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，在龈下沟生物膜中成熟的复杂微生物生态引发慢性免疫炎性病变，破坏牙周组织的软硬组织。识别治疗方法的能力，使更有效地控制和/或预防牙龈炎症，是当前改善人口口腔健康的商业战略的一个关键方面。这项I期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，这种口香糖可以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。提取物中具有生物活性的植物化学物质是多酚类物质，其中花青素最为显著。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，提取物已被发现具有抗氧化、抗癌、抗炎、抗菌和抗病毒的特性。在这个为期12个月的研究计划中，提出了以下四个具体目标：目标1：完善口香糖作为黑莓提取物的递送策略，作为一种有效的，天然的抗牙龈炎剂。为了实现这一目标，研究人员将：i)完成黑莓提取物和树胶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)开发从树胶中提取花青素和酚类的方法；iii)使用机械咀嚼装置确定花青素和酚类的释放率；iv)进行为期1个月的加速稳定性研究，并建立临床批次的初步释放规范。目的2：测试黑莓提取物中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，研究人员将：1)评估黑莓提取物在人类口腔上皮细胞和巨噬细胞中的抗炎特性；2)测试黑莓提取物对牙周病原体和人类疱疹病毒的抗菌特性。四老虎有限责任公司及其全资子公司berryceeuticals有限责任公司与美国东部最大的黑莓农场WindStone Farms合作，开发和商业化来自黑莓的健康和医疗产品。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、免疫学和口腔医学方面的专业知识。口香糖是一种现有的给药方法，它代表了一种实用的、潜在的高度通用的策略，以改善患者的口腔护理。具体来说，口香糖配方允许在口腔内局部释放稳定且高效的抗氧化和抗炎植物化学物质。预期的结果可能是改善牙龈炎和牙周病以及龋齿，口腔粘膜炎和其他口腔疾病的治疗。

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.