skin penetration

.[. Soc. Cosmetic Chemists 20 487-499 (1969) _ 1969 Society o[' Cosmetic Chemists of Great Britaht

Skin penetration C. W. BARRETT*

Presented at the symposium on "Skin", organised by the Society of Cosmetic Chemists of Great Britain, at Eastbourne, Sussex, on 20th November 1968.

Synopsis--The types of adverse reaction, both local and systemic due to penetration of the skin are summarised, and more recent views on pathways and mechanics of absorption discussed. Those factors influencing penetration are reviewed with particular reference to the physico-chemical properties of the penerrant, the vehicle, and the penerrant vehicle relationship. The usefulness of excised skin in diffusion cells as a method of determining penetration is described.

INTRODUCTION

Naturally occurring substances have been applied to the skin since the beginning of time, for belligerent and religious purposes as well as cosmetic and medicinal. That these substances might penetrate through the skin to produce serious toxic effects was not considered until the work of Schwenkenbecher in 1904 (1). He concluded from his experiments that the skin was permeable to lipid-soluble substances and gases, but practically impermeable to electrolytes and water.

The rapid development of sensitive analytical techniques in the last 50 years has enabled research workers to monitor the passage of substances into, and through, the skin and learn something of the factors which either hinder or enhance their progress.

Chemicals are being synthesised today in ever increasing numbers, for the dermatologist to treat skin conditions, for the cosmetic chemist to prepare a wider range of commercially available preparations and for an * The I,ondon Hospital, lx)ndon, E.1.

487

488 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

enormous variety of other purposes. In all cases though they have to be handled, and there is then a possibility that they will come in contact with the skin. It is impoitant therefore not just to the dermatologist and cosmetic chemist but to all those handling chemicals that the ability of a chemical to pass into, or through, the skin and produce toxic symptoms can be quickly and accurately assessed.

ADVERSE REACTIONS DUE TO PENETRATION OF THE SKIN

The toxicity of substances entering the skin has been reviewed by Malkinson and Rothman (2), Suskind (3), and Idson (4). Some substances will pass through the skin without eliciting an untoward reaction whilst others will produce skin reactions by penetrating only the upper layers of the stratum corneum.

Primary irritant reactions are caused by substances which directly damage or kill epidermal cells. Relatively strong acids and alkalis, and substances which are readily oxidised or reduced may act as primary irritants. The severity of the reaction may depend on the concentration applied, the frequency of reapplication, contact time, and the type of vehicle in which the substance is incorporated. Occasionally the skin may recover from the effects of a primary irritant and become resistant to further irritation (5).

Substances producing sensitivity reactions must penetrate the skin sufficiently to stimulate the formation of antibodies. This almost certainly means that they penetrate through the stratum corneum and into the Malpighian layer. Many substances have been shown to produce sensitivity reactions; of those which have been used in cosmetic preparations the p-phenylenediamine oxidation type hair dyes, eosin type lipstick colorants, the easily oxidisable aidehyde and ketone containing perfumes and lanolin may be mentioned and of the topically applied drugs, sulphonamides, penicillins, the antihistamines, local anaesthetics, and the hydroxybenzoic acid esters.

Many substances, however, produce serious systemic effects after penetrating through the skin and into the bloodstream. Piquet and Hem- meler (6) reported the occurrence of fatal poisoning from the percutaneous absorption of tetraethyl lead contained in petrol. Abrams, Hamblin and Marchand (7) reported 198 cases of poisoning due to organophosphorus insecticides absorbed partly through the skin during the first five years of their use in the U.S.A. The compounds are relatively volatile, possess good

SKIN PENETRATION 489

lipid solubility and slight water solubility which enables them to pass rapidly through the skin to produce cholinergic side effects.

Fitzpatrick, Griswold and Hicks (8) reported five instances of increased weight and ankle oedema in patients applying 0.2% fluorohydrocortisone acetate lotion for the treatment of eczematous dermatosis. The fluoro-

hydrocortisone had penetrated the skin sufficiently to produce systemic mineralocorticoid effects.

