title: Cryoprotection-lyophilization and physical stabilization of rifampicin-loaded flower-like polymeric micelles.
abstract: Rifampicin-loaded poly(ε-caprolactone)-b-poly(ethylene glycol)-poly(ε-caprolactone) flower-like polymeric micelles display low aqueous physical stability over time and undergo substantial secondary aggregation. To improve their physical stability, the lyoprotection-lyophilization process was thoroughly characterized. The preliminary cryoprotectant performance of mono- and disaccharides (e.g. maltose, glucose), hydroxypropyl-β-cyclodextrin (HPβCD) and poly(ethylene glycol) (PEG) of different molecular weights was assessed in freeze-thawing assays at -20°C, -80°C and -196°C. The size and size distribution of the micelles at the different stages were measured by dynamic light scattering (DLS). A cryoprotectant factor (f(c)) was determined by taking the ratio between the size immediately after the addition of the cryoprotectant and the size after the preliminary freeze-thawing assay. The benefit of a synergistic cryoprotection by means of saccharide/PEG mixtures was also assessed. Glucose (1 : 20), maltose (1 : 20), HPβCD (1 : 5) and glucose or maltose mixtures with PEG3350 (1 : 20) (copolymer:cryoprotectant weight ratio) were the most effective systems to protect 1 per cent micellar systems. Conversely, only HPβCD (1 : 5) cryoprotected more concentrated drug-loaded micelles (4% and 6%). Then, those micelle/cryoprotectant systems that displayed f(c) values smaller than 2 were freeze-dried. The morphology of freeze-dried powders was characterized by scanning electron microscopy and atomic force microscopy and the residual water content analysed by the Karl Fisher method. The HPβCD-added lyophilisates were brittle porous cakes (residual water was between 0.8% and 3%), easily redispersable in water to form transparent systems with a minimal increase in the micellar size, as determined by DLS.
authors.affiliation: The Group of Biomaterials and Nanotechnology for Improved Medicines (BIONIMED), Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires 1113, Argentina.
authors.forename: Marcela A
authors.initials: MA
authors.lastname: Moretton
authors.forename: Diego A
authors.initials: DA
authors.lastname: Chiappetta
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sosnik
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003451:Cryoprotective Agents / Q000737:chemistry*; D004187:Disaccharides; D016503:Drug Delivery Systems / Q000379:methods*; D005612:Freeze Drying / Q000379:methods*; D008823:Micelles; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D009005:Monosaccharides; D036103:Nanotechnology / Q000379:methods; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012293:Rifampin / Q000737:chemistry*; D012995:Solubility; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D003451:Cryoprotective Agents; D004187:Disaccharides; D008823:Micelles; D009005:Monosaccharides; D011091:Polyesters; C515340:poly(epsilon-caprolactone)-b-poly(ethyleneglycol)-b-poly(epsilon-caprolactone); D011092:Polyethylene Glycols; D012293:Rifampin