Intranasal Drug Delivery Of Donepezil Hydrochloride Loaded Poly Lactic Co-glycolic Acid Nanoparticles: A Non-invasive Approach For Brain Targeting

Abstract

Introduction: Alzheimer’s disease is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and a variety of neuropsychiatric symptoms. Genetic and environmental variables impact the chance of getting the illness, but age is the most important risk factor. Disease often present itself initially as short term memory loss, but eventually the disease leads to loss of body functioning and ultimately to death. The available cholinesterase inhibitors for the treatment of disease showed peripheral side effects such as muscle convulsions, nausea, diarrhea, anorexia etc. The major hurdle in its treatment is poor transportation of drug(s) to the brain via systemic circulation through the blood-brain barrier. Thus, there is a need to develop alternative and potential drug delivery systems for the transport of drugs to the brain bypassing the bloodbrain barrier. In this case intranasal administration looks to be preferable over oral administration as it avoid problems like first pass metabolism, restricted brain exposure etc. and it directly delivers the drug to brain via olfactory pathway due to which there is less wastage of drug through systemic clearance. This route is safe, easy, self-administered, noninvasive and have high level of patient compliance. But due to some reasons like poor drug permeability, mucocilliary clearance, nasal irritation, running nose affects the residence of drug in the nasal cavity. So there is a need of a suitable dosage form which can reside in the nasal mucosa and release the drug in the sufficient amount at the target site. Polymeric nanoparticles are one of those suitable dosage forms which can reside in the nasal mucosa and release the drug in a sustained manner when it is incorporated within the polymeric carrier. Objectives: This work deals with the preparation of polymeric nanoparticulate drug delivery system of donepezil hydrochloride for direct delivery of drug from nose to brain. The therapeutic chemicals are highly preserved in these polymeric dosage forms, which have the benefit of delivering medicines to tissues in a sustained manner, eliminating recurrent drug administration. These also offer the possibility of achieving site-specific distribution. Materials and method: The donepezil hydrochloride loaded nanoparticles were prepared using polylactic-co-glycolic acid as polymer and poloxamer-407 as a stabilizer by the emulsion-diffusion solvent evaporation method. PLGA is a widely used polymer in the preparation of nanoparticles. It is biocompatible, biodegradable in nature, and resorbable through neuronal pathways also has the ability to sustain or control the release of the drug. Manufacturing of PLGA NP-based medicinal products may be more efficient and of higher quality. The components ratio were optimized by using Central Composite Design. With the help of optimization studies we got in built quality in the formulation with the required attributes. Result and discussion: The prepared nanoparticles suspension were found to have pH (6.8) which shows the stability of the formulation because this pH matches the nasal physiological pH therefore is suitable for the nasal formulations and the particles were found to have a particle size (260.64 nm) which is suitable for the brain delivery because due to their small size these particles can penetrate through the nasal mucosa and reaches to brain in sufficient amount, zeta potential (+5mv) as the nanoparticles are having mucoadhesive nature the charge on these particles is suitable for nasal administration., drug payload (31.22%), and process yield (80.40%). The in-vitro drug release studies of optimized formulation show the 97.83% drug release and the ex-vivo permeation studies show the 22.88% drug permeation in 24 hours, both follow the Korsmeyer Peppas kinetic model i.e. for the sustained release from the polymeric system. Conclusion: The results have shown the promising potential of the developed formulation for the nose to brain delivery. Based on previously mentioned studies it can be concluded that donepezil loaded NPs were prepared successfully with suitable attributes for nasal administration. Further, pre-clinical and clinical studies need to be carried out to validate the therapeutic attribute of nanoparticles.