Boric acid, although now deleted from official pharmacopoeial preparations, has been widely used as a topical antiseptic for many years yet Meyler (9) describes several cases of fatal poisoning due to its penetration through the skin. This is a substance which does not penetrate normal skin in significant amounts but will penetrate inflamed or abraded skin to produce serious systemic toxic effects.

Occlusion with plastic film is now widely used to promote the absorption into the skin of topically applied anti-inflammatory corticosteroids. Plastic film dressings, however, must be used with care where the drug applied may produce toxic systemic effects. Vickers and Fritsch (10) reported six cases of toxic reactions after the application of naphazoline to the skin under polyethylene film.

PATHWAYS AND MECHANISMS OF PENETRATION

A substance may penetrate the skin either transepidermally or trans- appendageally. Palmar skin has been shown to be less permeable than other skin sites in man, even though it contains three times as many sweat glands per unit area. It seeIns unlikely, therefore, that the sweat glands represent a significant pathway of penetration.

In rodents, the number of hair follicles and therefore the relative area of invaginated epithelium within hair follicles per unit area of skin is greater than in man. Yet it has been shown for many substances that penetration of rodent skin is not correspondingly higher. Autoradiographic techniques have shown that substances do penetrate down the hair follicles {11). This suggests that penetration of the epithelium within the hair follicles is similar to that surrounding them. Tregear (12) showed that tri-n-butyl phosphate penetrated pig skin equally well, whether it contained hair follicles or not. As the stratified system constitutes the major area of the epidermis in man this is undoubtedly the major route of penetration.

With the exception of sodium ions and water which may be actively pulled into the skin(13) most substances are thought to penetrate the skin

4,6)0 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

by passive diffusion. This conclusion has been reached because most penerrants obey Fick's law, excised skin retains its impermeability for many days after it has been removed (14) and the stratum corneum, which is composed of metabolically inactive cells, is considered to be the major barrier to penetration.

A substance may cross the stratum corneum by passing either through or between the cells. Although much work has been carried out to discover which path is followed (13, 15-17) the question still remains unresolved.

FACTORS INFLUENCING PENETRATION

The factors influencing percutaneous absorption have been reviewed by Shelmire (18), Higuchi (19), Wagner (20), Barr (21) and Tregear (13). The following variables may be considered:-

1. Species differences. 2. Skin age and site. 3. Skin temperature and peripheral circulation. 4. The state of the skin (normal, abraded, or diseased). 5. The area of application, contact time and frequency of re-application. t3. The degree of hydration of the skin. 7. Pretreatment of the skin.

8. The physical characteristics of the penetrant. 9. The vehicle.

10. The penerrant vehicle relationship. It has been shown that skin permeability varies between species. Thus

rabbit skin is more permeable than that of the guinea-pig, while human skin is less permeable than both. This is a factor which must be considered when laboratory animals are used to evaluate the performance of new compounds.

Cronin and Stoughton (22) and Marzulli (2:3) have shown that substances penetrate different skin sites at different rates. Tregear (13) has shown that the permeability of rat skin to 5% aqueous triethyl phosphate solution decreases quite sharply during the seven days before birth, and more slowly after birth, even after the epidermis appears histologically mature.

Human skin, which is sparsely covered with hair, is subject to quite rapid variations in surface temperature depending on the environment. It has been shown that the penetration rate of some substances is significantly altered by this change in temperature. The state of the peripheral circula-


tion has little effect on penetration rates but would influence the length of time a substance would act. Thus, the local vasoconstriction produced by corticosteroids would be expected to delay their removal from the skin.

Penetration has been shown to be greatly enhanced when skin is abraded, broken or inflamed. Loeffler and Thomas (24) found that 50% of Sr 89 labelled strontium chloride was absorbed through abraded rat skin in contrast to 10% absorption in intact skin sites. Livingood (25) has shown that hydrocortisone-4-C14 penetrates several times faster through patches of irritative or atopic dermatitis than through normal skin.

