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

单次给药微针控制缓释非阿片类镇痛药治疗骨关节炎疼痛

• 批准号: 10618335
• 负责人: Thanh Nguyen
• 金额: $ 21.41万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618335
• 关键词: Absence of pain sensation; Adherence; Adverse event; Analgesics; Animals; Area; Arthralgia; Arthritis; Bandage; Biological Availability; Blood; Cardiovascular Diseases; Cartilage; Chronic; Country; Curcumin; Degenerative polyarthritis; Dermal; Dexamethasone; Disease; Dose; Drug Addiction; Drug Delivery Systems; Drug Modelings; Drug abuse; Engineering; Exhibits; Friends; Fumarates; Functional disorder; Gastric ulcer; Glucocorticoids; Hemorrhage; Home; Hospitalization; Human Resources; In Vitro; Inflammation; Injections; Intra-Articular Injections; Kinetics; Libraries; Medical; Medicine; Metabolism; Modeling; Musculoskeletal; Needles; Nerve Endings; Opiate Addiction; Opioid; Opioid Analgesics; Oral; Osteoporosis; Overdose reduction; Pain; Pain management; Painless; Patients; Penetration; Persons; Pharmaceutical Preparations; Rattus; Resistance to infection; Retina; Route; Self Administration; Skin; Stomach; Synovial Fluid; System; Tablets; Tenofovir; Therapeutic; Time; Touch sensation; Toxic effect; Training; absorption; arthritic pain; chronic musculoskeletal pain; chronic pain; chronic pain management; compliance behavior; cost; design; healing; high risk; in vivo; joint inflammation; non-opioid analgesic; novel; osteoarthritis pain; pain reduction; pain relief; side effect; timeline; treatment choice; treatment duration; treatment effect; ultrasound; wound

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.

抽象的 每年，数百万人患有关节炎，例如骨关节炎，这是一种与极端关节相关的疾病 疼痛和炎症。尽管阿片类药物对疼痛治疗有很强的作用，但该药物会引起严重的问题 药物滥用和成瘾。或者，其他镇痛药，包括非甾体抗炎药（非阿片类和非类固醇类抗炎药） 传统上，医生会开具处方药（炎症药物）和糖皮质激素来缓解 OA 疼痛，但无需 对阿片类药物成瘾的担忧。这些药物也有局限性，这很大程度上是由于其途径 行政。口腔表与首过代谢作斗争，因此需要大量的药物和 容易导致严重的全身副作用。例如，NSAID 药物通常具有较低的生物利用度，并且 大剂量口服 300-1000 毫克/天，会导致严重的胃肠道问题（例如胃病） 出血、胃溃疡）、视网膜功能障碍、心血管疾病等。糖皮质激素片剂，当 大量使用，还表现出抗感染能力降低、骨质疏松风险增加等副作用 等等12。除了口服给药外，关节内（IA）注射止痛药，特别是糖皮质激素，例如 地塞米松 (Dex)13、14 已显示出治疗 OA 疼痛的功效。然而，注射需要 重复多次以维持镇痛效果，带来了复杂性、成本和效果等重大问题。 不便，导致患者依从性/依从性低。重复 IA 注射的侵入性可能 还会造成更多的软骨损伤。在这方面，透皮微针（MN）作为一种 强大的系统可以穿透SC，促进各种药物的皮内输送。小 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士自行管理， 显着提高患者的依从性。在这里，我们提出了一种新型（经）皮可生物降解的 MN 系统可以一次完全嵌入皮肤，以执行良好控制的持续 长期释放非阿片类镇痛药用于治疗慢性肌肉骨骼疼痛。 我们在此 R21 中的目标是开发单次皮肤给药 MN 贴片以执行长期给药 常见的非阿片类糖皮质激素、地塞米松或 Dex（作为药物模型）。这些 MN 将是第一个 透皮系统提供对释放剂量和释放周期的单独控制，这可以 很容易长期延长治疗慢性骨关节炎疼痛。我们的总体假设是患者 患有 OA/关节炎疼痛的人甚至可以在家里自行将这种 MN 贴片贴在皮肤上（类似于伤口） 绷带）只需一次即可获得长期疼痛缓解，类似于使用绷带获得的镇痛效果 重复 IA 注射。我们设计项目有两个具体目标；目标 1 是表征释放动力学 核-壳 MN 的结构和释放曲线的工程参数（即剂量、延迟/滞后时间和释放） 期）体外；目标 2 是评估 MN 的体内释放并证明其镇痛效果。