Description of the intrafollicular delivery of large molecular weight molecules 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 intrafollicular disposition of drug as a function of size, charge, and formulation. First, fluorescein covalently linked to antisense oligonucleotides and rhodamine-conjugated dextrans were topically applied to fresh human scalp skin in vitro. The drug position in the follicle was qualitatively determined by examining histologic sections of hair-bearing skin taken parallel to the skin surface at various depths and dissected hair follicles via fluorescent microscopy. Using radiolabeled antisense oligonucleotides we demonstrated that these cross sections can also be used to quantitatively localize the intrafollicular delivery of large molecules to follicles of human scalp skin in vitro. Experimental results showed that cationic lipid-based formulations enhanced delivery of oligonucleotides within the follicle. The qualitative analysis also illustrated that cationic lipid-based formulations directed the intrafollicular permeation along the junction of the internal and external root sheath. The charged, lower molecular weight (MW) dextrans permeated into all components of the hair follicle, including the hair shaft. The higher MW dextrans were confined to the follicular structures immediately surrounding the hair shaft. The demonstration of quantitation showed that approximately 0.5% of the applied dose was delivered to the hair bulbs and the deeper skin strata within 24 h of a single application. We conclude that topically applied agents of relatively large MW, in properly formulated delivery vehicles; have the potential to reach pharmacologically active concentrations at the hair bulb. It also should be noted that delivery takes place via the junction of the internal and external root sheath.

Transfollicular drug delivery.

The hair follicle, hair shaft, and sebaceous gland collectively form what is recognized as the pilosebaceous unit. This complex, three-dimensional structure within the skin possesses a unique biochemistry, metabolism and immunology. Recent studies have focused on the hair follicle as a potential pathway for both localized and systemic drug delivery. Greater understanding of the structure and function of the hair follicle may facilitate rational design of drug formulations to target follicular delivery. Targeted drug delivery may enhance current therapeutic approaches to treating diseases of follicular origin. Presented here is a review of follicular drug delivery and a discussion of the feasibility of the pilosebaceous unit as a target site.

Follicular (pilosebaceous unit) deposition and pharmacological behavior of cimetidine as a function of formulation.

The effect of formulation on cimetidine delivery to the pilosebaceous unit and other skin phases was studied. In vitro and in vivo deposition determinations as well as a pharmacodynamic antiandrogenic sebaceous gland bioassays were made. A complex variety of factors influence how the formulation affects both the degree of drug deposition and its pharmacological activity in the pilosebaceous unit. When cimetidine was applied in formulations at pH values where it was predominately unionized, the thermodynamic driving force proved the dominant factor in influencing the extent of drug deposition into the pilosebaceous unit. Although more cimetidine was deposited into the pilosebaceous unit in vivo from the phospholipid-based liposomal formulation when cimetidine was ionized, this formulation was also the only one devoid of significant antiandrogenic action. Of great importance, it is clear from the studies that deposition from complex formulations, such as liposomes, where bilayer/drug interactions can persist in the skin, may give a false impression of the activity of a drug within a tissue. Moreover, data for cimetidine in 50% alcohol solution show that one can maintain local effects while reducing systemic activity by simply manipulating drug concentration in the application.

Topical delivery enhancement with multilamellar liposomes into pilosebaceous units: I. In vitro evaluation using fluorescent techniques with the hamster ear model.

Evidence suggesting liposomal delivery into the pilosebaceous unit of the male Syrian hamster ear membrane was found using two fluorescent techniques, quantitative fluorescence microscopy (QFM), and a scraping method where the various tissue strata of treated skin are analyzed using fluorescence spectrophotometry. Whole ears were mounted on Franz diffusion cells and treated for 24 h with 40 microliters of the following test formulations, each containing approximately 100 micrograms/ml carboxyfluorescein (CF): i) multilamellar phosphatidylcholine: cholesterol: phosphatidylserine liposomes; ii) HEPES buffer (pH, 7.4); iii) 5% propylene glycol; iv) 10% ethanol; v) 0.05% sodium lauryl sulfate; and vi) a suspension of the same lipids used to form the liposomes that were not processed so as to produce a bilayer configuration. Topical application of the liposomally based formulation resulted in a significantly higher accumulation of CF in the pilosebaceous units than the application of any of the other non-liposomal formulations. There was excellent correlation between the two analytical methods used to determine CF deposition into the sebaceous glands.