School of Pharmacy, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada.
Mol Pharm. 2010 Jun 7;7(3):751-62. doi: 10.1021/mp900283x.
Noninvasive delivery of macromolecules across intact skin is challenging but would allow for needle-free administration of many pharmaceuticals. Biphasic vesicles, a novel lipid-based topical delivery system, have been shown to deliver macromolecules into the skin. Investigation of the delivery mechanism of interferon alpha (IFN alpha), as a model protein, by biphasic vesicles could improve understanding of molecular transport through the stratum corneum and allow for the design of more effective delivery systems. The interaction of biphasic vesicles with human skin and isolated stratum corneum membrane was investigated by confocal microscopy, differential scanning calorimetry (DSC) and small- and wide-angle X-ray scattering (SAXS and WAXS). Confocal microscopy revealed that biphasic vesicles delivered IFN alpha intercellularly, to a depth of 70 microm, well below the stratum corneum and into the viable epidermis. DSC and SAXS/WAXS data suggest that the interaction of biphasic vesicles with SC lipids resulted in the formation of a three-dimensional cubic Pn3m polymorphic phase by the molecular rearrangement of intercellular lipids. This cubic phase could be an intercellular permeation nanopathway that may explain the increased delivery of IFN alpha by biphasic vesicles. Liposomes and submicrometer emulsion (the individual building blocks of biphasic vesicles) separately and methylcellulose gel, an alternative topical vehicle, did not induce a cubic phase and delivered low amounts of IFN alpha below the stratum corneum. Molecular modeling of the cubic Pn3m phase and lamellar-to-cubic phase transitions provides a plausible mechanism for transport of IFN alpha. It is hypothesized that induction of a Pn3m cubic phase in stratum corneum lipids could make dermal and transdermal delivery of other macromolecules also possible.
非侵入性地将大分子递送到完整的皮肤是具有挑战性的，但可以实现许多药物的无针给药。双相囊泡是一种新型的基于脂质的局部递药系统，已被证明可以将大分子递送到皮肤中。通过双相囊泡研究干扰素 α（IFN α）作为模型蛋白的递药机制，可以提高对分子通过角质层的传输的理解，并允许设计更有效的递药系统。通过共聚焦显微镜、差示扫描量热法（DSC）和小角及广角 X 射线散射（SAXS 和 WAXS）研究了双相囊泡与人皮肤和分离的角质层膜的相互作用。共聚焦显微镜显示，双相囊泡将 IFN α 细胞间递送到 70 μm 的深度，远低于角质层并进入有活力的表皮。DSC 和 SAXS/WAXS 数据表明，双相囊泡与 SC 脂质的相互作用导致通过细胞间脂质的分子重排形成了三维立方 Pn3m 多晶相。这种立方相可能是细胞间渗透的纳米途径，可解释双相囊泡增加 IFN α 的递药。脂质体和亚微米乳剂（双相囊泡的单个构建块）以及替代局部递药载体的甲基纤维素凝胶分别不会诱导立方相，并且仅在角质层下递送少量 IFN α。立方 Pn3m 相和层状到立方相转变的分子建模提供了 IFN α 传输的合理机制。假设诱导角质层脂质中的 Pn3m 立方相可能使其他大分子的真皮和经皮递药也成为可能。
