Sustained 3-Month Delivery of Olanzapine for Schizophrenia Maintenance Treatment

奥氮平持续 3 个月用于精神分裂症维持治疗

• 批准号: 9254370
• 负责人: FRANCIS JOSEPH MARTIN
• 金额: $ 22.44万
• 依托单位: DELPOR, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254370
• 关键词: Acids; Adopted; Adoption; Adverse effects; Antipsychotic Agents; Area; Automobile Driving; Bipolar Disorder; Brain Diseases; Caregivers; Chronic; Clinic; Clinical; Coma; Delirium; Destinations; Developed Countries; Developing Countries; Diffusion; Disease; Dose; Effectiveness; Emergency response; Equation; Equilibrium; Exhibits; Formulation; Goals; Health Care Costs; Health Personnel; Health care facility; Healthcare Systems; Hospitalization; Hour; Hydrolysis; Implant; Implantation procedure; In Vitro; Injection of therapeutic agent; Knowledge; Letters; Local anesthesia; Maintenance; Market Research; Medical Research; Mental disorders; Oral; Outcome; Patient Noncompliance; Patients; Pharmaceutical Economics; Pharmaceutical Preparations; Phase; Physicians; Plasma; Platelet Factor 4; Polymers; Procedures; Relapse; Research; Research Institute; Risk; Risperidone; Safety; Schizophrenia; Sedation procedure; Services; Solubility; Syndrome; System; Technology; Testing; Time; Uncertainty; Withdrawal; Work; alternative treatment; base; disability; improved; in vivo; medication compliance; olanzapine; outcome forecast; pre-clinical; protonation; relapse patients; research study; response; subcutaneous; success; technology validation

Lack of medication adherence has been shown to correlate strongly with relapse and re-hospitalization during schizophrenia maintenance treatment. With each successive relapse, the patient's long-term prognosis deteriorates and previous levels of functioning are rarely achieved. Patient non-adherence also places an additional burden on the US healthcare system, which is estimated at $2.3 Billion per year. Long-acting antipsychotics provide substantial benefits to patients by improving medication adherence. Currently, the only available long acting formulation of olanzapine is Zyprexa RelprevvTM (ZR), a 2-4 week depot injection. Unfortunately, the adoption of this product has been very limited due to concerns regarding its safety and efficacy. ZR carries the risk of post-injection delirium/sedation syndrome (PDSS), a serious condition which includes heavy sedation, coma, and delirium after injection. Patients need to be observed for 3 hours post-injection in a healthcare facility with emergency response services, and be accompanied from the facility to their destination. It takes 5-6 months for the systemic concentration of olanzapine to reach 100% of the intended level, and the steady-state peak-to-trough plasma concentration fluctuates by a factor of 4 for the dose interval, compared to 1.85 for oral. Similar to other depots, ZR cannot be withdrawn after administration. To move beyond the 2-4 week limit and substantially improve the safety profile of the product, this effort focuses on developing a small implant that releases olanzapine at a constant rate for 3 months. The proposed product is a matchstick-sized reservoir implanted during a simple, 15 minute, in-office procedure with local anesthesia. The benefits of such a product include eliminating the risk of PDSS, allowing for withdrawal of the medication if needed due to Adverse Effects, and delivering the medication in more favorable PK profile. The proposed product will also extend the release from 2-4 weeks to 3 months, further improving medication adherence and clinical outcomes. Although some subcutaneous implant technologies already exist, none of them is suitable for the delivery of olanzapine. Results of recent studies show that 86% of physicians and 50% of patients support the use of implants in this disease area. The technology is based on a unique formulation; a mixture of olanzapine and polylactic/polyglycolic (PLGA) polymers. The polymers produce weak, soluble acids over time as they hydrolyze, and, in doing so, promote the passive outward diffusion of olanzapine. The solubility of olanzapine is greatly enhanced upon protonation by acids, and thus the concentration gradient driving flux is greater under the acidic conditions provided by constant polymer hydrolysis within the reservoir.The technology has been validated preclinically with another drug (risperidone), which is expected to enter the clinic later this year. The current effort will test multiple formulations based on this technology in vitro and in vivo. The ultimate goal of this study is to show favorable PK and local tolerance and thus complete the preclinical proof-of-concept for the proposed olanzapine system.

缺乏药物依从性已被证明与复发和再住院密切相关 精神分裂症维持治疗。随着每次连续复发，患者的长期预后 恶化并且很少达到以前的功能水平。患者不依从治疗也会造成 给美国医疗保健系统带来每年约 23 亿美元的额外负担。 长效抗精神病药通过提高用药依从性为患者带来巨大益处。 目前，唯一可用的奥氮平长效制剂是 Zyprexa RelprevvTM (ZR)，一种 2-4 周的药物 储库注射。不幸的是，由于对其性能的担忧，该产品的采用非常有限。 安全性和有效性。 ZR 存在注射后谵妄/镇静综合征 (PDSS) 的风险，这是一种严重的 包括注射后严重镇静、昏迷和谵妄的情况。需要对患者进行观察 注射后 3 小时，在提供紧急响应服务的医疗机构中进行注射，并由医护人员陪同 设施到达目的地。奥氮平的全身浓度需要5-6个月才能达到100% 预期水平，稳态峰谷血浆浓度波动为 4 倍 剂量间隔，相比之下口服为 1.85。与其他仓库类似，ZR 给药后无法提取。 为了超越 2-4 周的限制并大幅提高产品的安全性，这项工作 专注于开发一种小型植入物，可在 3 个月内以恒定速率释放奥氮平。拟议的 该产品是一个火柴棍大小的储液器，通过一个简单的 15 分钟的办公室手术植入，并由当地医生进行 麻醉。这种产品的好处包括消除 PDSS 的风险，允许撤回 如果由于不良反应而需要药物治疗，并以更有利的 PK 曲线提供药物。这 拟议产品还将释放时间从 2-4 周延长至 3 个月，进一步改善药物治疗 依从性和临床结果。尽管一些皮下植入技术已经存在，但还没有 它们适用于奥氮平的输送。最近的研究结果表明，86% 的医生和 50% 的患者支持在该疾病领域使用植入物。 该技术基于独特的配方；奥氮平和聚乳酸/聚乙醇酸 (PLGA) 的混合物 聚合物。随着时间的推移，聚合物在水解时会产生弱的可溶性酸，并在此过程中促进 奥氮平的被动向外扩散。质子化后奥氮平的溶解度大大增强 由酸提供，因此在酸性条件下浓度梯度驱动通量更大 储层内恒定的聚合物水解。该技术已通过另一项技术的临床前验证 药物（利培酮），预计将于今年晚些时候进入临床。当前的工作将测试多个 基于该技术的体外和体内制剂。本研究的最终目的是展示有利的 PK 和局部耐受性，从而完成所提出的奥氮平系统的临床前概念验证。