A Dual-drug Delivery to Inhibit Causes of Periodontal Diseases

描述（由申请人提供）：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，辅助传统的抗菌治疗，宿主对感染的反应的调节（称为宿主调节治疗; 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。因此，这项工作的目标是从生物可降解/生物相容性交联壳聚糖制剂发展一种在牙周袋中控制/持续双重递送抗菌剂和HMT剂的系统。 该SBIR第一阶段申请提出开发交联壳聚糖与模型抗菌剂和HMT剂的干凝胶、膜/片制剂，并优化其以各自的有效剂量持续释放约30天的双药物。将研究从优化制剂中释放的组分，以证明其在体外口腔模型中控制牙周生物膜形成和生长的功效;还将测试相同的组分，以通过牙周伤口愈合模型中的成纤维细胞再增殖研究以及通过其对与牙周问题相关的成纤维细胞因子的调节的影响来验证其对HMT的贡献。如果成功，除了在局部持续递送牙周治疗器械中加入HMT外，由于已知器械基质的粘膜粘附特性，申报产品还可以轻松将器械放置在牙周袋中，并在放置部位更好地保持。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加以利用。 I期研究的信息将为 （c）为拟在其第二阶段进行的未来研究提供资金，其中将包括优化配制程序，随后为每批产品的质量控制建立标准操作程序，并扩大优化配制程序的规模。还将对该产品进行动物模型体内牙周袋研究以及毒性和生物相容性研究。所有这些研究在将来升级为临床研究之前都必须获得FDA的研究性新器械（IND）认证。B阶段II结束时，希望能够确定可上市产品，并提交上市前（510 K）通知申请。 长期目标是将该产品商业化，通过抗菌和HMT进行牙周病的完全局部持续治疗。该设备具有巨大的潜力，以帮助社会，因为近80%的成年美国人有牙周问题，这些问题索赔超过600亿美元的费用每年。 公共卫生相关性：该提案旨在开发一种交联的粘膜粘附制剂，用于在牙周袋中延长释放模型抗菌剂和宿主炎症调节剂（通常称为宿主调节疗法; HMT）。抗菌作用和HMT的结合将为牙周病提供一个完整的局部和持续的治疗。该配方解决了目前局部牙周治疗中尚未得到充分关注的一些问题，例如：1.加入HMT; 2.药物递送装置在其放置之后的保持; 3.延长持续递送活性成分的时间超过7天。该装置将被设计为干凝胶，便于放置在牙周袋中;然后它将成为粘膜粘附剂，以提高在牙周组织中保留的机会。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成功机会很高。

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.