The area of application, contact time and frequency of reapplication would be expected to have a direct effect on the extent of penetration.

McKenzie and Stoughton (26) have shown experimentally that penetration of corticosteroids may be increased 100-fold by occluding the site of application, and thus hydrating the stratum corneum. Vickers (27) has demonstrated that occlusion not only enhances penetration of corticosteroids but creates a depot effect in the stratum corneum. Although the penetration of many substances has been shown to be enhanced when the stratum corneumis hydrated, Brown (28) found that percutaneous LD so of parathion was greater when the skin was occluded than when it was left uncovered.

Pretreatment of the skin with organic solvents has variable effects on permeability. Treatment with ether did not alter the penetration rate of salicylates (29) or surfactants (30) whilst the polar solvents, acetone, alcohol and hexane greatly increased the penetration of water into the skin (31).

It is generally considered that the physico-chemical characteristics of a penetrant are the most important factors contributing to its penetration. Solubility, molecular size, particle size, crystalline form, volatility and polarity may all influence penetration rates. Stoughton, Clendenning and Kruze (32) using a series of nicotinic acid esters, Clendenning and Stoughton (33) using a series of phenylboronic acid compounds, and Treherne (34) using a series of non-electrolytes showed that those compounds that penetrated best had a lipid/water partition coefficient closest to one. However, some ions in aqueous solution have been shown to penetrate skin as rapidly as other aqueous solutes (34).

There appears to be some correlation between molecular size and penetration rate, small molecules penetrating faster than large ones, within a large range of molecular sizes. However, Iunin (35) has reported the trans- ference of colloidal sulphur across rabbit skin, and Lizgunova (36) has

49 JOURNAl. OF THE SOCIETY OF COSMETIC CHEMISTS

found bacteria below the skin after dipping rodents' tails in concentrated bacterial culture.

A reduction of the particle size of fluocinolone acetonide has been shown to enhance its penetration (37). Where a drug exists in more than one crystalline form the one with the highest thermodynamic activity would be expected to penetrate most rapidly, provided it is stable.

Cronin and Stoughton (38) using excised human skin showed that ethyl nicotinate penetrates 37,000 times better than nicotinic acid. This was attributed either to the difference in ether/water partition coefficient (ethyl nicotinate 0.136, nicotinic acid 9.25) or to the fact that ethyl nicotinate is 10,000 times as volatile as nicotinic acid. Certainly volatility would be expected to contribute to penetration provided the substance penetrates the skin in the vapour state. If a substance penetrates in solution then volatility vould only contribute to the initial build up at the skin surface.

Schlagel (39) reviewing topical anti-inflammatory steroids has shown that, with the exception of hydrocortisone acetate, the more polar and less mobile compounds have the lesser topical potencies. Thus triamcinolone acetonide has a topical activity one thousandfold greater (40) than the more polar triamcinolone.

The vehicle may enhance the penetration of a substance by making close contact with the skin surface, by being miscible with the skin lipid film and by providing an occlusive effect which would tend to hydrate the stratum corneum. Hovever, it is the physico-chemical relationship of penetrant to vehicle which is probably more important. The literature on the influence of vehicles on skin penetration is confusing and sometimes contradictory, firstly because a variety of experimental animals have been used, secondly because many different methods of estimating skin penetration have been used, and thirdly because of a lack of awareness of possible drug vehicle interactions and of the functions of different vehicles.

The following factors may be considered in the penetrant vehicle relationship:-

1. The solubility of penetrant in the vehicles or a constituent of the vehicle.

2. The rate of diffusion of penetrant within the vehicle. 3. The rate of release of penetrant from the vehicle. 4. The possible release of penetrant in solubilised form together with a

constituent of the vehicle.

