Brain‐targeted intranasal formulation of Centella asiatica: A potential strategy for treating Alzheimer’s disease

Abstract

AbstractBackgroundA major drawback associated with the conventional AD therapy is the inability of drugs to cross Blood Brain Barrier (BBB). Although, many drugs show potential to dissolve amyloid protein in vitro, only few mimics this action in vivo due to hindrance by BBB. One such drug is Centella asiatica containing asiaticoside that is proven to dissolves amyloid protein in vitro but lacks in vivo effects.MethodThe study was designed to develop a nasal formulation of an herbal drug (Centella asiatica) using brain targeted polymers to bypass the BBB to enhance the penetration of Centella in the brain.The extract of C. asiatica was first encapsulated into β‐ cyclodextrin by acid‐base precipitation method. These particles were nanonised and encapsulated into thiolated eudragit (TE) by ionic gelation method. The nanoparticles were characterized by FTIR, XRD, DLS, SEM, AFM and Ex ‐ vivo permeation studies. MTT assay was performed using Human Umbilical cord Vein Endothelial Cells (HUVECs) mimicking Blood‐Brain‐Barrier (BBB) to establish the safety and permeability of NPs. Further, the targeting efficacy was confirmed by molecular docking studies against receptors Sphingosine‐1‐Phosphate receptor 1 and Low‐density lipoprotein Receptor‐related Protein associated with BBB.ResultFTIR and XRD studies confirmed encapsulation of Centella into beta cyclodextrin and TE. Nanoparticle characterization confirmed the size and stability of the particles with zeta potential of −10.43 mV and Pdi of 0.260. NPs showed no signs of nasal ciliotoxicity and had good permeation of 88.44 ± 2.65 % (Mean ± SD, n=3) at 8h across nasal mucosa. MTT assay showed that the nanocomposite had lesser toxicity and better permeability compared to free drug (IC50 of Centella – 269.1 μg/mL and IC50 of nanoformulation – 310.625 μg/mL). The affinity of polymer to the receptors associated to BBB was proved by docking studies proves the ability of polymer‐based NPs to concentrate in brain post nasal administration.ConclusionThe study successfully showed that the NPs containing Centella had better permeability across BBB that could be beneficial in treating AD when administered intranasally.