PERCUTANEOUS ABSORPTION 505 corneum to Na + and K + and also cetyltrimethyl ammonium bromide and sodium sulphosuccinate lauric mono-iso-propanolamide polyglycol, which show an equally moderate depression of surface tension, have very different effects on permeability. Surfactants differ considerably in their ability to alter the permeability properties of the skin barrier. Unfortunately, the degree of lowering of the surface tension of water is not always given so that it is impossible to say to what extent this difference is related to the surface active property of the solution. The work of Bettley (45) would suggest that lowering the sur- face tension of water is not an important factor in enhancing skin permea- bility despite the possibility of removal of lipids when the surface tension of water is lowered. In vitro observations are obviously necessary before one can be certain on this point. The observations of Blank and Gould (94) and of Sprott (96) would indicate that the protein binding ability of the sur- factant and the consequent alteration of the structure of the stratum corneum has to be taken into account as one of the factors that influence the alteration of the permeability of the skin. Recent studies (146, 152) tend to confirm the importance of protein denaturation in the increased permeability of skin induced by some surfactants. Ointments, pastes and creams Although the mechanisms by which individual organic solvents affect percutaneous absorption are amenable to investigation and data exist on many such solvents, the influence of formulations, containing a mixture of organic substances, on percutaneous absorption is less understood (153) and Williams (154) pointed out that there is no 'solid scientific evidence to guide the prescription of an active ingredient in..., an ointment, or paste or a cream'. It is equally difficult to predict with any degree of certainty the likely influence of formulations of this sort on percutaneous absorption of cosmetic chemicals. A limited amount of information is, however, available which could form the basis of some sort of a guideline. The question of absorption of medicaments from ointment bases through the intact human skin was reviewed by Johnson and Lee (113). Many conflicting reports exist but in general most authorities considered that medicinals were absorbed more readily from animal and vegetable fats than from 'petroleum' bases. Experimentation in this field was hampered by the difficulty of accurately measuring the 'fatty materials and trace substances' in the tissues (113). The use of radio-isotopes considerably simplified these difficulties and Johnston and Lee (113) used NaC1, labelled

506 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS with a T-emitting isotope of Na as a tracer in order to study its absorption from four types of ointment formulations applied to the forearm of human volunteers. The ointments were anhydrous lanolin, white petroleum jelly, lard, a 'hydrophile ointment base of the cholesterol type' and a 'washable' ointment consisting of cetyl alcohol, white wax, propylene glycol, sodium lauryl sulphate and 72•o water. Observations over a 24 h period showed that absorption was best from anhydrous lanolin, next from lard, then from the hydrophile ointment and cetyl alcohol base and least of all from petroleum jelly. A better absorption of vitamin A in rats from an ointment containing lard than from one in which lard was substituted by petrolatum was reported by Sobel, Parnell, Burton, Sherman and Bradley (155). The more effective absorption of an electrolyte and an oil-soluble substance from lanolin and lard in these experiments, tended to confirm the reports of earlier workers. The effects of ointment bases in the form of w/o and o/w emulsions on percutaneous absorption have been investigated. Shelmire (20, 156), using skin irritation as a criterion for the penetration through the stratum corneum, studied the effect of incorporating croton oil (5•o), salicylic acid (2.5•o), mercury bichloride (1.5•o), resorcinol (5•o) and ephedrine hydrochloride (2•o) into petrolatum, a w/o emulsion, and o/w emulsion or Carbowax 1500 (a water-soluble ointment made up of equal quantities of polyethylene glycol 300 and 2540) and left in contact with the skin for 3 h. The oil-soluble croton oil and ephedrine produced a maximum degree of irritation when incorporated in petrolatum. The intensity was less when the w/o emulsion was used as an ointment base and least of all when the o/w emulsion was used for this pur- pose. No irritation occurred when Carbowax 1500 was used a sa base. On the other hand, the water-soluble substances salicylic acid, mercury bi- chloride or resorcinol were most effective when incorporated into the oint- ment base consisting of an o/w emulsion, other ointment bases gave a weak or no reaction. Similar results were obtained by Wahlberg (157) in his studies on the absorption of metallic test compounds from ointment bases. Experiments with other compounds did not show such a clear distinction. Thus, Barrett, Hadgraft and Sarkany (158) showed that methyl nicotinate is absorbed equally well from an o/w or a w/o cream. Studies on the percutaneous absorption of betamethazone 17-valerate and of fluocinolone acetonide (153) showed that vasoconstriction (assessed from the area of pallor), produced by the preparation containing the valerate in Carbowax 1500 was strikingly larger than that produced by