Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians-University Munich, Butenandtstr. 5, Haus B, D-81377 Munich, Germany.
Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians-University Munich, Butenandtstr. 5, Haus B, D-81377 Munich, Germany.
Eur J Pharm Biopharm. 2018 Jul;128:119-130. doi: 10.1016/j.ejpb.2018.04.008. Epub 2018 Apr 13.
The intradermal delivery of biologics has long been recognized as attractive approach for cutaneous immunotherapy, particularly vaccination. Although intradermal (i.d.) or subcutaneous (s.c.) injection provide reproducible dosing and good cost- and delivery efficiency, the major objective to avoid sharps and the need for enhanced storage stability have renewed the interest in alternative needle-free delivery strategies. This study presents a new concept for the delivery of macromolecules and nanoparticles to viable skin layers with a high density of professional antigen-presenting cells (APCs). Stable polyvinyl alcohol (PVA) polymer films as well as PVA blends with carboxymethyl cellulose (CMC) or cross-linked carbomer were prepared using an easily-scalable film casting technique. Fluorescein isothiocyanate (FITC) and rhodamine B-labeled dextrane 70 kDa (RD70), used as small and macromolecular model substances, or polystyrene (PS)-nano- and microparticles with diameters of 0.5 µm and 5 µm were directly incorporated into the polymer formulations at varying concentrations. The assembly of the polymer films with an occlusive backing tape created a film patch that provided a fast drug release upon dissolution of the water-soluble film and facilitated an intradermal drug delivery on laser microporated skin. The minimally-invasive P.L.E.A.S.E.® laser poration system (Pantec Biosolutions, Ruggell, Liechtenstein) provided access to viable skin layers by thermally ablating the superficial tissue with a pulsed Er:YAG laser (λ = 2.94 µm). In our in vitro study using excised pig skin, laser microporation induced a 4- to 5-fold increase of water transport (TEWL) through excised skin in a Franz diffusion cell compared to intact skin. The TEWL values detected were comparable to in vivo human skin. The increased water transport facilitated the dissolution of all topically applied dry PVA-based film formulations within 6 h. No dissolution of the films was seen on intact skin. The incubation of the film patches on laser microporated skin for 24 h led to a considerable intradermal delivery of RD70 or PS-nanoparticles, which was superior for pure PVA films compared to PVA-CMC or PVA-carbomer blend formulations. No intradermal delivery was observed on intact skin or when larger PS-microparticles with a diameter of 5 µm were investigated. The presented concept provides a unique opportunity to exploit the improved storage stability of sensitive drug molecules in dry film formulations while providing protection and functionality.
皮内给药长期以来一直被认为是一种有吸引力的皮肤免疫治疗方法，尤其是疫苗接种。虽然皮内（i.d.）或皮下（s.c.）注射可提供可重复的剂量，并且具有良好的成本效益和输送效率，但为了避免使用锐器和提高储存稳定性的主要目标，人们对替代无针输送策略重新产生了兴趣。本研究提出了一种将大分子和纳米颗粒递送至具有高浓度专业抗原呈递细胞（APC）的活皮层的新概念。使用易于扩展的薄膜铸造技术制备了稳定的聚乙烯醇（PVA）聚合物薄膜以及与羧甲基纤维素（CMC）或交联卡波姆混合的 PVA 共混物。荧光素异硫氰酸酯（FITC）和罗丹明 B 标记的葡聚糖 70 kDa（RD70）被用作小分子和大分子模型物质，或直径为 0.5 µm 和 5 µm 的聚苯乙烯（PS）纳米和微球直接掺入聚合物配方中，浓度不同。将聚合物膜与封闭背衬带组装在一起，形成了一个膜贴剂，当水溶性膜溶解时，它能快速释放药物，并促进激光微穿孔皮肤的皮内药物输送。微创性 P.L.E.A.S.E.®激光穿孔系统（Pantec Biosolutions，Ruggell，列支敦士登）通过使用脉冲 Er:YAG 激光（λ=2.94 µm）热烧蚀表面组织，为活皮层提供了通道。在我们使用离体猪皮进行的体外研究中，与完整皮肤相比，Franz 扩散池中的激光微穿孔使离体皮肤的水传输（TEWL）增加了 4 到 5 倍。检测到的 TEWL 值与体内人皮肤相当。增加的水传输有助于在 6 小时内溶解所有局部应用的干燥 PVA 基膜制剂。在完整皮肤上看不到膜的溶解。将膜贴片孵育在激光微穿孔皮肤上 24 小时，导致 RD70 或 PS 纳米颗粒的大量皮内递送，与 PVA-CMC 或 PVA-卡波姆共混物制剂相比，这对纯 PVA 膜更为有利。在完整皮肤或研究直径为 5 µm 的较大 PS 微球时，未观察到皮内递送。所提出的概念为利用干燥膜制剂中敏感药物分子的改善储存稳定性提供了独特的机会，同时提供了保护和功能。
