Pre-clinical progressive selection of a tenofovir analog enema

我们的总体目标是优化低张直肠灌肠制剂，以提供替诺福韦(TFV)和TFV 类似于整个结直肠表面，剂量尽可能高，可以安全地给药。我们已经调查了 灌肠载体紧张性在小鼠直肠给药中的作用，包括 导致腔内水分迅速吸收，以及高渗配方导致水分迅速分泌到 管腔。我们的结果与亨德里克斯和他的同事在人类 结肠直肠：(I)自来水是一种最低张的制剂，可促进药物的局部输送和吸收，以及 (Ii)舰队灌肠，一种明显的高渗剂，会引起液体 阻止药物均匀分布的分泌物。相比之下，适度的低渗配方提供了 最好的表面分布，而且他们做得很快。低渗制剂提供药物和载药量 由钠(Na+)驱动、渗透诱导的水从管腔流动引起的平流引起的纳米晶体 进入组织，类似于结肠直肠脱水粪便的自然过程。重要的是 精液中相对较高的Na+使其在结肠直肠内处于低渗状态，这可能会将艾滋病毒迅速传播给 因此，我们的中等低张灌肠给药方法可能是 这对于确保将药物运送到艾滋病毒可以到达的所有表面至关重要。在目标1中，我们将温和地优化 TFV和TFV类似物在小鼠结肠和非人类体内的低渗给药 灵长类(NHP)，选择增强型生物利用度产品用于项目1和4的临床研究。 在目标2中，我们将设计一种增强型灌肠产品，以提高生物利用度和持续药物 放手。在目标2A中，我们将确定粘液穿透药物纳米晶是否可以延长持续时间 TFV和TFV类似物在小鼠体内的预防药物浓度，然后在NHP中。在目标2B中，我们将测试 一种假说，即胶凝剂会延长结直肠表面的滞留时间，并可能形成屏障 为艾滋病毒干杯。在目标2C中，我们将使用生物利用度增强剂和生物利用度增强剂的优化组合来测试产品 用于保护NHP中的SIV挑战的持续释放特性。

Our overall goal is to optimize hypotonic rectal enema formulations for delivering tenofovir (TFV) and TFV analogs to the entire colorectal surface with as high a dose as can be delivered safely. We have investigated the role of enema vehicle tonicity in drug delivery in the mouse rectum, including hypotonic formulations that cause rapid water uptake from the lumen, and hypertonic formulations that cause rapid secretion of water into the lumen. Our results are consistent with the studies done by Hendrix and coworkers in the human colorectum: (i) tap water, a maximally hypotonic formulation, drives drug delivery and absorption locally, and not as far up the colon as is likely necessary, and (ii) Fleet enema, a markedly hypertonic vehicle, causes fluid secretion that prevents uniform drug distribution. In contrast, moderately hypotonic formulations provide the best surface distribution, and they do so rapidly. Hypotonic formulations deliver drugs and drug-loaded nanocrystals by advection caused by sodium (Na+)-driven, osmotically-induced flow of water from the lumen into the tissues, similar to the natural process by which the colorectum dehydrates the feces. Importantly, relatively high Na+ in semen makes it hypotonic in the colorectum, which is likely to deliver HIV rapidly to the epithelium by advection, thus suggesting that our moderately-hypotonic enema drug delivery method may be critical to ensure that drug is delivered to all surfaces where HIV can reach. In Aim 1, we will optimize a mildly hypotonic formulation for delivering TFV and TFV analogs to the colorectum of mice, and then in non-human primates (NHP), to select the enhanced bioavailability product to be used in clinical studies in Projects 1 and 4. In Aim 2, we will be designing an enhanced enema product for increased bioavailability, and sustained drug release. In Aim 2A, we will determine whether mucus-penetrating drug nanocrystals can prolong the duration of prophylactic drug concentrations of TFV and TFV analogs in mice, and then in NHP. In Aim 2B, we will test the hypothesis that a gelling agent will prolong retention on the colorectal surface, and possibly form a barrier to HIV. In Aim 2C, we will test the product with the optimized combination of bioavailability enhancements and sustained release properties for protection against SHIV challenge in NHP.