The direction of flow in a system is from higher thermodynamic potential

Figure 1 ()cclusive technique for topical corticosteroid preparations.

[acing page 492

C

Figure 2 Comparison of the vasoconstrictor response to:

A. T.H.F.A. cream vehicle, unmedicated. B. Hydrocortisone 0.1 /o in T.H.F.A. cream vehicle. C. Betamethasone - 17 - valerate 0.1 o in aqueous cream B.P. D. Hydrocortisone 1 o in T.H.F.A. cream vehicle. E. Betamethasone - 17 - valerate 0.05 % in aqueous cream B.P.

Facing page 493


to lower thermodynamic potential. It is thus important that the thermodynamic activity of a penetrant in the vehicle is high. Thermodynamic activity is a product of the concentration and activity coefficient of the penetrant in the vehicle. Thus a weakly acid compound buffered to a weakly acid pH will have a higher activity than if it were buffered at an alkaline pH, and consequently its release will be dramatically improved in the former case. The converse is true of weakly basic compounds.

Similarly solutes held firmly by the vehicle, such as the complexing of phenolics and polyethylene glycols (41), are released slowly. Solutes held loosely by the vehicle exhibit high activities and are released quickly. Thus an oil-soluble drug would be released rapidly by a polyethylene glycol vehicle. Blank (41) has demonstrated this well in the study of a series of simple alcohols. Thus the water-soluble ethanol penetrates better from an oily than from an aqueous vehicle, whereas the oil-soluble pentanol penetrates better from an aqueous than from an oily vehicle.

Using a modification of the occlusive technique of McKenzie and Stoughton (26), Barrett et al (43) investigated the effect of formulation on the penetration of hydrocortisone free alcohol. Standard test discs of ointment (37) were prepared on 16 mm squares of polyethylene film which were then arranged, ointment uppermost, on a strip of cellulose tape leaving a border of approx. 25 mm of tape around each square of film (Fig. 1). The complete dressing was then applied to the flexor aspect of the fore- arm and left in place for 16 h. The resultant vasoconstriction was scored subjectively as follows:-

0 - no vasoconstriction

1 - slight vasoconstriction 2 - obvious vasoconstriction

13 - pronounced vasoconstriction Whereas no vasoconstrictor response could be demonstrated from

hydrocortisone 1% ointment BP or cream BPC, a significant vasoconstriction was obtained from o/w creams containing 25% tetrahydrofurfuryl alcohol (T.H.F.A.) or 25% dimethylacetamide, and ointments containing 15% T.H.F.A., or 10% dimethylacetamide (44). (Tables I and II). Both T.H.F.A. and dimethylacetamide are water-miscible and solubilise hydrocortisone, and were present in the o/w creams in sufficient amounts to keep the hydrocortisone in solution.

Fig. shows the vasoconstrictor response to 0.1% and 1% hydrocortisone in T.H.F.A. cream vehicle as compared vith the response to 0.1% and 0.05% betamethasone-17-valerate in aqueous cream B.P.

494' JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Table I

The percutaneous penetration of hydrocortisone from vehicles containing T.H.F.A.

Preparation

T.H.F.A. ointment vehicle containing: 1 o hydrocortisone 0.5 o hydrocortisone 0.25 o hydrocortisone 0.1 o hydrocortisone 0.05 o hydrocortisone Unmedicated vehicle Hydrocortisone 1 o ointment B.P.

T.H.F.A. cream vehicle containing: 1 o hydrocortisone 0.5 o hydrocortisone 0.25 o hydrocortisone 0.1 o hydrocortisone 0.05 o hydrocortisone Unmedicated vehicle Hydrocortisone 1 cream B.P.

