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（由申请人提供）：由于避免了第一次肝代谢和胃肠道刺激，丢血管内给药是全身输送药物的有吸引力的选择。当前的阴道药物输送研究主要使用FDA认可的兔模型进行。但是，这样的研究是昂贵且耗时的。另外，动物实验通常是高度可变的。为了避免这些问题，我们建议使用高度分化和可重现的体外重建人类阴道宫颈（VEC）组织模型，例如Mattek epivaginaltm模型。然而，需要优化相关模型的屏障特性，以便它们准确地匹配天然体内组织的屏障。 。 阶段IRESEARCH将产生各种研究培养物，其中已修改组织表型。这些组织将以组织学，屏障特性（通过横向上的电阻测量）来表征，并且在确定粘膜屏障特性（例如脱骨体和紧密连接）中的细胞器的存在很重要。另外，将量化屏障脂质的水平。最有希望的组织将使用一组模型药物进行药物渗透率研究，以便为历史药代动力学内部阴道兔数据提供。将比较体外和体内数据，以选择具有优化屏障特性的组织。最后，将比较利用体外组织模型进行临床前的阴道前药物递送研究与兔子研究的经济学。 公共卫生相关性：阴道途径由于其较大的表面积，高血管化，对包括肽和蛋白质在内的多种化合物的渗透性以及避免肝第一通代谢和胃肠道刺激的范围，具有巨大的全身药物输送潜力。由于药物吸收潜力已成为药物发现过程早期决策的重要标准，因此非常需要开发可靠的筛查方法，以通过阴道途径进行药物吸附。该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。