Chlorhexidine polyphosphates: mechanistic aspects and orthopaedic applications

Lead Research Organisation: University of Bristol
Department Name: Physics

Abstract

Chlorhexidine polyphosphates are sparingly soluble salts of the broad-spectrum antiseptic, chlorhexidine (CHX). CHX is widely used in medicinal products and medical devices including catheter securement devices, mouthwashes, and topical skin disinfectants prior to surgical procedures. Due to its non-specific mechanism of action, the chance of microbes becoming resistant to CHX is much lower than for antibiotics. However, current CHX-based treatments contain CHX digluconate, which is highly water soluble. After application, the CHX is rapidly released and washed away, meaning the treatments must be regularly reapplied to maintain the required dose. This is undesirable.
CHX polyphosphates are produced by Pertinax Pharma (a University of Bristol spin-out company and industrial sponsor of this project) and can be incorporated into various substrates used in medical devices. When placed in an aqueous environment, CHX polyphosphates slowly release CHX over a sustained period, overcoming the limitations associated with CHX digluconate. The release can be also tuned for different applications depending on the formulation and substrate.
Currently, the underlying mechanism which determines CHX release under different conditions is not fully elucidated. This project will begin with physicochemical characterisation of selected CHX polyphosphates, including determining solubility products, identifying the phosphate species present at equilibrium and ultimately determining the mechanism(s) that control CHX release. Interactions of phosphates and CHX polyphosphates on model cell membranes and vesicles will also be investigated. This work will aim to establish whether phosphate ions affect the antimicrobial efficacy of CHX when released from CHX polyphosphates.
The remainder of the project will focus on applying CHX polyphosphates for use in a new generation of orthopaedic materials. Antibiotic-laced orthopaedic materials are widely used to prevent and treat infections associated with joint replacement, but antibiotic resistance in the pathogens associated with these infections is rendering these materials less effective and infections harder to treat. The CHX polyphosphate orthopaedic materials offer an opportunity to circumvent the need for antibiotics by using antiseptic to suppress infection during the post-surgical period. This will include studying the release of CHX from these substrates and the resulting antimicrobial efficacy, biocompatibility and toxicity, comparing to existing commercial products.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R51245X/1 01/10/2017 30/09/2021
1961481 Studentship EP/R51245X/1 11/09/2017 30/09/2021 Matthew Keith Skeats
 
Description Solubility of chlorhexidine polyphosphates and release of the common antiseptic chlorhexidine from these materials has been studied. This provided insights on the mechanism of release of chlorhexidine from these novel antimicrobial materials into an aqueous environment, which is useful for the rest of this project and other projects using these materials.

The remainder of the project is based on preparing orthopaedic bone cements containing chlorhexidine polyphosphates. The aim is that these cements will provide a sustained release of chlorhexidine for prolonged antimicrobial efficacy, with lower risk of antimicrobial resistance developing than antibiotic cements, while maintaining the important mechanical, physical and chemical properties of antibiotic bone cements.

A method has been developed for incorporation of chlorhexidine polyphopshates into an existing, clinically used bone cement formulation in the place of antibiotics. Cement samples have been prepared using this method and tested for compressive strength and elution of chlorhexidine. Loading cements with 1-12 % by mass of chlorhexidine triphosphate (CHX-TP) did not cause any deterioration in compressive strength compared to antibiotic-loaded and non-antimicrobial bone cement control specimens. Cements containing CHX-TP showed successful release of chlorhexidine into water. Release of chlorhexidine was sustained for 10 days from bone cements loaded with 1% CHX-TP, and is ongoing after 130 days with cements containing 4, 7 and 12 % CHX-TP.

Ongoing work is measuring other important mechanical and mixing properties of the cements and testing their efficacy against bacteria which cause infections in orthopaedic surgery.
Exploitation Route Ultimately, if the CHX polyphosphate loaded bone cements met all the required mechanical, chemical and physical properties of orthopaedic bone cements and provided equal or improved antimicrobial efficacy compared with existing antibiotic loaded cements, then CHX polyphosphate loaded cements could be suitable for consideration as a replacements for existing antibiotic cements. However, it is much too early to say how the outcomes will be taken forward as the award is ongoing and the cements require significant further testing before it can be concluded if they would be suitable for taking forward to development as a genuine alternative to existing antibiotic bone cements.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology