Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 105, Issue 3, Pages 1209-1220Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.xphs.2015.12.016
Keywords
Parkinson's disease; rheology; nasal; RPMI 2650; nose to brain; thermoresponsive
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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 (R) 127 and either carboxymethyl cellulose or chitosan which demonstrated gel transition at nasal cavity temperatures (34 +/- 1 degrees C). Rheologically, the loss tangent (Tan delta) confirmed a 3-stage gelation phenomena at 34 +/- 1 degrees C and non Newtonian behavior. Storage of optimized formulation carboxymethyl cellulose and optimal formulation chitosan at 4 degrees C for 8 weeks resulted in repeatable release profiles at 34 degrees C when sampled, with a Fickian mechanism earlier on but moving toward anomalous transport by week 8. Polymers (Pluronic (R) 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 degrees) resulted in greater deposition in the bulk of the nasal cavity. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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