Development of long-acting Naltrexone loaded EVA subcutaneous implants for the treatment of opioid dependence

Drávavölgyi, Gábor (2022). Development of long-acting Naltrexone loaded EVA subcutaneous implants for the treatment of opioid dependence. University of Birmingham. Ph.D.

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Abstract

Opioid dependence has become an essential and severe public health crisis in the last two decades. An overwhelming increase in overdose deaths and public health department visits linked to the misuse of illicit and prescription opioids are highly publicised aspects of the opioid epidemic. Among several strategies, medication-assisted therapies have proven to be the most effective way to tackle the opioid epidemic. Naltrexone (NTX) is one of the most widely used drugs among the accepted pharmaceutical treatment options. Oral dosage forms of NTX have been commercially available since 1994 to treat opioid dependence. However, orally taken NTX formulations have several limitations, which may subsequently reduce the efficacy of the pharmacotherapy. First, the oral bioavailability of NTX is low, ranging from 5 to 40%, due to the extensive first-pass hepatic metabolism. Therefore, high orally taken daily doses are required to achieve an effective pharmacological response. This results in a repetitive fluctuation in drug plasma concentration that may cause mild or severe side effects. Second, the oral route of administration requires strict patient dosing compliance.

Several attempts have been made to develop innovative NTX formulations to address these limitations. These subdermal implantable or injectable extended-release NTX formulations bypass the gastrointestinal tract, enhance patients’ adherence to the medication, ensure constant NTX blood levels and improve patient convenience by reducing dosing frequency. Unfortunately, most of them are under development or in a clinical phase. Moreover, they require complex manufacturing processes, increasing the cost of the final products and consequently decreasing the accessibility of such innovative and more effective NTX-based pharmacotherapies for poorer social classes.

In this research project, the main aim was to develop novel subcutaneously implantable long-acting poly(ethylene-co-vinyl) acetate (EVA)-based formulations of both the hydrochloride salt form of NTX (NTX HCl) and its neutral base form (NTX base) prepared using a cost-effective one-step hot-melt extrusion (HME) process. HME is a solvent-free, continuous technology that can be easily scaled for mass production. The prepared Implantable Drug Delivery Systems (IDDS) demonstrated sustained release for over 90 days, which can provide long-term delivery of NTX into the bloodstream from the subcutaneous tissue, eliminating mild or severe side effects due to the repetitive fluctuation in the NTX plasma concentration, which can otherwise be caused by conventional daily oral administration. Such long-acting simple matrix devices might be new, cost-effective alternatives on the market to support abstinence-based treatment for patients suffering from opioid addiction.

First, appropriate analytical protocols were developed and validated. Then, monolithic dispersion NTX HCl-EVA systems were developed. Different parameters influencing processability and critical quality attributes (CQA) of the formulations were investigated. In vivo investigations of the chosen final formulation showed long-term blood concentrations in male beagle dogs.

The manufacturing HME process of the final monolithic dispersion NTX HCl-EVA formulation was also further investigated. A process window was determined by analysing six HME process settings. The impact of process temperature and screw speed on CQAs was determined, and where appropriate, identification of any relationship was supported by statistical analysis. After selecting the most appropriate HME process setting, a larger batch size (approximately 100 implants) was manufactured, and their stability was assessed over six months under accelerated conditions (40 °C/ 75% RH). The stability study confirmed that no changes occurred in the final NTX HCl-EVA formulations under accelerated stability conditions, which could significantly affect their CQAs.

Our study also aimed to explore the influence of different cellulose-ether (CE) additives, namely hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC), as swelling or pore-forming agents on NTX HCl release from EVA subcutaneous IDDSs. The results showed that the drug release could be tailored effectively by the incorporation of CE-additives, reducing the required initial NTX HCl concentration in the systems. This would result in significant cost savings as the NTX HCl is more expensive than CE-additives.

Finally, novel NTX base-loaded EVA IDDSs were manufactured, and their several CQAs were assessed and compared to NTX HCl-loaded EVA systems. This study explored that if the drug release mechanism was based on pure Fickian-diffusion through the polymeric EVA matrices, a significantly higher drug release rate could be achieved with the same drug level.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):