Development and In Vitro-Ex Vivo Evaluation of Novel Polymeric Nasal Donepezil Films for Potential Use in Alzheimer’s Disease Using Experimental Design

Abstract

The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer’s disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, as permeation enhancer (factor C), were prepared and characterized in vitro and ex vivo. An experimental design was used to determine the effects of the selected factors on permeation profile of DH through rabbit nasal mucosa (response 1), and on film flexibility/foldability (response 2). A face centered central composite design with three levels was applied and 17 experiments were performed in triplicate. The prepared films exhibited good uniformity of DH content (90.0 ± 1.6%–99.8 ± 4.9%) and thickness (19.6 ± 1.9–170.8 ± 11.5 μm), storage stability characteristics, and % residual humidity (<3%), as well as favourable swelling and mucoadhesive properties. Response surface methodology determined the optimum composition for flexible nasal film with maximized DH permeation. All selected factors interacted with each other and the effect of these interactions on responses is strongly related to the factor’s concentration ratios. Based on these encouraging results, in vivo serum and brain pharmacokinetic study of the optimized nasal film, in comparison to DH oral administration, is ongoing in an animal model.

Donepezil Brain and Blood Pharmacokinetic Modeling after Nasal Film and Oral Solution Administration in Mice

“…However, limited information on pharmacokinetic modeling has been formerly published to serve this purpose. In the present study, a four-stage compartmental PK approach was built based on the Per Os and IN data of donepezil oral solution and the recently developed nasal film [ 29 ]. The effectiveness of this nasal film compared to an oral solution on donepezil delivery in both brain and systemic circulation is depicted in C max (5.7 and 3.9 times higher, respectively, at each site) and AUC values (3.1 and 1.4 times higher, respectively, at each site) obtained using the non-compartmental analysis performed in our previous work [ 23 ].…”

The Potential of Films as Transmucosal Drug Delivery Systems

“…The polymers used to manufacture the films were PVA and HPMC, the latter being the most cited. In all studies, the production method used was solvent casting and the intended administration was through the blood-brain barrier to reach the CNS; two of them were used for Alzheimer's disease treatment [108,109] and the other was used for treatment of anosmia in patients after COVID-19 infection [110]. Below, we will explore an example of recently published studies that were successful in the development of nasal films.…”

“…Mucoadhesive Nasal Film for Nose-to-Brain Delivery of Donezepil Papakyriakopoulou et al [108] developed HPMC films containing donepezil hydrochloride, a reversible acetylcholinesterase inhibitor (AChEI), for nose-to-brain administration for treatment of Alzheimer's disease. PEG 400 was used as a plasticizer, and methyl -β-cyclodextrin (Me-β-CD) was used as an absorption promoter.…”