Preclinical Development of an Absorbable Antibacterial Bone Hemostatic Agent

描述（由申请人提供）：Ostene TM是一种柔软的可塑性粘合材料，可很好地粘附在出血的骨表面。它是由南加州大学和CHLA的研究人员发明的，作为标准骨蜡的替代品，骨蜡是一种基于蜂蜡的材料，会引起局部炎症，并且已知会增加手术后感染的风险。相比之下，Ostene是生物相容性水溶性聚合物的组合，在植入后2-3天内完全吸收;它是非炎症性的，并且由于其能够防止细菌粘附到表面而具有内在的抗感染作用。这些特性的组合使Ostene成为在任何涉及切割骨的外科手术中将抗生素直接输送到伤口的理想材料。本项目的目的是开发一种Ostene与庆大霉素的制剂，该制剂保留其止血特性，但在术后即刻释放庆大霉素，以预防骨感染（骨髓炎）或伤口其余部分。本申请描述了初始制剂开发、体外验证、生物相容性试验和体内动物药代动力学研究。这些临床前研究将构成510（k）/ IND提交的基础，随后将进行II期临床研究，该研究将检查心胸手术中Ostene+庆大霉素的术中使用是否可以降低胸骨伤口感染（SWI）的发生率。SWI相对常见（6-9%），引起显著的发病率和死亡率（1-2%），并且具有高治疗成本（平均每个病例> 20，000美元）。通过对既往研究的扩展，Ostene+庆大霉素的成功开发和部署可能将SWI的发生率降低50%，这将对SWI相关死亡、残疾和治疗费用产生重大影响。 公共卫生相关性：胸骨伤口感染（SWI）是心脏手术相对常见的并发症。在最近的研究中，据报道，胸骨切开术后SWI的发生率为6- 9%，其中约三分之二被归类为浅表性SWI，三分之一（总计2-3%）被归类为深部SWI或纵膈炎，这些疾病与严重的发病率相关，通常需要长期住院治疗，死亡率在10 - 20%之间。在美国，治疗SWI的费用估计为20，000美元至40，000美元。这些数字与其他国家的研究一致，例如，荷兰16，600美元，瑞典18，500美元，澳大利亚23，250美元。假设目前美国一个SWI的平均治疗费用为25，000美元，每年有646，000例心脏手术，SWI的发病率为5%，则由于这一潜在可预防的并发症而导致的额外医疗保健费用总额为每年8亿美元。通过胶原海绵植入物将庆大霉素局部递送至手术部位已被证明可将SWI的发生率降低约50%。根据该提案开发的产品Ostene+庆大霉素，预计至少与胶原基植入物一样有效预防SWI，但也将大大降低成本，并且在手术期间更容易使用。Ostene在1-3天内完全吸收，与胶原海绵相比，这是更适合抗生素预防的时间范围，胶原海绵在该部位保留2-3周。Ostene越来越多地用于心脏手术中的止血，作为骨蜡或其他止血材料（例如，Avitene）。因此，一旦开发完成，Ostene+庆大霉素组合预期不会遇到任何重大验收障碍。

DESCRIPTION (provided by applicant): OsteneTM is a soft moldable adhesive material that sticks well to bleeding bone surfaces. It was invented by researchers at USC and CHLA as a replacement for standard bone wax, a beeswax-based material that causes local inflammation and is known to increase the risk of infection after surgery. In contrast, Ostene is a combination of biocompatible water-soluble polymers which is absorbed completely within 2-3 days of implantation; it is non-inflammatory and also has an intrinsic anti-infective effect due to its ability to prevent bacterial adhesion to surfaces. This combination of properties makes Ostene an ideal material for delivery of antibiotics directly to the wound during any surgical procedure that involves the cutting of bone. The objective of this project is to develop a formulation of Ostene with Gentamicin which retains its hemostatic properties but also releases gentamicin during the immediate post-operative period to prevent infection of the bone (osteomyelitis) or the rest of the wound. This application describes the initial formulation development, in vitro validations, biocompatibility testing and in vivo animal pharmacokinetic studies. These pre-clinical studies will form the basis for a 510(k) / IND submission, to be followed by a clinical study in phase II, which will examine whether the interoperative use of Ostene+Gentamicin in cardiothoracic surgery can reduce the incidence of sternal wound infections (SWIs). SWIs are relatively common (6-9%), cause significant morbidity and mortality (1-2%) and have a high cost of treatment (average >$20,000 per case). By extension from previous studies, successful development and deployment of Ostene+Gentamicin could potentially reduce the incidence of SWIs by 50%, which would have a major impact on SWI related deaths, disability and treatment costs. PUBLIC HEALTH RELEVANCE: Sternal wound infections (SWIs) are a relatively common complication of cardiac surgery. In recent studies, the reported incidence of SWI after sternotomy was 6-9%, of which about two- thirds were classified as superficial, and one-third of (2-3% in total) as deep SWI or mediastinitis, which are associated with significant morbidity, often require prolonged inpatient treatment, and have a mortality rate between 10 and 20%. In the US, cost estimates for treatment of an SWI range from $20,000 to $40,000. These numbers are consistent with studies from other countries, e.g., $16,600 in the Netherlands, $18,500 (Sweden) and $23,250 (Australia). Assuming a current average treatment cost of one SWI in the US to be $25,000, with 646,000 cardiac operations per year and an SWI incidence of 5%, the total additional health care cost due to this one potentially preventable complication amounts to $800,000,000 annually. Local delivery of Gentamicin to the surgical site via a collagen sponge implant has been shown to reduce the incidence of SWI by about 50%. The product to be developed under this proposal Ostene+Gentamicin, is expected to be at least as effective for prevention of SWI as the collagen-based implant, but will also be considerably less expensive and much easier to use during surgery. Ostene is fully resorbed within 1-3 days, a more appropriate time frame for antibiotic prophylaxis compared to the collagen sponge, which remains at the site for 2-3 weeks. Ostene is increasingly used for hemostasis in cardiac surgery as a preferred alternative to bonewax or other hemostatic materials (e.g., Avitene). Thus, once developed, the Ostene+ Gentamicin combination would be not expected to meet any major barrier to acceptance.