In Vitro Human Tissue Model for Intravaginal Drug Delivery

用于阴道内药物输送的体外人体组织模型

• 批准号: 7910090
• 负责人: Seyoum Ayehunie
• 金额: $ 26.79万
• 依托单位: MATTEK CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-06 至 2012-03-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910090
• 关键词: AIDS/HIV problem; Adsorption; Animal Experiments; Area; Biological Assay; Biological Availability; Blood; Blood Vessels; Characteristics; Communication; Cream; Data; Desmosomes; Development; Disease; Dosage Forms; Drainage procedure; Drug Compounding; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Dysmenorrhea; Economics; Electrical Resistance; Exhibits; FDA approved; Gel; Goals; Growth Factor; Hepatic; Histology; Human; In Vitro; Intravaginal Administration; Lead; Lipids; Liver; Malignant Neoplasms; Measurement; Measures; Metabolism; Methods; Migraine; Modeling; Morphology; Mucous Membrane; Muscle Cramp; Oral; Oral Administration; Organ; Organelles; Oryctolagus cuniculus; Osteoporosis; Patients; Peptides; Permeability; Pessaries; Pharmaceutical Preparations; Phase; Phenotype; Prevention; Process; Property; Proteins; Research; Route; Safety; Screening procedure; Suppositories; Surface; Therapeutic; Thick; Tight Junctions; Time; Tissue Model; Tissue Viability; Tissues; Toxic effect; Vagina; Vaginal Ring; Vaginitis; Vascularization; Vomiting; absorption; drug discovery; gastrointestinal; human female; human tissue; in vitro Model; in vivo; infectious disease treatment; irritation; keratinization; microbicide; pre-clinical; protein expression; public health relevance

DESCRIPTION (provided by applicant): Due to the avoidance of first-pass hepatic metabolism and gastrointestinal irritation, intravaginal administration is an attractive option for systemic delivery of drugs. Current vaginal drug delivery studies are primarily performed using the FDA-accepted rabbit model. However, such studies are costly and time consuming. In addition, animal experiments are often highly variable. To avoid these problems, we propose use of a highly differentiated and reproducible, in vitro reconstructed human vaginal ectocervical (VEC) tissue model such as MatTek EpiVaginalTM model. However, the barrier properties of the EpiVaginal model need to be optimized so that they accurately match those of native in vivo tissue. . Phase Iresearch will produce various EpiVaginal cultures in which the tissue phenotype has been modified. These tissues will be characterized in terms of histology, barrier properties (measured by transepithelial electrical resistance), and the presence of organelles important in determining mucosal barrier properties such as desmosomes and tight junctions. In addition, the levels of barrier lipids will be quantified. The most promising tissues will be selected for drug permeability studies using a set of model drugs for which historical pharmacokinetic intravaginal rabbit data are available. The in vitro and in vivo data will be compared to choose the tissue with optimized barrier properties. Finally, the economics of utilizing the in vitro tissue model for pre-clinical intravaginal drug delivery studies versus rabbit studies will be compared. PUBLIC HEALTH RELEVANCE: The vaginal route has a great potential for systemic drug delivery due to its large surface area, high vascularization, permeability to a wide range of compounds including peptides and proteins, and avoidance of the hepatic first-pass metabolism and gastrointestinal irritation. Since drug absorption potential has become important criterion for decisions early in the drug discovery process, there is a great need to develop a reliable screening method for drug adsorption through the vaginal route. This proposal will optimize a highly differentiated, human vaginal tissue model to facilitate such studies.

描述(申请人提供)：由于避免了首次通过的肝脏代谢和胃肠道刺激，阴道给药是全身给药的一个有吸引力的选择。目前的阴道给药研究主要使用FDA认可的兔模型进行。然而，这样的研究既昂贵又耗时。此外，动物实验往往是高度多变的。为了避免这些问题，我们建议使用高度分化和可重复性的体外重建的人阴道外宫颈(VEC)组织模型，如Mattek EpiVaginalTM模型。然而，表阴道模型的屏障特性需要优化，以便它们与体内天然组织的屏障特性准确匹配。。IResearch阶段将生产各种组织表型已被修改的外阴培养物。这些组织将根据组织学、屏障特性(通过跨上皮电阻测量)以及在确定粘膜屏障特性中重要的细胞器的存在来表征，如桥粒和紧密连接。此外，还将量化屏障脂类的水平。最有希望的组织将被选择用于药物渗透性研究，使用一组模型药物，这些药物的历史药代动力学数据可以在兔阴道内获得。体外和体内的数据将进行比较，以选择具有最佳屏障性能的组织。最后，将利用体外组织模型进行临床前阴道给药研究与兔研究的经济性进行比较。 公共卫生相关性：阴道途径具有巨大的表面积、高度的血管化、对包括多肽和蛋白质在内的多种化合物的渗透性，以及避免肝脏首过代谢和胃肠道刺激，因此在全身给药方面具有巨大的潜力。由于药物吸收潜力已经成为药物发现过程早期决策的重要标准，因此迫切需要开发一种可靠的药物经阴道吸附的筛选方法。这一建议将优化高度分化的人类阴道组织模型，以促进此类研究。