Chlorhexidine polyphosphates: mechanistic aspects and orthopaedic applications

氯己定多磷酸盐是广谱杀菌剂氯己定（CHX）的难溶盐。CHX广泛用于医药产品和医疗器械，包括导管固定装置、漱口水和外科手术前的局部皮肤消毒剂。由于其非特异性作用机制，微生物对CHX产生耐药性的几率远低于抗生素。然而，目前基于CHX的处理含有CHX二光酸盐，它是高度水溶性的。应用后，CHX迅速释放并冲走，这意味着必须定期重新应用以保持所需剂量。这是不可取的。CHX多磷酸盐由Pertinax Pharma公司（布里斯托尔大学的衍生公司和该项目的工业赞助商）生产，可以掺入医疗设备中使用的各种基材中。当置于水环境中时，CHX多磷酸盐在一段时间内缓慢释放CHX，克服了二光酸CHX的局限性。释放也可以根据配方和基材调整为不同的应用。目前，决定不同条件下CHX释放的潜在机制尚未完全阐明。该项目将从选定的CHX多磷酸盐的物理化学特征开始，包括确定溶解度产物，确定平衡状态下存在的磷酸盐种类，并最终确定控制CHX释放的机制。磷酸盐和CHX多磷酸盐在模型细胞膜和囊泡上的相互作用也将被研究。本研究旨在确定从CHX聚磷酸盐中释放的磷酸根离子是否会影响CHX的抗菌效果。项目的其余部分将集中于应用CHX聚磷酸盐用于新一代骨科材料。含有抗生素的骨科材料被广泛用于预防和治疗与关节置换术相关的感染，但与这些感染相关的病原体中的抗生素耐药性使这些材料的效果降低，感染更难治疗。CHX多磷酸盐骨科材料提供了一个机会，通过使用防腐剂来抑制术后感染，从而避免了对抗生素的需求。这将包括研究CHX从这些底物中的释放，以及由此产生的抗菌功效、生物相容性和毒性，并与现有的商业产品进行比较。

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.