Development of an Intra-peritoneal Implant for the Sustained Release of Lidocaine Following Abdominal Surgery

Abstract

Introduction: Patients experience post-operative pain and fatigue following abdominal surgery due to damage to the peritoneal lining of the abdominal cavity. Recent studies have demonstrated that it is possible to decrease pain and fatigue effectively through the continuous infusion of local anaesthetic into the peritoneal cavity for 72 h following abdominal surgery. It seems likley that additional benefits may be evident if delivery of local anaesthetics could be prolonged over 10 days. Poly(ethylene-co-vinyl acetate) (EVA) has a long history of clinical use as a polymeric carrier to provide sustained release of drug over an extended period of time. However, drug solubility in EVA matrices is often limited, leading to instability issues with the potential for dispersed drug to recrystallise. The aim of this thesis was to develop a controlled release EVA based formulation capable of releasing lidocaine in a sustained manner, for use following abdominal surgery. Methods: A stability indicating high-performance liquid chromatography (HPLC) method was developed for the quantification of lidocaine from forced degradation samples, EVA matrices and biological fluids using an Agilent Series 1260 HPLC system. The compatibility of lidocaine with EVA was then assessed using various analytical tools, including thermo gravimetric analysis, differential scanning calorimetry, nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy (FTIR) and HPLC. Additionally, potential interactions between lidocaine and EVA, alongside fatty acid additives, were investigated using FTIR. A detailed characterisation of human peritoneal fluid collected following abdominal surgery was performed to determine its composition, physicochemical properties and rheological parameters to build an understanding of the intra-peritoneal environment. The key physicochemical properties of peritoneal fluid were then compared with phosphate buffered saline, a commonly used synthetic media for the evaluation of the in vitro release performance of intra-peritoneal drug delivery systems. Finally, the differences between peritoneal fluid and phosphate buffered saline were further explored by comparing lidocaine solubility and the release performance of the EVA based formulation in the two media. Results and Discussion: An efficient and cost-effective quantification method was developed to determine lidocaine from force degradation samples, EVA matrices and biological fluids. Compatibility studies confirmed the stability of lidocaine in the presence of EVA, regardless of vinyl acetate composition. An interaction was demonstrated between EVA and lidocaine by FTIR, possibly in the form of hydrogen bonding. This interaction was more pronounced in the presence of myristic acid, resulting in the formation of a transparent formulation thereby demonstrating the fatty acid’s ability to prevent the recrystallisation of lidocaine in EVA matrices. The composition and physicochemical properties of peritoneal fluid varied between different patients and within the same patient over time. Inter-patient variations were observed with regard to pH (p<0.001), buffer capacity (p<0.05), osmolality (p<0.001) and surface tension (p<0.05). Rheological examination of peritoneal fluid demonstrated non-Newtonian shear thinning behaviour and the fluid predominantly exhibited the characteristics of an entangled network. The investigated physicochemical properties of peritoneal fluid all differed from phosphate buffered saline (p<0.001). The solubility of lidocaine was significantly higher in peritoneal fluid compared to phosphate buffered saline. The release of lidocaine occurred in a sustained manner from EVA matrices in both peritoneal fluid and phosphate buffered saline, with a relatively higher release rate of lidocaine observed in peritoneal fluid. When the experimental set-up was changed from sink to non-sink conditions the release rate slowed, possibly due to the formation of a boundary layer. Conclusions: Detailed investigations were performed supporting the development process for an implantable formulation for the sustained delivery of lidocaine into the peritoneal cavity. EVA was shown to be a suitable polymer to disperse lidocaine and to achieve controlled release over 10 days. The properties of peritoneal fluid are markedly different to phosphate buffered saline, and release of lidocaine from the formulation occurred at a faster rate into peritoneal fluid than the synthetic phosphate buffered saline. Future work could seek to develop a bio-relevant media for intra-peritoneal drug delivery systems. To translate the data in this thesis into an implant ready for patients, future studies should focus on evaluating formulation performance in animal models to assess local and systemic toxicity before proceeding into human clinical trials.