250 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS rapidly increase the hydration of the stratum corneum, rapidly increase the con- centration gradient of water across the layer of vehicle and the actual percentage ooe occlusivity would vary in these circumstances. Nevertheless, the point can be made that if you can demonstrate under conditions of low stratum corneum hydration that your vehicle has occlusive properties, you know that this is going to be even greater under clinical circumstances, whereas if even with thick layers you cannot demon- strate any occlusivity at all, then probably conditions of sweating would have to be extreme for your vehicle in practice to influence stratum corneum hydration and increase penetration. MR. N.J. VAN ABBr.: It seems to me that there is a big assumption to talk in terms of a layer, as Dr. Spruyt was doing, taking into account things.like the topo- graphy of the skin's surface and saturation of the horny layer with the vehicle. What you are applying will be anything but a uniform layer of X gm thickness? THE LECTURER: I agree. One is not putting on an absolutely uniform layer, it depends how the skin is stretched it may be that in the areas of creases or of sweat ducts, aso, there is increased thickness. Nevertheless, I think that although one would want to study minute areas of uniform conditions individually, in practice the net clinical effect depends upon your treatment of a considerable area and, therefore, one has to have an approximation of what is happening. The fact that there are area- to-area variations within this piece of skin does not matter too much from the biological and clinical point of view. MR. J. M. B•,AK•.WA¾. You make no reference as to how long this anhidrosic con- dition of the skin persists I presume you have measured this and followed it for long periods. TH• LECTUR•-R: It depends, of course, on the concentration used. Using poldine methosulphate with one application applied overnight on normal human forearm one can get complete anhidrosis for periods varying from 16•30 h. If you want to work for a longer period, then you have to re-apply the poldine. The occasional patient will remain anhidrotic for 48 or even 60 h. We in fact repeat the application every 24 h, allowing a drying-out in between and, therefore, ensure that throughout the whole period of the experiment the skin is not sweating. This can be tested by thermal or emotional stress. MR. A. F. HEA•.D: Would you like to speculate on the state of hydration of the stratum corneum after application of DMSO. You have discussed occlusivity and your work is very impressive where the white soft paraffin reduces the transepidermal water loss with the solvents which are supposed to improve percutaneous absorption, we have completely opposite effects--an enormous transepidermal water loss. T•E LEc'ruRER: It is important to realise that the measurement of water loss from the surface is being used in two different ways in the first set of experiments the in- hibition of water loss was used to measure indirectly the resistance of the layer of vehicle applied on the surface, and this in turn will lead to hydration. The other use involves using transepidermal water loss as a parameter of the integrity of the stratum corneum, and •ve know that the movement of molecules across the stratum corneum is a passive process which does not depend upon any vital mechanisms and

EXPERIMENTAL STUDIES ON PERCUTANEOUS ABSORPTION 251 which is dependent upon a variety of physical factors: in vitro one can work with epidermal or stratum corneum membranes and turn them round, it does not really matter which way you have the membranes. The assumption is made in relation to DMSO, aso, that if large amounts of water pour out through an anhidrotic epidermis, then the barrier is impaired and similarly the barrier would be impaired for any molecules trying to go the other way. There is a good deal of experimental evidence by Kligman and others that this is so DMSO will enable almost anything to penetrate the skin in vastly increased amounts, so these are two separate factors and in certain circumstances they will pull against each other. As to the actual mechanism of the way in which DMSO works, this is not too clear one hypothesis is that it does so by greatly increasing the hydralion of the stratum corneum and it is feasible that this is the main factor. We know, for instance, from the original vasoconstriction studies of Mackenzie and Sloughton (4), that hydrating the stratum corncure under polythene can reduce the threshold concentration of asteroid producing vasoconstriction by a factor of 100 so that there is no reason to disbelieve the proposition that this sort of hydralion can have a very dramatic effect. There is one hypothesis which is really the direct opposite, and this is that DMSO, because of its affinity for water, is in fact dehydrating the stratum comeurn and altering the physical-chemical state of the barrier and, therefore, doing something which allows molecules through. This problem, as far as I know at the moment, has not been resolved. MR. N.J. VA• ABB•: Your data in Table I on the partial occlusivity of a base containing solids. such as zinc oxide, has been referred to once or twice in the literature as being a means of not occluding too much with an ointment, but I do not think I have seen data before and I wonder if you have, or would like to say what effect, for instance, the particle size of the zinc oxide has, or the method of processing the paste, which could obviously make a big difference to the aggregate size of the zinc oxide. Could one get a whole range of different occlusivities according to the way in which a paste is made? T•E L•cTrmEm There certainly would be some variation. 1 have not done this, it is time-consuming and this is just a question of repeating the experiment under a variety of different conditions and I do not know of any other work that has been done on this point, I would expect only minor variations, and I doubt whether one would get differences of much more than + 25%. I use one compound zinc paste that is made up by our pharmacist for clinical use. M•. J. D. Mm•ETON: One knows that DMSO is a highly hygroscopic coinpound and would be expected to pick up water not only from the deeper layers of the skin but also from the atmosphere. Are DMF and DMA hygroscopic? Can you explain their action on this basis? I know that they are miscible with water but I am not sure about their hygroscopic properties. TaE LECTURER: All three are hygroscopic. Also when DMSO, for instance, is mixed with water one gets heat of hydralion and this has a small effect on the stratum corneum temperature. We know, according to simple physical laws, that the temper- ature of the membrane is one of the factors which determines the penetration of molecules through it. The only point is that at the moment no-one has demonstrate{l, or been able to measure, the exact degree of hydralion produced by DMSO.