Development of Ultra Long-Acting Oral HIV Therapies

超长效口服 HIV 疗法的开发

• 批准号: 9325355
• 负责人: Andrew Martin Bellinger
• 金额: $ 132.35万
• 依托单位: LYNDRA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-22 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325355
• 关键词: Acquired Immunodeficiency Syndrome; Adherence; Affect; Animal Model; Animals; Anti-Retroviral Agents; Antimalarials; Attention; Canis familiaris; Chronic; Clinical; Combined Modality Therapy; Coupled; Development; Devices; Diagnostic radiologic examination; Diffusion; Disease; Disease Progression; Dosage Forms; Dose; Drug Delivery Systems; Drug Kinetics; Drug resistance; Engineering; Ensure; Enteral; Environment; Enzymes; Event; Excipients; FDA approved; Fatigue; Formulation; Future; Gastrointestinal tract structure; HIV; HIV Infections; HIV antiretroviral; HIV drug resistance; HIV therapy; Half-Life; Health Benefit; Highly Active Antiretroviral Therapy; Hour; Human; Hydrophobicity; In Vitro; Infection; Injectable; Integrase Inhibitors; Intestines; Intramuscular; Ivermectin; Kinetics; Length; Location; Methods; Microspheres; Modeling; Monitor; Morbidity - disease rate; Oral; Particle Size; Patients; Pharmaceutical Preparations; Pharmacotherapy; Polymers; Population; Process; Public Health; Publications; Regimen; Reporting; Reproducibility; Research; Risk; Route; Serum; Side; Stomach; Suspensions; System; Tail; Testing; Therapeutic; Tissues; Tracer; Translational Research; Translations; Uncertain Risk; Viral Load result; arm; base; capsule; chemical stability; design; dosage; drug resistant virus; elastomeric; experience; improved; melting; mortality; nano; non-compliance; novel; novel therapeutics; oral HIV; pill; pre-exposure prophylaxis; prototype; residence; resistant strain; small molecule; subcutaneous; success; translational medicine; vector control

ABSTRACT A common problem with any chronic drug therapy is non-adherence. Non-adherence to therapy, including HIV anti-retroviral therapy, can be due to a combination of factors including pill fatigue, intolerable side-affects, and the complexity of therapeutic regimens. Non-adherence is associated with a rebound in viral loads which can be accompanied by the emergence of drug-resistant HIV strains. This poses a major public health threat not only because of ensuing disease progression, but also because drug-resistant strains are spread in the population through de novo infections. Even as the HIV drug pipeline continues to generate novel and potent anti-retroviral compounds, much attention is now being directed towards developing long-lasting drug delivery options. In order for combination therapy with HAART to continue to be effective in improving AIDS-related morbidity and mortality, therapies need to be formulated so as to require infrequent and convenient dosing while achieving sustained and effective tissue concentrations. To date, the most successful strategy for prolonged and controlled delivery of small molecule treatments relies on slow-releasing nano-suspensions or polymeric microspheres that are injected either subcutaneously or intramuscularly. There are, however, many drawbacks to the injectable approach. Injectables are limited to highly potent, very hydrophobic molecules, and can produce long, sub-therapeutic tails with uncertain risk. Long-acting oral therapies are potentially the most convenient route for patients, and may offer significant advantages over injectable solutions. But no existing oral delivery system can provide more than 12-24 hours of sustained release of small molecule therapies. Lyndra has developed an orally-available, gastric-resident dosage form engineered to deliver therapeutic doses of drug(s) over a period of a week, before disintegrating and safely passing out of the body. The basic modules of the device are an elastomeric center fused to six arms made of a polymer-drug blend; break points called linkers are strategically placed in the arms to ensure timed disintegration of the dosage form, leading to quick and safe passage out of the body. We have demonstrated in large animal models that this platform is capable of once weekly administration with near steady-state pharmacokinetics for a variety of small molecule therapies. The objective of this proposal is to integrate a highly potent anti-HIV molecule into this platform for a once weekly oral regimen. In Aim 1, we will optimize a formulation of Dolutegravir, a potent integrase inhibitor, for sustained delivery from a polymeric matrix blended with various excipients that control the rate of release. In Aim 2, we will develop novel, enteric linkers that quickly dissolve in the intestinal environment. A tracer system to monitor residence of drug-loaded doses will be based on release of sub-therapeutic doses of short half-life FDA-approved drugs. Finally, in Aim 3, we propose to test gastric residence as well as pharmacokinetics of drug and tracer release in a large animal model. Our target product is a 0-size capsule comprising a single dosage form loaded with enough Dolutegravir to sustain serum levels similar to those achieved by the current clinical regimen, for one week. In the long term, we plan to develop formulations that carry combinations of highly potent anti-retrovirals and tracers that allow patients to self-track the presence of the doses.

摘要 任何慢性药物治疗的一个常见问题是不依从性。不坚持治疗， 包括艾滋病毒抗逆转录病毒治疗，可能是由于多种因素的综合作用， 疲劳、无法忍受的副作用以及治疗方案的复杂性。不遵守是 与病毒载量反弹相关，这可能伴随着 抗药性艾滋病毒株。这对公共卫生构成了重大威胁， 疾病进展，但也因为耐药菌株在人群中传播， 新发感染。即使艾滋病毒药物管道继续产生新的和有效的 抗逆转录病毒化合物，现在很多注意力都集中在开发持久的 药物输送选项。为了使与HAART的联合治疗在以下患者中继续有效： 为了改善艾滋病相关的发病率和死亡率，需要制定治疗方法， 不频繁和方便的给药，同时实现持续和有效的组织浓度。到 日期，最成功的策略，延长和控制交付的小分子 治疗依赖于缓慢释放的纳米悬浮液或聚合物微球， 皮下或肌肉注射。然而，可注射药物也存在许多缺点。 approach.注射剂仅限于高效、非常疏水的分子，并且可以产生 风险不确定的长期、亚治疗性尾部。 长效口服疗法可能是患者最方便的途径， 与注射液相比具有显著优势。但是现有的口服给药系统 超过12-24小时的小分子药物缓释。Lyndra开发了一种 经设计以递送治疗剂量的药物的口服可得的胃驻留剂型 在一周的时间内，在分解并安全地从身体中排出之前。基本 该装置的模块是融合到由聚合物-药物共混物制成的六个臂的弹性体中心; 被称为接头的断裂点被策略性地放置在臂中，以确保 剂型，导致快速和安全地排出体外。我们已经证明了 动物模型表明该平台能够每周一次给药，接近稳态 用于各种小分子疗法的药代动力学。这项建议的目的是 将高效抗HIV分子整合到该平台中，用于每周一次口服方案。在 目的1，我们将优化一种有效的整合酶抑制剂Dolutegravir的制剂，用于持续 从与控制释放速率的各种赋形剂共混的聚合物基质递送。 在目标2中，我们将开发新型肠溶连接剂， 环境监测载药剂量驻留的示踪剂系统将基于药物的释放。 FDA批准的短半衰期药物的亚治疗剂量。最后，在目标3中，我们建议测试 胃驻留以及药物和示踪剂在大型动物模型中释放的药代动力学。 我们的目标产品是一个0大小的胶囊，包含一个单一的剂型， 多鲁特韦维持与当前临床方案相似的血清水平， 一周从长远来看，我们计划开发含有高浓度的组合的配方 有效的抗逆转录病毒药物和示踪剂，使患者能够自我跟踪剂量的存在。