Delivery of Polyphenols in Gum for Treatment of Gingivitis

描述（由申请人提供）：牙周炎是一种多微生物疾病，其中在龈下沟中的生物膜中成熟的复杂微生物生态引发慢性免疫炎症病变，破坏牙周组织的软组织和硬组织。鉴定治疗剂以能够更有效地控制和/或预防牙龈炎症的能力是目前改善人群口腔健康的商业策略的关键方面。该第一阶段提案的目标是进一步开发一种含有黑莓提取物的新型口香糖，该口香糖将生物活性植物化学物质输送到口腔，并测试其预防牙龈炎的功效。提取物中的生物活性植物化学物质是多酚，最值得注意的是花青素。已经开发了制备和稳定提取物的方法，以及两克黑莓提取物口香糖的原型。此外，已经发现该提取物具有抗氧化、抗癌、抗炎、抗菌和抗病毒特性。在这项为期12个月的研究计划中，提出了以下四个具体目标：目标1：完善口香糖的开发，作为黑莓提取物作为一种有效的天然抗牙龈炎剂的输送策略。为了实现这一目标，研究者将：i）完成黑莓提取物和口香糖原型中花青素和酚类的合格稳定性指示分析方法的开发，ii）开发从口香糖中提取花青素和酚类的方法，iii）使用机械咀嚼装置测定花青素和酚类的释放速率，iv）进行加速1个月稳定性研究，并建立临床批次的初步放行质量标准。目的2：测试黑莓提取物中的生物活性植物化学物质抑制牙龈炎相关机制的假设。为了实现这一目标，研究者将：i）评价黑莓提取物在人口腔上皮细胞和巨噬细胞中的抗炎特性，ii）测试黑莓提取物对牙周病原体和人疱疹病毒的抗菌特性。Four Tigers LLC及其全资子公司Berryceuticals LLC与美国东部最大的黑莓农场WindStone Farms合作，开发和商业化黑莓衍生的健康和医疗产品。研究人员组建了一个高度跨学科的研究团队，包括药剂学、口腔新型药物输送系统、牙周病学、免疫学和口腔医学方面的专业知识。口香糖是一种现有的药物递送方法，其代表了改善患者口腔护理的实用且潜在的高度通用的策略。具体地，口香糖制剂允许稳定的和高效的抗氧化剂和抗炎植物化学物质在口腔内的局部释放。预期的结果可以是牙龈炎和牙周病以及龋齿、口腔粘膜炎和口腔的其它病症和疾病的改善的治疗。 公共卫生相关性：鉴定治疗剂以能够更有效地控制和/或预防牙龈炎症的能力是目前改善人群口腔健康的商业策略的关键方面。该第一阶段提案的目标是进一步开发一种含有黑莓提取物的新型口香糖递送系统，该系统将生物活性天然化合物递送到口腔，并测试其预防牙龈炎的功效。黑莓提取物中的生物活性化合物是多酚，最值得注意的是花青素。这些多酚已被证明具有非常显著的抗炎和抗微生物特性，以及其他生物活性。预期的结果可以是牙龈炎和牙周病以及龋齿、口腔粘膜炎和口腔的其它病症和疾病的改善的治疗。该产品是FDA在其2004年指导文件中定义的首批“植物药产品”之一。

DESCRIPTION (provided by applicant): Periodontitis represents a polymicrobial disease, in which a complex microbial ecology that matures in biofilms in the subgingival sulcus triggers a chronic immunoinflammatory lesion that destroys soft and hard tissues of the periodontium. The ability to identify therapeutics, to enable more effective control and/or prevention of gingival inflammation, is a critical facet of current commercial strategies to improve oral health of the population. The goal of this Phase I proposal is to further develop a novel chewing gum containing blackberry extract that delivers bioactive phytochemicals to the oral cavity and test its efficacy in preventing gingivitis. The bioactive phytochemicals in the extract are polyphenols with the most notable being anthocyanins. Methods to prepare and stabilize the extract have already been developed, as well as a prototype two gram blackberry extract chewing gum. In addition, the extract has already been found to have anti-oxidant, anti-cancer, anti- inflammatory, anti-bacterial, and anti-viral properties. In this 12 month research plan, four Specific Aims are proposed as follows: Aim 1: Refine the development of chewing gum as a delivery strategy for blackberry extract as a potent, natural anti-gingivitis agent. To achieve this Aim, the Investigators will, i) complete development of qualified stability-indicating analytical method for anthocyanins and phenols in the blackberry extract and the gum prototype, ii) develop methods to extract anthocyanins and phenols from the gum, iii) determine the release rate of anthocyanins and phenols using a mechanical chewing device, iv) perform an accelerated 1 month stability study and establish preliminary release specifications for the clinical batches. Aim 2: Test the hypothesis that bioactive phytochemicals in blackberry extract inhibit mechanisms associated with gingivitis. To achieve this Aim, the Investigators will, i) evaluate the anti-inflammatory properties of the blackberry extract in human oral epithelial cells and macrophages, and ii) test the antimicrobial properties of the blackberry extract against periodontal pathogens and human herpes viruses. Four Tigers LLC, and its wholly-owned subsidiary Berryceuticals LLC, has partnered with WindStone Farms, the largest blackberry farm in the eastern part of the United States, to develop and commercialize health and medical products derived from blackberries. The investigators have assembled a highly interdisciplinary team of investigators encompassing expertise in pharmaceutics, novel drug delivery systems for the oral cavity, periodontics, immunology, and oral medicine. The chewing gum is an existing drug delivery approach that represents a practical and potentially highly versatile strategy to improve patient oral care. Specifically, the gum formulation allows for the localized release of stabilized and highly potent anti-oxidant and anti- inflammatory phytochemicals within the oral cavity. The expected outcome may be improved treatments of gingivitis and periodontal disease as well as caries, oral mucositis, and other disorders and diseases of the oral cavity. PUBLIC HEALTH RELEVANCE: The ability to identify therapeutics, to enable more effective control and/or prevention of gingival inflammation, is a critical facet of current commercial strategies to improve oral health of the population. The goal of this Phase I proposal is to further develop a novel chewing gum delivery system containing blackberry extract that delivers bioactive natural compounds to the oral cavity and test its efficacy in preventing gingivitis. The bioactive compounds in the blackberry extract are polyphenols with the most notable being anthocyanins. These polyphenols have been shown to have very significant anti-inflammatory and anti-microbial properties, among other biological activities. The expected outcome may be improved treatments of gingivitis and periodontal disease as well as caries, oral mucositis, and other disorders and diseases of the oral cavity. This product is being developed as one of the first "Botanical Drug Products" as defined by the FDA in their 2004 Guidance Document.