Nanoparticles based drug delivery platform to improve oral uptake for the treatment of Alzheimer’s disease
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AbstractAlzheimer’s disease (AD) is a rapidly progressive chronic neurodegenerative disease, which eventually leads to brain damage. Despite combined efforts of the research community, no fully effective treatment has been identified yet. Drug delivery is a major issue in neurodegenerative diseases due to the complexity of the diseases but the difficulty in accessing targets. A medicine is only effective if it reaches its target. As such, while some active molecules can be demonstrated very efficiently in vitro, side effects and unreachable targets bring delivery at the forefront of drug efficiency. Rivastigmine is one of the reversible Acetylcholinesterase (AChE) Inhibitors, which is used for the treatment of mild to moderate dementia of either AD or Parkinson’s disease (PD). As a cholinesterase inhibitor, its role is to inhibit AChE activity to maintain ACh level by decreasing its breakdown rate, therefore boosting cholinergic neurotransmission in forebrain regions and compensate for the loss of functioning brain cells Rivastigmine has shown some success in improving ACh level in AD patients and also inhibiting amyloid plaques deposition in the brain. It is commercially available in different forms including oral solutions, tablets, and patches but therapeutic regimens require frequent dosing causing fluctuations is the plasma level. Whereas the oral form has been associated with a high incidence of gastrointestinal side effects, the transdermal patch formulation has been shown to have a better tolerability profile but adverse dermatologic reactions remain a concern. In addition, an important safety concern persists with dermal application with the risk of treatment overdose by administering multiple patches at the same time, potentially leading to fatal outcomes. Therefore, the oral form could be safer if its side effects could be controlled. Following initial uptake, crossing the blood-‐brain barrier (BBB) is another major obstacle to be considered. Due to its hydrophilic nature, rivastigmine efficacy is also restricted by its poor ability to cross BBB. Its bioavailability is reported to be only up to 35%. To overcome these issues, this work has focused on the delivery of rivastigmine, particularly its uptake with nanoparticle-‐based formulations that can facilitate uptake, protect the active molecule from early degradation, and provide targeted delivery while preventing side effects due to unwanted interactions. Rivastigmine loaded nanoparticles have previously been designed and proven to have numerous fundamental properties that assist their effectiveness such as biocompatibility, lack of toxicity, reduced side effects, and increased tolerated dose of the drug but not effective enough for the treatment. Their enhanced retention time within the systemic circulation and their ability to cross BBB still remains challenging. The novel formulations designed in this study were designed for slow release to prevent cytotoxicity while providing stability and high uptake in GI tract to reach the systemic circulation. Biodegradable composition of these formulations will prevent the risks that may contribute to accumulation of inorganic material inside the brain. As the aim of the research is the successful targeted delivery of Rivastigmine, the first objective of this study was to design an efficient method to monitor and analyse delivery, using UPLC in an analytical set up standardised using in house developed standard solutions. In the second part of this study, several formulations were designed and investigated to improve rivastigmine intestinal uptake, where both negatively and positively charges drug loaded nanoparticles were formulated. In the third part of this work ,a Caco-‐2 cell duodenal model was used to assess membrane permeability, uptake, and intake of Rivastigmine. Cytotoxicity of nanoformulations was determined by MTT assay showing low toxicity in the case of rivastigmine-‐loaded nanoparticles. The final results of this study demonstrate that nanoparticle formulations provide a slower stable release of rivastigmine from nanoparticles than previously designed nanoformulations. I addition, some of these formulations provide high bioavailability over both apical and basal membrane, therefore, providing higher intake to target the BBB, with limited unwanted interaction in the intestine therefore limiting the major concern about side effects
CitationKaur, G. (2020) 'Nanoparticles based drug delivery platform to improve oral uptake for the treatment of Alzheimer’s disease'. Master of Philosophy. University of Bedfordshire.
PublisherUniversity of Bedfordshire
TypeThesis or dissertation
DescriptionA thesis submitted to the University of Bedfordshire, in partial fulfilment of the requirements for the degree of Master of Phiosophy.
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