Abstract
Alzheimer's disease is a chronic progressive neurodegenerative disorder associated with depletion of acetylcholine. Oral treatment with tacrine hydrochloride; a reversible inhibitor of acetylcholinesterase, finds limited use in Alzheimer's disease due to frequent dosing, hepatotoxicity and extensive pre-systemic metabolism. The objective of the study was to evaluate pharmacokinetic, pharmacodynamic, safety and stability profile of transdermal w/o nanoemulsion gel of tacrine hydrochloride and determine its relative bioavailability from transdermal nanogel in contrast to marketed capsule and conventional hydrogel. The optimized nanoemulsion gel NEGT4 (droplet size 156.4 ±0.48 nm, with poly dispersity index 0.36 ±0.4, permeation flux 6.172±2.94 µg/cm2/h across rat skin) was prepared by spontaneous emulsification followed by sonication. NEGT4 contained 7 mg of drug in 10% w/w distilled water, 30% w/w surfactant (Labrafil M) and cosurfactant (Transcutol P) mixture in ratio 1:4 and 60 % Capryol 90 as oily phase thickened with 98.9 mg ethyl cellulose (20 cps). In vivo studies were carried out on male Wistar rats following standard guidelines. Scopolamine was used to induce amnesia in rats which is a characteristic of Alzheimer's disease. Various formulations were compared by performing pharmacokinetic, histopathological, behavioural and biochemical studies on rats. Stability studies on nanoemulsion gels were carried out in accordance with The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Pharmacokinetic studies exhibited significantly greater extent of absorption from NEGT4 in comparison to capsule and hydrogel with a 2.18 and 5.26-fold increase respectively. Significant improvement in neurobehavioral parameters was observed with NEGT4 in scopolamine-induced amnesic rats. Biochemical assessment showed superior anti-amnesic activity of NEGT4 through augmentation of antioxidant enzymes, decreased lipid peroxidation and acetylcholinesterase activity. Low value of serum aminotransferase in rats treated with NEGT4 indicated the absence of hepatotoxicity. NEGT4 was found to be non-irritant and possessed a shelf life of 4.11 years. Developed nanoemulsion gel of tacrine hydrochloride was found to be safe, stable, and efficacious and has immense potential to be used in the therapy of Alzheimer's disease.
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