Untitled

Abstract

Aim: The purpose of the present study was to formulate in situ gelling formulation combining nanostructured lipid carrier of donepezil and an ionic-triggered gellan gum matrix following intranasal administration for the treatment of Alzheimer's disease. Materials and Methods: Donepezil-loaded lipid carrier was prepared by a melt emulsification-probe sonication method, optimized, and characterized. Nanostructured lipid carrier was incorporated into gellan gum-based in situ gel and characterized for in situ gelling properties, rheological properties, and texture analysis. The developed formulation was evaluated in vivo through pharmacodynamic and pharmacokinetic study in rats. Results and Discussion: In vivo efficacy tested in scopolamine-induced amnesia model indicated a significant improvement in cognitive function in rat treated with in situ gel as compared to the marketed formulation. A pharmacokinetic study showed the higher drug distribution in brain and lower drug concentration in plasma from a developed formulation which indicates its higher safety and efficacy through a nasal route. Conclusion: Thus, nanostructured lipid carrier-based in situ gel administered through intranasal route can be clinically promising approach for enhancing efficacy through the brain and reducing toxicity to other organs.

Combined Donepezil with Astaxanthin via Nanostructured Lipid Carriers Effective Delivery to Brain for Alzheimer’s Disease in Rat Model

“…Su et al 65 demonstrated that donepezil prevented spatial memory impairment induced by isoflurane. Butani 16 reported that rats treated with DPL–NLC gel (IN) showed a significant enhancement in cognitive function compared to the marketed oral donepezil formulation in a scopolamine-induced amnesia model in the MWM test.…”

“… 20 , 30 Oral administration of donepezil produces gastrointestinal adverse events, and in addition it has poor ability to penetrate the BBB as it is a hydrophilic drug, and it suffers from hepatic first-pass metabolism. 8 , 16 Astaxanthin shows low oral bioavailability due to its high lipophilicity. 27 The intranasal (IN) route was used in the present study as an alternative non-invasive approach to restrict the limitations associated with oral administration of donepezil and astaxanthin for better brain targeting of both drugs.…”

“… 211 , 212 Furthermore, NLCs can accommodate both hydrophilic and lipophilic drugs, and dual drug-loaded NLCs have been successfully prepared in previous studies. 33 , 34 , 213 In previous studies, NLCs have been shown to successfully deliver hydrophilic donepezil 16 or lipophilic astaxanthin 29 individually to the brain through the IN route, and they showed sustained drug release and high encapsulation efficiency and stability. In our previous study, astaxanthin was loaded alone in NLCs for IN delivery to the brain, and we examined the different neuroprotective effects of astaxanthin in AD-like model.…”

“… 7 , 8 In several previous studies, the intranasal (IN) route was used as an alternative non-invasive approach in order to avoid these issues, which allows direct delivery of donepezil to the brain through the trigeminal and olfactory pathways in the nose, avoiding the BBB and hepatic first-pass metabolism and minimized systemic exposure and side effects associated with the oral administration of donepezil. 12 In addition, donepezil was incorporated in different nanosystems, like nanoemulsions, 13 solid lipid nanoparticles (SLNs), 14 liposomes, 15 and nanostructured lipid carriers (NLCs), 16 in order to overcome the enzymatic degradation and quick removal of donepezil from the nasal cavity and to extend its nasal residence in order to improve the nasomucosal permeability and enhance nose to brain delivery of donepezil for better brain targeting. 17 Clinically, early and continuous long-term treatment of AD with donepezil is considered to preserve cognitive function more effectively than delayed treatment.…”

“…In previous studies, NLCs have been shown to successfully deliver hydrophilic donepezil or lipophilic astaxanthin individually through the IN route to the brain. Butani 16 prepared NLCs loaded with donepezil and incorporated the developed DPL–NLCs in an in situ gel formulation for the treatment of AD. IN treatment of AD-like rats with the developed DPL–NLC gel formulation showed a significant enhancement in cognitive function and higher drug concentration in the brain than the marketed oral donepezil formulation.…”