Single-administration microneedles with controlled sustained release of non-opioid analgesics to treat osteoarthritis pain

摘要 每年，数以百万计的人患有关节炎，如骨关节炎，一种与极端关节炎相关的疾病。 疼痛和炎症。尽管阿片类药物对疼痛治疗有很强的效果，但这种药物会引起严重的问题 药物滥用和成瘾。或者，也可以使用其他镇痛剂，包括NSAID（非阿片类和非甾体类抗抑郁药）。 炎症药物）和糖皮质激素传统上被开处方以减轻OA疼痛， 阿片类药物成瘾。这些药物也有局限性，这在很大程度上是由于药物的给药途径。 局口服片剂与首过代谢作斗争，因此需要大量的药物， 容易导致严重的全身副作用。例如，NSAID药物通常具有低生物利用度， 以300-1000 mg/天的大剂量口服处方，这会导致严重的GI问题（例如胃 出血和胃溃疡），视网膜功能障碍，心血管疾病等。 大量使用，也表现出对感染抵抗力降低，骨质疏松风险增加的副作用 etc.12.除了口服递送之外，关节内（IA）注射止痛药，特别是糖皮质激素，如 如地塞米松（Dex）13、14，已经显示出治疗OA疼痛的功效。但是，注射必须 重复多次以维持镇痛效果，这带来了复杂性、成本和 不方便，导致患者依从性/依从性低。反复IA注射的侵袭性可能 也会造成更多的软骨损伤。在这方面，透皮微针（MN）已经作为一种新的治疗方法出现。 强大的系统渗透SC，促进各种药物的皮肤内输送。微小的MN避免接触 神经末梢来极大地减轻疼痛，甚至可以由非专业人士自我管理， 显著提高患者依从性。在这里，我们提出了一种新的（经）皮生物降解MN 系统可以完全嵌入皮肤在一个单一的时间，以执行良好的控制持续 长期释放非阿片类镇痛剂，用于治疗慢性肌肉骨骼疼痛。 我们在R21中的目标是开发一种单次皮肤给药MN贴剂，以进行长期给药 一种常见的非阿片类糖皮质激素，地塞米松或地塞米松（作为药物模型）。这些MN将是第一批 透皮系统以提供对释放剂量和释放时间的单独控制，其可 可以很容易地长期延长，以治疗慢性OA疼痛。我们的总体假设是， 患有OA/关节炎疼痛的人甚至在家里也能够在皮肤上自行应用这种MN贴片（类似于伤口 绷带），以获得长期的疼痛缓解，类似于从 重复IA注射。我们设计我们的项目有两个具体目标;目标1是表征释放动力学 的核-壳MN和释放曲线的工程参数（即剂量、延迟/滞后时间和释放 目的2是评估MN的体内释放并证明MN的镇痛作用。

Abstract Every year, millions of people suffer from arthritis such as osteoarthritis, a disease associated with extreme joint pain and inflammation. Despite the strong effect of opioids for pain treatment, the drug causes serious problems of drug abuse and addiction. Alternatively, other analgesics including NSAIDs (non-opiate and non-steroid anti- inflammation drugs) and glucocorticoids have been traditionally prescribed to alleviate OA pain without the concern of opioid addiction. These drugs also have limitations, which are largely due to the routes of administration. Oral tables struggle with the first-pass metabolism, thus requiring a large amount of drugs and easily leading to severe systemic side effects. For example, NSAID drugs often have low bioavailability and are prescribed with a large oral dose of 300-1000 mg/day, which causes significant GI problems (e.g. stomach bleeding, and stomach ulcers), retinal disfunction, cardiovascular diseases etc. Glucocorticoid tablets, when used with a large quantity, also exhibit side effects of lower resistance to infection, higher risk of osteoporosis etc.12. Besides oral delivery, intra-articular (IA) injections of pain medicines, especially for glucocorticoids such as Dexamethasone (Dex)13, 14, have shown the efficacy to treat OA pain. However, the injections need to be repeated multiple times to sustain the analgesic effect, posing significant problems of complexity, cost, and inconvenience, leading to low patient compliance/adherence. The invasiveness of repeated IA injections could also cause more cartilage damages. In this regard, transdermal microneedles (MNs) have appeared as a powerful system to penetrate the SC, facilitating the intra-skin delivery of various drugs. Tiny MNs avoid touching the nerve endings to tremendously reduce pain and can be even self-administered by non-professionals, significantly increasing patient compliance. Here, we propose a novel (trans)dermal biodegradable MN system which can be fully embedded into the skin at a single-time to perform a well-controlled sustained release of non-opioid analgesics over a long period for the treatment of chronic musculoskeletal pains. Our objective in this R21 is to develop a single-time skin administration MN patch to perform a long-term delivery of a common non-opioid glucocorticoid, Dexamethasone or Dex (as a drug model). These MNs will be the first transdermal system to provide a separate control over the release dose and the release period, which can be easily extended over a long period to treat chronic OA pain. Our overarching hypothesis is that patients with OA/arthritis pains would be able to self-apply such a MN patch on the skin even at home (similar to a wound bandage) at just a single time to obtain a long-term pain relief, similar to the analgesic effect obtained from the repeated IA injections. We design our project with two specific aims; Aim 1 is to characterize the release kinetics of the core-shell MNs and engineering parameters of the release profile (i.e. dose, delay/lag time, and release period) in vitro; Aim 2 is to assess the in vivo release and demonstrate the analgesic effect of the MNs.