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，这是一种与极端关节有关的疾病 疼痛和炎症。尽管阿片类药物治疗疼痛的效果很强，但这种药物会带来严重的问题 滥用药物和吸毒成瘾。或者，其他镇痛剂包括非类固醇抗炎药(非阿片类药物和非类固醇抗炎药) 炎症药物)和糖皮质激素传统上被用来减轻骨性关节炎的疼痛，而不是 对阿片成瘾的担忧。这些药物也有局限性，这很大程度上是由于 行政管理。口服桌子与第一次通过代谢作斗争，因此需要大量的药物和 容易导致严重的全身副作用。例如，非甾体抗炎药的生物利用度往往很低，而且 每天服用300-1000毫克的大剂量处方，这会导致严重的胃肠道问题(如胃部 出血，胃溃疡)，视网膜功能障碍，心血管疾病等。糖皮质激素片，当 大量使用，也会表现出较低的抗感染能力和较高的骨质疏松风险的副作用。 等12.除了口服外，关节内(IA)注射止痛药，尤其是糖皮质激素，如 如地塞米松(Dex)13、14已显示出治疗骨性关节炎疼痛的疗效。然而，注射需要是 重复多次以维持止痛效果，带来了复杂性、成本和 不便，导致患者依从性/依从性较低。反复注射IA的侵袭性可能 也会造成更多的软骨损伤。在这方面，经皮微针(MN)已经成为一种 强大的穿透SC系统，方便各种药物的皮肤内给药。微小的MN避免接触 神经末梢可以极大地减轻疼痛，甚至可以由非专业人员自行给药， 显著提高患者的依从性。在这里，我们提出了一种新的(经)真皮可生物降解的MN 该系统可以一次完全嵌入皮肤中，进行可控持续的 长期释放非阿片类止痛药治疗慢性肌肉骨骼疼痛。 我们在R21中的目标是开发一种一次性皮肤给药MN贴片来执行长期递送 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将是第一个 透皮系统，以提供对释放剂量和释放期限的单独控制，这可以 可以很容易地延长很长一段时间来治疗慢性骨性关节炎疼痛。我们最重要的假设是患者 患有骨关节炎/关节炎疼痛的人即使在家里也能在皮肤上自行贴上这样的MN贴片(类似于伤口 绷带)只需一次即可获得长期的止痛效果，类似于从 重复注射IA。我们设计我们的项目有两个特定的目标；目标1是表征释放动力学 核壳MN和释放分布的工程参数(即剂量、延迟/滞后时间和释放 目的2评价微球在体内的释放，并验证微球的镇痛作用。

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.