Transdermal sustained delivery of a hydrophobic drug substance using novel polymeric microneedle systems

Abstract

Schizophrenia is a chronic mental disorder, representing a massive obstacle in patients life. It affects patients in several aspects, including their relationship with reality, productivity and independency. Families that have a member with schizophrenia are highly affected, due to the dependency of patients on their families and the economic considerations related to the treatment cost or the unproductivity of patients. Furthermore, these economic consequences reflect a burden on the economy of the entire society. For instance, schizophrenia cost the United States of America (USA) $281.6 billion in 2020. The significant impact of schizophrenia can be reduced by managing the symptoms and enhancing the life quality of patients. To manage schizophrenia symptoms and reduce the risk of relapse, a regular intake of antipsychotics as prescribed is required. Mention should be made that patients with chronic conditions generally tend to poorly adhere to their prescribed medications. With schizophrenia, lack of illness insight is an additional factor contributing to the poor medication adherence that patients tend to have. Antipsychotics are available in limited dosage forms, mainly oral and injectable formulations. Once or twice daily intake is required for oral forms, whereas injectable formulations are administered once or twice per month.
However, although injectable antipsychotics were designed to enhance adherence, they are invasive, painful, and require a professional healthcare provider which negatively impacts the compliance of patients. More interests are being directed toward transdermal antipsychotic formulation as a non or mini-invasive self-administered dosage forms. Microneedles (MNs) technology is an emerging transdermal delivery system allows overcoming the skin physical barrier and delivers molecules into the systemic circulation. For sustaining drug release using MNs, formulation compositions can be modulated to incorporate the drug and extend the release over time. In this work, three MNs systems were developed to deliver Fluphenazine (FLU), namely dissolving MNs, nanoemulsion (NE) loaded MNs and poly(lactic-co-glycolic acid) (PLGA) tipped MNs. All MNs systems were characterised based on their insertion properties, drug loading, short application time and ex vivo delivery efficacy using full thickness neonatal porcine skin. Eventually, FLU sustained transdermal delivery from each of the three systems was investigated through plasma pharmacokinetics in vivo study on rats, where FLU plasma release profile was compared to an intramuscular injection (IM) of FLU-D in sesame oil and oral FLU suspension as controls. The successful intradermal delivery of FLU using each of the developed MNs systems proves the feasibility of MNs in delivering hydrophobic antipsychotics intradermally. This novel work supports the ability, flexibility and efficacy of MNs to deliver drugs into the systemic circulation. Before translating these MNs formulations into the market, several regulatory and manufacturing considerations must be standardised.

Thesis embargoed until 31 July 2027

Date of Award	Jul 2022
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Isra University
Supervisor	Ryan Donnelly (Supervisor) & Eneko Larrañeta (Supervisor)