Degree of vasoconstriction Mean

(Ten subjects, two tests)

1.8 1.5 1.3 1.0 0.5 0 0

1.9 1.8 1.4 1.2 0.7 0 0

Range

1-3 1-2 1-2 0-2 0-1

1-3 1-3 1-2 0-2 0-2

_

Table II

The percutaneous penetration of hydrocortisone from vehicles containing dimethylacetamide

Preparation Degree of vasoconstriction

Mean (Ten subjects, two tests)

Dimethylacetamide ointment vehicle containing:

1 o hydrocortisone 1.6 0.5 o hydrocortisone 1.3 0.25 hydrocortisone 0.8 0.1 o hydrocortisone 0.4 0.05 o hydrocortisone 0 Unmedicated vehicle 0

Dimethylacetamide cream vehicle containing:

1 o hydrocortisone 0.5 o hydrocortisone 0.25 o hydrocortisone 0.1 o hydrocortisone 0.05 o hydrocortisone Unmedicated vehicle

1.9 1.5 1.3 0.7 0.3 0

Range

1-2 0-2 0-2 0-1

--

1-3 0-3 O-3 0-2 0-1

--


The in vitro penetration of hydrocortisone from T.H.F.A. cream vehicle across a cuprophane film and into purified water was measured (Fig. 3). In fact both hydrocortisone and T.H.F.A. penetrated across the film. The

looo

2 5% IH.EA

E 8OO

,-' 600- o

.o2_ 20% T, HF.A.

o 15% T.H.EA. o 400- 10% T,H.EA, -u 5% T.H.F.A. 'T- 0% T. H.F..A.

200-

20 4'0 40 'oo Tim (hr')

Figure $ The in vitro release of hydrocortisone from 1% hydrocortisone creams containing 0-25 % T.H.F.A. (Each point is the mean of three readings.)

influence of T.H.F.A. on the ether/water partition coefficient of hydrocortisone was also measured (Fig. t). T.H.F.A. lowers the ether water partition coefficient of hydrocortisone primarily by increasing the solubility of ether in water.

Although it has often been stated that a vehicle cannot 'carry' a penerrant into the skin, these experiments tend to suggest that if a vehicle contains a solvent which is in itself a penetrant, and which will solubilise the true penetrant, then it might diffuse from the vehicle and into the stratum corneum carrying the penetrant in solution. Although the existence of the solubilised system as such in the skin may be short lived, the major barrier to penetration might quite possibly have been overcome within this period.


c 1.2

o c

o c

.o, 0.8

.4.-,, b o

o i::::).. u

o4

! i i !

5 10 15 20 25 "[H.F.A. (':'/o)

Figure 4 The influence of T.H.F.A. on the ether/water partition coefficient of hydrocortisone.

METHODS OF DETERMINING PENETRATION

Many methods for determining percutaneous penetration have been adopted and these have been reviewed by Blank (45). The disadvantage of most of them is that they do not give comparable quantitative data.

The use of excised skin in diffusion cells (14) has now enabled quantitative data to be collected. When using excised skin it is necessary to assume that no living process affects the skin's impermeability, that the dermis does not affect penetration, and that the skin surface conditions are similar to those in life.

Burch and Winsor (4t3) measuring the permeability of water, and Dirnhuber and Tregear (47) measuriug the permeability of tri-n-butyl


phosphate have shown the similarity of results using excised and intact skin. Bettley and Donoghue (48) have used excised skin for several days without noticeable change in the results.

Where full thickness skin is used the penetrant has to cross the dermis, whereas in intact skin it would probably be picked up by the capillary network at the dermo-epidermal junction. For aqueous solutes the difference would probably be small, whereas for sparingly water soluble pene- trants it may be significant. The use of epidermis alone has the disadvantage that it is fragile and holes appear at the hair follicles.

In practice, however, this technique is relatively simple, will give rapid and reproducible results and allows direct measurement of the amount of penetrant diffusing, the rate of diffusion and the amount retained by the skin.

CONCLUSIONS

With the ever increasing production of new synthetic chemicals and their widespread use in our daily lives, the need to ensure that they are not harmful to the skin, or by penetrating the skin, is becoming more necessary.

