title: Nanoparticle agglomerates of indomethacin: The role of poloxamers and matrix former on their dissolution and aerosolisation efficiency.
abstract: Nanoparticles (NPs) were prepared and assembled to microsized agglomerates with and without matrix formers (mannitol and L-leucine) by coupling wet milling and spray drying to harmonise the advantages of NPs with handling and aerodynamics of microparticles without induction of amorphisation. Indomethacin was selected as poorly water-soluble drug and poloxamers with different ratios of hydrophilic to hydrophobic domains were evaluated as stabilisers comparatively to D-α-Tocopherol polyethylene-glycol succinate (TPGS). Particle size of nanosuspensions and morphology, size, crystal form, drug loading, redispersibility, in vitro dissolution, and in vitro aerosolisation of NP-agglomerates were determined. Molecular weight of stabilisers affected the rate but not the limit of NP size reduction and the length of hydrophilic segment in poloxamers was found important for the nanosuspension stabilisation. SEM revealed the structure of agglomerates consisting of nanocrystal assemblies. XRPD with DSC proved that NP agglomerates retained their crystallinity. NP-agglomerates exhibited enhanced dissolution compared to physical mixtures of drug and stabilisers while incorporation of matrix formers enabled redispersibility upon hydration and further increased the drug dissolution. Also, matrix formers resulted in significantly improved aerosolisation with higher fine particle fractions (49-62%) and smaller mass median aerodynamic diameters (<3.5 μm), compared to cases without matrix formers (34-43% and <4.5 μm).
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Malamatari
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Somavarapu
authors.affiliation: GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Bloxham
authors.affiliation: UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK. Electronic address: g.buckton@ucl.ac.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Buckton
mesh_terms: D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000379:methods; D065546:Drug Liberation; D058995:Dry Powder Inhalers; D007213:Indomethacin / Q000008:administration & dosage* / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014961:X-Ray Diffraction
chemical_list: D020442:Poloxamer; D007213:Indomethacin
keywords: Dry powder inhalation; Indomethacin; Nanomilling; Nanoparticle agglomerates; Poloxamers; Spray drying