ABSTRACT
The use of fluid bed granulation for drying of pharmaceutical nanoparticulates on micron-sized granule substrates is a relatively new technique, with limited understanding in the current literature of the effects of process parameters on the physical properties of the dried nanoparticle powders. This work evaluated the effects of spray mode, spray rate and atomizing pressure for spray granulation of drug nanosuspensions through a systematic study. Naproxen and a proprietary Novartis compound were converted into nanosuspensions through wet media milling and dried onto a mannitol based substrate using spray granulation. For naproxen, various physical properties of the granules, as well as the in vitro re-dispersion and dissolution characteristics of the nano-crystals, were measured. It was found that the spray mode had the most drastic effect, where top spray yielded smaller re-dispersed particle sizes and faster release rates of drug from granules than bottom spray. This was attributed to the co-current spraying in bottom spray resulting in denser, homogenous films on the substrate. Similar in vitro results were obtained for the proprietary molecule, Compound A. In vivo studies in beagle dogs with Compound A showed no significant difference between the liquid and the dried forms of the nanosuspension in terms of overall AUC, differences were observed in the tmax which correlated with the rank ordering observed from the in vitro dissolution profiles. These findings make spray granulation amenable to the production of powders with desired processing and handling properties, without compromising the overall exposure of the compound under investigation.
Subject(s)
Nanoparticles/chemistry , Naproxen/chemistry , Technology, Pharmaceutical/methods , Animals , Area Under Curve , Chemistry, Pharmaceutical/methods , Desiccation , Dogs , Drug Stability , Male , Mannitol/chemistry , Microscopy, Electron, Scanning , Nanotechnology , Particle Size , Powders/chemistry , Solubility , Surface Properties , X-Ray DiffractionABSTRACT
BACKGROUND: Freeze-drying is an attractive method for converting nanoparticulate pharmaceutical dispersions into a stable form with a long shelf life. However, practical challenges in translating laboratory practice to the clinic, such as high protectant osmolarity and infeasible reconstitution methods, currently limit lyophilized formulation development of nanoparticle therapeutics. RESULTS: We demonstrate the use of effervescent redispersion for the reconstitution of lyophilized polymeric nanoparticles and we show that a 3:1 mass ratio of effervescent salt produced the optimum redispersibility. With only low-energy hand agitation, reconstitution to sizes less than 600 nm was achieved. Second, the effect of nanoparticle formulation parameters (dispersion concentration, molecular weight of the stabilizing polymer, and physical state of the nanoparticle core) on particle redispersibility were examined. CONCLUSION: This novel freeze-drying and reconstitution method offers a route to producing redispersible dry powders of nanoparticle therapeutics.
Subject(s)
Drug Compounding/methods , Nanoparticles , Polymers/chemistry , Drug Stability , Drug Storage , Freeze Drying , Molecular Weight , Particle Size , Polyethylene Glycols/chemistry , Polystyrenes/chemistry , Powders , Salts/chemistryABSTRACT
BACKGROUND: Progesterone (PG), a promising therapeutic for treating traumatic brain injury, has been difficult to formulate into a high-dose/low-volume form for emergency intravenous administration due to its hydrophobicity and crystallinity. RESULTS: This work demonstrates the use of Flash NanoPrecipitation to produce 300-nm PG-loaded polymeric nanoparticles with approximately 24 wt% drug loading using only components that are classified by the US FDA as generally recognized as safe. Approximately 80% of the encapsulated PG is in dissolved, rather than crystalline form. For prolonged stability, the nanoparticles are freeze-dried with Pluronic F68 and can be reproducibly reconstituted by hand agitation for 1 min without particle aggregation to produce injectable formulations with approximately 30-mg/ml PG, which is more than ten-times higher than has been previously reported. CONCLUSION: This formulation can allow for administration of therapeutically viable concentrations of PG, which has been impossible with all previously reported nanoparticulate formulations because of low drug loadings and concentrations.
