Chlorhexidine polyphosphates: mechanistic aspects and orthopaedic applications

氯己定多磷酸盐是广谱防腐剂氯己定（CHX）的微溶盐。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。由于它的非特异性作用机制，微生物对CHX产生耐药性的机会比抗生素低得多。然而，目前的基于CHX的处理含有CHX二葡糖酸盐，其是高度水溶性的。应用后，CHX迅速释放并被冲走，这意味着必须定期重新应用治疗以维持所需的剂量。这是不可取的。CHX多磷酸盐由Pertinax Pharma（一家布里斯托大学的分拆公司和该项目的工业赞助商）生产，可掺入医疗器械中使用的各种基质中。当置于水性环境中时，CHX多磷酸盐在持续的时间内缓慢释放CHX，克服了与CHX二葡萄糖酸盐相关的限制。释放也可以根据配方和基质针对不同的应用进行调整。目前，决定CHX在不同条件下释放的潜在机制尚未完全阐明。本项目将开始，对选定的CHX多磷酸盐进行物理化学表征，包括确定溶度积，确定平衡时存在的磷酸盐种类，并最终确定控制CHX释放的机制。还将研究磷酸盐和CHX多磷酸盐对模型细胞膜和囊泡的相互作用。这项工作的目的是确定磷酸根离子是否会影响CHX的抗菌效果，当从CHX多磷酸盐中释放出来时。该项目的其余部分将集中于将CHX多磷酸盐应用于新一代骨科材料。含抗生素的骨科材料被广泛用于预防和治疗关节置换相关感染，但与这些感染相关的病原体的抗生素耐药性使这些材料的有效性降低，感染更难治疗。CHX聚磷酸盐骨科材料提供了一个机会，通过使用抗菌剂来抑制术后感染，从而避免对抗生素的需求。这将包括研究CHX从这些基质中的释放，以及与现有商业产品相比所产生的抗菌功效，生物相容性和毒性。

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.