Sustained release steroid to reduce frequent epidural injections for back pain

 描述(由申请人提供)：背部疼痛是一个普遍的健康问题，也是医疗保健支出的一个重要领域。在更保守的治疗方案失败后，硬膜外类固醇注射(ESI)通常用于治疗背痛。ESI是昂贵的，而且持续时间短。在治疗的前3个月重复注射是很常见的。所有这些都是在标签外使用非专利的、可注射的类固醇。与水溶性类固醇相比，医生历来倾向于使用不溶于水的类固醇混悬剂，如甲基强的松龙醋酸酯，以延长类固醇的暴露时间。最近，不溶于水的类固醇悬浮剂被认为与硬膜外注射失败后瘫痪或死亡有关，硬膜外注射失败导致注射到穿过硬膜外间隙的动脉，并向脊髓供应血液。这些不溶于水的类固醇悬浮液中的颗粒比毛细血管床大得多，被认为会导致血管闭塞。研究人员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，使用的是水不溶的类固醇悬浮液，而不是水溶的类固醇溶液。SpineThera旨在证明一种缓释、可生物降解的微粒子类固醇制剂的可行性，如果无意中将该制剂注入脊髓动脉，将不会导致血管闭塞。这样的配方可以消除在药物释放期间或更长时间内重复ESI的需要，并消除与某些仿制药相关的瘫痪风险。药物释放的持续时间要比非专利的、水不溶的类固醇混悬剂长得多。SpineThera建议利用以前建立的体外药物释放测试，并将这些测试与体内释放曲线进行比较，以证明可生物降解的微粒配方可以实现28天的药物释放，其颗粒尺寸足够小，不会导致直接的毛细血管床堵塞。生物可降解聚合物化学、微胶囊加工技术和活性药物成分的物理形式等变量将利用质量设计方法进行研究。可生物降解的微粒还将包括旨在防止团聚和血小板粘连的表面修饰。符合28天药物释放、颗粒大小、非聚集性和表面化学标准的制剂将进一步研究。选定的配方将作为直接注射到猪的脊髓动脉(n=13)。血管闭塞将通过血管造影术进行评估，并与注射水不溶类固醇混悬液(在先前的研究中显示为闭塞)和水溶性类固醇溶液(在先前的研究中为非闭塞)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).