Transappendageal Transport

The role of appendages in skin transport has been controversial and remains so. The earliest evidence to support the existence of the transfollicular route of transdermal

Figure 32 (A) Correlation between in vivo and in vitro transdermal drug flux: each datapoint represents a different drug, dashed line indicates perfect correlation between in vivo and in vitro transdermal drug flux; (B) fraction of total concentration of topically applied methylsalicylate determined in microdialysate or in vitro diffusion cell studies present as salicylate following application of a 20% methylsalicylate formulation. (From Refs. 332[A]; 119[B].)

Figure 32 (A) Correlation between in vivo and in vitro transdermal drug flux: each datapoint represents a different drug, dashed line indicates perfect correlation between in vivo and in vitro transdermal drug flux; (B) fraction of total concentration of topically applied methylsalicylate determined in microdialysate or in vitro diffusion cell studies present as salicylate following application of a 20% methylsalicylate formulation. (From Refs. 332[A]; 119[B].)

Figure 33 (A) Effect of species on the in vitro absorption of water and paraquat through excised skin; (B) the influence of skin application site on topical bioavailability determined from cumulative urinary recovery of salicylate following application of 5 g Metsal (methyl-salicylate)/50 cm2 for 10 h in human volunteers. (From Refs. 227[A]; 224[B].)

Figure 33 (A) Effect of species on the in vitro absorption of water and paraquat through excised skin; (B) the influence of skin application site on topical bioavailability determined from cumulative urinary recovery of salicylate following application of 5 g Metsal (methyl-salicylate)/50 cm2 for 10 h in human volunteers. (From Refs. 227[A]; 224[B].)

transport, back in the 1940s, were largely qualitative histological studies based on stain and dye localization within the appendages (Table 10). Table 11 outlines some of the literature supporting the existence of follicular penetration of topically applied solutes. Scheuplein (91) suggested that appendageal route dominates transport early before the lag time is reached for transcellular transport. However, at longer times, transcellular transport dominates (Fig. 34). Although it remains generally accepted

Table 10 Historical Evidence for the Existence of Transfollicular Penetration Following Topical Application

Evidence

Preferential staining of hair follicles following topical application of iron, bismuth, sulfonamides, and dyes in a number of different vehicles Changes in pharmacological response to epinephrine and histamine applied in propylene glycol observed with changes in follicular density Follicular deposition of vitamin A observed by quantitative fluorescent microscopy following application in various solvents 14C-Labeled pesticide absorption and urinary excretion increased over follicle-rich areas such as the scalp and forehead, follicular route "possibly" contributing Trichlorocarbanalide compound deposition in follicles and sebaceous glands seen to vary with vehicle [3H]hydrocortisone from hydroalcoholic vehicle penetrates normal skin 50-fold faster than follicle-free skin. Retention also 20 to 30-fold higher in normal skin Particle size dependency of follicular penetration, optimum 5 ¡im Greater concentrations of hydrocortisone and testosterone observed in epidermis and dermis of normal skin, particularly at the depth of sebaceous glands, compared with follicle-free skin. In vivo effect less pronounced than in vitro Flux and absorption of caffeine, niflumic acid, and p-aminobenzoate threefold slower in follicle-free skin Particle size dependency of follicular penetration, optimum 5 ¡ m. Targeting of the antiacne drug adapalene into follicles is achieved using 5-^m microspheres as particulate carriers

Skin Ref.

Guinea pig, Mackee et al. (261) human

Human Shelley and Melton (311)

Guinea pig Montagna (232)

Human Maibach et al. (236)

Guinea pig Black et al. (312)

Rat Illel and Schaefer (313)

Rat Schaefer et al. (314)

Mouse, Rolland et al. (230) human

Table 11 Summary of Studies Examining Formulation Effects on Transfollicular Transport

Evidence

Skin

Ref.

Deposition of vitamin A into the follicular Guinea pig duct and sebaceous glands was seen within 10 min of application in ethanol or chloroform vehicles, compared with much slower penetration from oleic acid or petrolatum.

Penetration of a trichlorocarbanalide Guinea pig compound into follicles and sebaceous glands seen after application in a nonsoap sodium alkoyl isothionate detergent, compared with a soapy vehicle, which resulted in penetration into the stratum corneum.

Within 2 h of application of [3H]estradiol in Rat DMSO, ethylene glycol, or sesame oil vehicles, radioactivity could be detected in the epidermis, follicles, and sebaceous glands. At 24 h hair follicles and sebaceous glands still retained high activity—possible depot function.

Increased deposition of fluorescent beads Rat into follicles following application in lipoidal vehicles.

Liposomal entrapment of calcein, melanin, and DNA allowed delivery into follicles compared with control aqueous solutions.

Migration of topically applied steroids Rat through the follicular duct or accumulation in the sebaceous glands varied with the polarity of the steroid and the lipophilicity of the vehicle.

Vehicles favoring the transfollicular Rat penetration of pyridostigmine included ethanol, DMSO, and propylene glycol.

50% ethanol, glyceryl dilaurate-based Hamster ears nonionic liposomes and egg phosphatidylcholine-based liposomes all achieved appreciable deposits of cimetidine into the pilosebaceous unit, although possible ion-pairing of cimetidine to phospholipids reduced its pharmacological activity in these formulations.

Nonionic liposome formulations were Hamster ears superior to phospholipid-based formulations for delivery of interferon-« and cyclosporine to follicles. Both formulations were far superior to aqueous solutions.

Montagna (232)

Rutherford and Black (316)

Schaefer et al. (314)

Histocultured mouse Li et al. (319,320) skin

Bamba and Wepierre (235)

Niemiec et al. (323)

Figure 34 Suggested domination of transappendageal transport during the earlier stages of percutaneous penetration. (From Ref. 91.)

that the intercellular route may dominate during the steady-state penetration of compounds, it has been argued that the skin appendages (hair follicles, pilosebaceous and eccrine glands) may offer an alternative pathway for a diffusing molecule.

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