Sustained release steroid to reduce frequent epidural injections for back pain

 描述（由申请人提供）：背痛是一种普遍的健康问题，也是医疗保健支出的一个重要领域。硬膜外类固醇注射（ESI）通常用于治疗保守治疗失败后的背痛。ESI的价格昂贵，寿命短。在治疗的前3个月重复注射是常见的。所有这些都是用普通的可注射类固醇进行的。与水溶性类固醇相比，医生历来更喜欢水不溶性类固醇混悬液，如醋酸甲泼尼龙，以延长类固醇暴露的持续时间。最近，不溶于水的类固醇悬浮液与硬膜外注射失败后的瘫痪或死亡有关，硬膜外注射失败导致输送到穿过硬膜外腔并向脊髓供应血液的动脉。这些水不溶性类固醇混悬液中的颗粒明显大于毛细血管床，据信会导致血管闭塞。研究人员已经在猪身上复制了直接动脉注射，并表明这种注射会导致神经损伤，但不溶于水的类固醇混悬液不会导致神经损伤，而水溶性类固醇溶液则不会。SpineThera旨在证明一种缓释、可生物降解的微粒-类固醇制剂的可行性，如果不慎注射到脊髓动脉中，该制剂不会导致血管闭塞。这样的制剂可以消除在药物释放时间段或更长时间内重复ESI的需要，并且消除与一些仿制药相关的瘫痪风险。药物释放的持续时间旨在显著长于通用的水不溶性类固醇混悬液。SpineThera建议使用先前建立的体外药物释放试验，并将其与体内释放曲线进行比较，以证明可生物降解的微粒制剂可以实现28天的药物释放，其粒径足够小，不会导致直接毛细血管床阻塞。将利用设计质量方法研究生物可降解聚合物化学、微囊化加工技术和活性药物成分的物理形式等变量。可生物降解的微粒将进一步包括旨在防止团聚和血小板粘附的表面改性。将进一步研究符合28天药物释放、粒度、非聚集和表面化学标准的制剂。所选制剂将直接注射至猪的脊髓动脉中（n=13）。将通过血管造影术评估血管闭塞，并与注射水不溶性类固醇混悬液（在先前研究中显示闭塞）和水溶性类固醇溶液（在先前研究中未闭塞）进行比较。

 DESCRIPTION (provided by applicant): Back pain is a pervasive health problem and a significant area of healthcare expenditure. Epidural steroid injections (ESI) are commonly given to treat back pain after more conservative treatment options have failed. ESI's are expensive and short-lasting. Repeat injections are common over the first 3 months of treatment. All are done off-label with generic, injectable steroids. Physicians historically preferred the water-insoluble steroid suspensions, such as methylprednisolone acetate, to prolong the duration of steroid exposure compared to a water-soluble steroid. Recently, the water-insoluble steroid suspensions have been linked to paralysis or death after failed epidural injections that resulted in delivery to an artery that passes through the epidural space and which supplies blood to the spinal cord. The particles in these water-insoluble steroid suspensions are significantly larger than capillary beds and are believed to result in vascular occlusion. Researchers have replicated a direct arterial injection in pigs and have shown that such an injection leads to neurological injury with a water-insoluble steroid suspension but not with a water-soluble steroid solution. SpineThera aims to demonstrate feasibility of a sustained-release, biodegradable microparticle-steroid formulation that will not result in vascular occlusion if inadvertently injeced into a spinal artery. Such a formulation may eliminate the need for repeat ESI's over the drug release time period, or longer, and eliminate the risk of paralysis associated with some generics. The duration of drug release is intended to be significantly longer than from the generic, water-insoluble steroid suspensions. SpineThera proposes to utilize previously established in-vitro drug release tests that have been compared to in-vivo release profiles to demonstrate that 28-days of drug release can be achieved from a biodegradable microparticle formulation whose particle size is small enough to not lead to direct capillary bed occlusion. Variables such as biodegradable polymer chemistry, microencapsulation processing technique, and physical form of the active pharmaceutical ingredient will be studied utilizing a Quality by Design approach. The biodegradable microparticles will further include a surface modification intended to prevent agglomeration and platelet adhesion. Formulations that meet the 28-day drug release, particle size, non-aggregating, and surface chemistry criteria will be further studied. The selected formulations will be given as a direct injection into a spinal artery of a pig (n=13). Vascular occlusion will be assessed by angiography and compared to injections of a water-insoluble steroid suspension (which has shown occlusion in previous study) and a water- soluble steroid solution (non-occluding in previous study).