Although a considerable volume of work has been carried out to elucidate skin structure, physiology, barrier properties and the mechanisms by which substances enter and cross the skin, there is clearly still much to learn.

It is necessary to elucidate, eventually at the molecular level, how the skin keeps many invading chemicals at bay. For those substances that do penetrate the skin, those physico-chemical properties, or combination of properties, which enable them to breach the skin barrier must be worked out. With this information it might then be possible to spot a potential skin penetrant at an early stage. In particular, information on the influence of vehicles on skin penetration is still sparse and often contradictory. There is much scope for developing vehicles which will enable the drug to reach the site of action rapidly and which will maintain a sufficient concentration at the site for the required length of time.

(Received: 9th September 168)

REFERENCES

(1) Schwenkenbecher, A. Arch. Anat. _Physiol. 121-165. (1904). (2) Mallkinson, F. D. and Rothman, S. Handbuch der Haut und Geschlechtshranhheiten. in

J. Jadassohn. (1963). (Springer, Berlin).


(3) Suskind, R. R. The evaluation of therapetuic agents and cosmetics. in Sternberg. T. H. and Newcomer, V. D., in (1964). (McGraw-Hill Book Co. N.Y.) 171

(4) Idson, B. J. Pharm. Sci., ?, 1 (1968). (5) McOsker, D. E. and Beck, L. W. J. Invest. Dermatol., 48, 372 (1967). (6) Piquet, J. C. and Hemmeier, G. Aertxl. Monatsh. 4, 181. (1948). (7) Abrams, K. H., Hamblin, D. O. andMarchand, J.F.J. Am. Me&Assoc., 144,107 (1950). (8) Fitzpatrick, T. B., Griswold, H. C. and Hicks, J. H. J. Am. Med. Assoc., 18, 1149 (1955). (9) Meyler, L. Side effects of drugs. Excerpta Medica Foundation. (1966).

(10) Vickers, C. F. H. and Fritsch, W. C. Arch. Dermatol., 87, 633 (1963). (11) Choman, B. R. J. Soc. Cosmetic Chemists, 11, 127 (1960). (12) Tregear, R. T. J. Physiol. 10, 303 (1961). (13) Tregear, R. T. Physical functions of the skin. (1966). (Academic Press, London and New

York). (14) Ainsworth, M. J. Soc. Cosmetic Chemists, 11, 69 (1960). (15) Scheuplin, R. J. J. Invest. Dermatol., 4, 334 (1965). (16) Scheuplin, R. J. J. Invest. Dermatol., 48, 79 (1967). (17) Blank, I. H. and Scheuplein, R. J. J. Invest Dermatol., 40, 582 (1967). (18) Shelmire, A. Arch. Dermatol., 8,, 24 (1960). (19) Higuchi, I. J. Soc. Cosmetic Chemists, 11, 85 (1960). (20) Wagner, J. G. J. Pharm. Sci., 0, 359 (1961). (21) Barr, M. J. Pharm. Sci. 1, 395 (1962). (22) Cronin, E. and Stoughton, R. B. Brit. J. Dermatol., ?4, 265 (1962). (23) Marzulli, F. N.J. Invest. Dermatol., 87, 387 (1962). (24) Loeffier, R. K. and Thomas, V. U.S. Atomic Energy Comm. Rept. AD-225. B. Nucl.

Sci. Abstr. , No. 323 (1951). (25) Livingood, S.C. Discussion of F. D. Malkinson (1958). (26) McKenzie, A. W. and Stoughton, R. B. Arch. Dermatol., 80, 608 (1962). (27) Vickers, C. F. H. Arch. Dermatol., 88, 20 (1963). (28) Brown, V. K. Structure and Function of Epidermal Barriers. International Symposium,

