DESCRIPTION OF THE INTRAFOLLICULAR DELIVERY OF LARGE MOLECULAR-WEIGHTMOLECULES TO FOLLICLES OF HUMAN SCALP SKIN IN-VITRO

The objective of this study was to ascertain the elements that govern the intrafollicular delivery of large molecules to follicles of human scalp skin in vitro. The experiments were designed to assess the intra follicular disposition of drug as a function of size, charge, and form ulation. First, fluorescein covalently linked to antisense oligonucleo tides and rhodamine-conjugated dextrans were topically applied to fres h human scalp skin in vitro. The drug position in the follicle was qua litatively determined by examining histologic sections of hair-bearing skin taken parallel to the skin surface at various depths and dissect ed hair follicles via fluorescent microscopy. Using radiolabeled antis ense oligonucleotides we demonstrated that these cross sections can al so be used to quantitatively localize the intrafollicular delivery of large molecules to follicles of human scalp skin in vitro. Experimenta l results showed that cationic lipid-based formulations enhanced deliv ery of oligonucleotides within the follicle. The qualitative analysis also illustrated that cationic lipid-based formulations directed the i ntrafollicular permeation along the junction of the internal and exter nal root sheath. The charged, lower molecular weight (MW) dextrans per meated into all components of the hair follicle, including the hair sh aft. The higher MW dextrans were confined to the follicular structures immediately surrounding the hair shaft. The demonstration of quantita tion showed that similar to 0.5% of the applied dose was delivered to the hair bulbs and the deeper skin strata within 24 h of a single appl ication. We conclude that topically applied agents of relatively large MW, in properly formulated delivery vehicles, have the potential to r each pharmacologically active concentrations at the hair bulb. It also should be noted that delivery takes place via the junction of the int ernal and external root sheath.