Pharmacokinetics of Lidocaine and Preformulation Steps towards the Design of a Controlled Delivery System for Advancing Recovery after Hernia Repair

Abstract

Introduction – Hernia repair involves implantation of a flexible polymeric mesh to provide mechanical support to weakened muscles in the abdominal wall. Local anaesthetics (LAs) such as lidocaine have demonstrated great efficacy in alleviating postoperative pain following hernia repairs. Current methods of LA delivery into the operative site are inconvenient and ill-suited to an outpatient setting. A sustained lidocaine eluting hernia repair mesh is envisioned to challenge these issues by reducing convalescence and improving patient recovery. However, the pharmacokinetic (PK) properties of lidocaine must be understood to allow for individualised therapy in different patient groups. Aims – This thesis aimed to identify the effect of comorbidities and different physiological states on the pharmacokinetics of lidocaine. These PK properties informed the aim of formulating lidocaine loaded polycaprolactone (PCL) films suitable for use as a component of a drug eluting hernia repair mesh. Methods – Plasma concentration data obtained from various studies were modelled using 1 and 2 compartment PK models with first order elimination. The parameters, clearance (CL) and volume of distribution at steady state (Vss) were scaled to a standard weight of 70 kg using allometric scaling. The Akaike information criterion (AIC) was used to identify which models provided the best fit. A meta-analysis was then performed to try to identify the effect of body size, sex, age and route of administration on the CL and Vss of lidocaine. To make steps towards developing a lidocaine eluting hernia repair mesh, interactions between lidocaine and the polymer PCL were investigated using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Lidocaine loaded PCL films were formulated by solvent casting and evaluated for drug loading and release using high performance liquid chromatography (HPLC). The mass balance profile of PCL with and without lidocaine was also investigated to determine the weight gain potential of PCL after immersion in phosphate-buffered saline (PBS). Results – Large variability was observed in the CL and Vss of lidocaine in different patient groups. CL/F ranged from 367 L/h/70 kg in smokers administered lidocaine orally to 14 L/h/70 kg in patients with heart failure administered lidocaine intravenously (IV). Vss/F ranged from 347 L/70 kg in smokers administered lidocaine orally to 17 L/70 kg in healthy young patients administered lidocaine IV. The 2 compartment model was preferred for plasma concentration curves reflecting IV administration, as determined by lower AIC outputs. However studies that administered lidocaine via extravascular routes predominantly favoured the 1 compartment model. Meta-analysis findings were mixed and revealed females have a 51% larger CL and a 49% smaller Vss than that of males with marginal support for an effect of weight. The bioavailability after oral and vaginal administration was ≤ 50%. FTIR demonstrated that PCL is compatible with lidocaine as determined by the absence of new spectral peaks, signifying that no new chemical bonds were formed. However shifts in peaks were observed indicating some interactions between polymer and drug. Interactions in the form of hydrogen bonds and Van der Waals forces are useful as they have the potential to stabilise the formulation and possibly slow drug release. DSC revealed that as drug loading increased from 10-50% (w/w) the melting temperature of PCL decreased from 61 to 51.5oC. PCL released most (80-100%) of its loaded lidocaine over 72 hours, with a burst release (30-40%) observed within 3 hours. The effect of PCL molecular weight and drug loading on drug release was not significant (p > 0.05). Mass balance analysis revealed only slight changes in weight of PCL after accounting for drug loading, and therefore the polymer is not expected to swell in vivo. Discussion – PK modelling helped reveal the influence of different comorbidities, physiological states and sites of administration on the PK properties of lidocaine. Absorption kinetics following extravascular administration may have limited the identification of the time course of distribution of lidocaine compared to IV. The PK data collected in different patient groups could help guide the formulation of individualised lidocaine releasing hernia repair mesh prosthetics, to effectively alleviate postoperative pain following surgery. Additionally, the compatibility of PCL with lidocaine demonstrates that the development of a hernia repair mesh with drug releasing functionality is possible. However, additional formulation approaches must be explored to further sustain the release profile of lidocaine from PCL. Conclusion – The effect of comorbidities and different physiological states on the PK properties of lidocaine were identified, with large variations found in the CL and Vss of lidocaine in different patient groups. Additionally a compatible lidocaine loaded PCL formulation was developed suitable for use in the development of a novel LA eluting hernia repair mesh.