Minimally invasive delivery of peptide and protein molecules represents a significant opportunity for product differentiation and value creation versus standard injectable routes of administration. One such technology utilizes microneedle (MN) patches and it has made considerable clinical advances in systemic delivery of potent macromolecules and vaccines. A sub-class of this technology has focused on preparation of solid dense MN arrays followed by precision formulation coating on the tips of the MN. The objective of this study was to develop a drug product using the MN technology that has similar bioperformance when compared to subcutaneous route of delivery and can provide improved stability under storage. Therapeutic peptide (Peptide A, Merck & Co., Inc., Kenilworth, NJ, USA) is being developed as a subcutaneous injection for chronic dosing with a submilligram estimated therapeutic dose. Peptide A has chemical and physical stability challenges in solution and this led to exploration of a viable drug product which could provide therapeutic dosages while overcoming the stability issues seen with the compound. This work focused on developing a coated solid microstructure transdermal system (sMTS) for Peptide A followed by detailed in vitro and preclinical evaluation for two different coating formulations. Based on initial assessment, ~250 μg of Peptide A could be coated with precision on a 1.27cm² patch which contained 316 MN’s. The delivery from these systems was achieved with absolute bioavailability being similar to the subcutaneous delivery (88% and 74% for coated sMTS 1 & 2 and 75% for subcutaneous delivery). Stability of Peptide A was also found to be significantly improved when coated on the sMTS system with minimal degradation recorded at room temperature storage as compared to the subcutaneous liquid formulation. Additionally, skin irritation (on pig skin) was also measured in this study and it was found to be minimal and self-resolving. This evaluation provided a viable option for developing a drug product with improved stability and successful delivery of the investigated molecule.

Schematic showing uncoated sMTS, resulting product with coated peptide, successful skin penetration with high delivery efficiency and bioavailability.

中文翻译：

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用于有效药物肽的透皮递送的包被的微针。

与标准注射途径相比，肽和蛋白质分子的微创递送代表了产品差异化和价值创造的重大机会。一种这样的技术利用微针（MN）贴剂，并且在有效递送大分子和疫苗的系统递送方面取得了可观的临床进展。该技术的一个子类专注于制备固体致密MN阵列，然后在MN的尖端上进行精确的配方涂层。这项研究的目的是开发一种使用MN技术的药物产品，该产品与皮下给药途径相比具有相似的生物性能，并且可以提供改善的储存稳定性。治疗性肽（肽A，默克公司，新泽西州Kenilworth，美国（美国）正在开发一种皮下注射剂，用于慢性给药，其皮下注射剂量估计在治疗剂量以下。肽A在溶液中具有化学和物理稳定性方面的挑战，这导致人们探索一种可行的药物产品，该产品可提供治疗剂量，同时克服该化合物存在的稳定性问题。这项工作的重点是为肽A开发一种包衣的固体微结构透皮系统（sMTS），然后对两种不同的包衣配方进行详细的体外和临床前评估。根据初步评估，约250μg的肽A可以在1.27厘米处精确涂覆 肽A在溶液中具有化学和物理稳定性方面的挑战，这导致人们探索一种可行的药物产品，该产品可提供治疗剂量，同时克服该化合物存在的稳定性问题。这项工作的重点是为肽A开发一种包衣的固体微结构透皮系统（sMTS），然后对两种不同的包衣配方进行详细的体外和临床前评估。根据初步评估，约250μg的肽A可以在1.27厘米处精确涂覆 肽A在溶液中具有化学和物理稳定性方面的挑战，这导致人们探索一种可行的药物产品，该产品可提供治疗剂量，同时克服该化合物存在的稳定性问题。这项工作的重点是为肽A开发一种包衣的固体微结构透皮系统（sMTS），然后对两种不同的包衣配方进行详细的体外和临床前评估。根据初步评估，约250μg的肽A可以在1.27厘米处精确涂覆^2个补丁，其中包含316 MN。通过这些系统实现的递送具有与皮下递送相似的绝对生物利用度（包被的sMTS 1和2分别为88％和74％，皮下递送为75％）。与皮下液体制剂相比，当在sMTS系统上包被时，还发现肽A的稳定性得到显着改善，在室温下储存时记录的降解最小。此外，在这项研究中还测量了对皮肤的刺激（对猪皮的刺激性），发现刺激性很小并且可以自行解决。该评价为开发具有改进的稳定性和成功递送所研究的分子的药物产品提供了可行的选择。

示意图显示未包被的sMTS，带有被包被的肽的最终产品，成功的皮肤渗透以及高的递送效率和生物利用度。