Optimisation and enhancement of a liposomal delivery system

Hansal, Peter 2022. Optimisation and enhancement of a liposomal delivery system. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Polymethyl methacrylate (PMMA) bone cement is commonly used for implant fixation in total joint replacement surgery (TJR), for the treatment of end stage arthritis. The use of antibiotic loaded bone cement (ALBC) is well-established in the prevention of post-surgical infections. Currently, elution of antibiotics from ALBCs occurs in a biphasic profile, with a high initial burst release within the first hours of application, followed by release of sub-inhibitory concentrations over long periods of time. Due to the inability of ALBCs to release clinically effective concentrations of antibiotic over an extended time-period, infections are still a major challenge; moreover, sub-inhibitory antibiotic release may increase the potential for antimicrobial resistance. The aim of this study was to develop and test a new bone cement formulation with optimised sustained antibiotic release, whilst maintaining the mechanical properties of the commercial bone cement. A liposomal bone cement delivery system containing gentamicin sulfate was produced and validated. The liposomal bone cement released a lower mass quantity of gentamicin than commercial ALBC; however, it released a higher percentage of its total incorporated gentamicin content compared to the commercial ALBC, whilst maintaining the antimicrobial efficacy and the mechanical properties of the commercial bone cement. Fluorescent labelled liposomes were used to determine that no measurable quantity of lipid was released from the bone cement. A freeze-dried liposomal formulation was investigated as a means to make the liposomal bone cement a more commercially feasible product. Gentamicin loaded liposomes were freeze-dried and incorporated into bone cement at gentamicin base concentrations of 0.15% w/w - 0.60% w/w of the PMMA bone cement. Whilst these cements showed improved antimicrobial properties, antibiotic release was generally below the limit of detection and mechanical properties were only maintained for the cement containing 0.15% w/w gentamicin. The process was also relatively inefficient, with freeze-drying causing a reduction in lipid and gentamicin content to around half of the initial mass quantities used. Given the limited functionality of the freeze-dried formulation and the commercial impracticality of the non-freeze-dried liposomal bone cement, alternative bone cement formulations were investigated. ALBC containing different mass quantities of hydrophilic (lactose) and hydrophobic (magnesium stearate) additives at concentrations of 10% w/w - 25% w/w of the PMMA bone cement were prepared. Cement containing lactose, released much higher mass quantities of gentamicin than the commercial ALBC and the magnesium stearate cements, although the magnesium stearate cements had a more gradual drug release profile. All cements containing additives had comparable antimicrobial properties to the commercial ALBC, however, the mechanical properties were only maintained for the 10% w/w lactose cement. Since magnesium stearate cements had a more extended drug-release profile, magnesium stearate was used to dry particle coat gentamicin sulfate using different mixing methods of varying shear (tumble mixer, pestle and mortar, ball mill). All bone cements made from dry powder coated gentamicin sulfate, released a similar mass of gentamicin, which was significantly lower than the gentamicin dose released in the commercial ALBC. Antimicrobial activity was maintained, and mechanical properties were comparable to the commercial ALBC. This research has shown that incorporating liposomal antibiotic formulations in bone cements, in a manner that is commercially feasible, is extremely challenging. Whilst the use of liposomes can improve the drug release profile, the manufacturing process can result in significant loss of the active ingredient. Dry particle coating of gentamicin, using small mass quantities of magnesium stearate, could be used as an alternative approach to modify the drug release profile from bone cement, however, further investigation is required to optimise parameters such as mixing method, particle size and type of guest particle, and to establish the potential impact of this approach on toxicity and cement longevity.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Pharmacy
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	29 June 2022
Last Modified:	29 Jun 2022 09:50
URI:	https://orca.cardiff.ac.uk/id/eprint/150846

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