Sustained 3-Month Delivery of Olanzapine for Schizophrenia Maintenance Treatment

已证明缺乏药物依从性与复发和再住院密切相关， 精神分裂症维持治疗随着每次复发，病人的长期预后 恶化，以前的功能水平很少达到。患者不依从也会导致 美国医疗保健系统的额外负担，估计每年为23亿美元。 长效抗精神病药物通过改善药物依从性为患者提供实质性益处。 目前，奥氮平唯一可用的长效制剂是再普乐RelaxivTM（ZR），2-4周 长效注射剂。不幸的是，由于对它的关注， 安全性和有效性。ZR具有注射后谵妄/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、昏迷和谵妄的状况。需要观察患者 注射后3小时，在具有紧急响应服务的医疗机构，并陪同 设施到达目的地。奥氮平的全身浓度达到100%需要5-6个月。 预期水平，稳态峰谷血药浓度波动系数为4， 给药间隔，而口服给药间隔为1.85。与其他长效制剂相似，ZR给药后不能停药。 为了超越2-4周的限制并大幅提高产品的安全性， 专注于开发一种小的植入物，以恒定的速度释放奥氮平3个月。拟议 产品是一个火柴杆大小的储液囊，在一个简单的15分钟的办公室手术中植入， 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，并以更有利的PK特征输送药物。的 拟议的产品还将延长释放从2-4周至3个月，进一步改善药物 依从性和临床结果。虽然已经存在一些皮下植入技术，但没有一种 它们适合于奥氮平的递送。最近的研究结果表明，86%的医生和50%的 的患者支持在该疾病领域使用植入物。 该技术基于一种独特的配方;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，聚合物在水解时产生弱的可溶性酸，并且在这样做的过程中， 奥氮平的被动向外扩散。奥氮平的溶解度在质子化后大大增强 因此，在由酸提供的酸性条件下，浓度梯度驱动通量更大， 储层内恒定的聚合物水解。该技术已通过另一种 药物（利培酮），预计将在今年晚些时候进入临床。目前的努力将测试多个 基于该技术的制剂在体外和体内。这项研究的最终目的是显示有利的 PK和局部耐受性，从而完成拟定奥氮平系统的临床前概念验证。

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 Similar to other depots, ZR cannot be withdrawn after administration.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.