A Dual-drug Delivery to Inhibit Causes of Periodontal Diseases

描述(申请人提供)：牙周病的致病性主要与革兰氏阴性厌氧菌和宿主对感染的反应引起的组织损伤有关。因此，在常规抗菌疗法的辅助下，宿主对感染反应的调节(称为宿主调节疗法；HMT)也必须伴随其完整的治疗。目前的局部和持续牙周治疗都不包括这方面的内容。因此，这项工作的目标是从可生物降解/生物相容的交联壳聚糖制剂中进化出一种可控/持续的牙周袋中抗菌和HMT双重给药系统。这项SBIR第一阶段申请建议开发一种含有模型抗菌剂和HMT试剂的交联壳聚糖干凝胶、薄膜/片剂配方，并对其进行优化，以在各自的有效剂量下持续释放双药约30天。从优化配方中释放的成分将在体外口腔模型中进行研究，以证明它们在控制牙周生物膜的形成和生长方面的有效性；还将通过牙周伤口愈合模型中的成纤维细胞再繁殖研究，以及通过它们对与牙周问题相关的成纤维细胞细胞因子的调节作用，来测试相同的成分，以验证它们对HMT的贡献。如果成功，除了将HMT整合到局部缓释牙周治疗装置中外，建议的产品还将使装置易于放置在牙周袋中，并由于了解装置基质的粘附性而更好地保持在放置位置。因此，所用成分的智能聚合物特性也将在这项拟议的研究中得到开发。来自第一阶段研究的信息将提供一个基础 在第二阶段提出的未来研究将包括优化配方程序，随后为每批产品的质量控制建立标准作业程序，并扩大优化配方程序的规模。该产品还将用于动物模型的活体牙周袋研究，以及毒性和生物相容性研究。所有这些研究都要求FDA的研究新设备(IND)认证，然后才能升级到未来的临床研究。B在第二阶段结束时，希望将确定一种适销对路的产品，并提交上市前(510K)通知申请。长期目标是将该产品商业化，通过抗菌和HMT对牙周病进行全面的局部持续治疗。该设备具有巨大的社会潜力，因为几乎80%的美国成年人都有牙周问题，这些问题每年需要花费超过600亿美元。 与公共健康相关：这项建议寻求开发一种交联型粘附剂配方，用于在牙周袋中延长模型抗菌剂和宿主炎症调节剂(通常称为宿主调节疗法；HMT)的释放。抗菌作用与HMT的结合将为牙周病提供一种完整的局部持续治疗方法。这一配方解决了目前牙周局部治疗中迄今关注不足的几个问题，例如：1.加入HMT；2.药物输送装置在放置后的保留；3.延长有效成分的持续输送时间超过7天。该装置将被设计为干凝胶，便于放置到牙周袋中；然后它将成为粘附剂，以提高在牙周组织中固位的机会。最后，它将同时提供用于微生物控制和HMT的试剂，时间长达一个月左右，同时执行所有任务。因此，该产品成功治疗牙周病的机会很高。

DESCRIPTION (provided by applicant): The pathogenicity of periodontal disease is linked mainly with gram-negative anaerobic bacteria and with tissue damage caused by the host response to infection. Therefore, adjuvant to conventional antimicrobial therapies, the modulation of host response to infection (termed as host modulatory therapy; HMT) must also be accompanied for its complete therapy. None of the current local and sustained periodontal therapies include this aspect. Thus, the goal of this work is to evolve a system of controlled/sustained dual delivery of antibacterial & HMT agents in periodontal pockets from biodegradable/biocompatible cross-linked chitosan formulations. This SBIR phase-I application proposes to develop a xerogel, film/sheet formulation of a cross-linked chitosan with a model antibacterial agent and a HMT agent and to optimize it for sustained dual-drug release in their respective effective doses for about 30 days. The released components from the optimized formulations would be investigated to prove their efficacy in controlling the formation and growth of periodontal biofilm in an in-vitro mouth model; the same components will also tested to verify their contribution to HMT through a fibroblast repopulation study in a periodontal wound healing model and through their effect on modulation of fibroblastic cytokines related to periodontal problems. If successful, besides incorporation of HMT in the local sustained delivery periodontal treatment device, the proposed product will also allow ease of placement of device in periodontal pockets and its better retention at the site of placement due to know mucoadhesive properties of the device matrix. Thus, the smart polymer properties of the used ingredients will also be exploited in this proposed study. Information from this phase-I study will provide a basis for future studies to be proposed in its phase-II, which will include optimization of formulation procedures, followed by the establishment of standard operating procedures (SOPs) for quality control of each batch of product, and scale-up of optimized formulations procedures. The product will also be investigated for in-vivo periodontal pocket studies in animal models and also in toxicity and biocompatibility studied. All of these studies are mandated for FDA's Investigational New Device (IND) certification before its upgrade for clinical studies in future. B the end of Phase- II, it is hoped that a marketable product will be identified and the application for pre-market (510 K) notifications will be filed. The long term objective is to commercialize ths product for a complete local sustained therapy of periodontal disease through antibacterial as well as HMT. The device has a huge potential to help the society, as almost 80% of adult Americans have periodontal problems and these problems claim more than $60 billion in expenses yearly. PUBLIC HEALTH RELEVANCE: This proposal seeks to evolve a cross-linked mucoadhesive formulation for the extended release of a model antibacterial agent and a host inflammation modulator (commonly referred to as Host Modulation Therapy; HMT) in periodontal pockets. The combination of antibacterial action and HMT would provide a complete local and sustained therapy for periodontal disease. This formulation addresses few issues that have been under-focused so far in current local periodontal therapies, e.g.: 1. incorporation of HMT; 2. retention of drug delivery device after its placement; 3. enhancement of period for sustained delivery of active ingredients beyond 7 days. The device will be designed as a xerogel for the ease of placement in to periodontal pockets; it would then become mucoadhesive to improve the chances of retention in periodontal tissue. Finally it would concomitantly deliver agents for microbial control and for HMT for up to a month or so, performing all tasks at the same time. Thus, the chances of success of this product in successfully treating the periodontal disease are high.