title: Development and Evaluation of a Novel Intranasal Spray for the Delivery of Amantadine.
abstract: The aim of this study was to develop and characterize an intranasal delivery system for amantadine hydrochloride (AMT). Optimal formulations consisted of a thermosensitive polymer Pluronic® 127 and either carboxymethyl cellulose or chitosan which demonstrated gel transition at nasal cavity temperatures (34 ± 1°C). Rheologically, the loss tangent (Tan δ) confirmed a 3-stage gelation phenomena at 34 ± 1°C and non-Newtonian behavior. Storage of optimized formulation carboxymethyl cellulose and optimal formulation chitosan at 4°C for 8 weeks resulted in repeatable release profiles at 34°C when sampled, with a Fickian mechanism earlier on but moving toward anomalous transport by week 8. Polymers (Pluronic® 127, carboxymethyl cellulose, and chitosan) demonstrated no significant cellular toxicity to human nasal epithelial cells up to 4 mg/mL and up to 1 mM for AMT (IC50: 4.5 ± 0.05 mM). Optimized formulation carboxymethyl cellulose and optimal formulation chitosan demonstrated slower release across an in vitro human nasal airway model (43%-44% vs 79 ± 4.58% for AMT). Using a human nasal cast model, deposition into the olfactory regions (potential nose-to-brain) was demonstrated on nozzle insertion (5 mm), whereas tilting of the head forward (15°) resulted in greater deposition in the bulk of the nasal cavity.
authors.affiliation: School of Life and Health Sciences, Department of Pharmacy, Aston University, Birmingham, UK.
authors.forename: Shital
authors.initials: S
authors.lastname: Lungare
authors.affiliation: Department of Engineering and Innovation, The Open University, Milton Keynes, UK; School of Chemical Engineering, University of Birmingham, Birmingham, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bowen
authors.affiliation: Aston Research Centre for Healthy Ageing, Life and Health Sciences, Aston University, Birmingham, UK. Electronic address: r.k.s.badhan@aston.ac.uk.
authors.forename: Raj
authors.initials: R
authors.lastname: Badhan
mesh_terms: D000281:Administration, Intranasal; D000547:Amantadine / Q000008:administration & dosage* / Q000737:chemistry*; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods; D048271:Chitosan / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004847:Epithelial Cells / Q000378:metabolism; D005782:Gels / Q000737:chemistry; D006801:Humans; D009296:Nasal Cavity / Q000187:drug effects*; D059085:Nasal Sprays; D020442:Poloxamer / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D013696:Temperature; D014783:Viscosity
chemical_list: D005782:Gels; D059085:Nasal Sprays; D011108:Polymers; D020442:Poloxamer; D048271:Chitosan; D000547:Amantadine; D002266:Carboxymethylcellulose Sodium
keywords: Parkinson's disease; RPMI 2650; nasal; nose to brain; rheology; thermoresponsive