, a shift in the absorption maximum of the probe towards that of pure water was observed as the water-to-surfactant ratio increases. A similar but more pronounced shift was observed in the presence of a co-solvent. The nature of the aqueous environment associated with the aggregates is discussed based on the spectroscopic results. The microstructure of the aggregates is investigated by SANS. Scattering curves were also used to confirm the uptake of a model protein in the reverse aggregates. The relevance of this work stems from the fact that reverse aggregates of water in HFA134a are potential candidate formulations for the delivery of hydrophilic drugs, including biomolecules, to and through the lungs.

Nanoparticle-stabilized colloids in compressible hydrofluoroalkanes.

In this work, we show that nanoparticles (NPs) dispersed in compressible hydrofluoroalkanes (HFAs) at small volume fractions are capable of stabilizing micrometer-sized particle colloids, which otherwise flocculate due to strong van der Waals forces. Water-soluble, biodegradable NPs with a chitosan (CS) core, grafted with highly HFA-philic moieties, can be readily dispersed in the low dielectric HFAs and are capable of imparting stability to a wide range of therapeutic particles having different chemistries (polar or hydrophobic; small and large molecular weight, including peptides and proteins) and morphologies (micronized crystals or amorphous). These NP systems thus serve as a broadly applicable platform for the noninvasive delivery of therapeutics to and through the lungs using propellant-based, portable inhalers, and are also of potential relevance in other industries where HFAs are employed as solvents or propellants. This concept may also be applicable to other compressible solvents.