Development of implantable devices for schizophrenia treatment

Abstract

Schizophrenia is a psychotic condition produced by abnormal levels of neurotransmitters in the brain. One of the drugs that is commonly prescribed to treat schizophrenia is risperidone (RIS). This drug is administered through the oral route (e.g. tablets). Accordingly, the drug is exposed to first-pass metabolism and enzymatic degradation in the gastrointestinal tract. Besides, it also can be administered as long-acting intramuscular injections. However, the administration of this injection is painful and not comfortable. Importantly, the target site of RIS is the central nervous system and accordingly, this drug needs to cross the blood-brain barrier. This drug is capable of crossing the barrier by first circulating systemically causing potential side effects. To overcome this problem, intranasal administration can be an alternative not only to improve brain-targeting drug efficacy, but also to reduce drug dosage and minimise systemic side effects since the human nasal cavity provides direct transport from the nose to the brain. Therefore, intranasal implantable devices containing RIS was developed in this thesis to provide improved treatment of schizophrenia. This approach combines the advantages of implantable drug delivery systems and intranasal drug delivery systems. These implants can provide a prolonged and more efficient drug delivery into the brain. In order to develop this type of system, the first step was to validate an appropriate analytical method according to ICH guidelines for drug content and drug release analysis. RIS-loaded implants were developed using poly(caprolactone) (PCL), a biodegradable and biocompatible polymer. In addition, PCL was also combined with poly(ethylene glycol) (PEG) 600, PEG 3000, and Tween® 80 in order to modify drug release profiles. The obtained implants were subsequently characterised. It was revealed that implants made of the combinations of PCL and PEG 600, PEG 3000, and Tween® 80 exhibited significant faster release profiles compared to pure PCL-based implants. Moreover, a lower concentration of RIS in the formulations was able to provide more sustained drug release profiles. The permeability of RIS released from the implants through a model membrane simulating nasal mucosa was subsequently evaluated. Finally, following in vitro biocompatibility studies, PCL and PCL containing RIS showed acceptable biocompatibility. These studies were still at an early stage, hence further investigations, including pharmacokinetics, drug distributions and pharmacodynamics studies, are required in order to assess the benefits of the proposed devices using suitable animal models. Moving forward, clinical studies are also important to ensure drug safety, drug efficacy, and patient acceptability before this type of devices can be marketed.

Thesis embargoed until 31 December 2026.

Date of Award	Dec 2021
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Eneko Larrañeta (Supervisor), Ryan Donnelly (Supervisor) & Juan Dominguez Robles (Supervisor)