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: 10425794
• 负责人: Thanh Nguyen
• 金额: $ 17.71万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425794
• 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; Fumarates; Gastric ulcer; Glucocorticoids; Hemorrhage; Home; Hospitalization; Human Resources; In Vitro; Inflammation; Injections; Intra-Articular Injections; Kinetics; Libraries; Medical; Medicine; Metabolism; Modeling; Musculoskeletal; Nerve Endings; Non-Steroidal Anti-Inflammatory Agents; Opiate Addiction; Opioid; Opioid Analgesics; Oral; Osteoporosis; Overdose reduction; Pain; Pain management; Painless; Patients; Persons; Pharmaceutical Preparations; Rattus; Resistance to infection; Retina; Route; Self Administration; Skin; Stomach; Synovial Fluid; System; Tablets; Tenofovir; Therapeutic; Time; TimeLine; 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; 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，这种疾病与极端关节有关 疼痛和炎症。尽管阿片类药物对疼痛治疗产生了强烈的作用，但该药物会引起严重问题 药物滥用和成瘾。另外，其他镇痛药在内 传统上，炎症药物和糖皮质激素已开处方以减轻OA疼痛而没有 关注阿片类药物成瘾。这些药物也有局限性，这主要是由于 行政。口服表与第一通代谢斗争，因此需要大量药物 很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 大量口服剂量为300-1000 mg/天，这会引起严重的胃肠道问题（例如胃 出血和胃溃疡），视网膜功能不全，心血管疾病等。糖皮质激素片剂 大量使用，也表现出较低抗感染的副作用，骨质疏松症的风险较高 等12。除了口服递送，关节内（IA）注射止痛药，尤其是针对糖皮质激素 正如地塞米松（Dex）13，14所示，显示了治疗OA疼痛的功效。但是，注射必须是 重复多次以维持镇痛作用，提出复杂性，成本和 不便，导致患者的依从性/依从性低。重复注射IA的侵入性可能 还会造成更多的软骨损坏。在这方面，透皮微针（MN）已作为一个 强大的系统穿透SC，促进各种药物的皮肤内输送。微小的MN避免触摸 神经末日会大大减轻疼痛，甚至可以由非专业人士自我管理， 显着提高患者的依从性。在这里，我们提出了一种新颖的（反式）真皮生物降解的Mn 可以单时间完全嵌入皮肤的系统，以执行良好的控制持续 长期释放非阿片类镇痛药，以治疗慢性肌肉骨骼疼痛。 我们在此R21中的目标是开发单个皮肤给药MN贴片以进行长期交付 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 透皮系统可提供对发布剂量和发布期的单独控制，这可以 很容易长时间延伸以治疗慢性OA疼痛。我们的总体假设是患者 如果在家中，有OA/关节炎疼痛也能够在皮肤上自我贴上（类似于伤口） 绷带）仅一次获得长期疼痛的缓解，类似于从 重复注射IA。我们以两个具体的目标设计我们的项目。目标1是表征释放动力学 发行轮廓的Core-Shell MN和工程参数（即剂量，延迟/滞后时间和释放 时期）体外；目的2是评估体内释放并证明MN的镇痛作用。