pH-responsive microparticles of rifampicin for augmented intramacrophage uptake and enhanced antitubercular efficacy.

In this study we present pH-responsive rifampicin (RIF) microparticles comprising lecithin and a biodegradable hydrophobic polymer, polyethylene sebacate (PES), to achieve high intramacrophage delivery and enhanced antitubercular efficacy. PES and PES-lecithin combination microparticles (PL MPs) prepared by single step precipitation revealed average size of 1.5 to 2.7 µm, entrapment efficiency âˆ¼ 60 %, drug loading 12-15 % and negative zeta potential. Increase in lecithin concentration enhanced hydrophilicity. PES MPs demonstrated faster release in simulated lung fluid pH 7.4, while lecithin MPs facilitated faster and concentration dependent release in acidic artificial lysosomal fluid (ALF) pH 4.5 due to swelling and destabilization confirmed by TEM. PES and PL (1:2) MPs exhibited comparable macrophage uptake which was âˆ¼ 5-fold superior than free RIF, in the RAW 264.7 macrophage cells. Confocal microscopy depicted intensified accumulation of the MPs in the lysosomal compartment, with augmented release of coumarin dye from the PL MPs, confirming pH-triggered increased intracellular release. Although, PES MPs and PL (1:2) MPs displayed comparable and high macrophage uptake, antitubercular efficacy against macrophage internalised M. tuberculosis was significantly higher with PL (1:2) MPs. This suggested great promise of the pH-sensitive PL (1:2) MPs for enhanced antitubercular efficacy.

Investigating the effects of the core nitrogen atom configuration on the thermodynamic solubility of 6,5-bicyclic heterocycles.

Physicochemical properties, such as solubility, are important when prioritising compounds for progression on a drug discovery project. There is limited literature around the systematic effects of core changes on thermodynamic solubility. This work details the synthesis of nitrogen containing 6,5-bicyclic heterocyclic cores which are common scaffolds in medicinal chemistry and the analysis of their physicochemical properties, particularly, thermodynamic solubility. Crystalline solids were obtained where possible to enable a robust comparison of the thermodynamic solubility. Other parameters such as pKa, melting point and lipophilicity were also measured to determine the key factors affecting the observed solubility.

Design and development of a biorelevant simulated human lung fluid.

Biorelevant fluids are required to enable meaningful in vitro experimental determinations of the biopharmaceutical properties of inhaled medicines, e.g. drug solubility, particle dissolution, cellular uptake. Our aim was to develop a biorelevant simulated lung fluid (SLF) with a well-defined composition and evidence-based directions for use. The SLF contained dipalmitoylphosphotidylcholine, dipalmitoylphosphatidylglycerol, cholesterol, albumin, IgG, transferrin and antioxidants. Freshly made SLF had pH 7.2, viscosity 1.138 × 10-3 Pa s, conductivity 14.5 mS/m, surface tension 54.9 mN/m and density 0.999 g/cm3. Colour, surface tension and conductivity were the most sensitive indicators of product deterioration. The simulant was stable for 24 h and 48 h at 37 °C and 21 °C, respectively, (in-use stability) and for 14 days when stored in a refrigerator (storage stability). To extend stability, the SLF was vacuum freeze-dried in batches to produce lyophilised powder that can be reconstituted readily when needed at the point of use. In conclusion, we have reported the composition and manufacture of a biorelevant, synthetic SLF, provided a detailed physico-chemical characterisation and recommendations for how to store and use a product that can be used to generate experimental data to provide inputs to computational models that predict drug bioavailability in the lungs.