Sustained 3-Month Delivery of Olanzapine for Schizophrenia Maintenance Treatment

缺乏服药依从性已被证明与复发和再次住院密切相关 精神分裂症维持治疗。每次连续复发，患者的长期预后 恶化和以前的功能水平很少实现。患者不遵守医嘱也会使 美国医疗体系的额外负担，估计每年23亿美元。 长效抗精神病药物通过改善用药依从性为患者提供实质性的好处。 目前，奥氮平唯一可用的长效制剂是Zyprexa RelprevvTM(ZR)，为期2-4周 仓库注射。不幸的是，由于对该产品的担忧，该产品的采用一直非常有限 安全性和有效性。ZR存在注射后精神障碍/镇静综合征(PDSS)的风险，这是一种严重的 注射后出现重度镇静、昏迷和精神错乱的状态。需要对患者进行观察 在有急救服务的医疗机构注射后3小时，并从 到目的地的便利设施。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系数为4。 剂量间隔，相比之下，口服为1.85。与其他仓库类似，ZR在管理后不能收回。 为了超越2-4周的限制并显著改善产品的安全状况，这一努力 专注于开发一种小型植入物，以恒定的速度释放奥氮平3个月。建议数 该产品是一个火柴棒大小的储液罐，植入过程简单，15分钟，在办公室与当地 麻醉。这种产品的好处包括消除了PDSS的风险，允许提取 如果因不良反应需要用药，并以更有利的PK配置文件提供药物。这个 拟议的产品还将把缓释期从2-4周延长到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，但没有一种 它们适用于奥氮平的释药。最近的研究结果显示，86%的医生和50%的医生 的患者支持在这一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，这种聚合物会产生弱的、可溶的酸，并在这样做的过程中，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提高 在酸性条件下，浓度梯度驱动通量较大 储集层内持续的聚合物水解。这项技术已经在临床前得到了验证 药物(利培酮)，预计将于今年晚些时候进入临床。目前的努力将测试多个 基于这项技术的体外和体内制剂。这项研究的最终目的是展示有利的 PK和局部耐受性，从而完成了拟议的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 Similar to other depots, ZR cannot be withdrawn after administration.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.