Brno. (1964). (29) Wurster, D. E. and Kramer, S. F. J. Pha'm. Sci., 0, 288 (1961). (30) Blank, I. H. and Gould, E. J. Invest. Dermatol., 87, 311 (1962). (31) Onken, H. D. and Moyer, C .A. Arch. Dermatol., 87, 584 (1963). (32) Stoughton, R. B., Clendenning, W. E. and Kruse, D. J. Invest. Dermatol., $5, 337

(1960). (33) Clendenning, W. E. and Stoughton, R. B. J. Invest. Dermatol., 89, 47 (1962). (34) Treherne, J.E.J. Physiol., 188, 171 (1956). (35) Iunin, A. N. Intern. Abstr. Me& Sci., 14, 2331 (1958). (36) Lizgunova, A. V. Bull. Exp. Biol. Med. U.S.S.R. l{nglish Transl., 47, 28 (1959). (37) Barrett, C. W., Hadgraft, J. W. and Sarkany, I. Brit. J. Dermatol., 76, 479 (1964). (38) Cronin, E. and Stoughton, R. B. Arch. Dermatol., 87, 445 (1963). (39) Schlagel, C. A. J. Pharm. Sci., 54, 335 (1965). (40) McKenzie, A. W. Arch. Dermatol., 86, 611 (1962). (41) Guttman, D. and Higuchi, T. J. Pharm. Sci., 45, 659 (1956). (42) Blank, I. H. j'. Invest. Dermatol., 48, 415 (1964). (43) Barrett, C. 5V., Hadgraft, J. W., Caron, G. A. and Sarkany, I. Brit. J. Dermatol., 77,

576 (1965). (44) Sarkany, I., Hadgraft, J. r., Caron, G. A. and Barrett, C. W. Brit. J. Dermatol., 77,

569 (1965). (45) Blank, I. H. J. Soc. Cosmetic Chemists, 11, 59 (1960). (46) Burch, G. E. and Winsor, T. Arch. Intern. Med. 74, 437 (1946). (47) Dirnhuber, P. and Tregear, R. T. J. Physiol., 152, 58 (1960). (48) Bettley, F. R. a.nd Donoghue Nature, 185, 17 (1960).


DISCUSSION

MR. M. J. BUSSE: I think if you plot the results in Tables I and JI on the effect of hydrocortisone in vehicles containing T.H.F.A. and dimethylacetamide on the vasoconstriction response you will show a very approximate linear relationship between log concentration of hydrocortisone and the vasoconstrictor response, and I suspect that if you had slightly extended the concentrations in the upper and lower range of hydrocortisone, you would have obtained a Sigmoid-shaped curve. In _Fig. the responses are shown to 0.5% and 0.1% betamethasone-17-valerate in a cream base.

In my laboratory work I have shown that if you plot log concentration of tetra- methasone valerate in a cream base against the vasoconstrictor response, one gets the classical biological response Sigmoid-shaped curve and the linear portion of this Sigmoid-shaped curve lies between concentrations of 0.0001% and 0.001% of betamethasone-17-valerate, and the 0.5% and 0.01% concentrations shown in _Fig. would appear to be supramaximal for vasoconstriction. When I calculated the doses of betamethasone-17-valerate in cream base required to cause vasoconstriction in 50% of subjects, the actual dosage in gg correlate very closely with those found origin- ally in the work of McKenzie and Atkinson (49).

THE LECTURER: We have tried unsuccessfully to produce a vasoconstriction using concentrations of betamethasone-17-valerate lower than 0.05%. I think it is important to remember the technique that we were using, i.e. applying approx. 7.Smg of medicaments (viz. vehicle with betamethasone valerate, not betamethasone- 17-valerate) to a small area of skin and, therefore, one cannot necessarily compare results unless one has a similar experimental scheme. This is quite a small amount of vehicle to apply to the skin, but we thought that the thickness applied was fairly close to that which would be apphed in a normal condition, and we did not produce vasoconstriction at concentrations lower than 0.05%, possibly because of our technique.

MR. M. J. 13USSE: Using your technique have you tried concentrations of betamethasone-17-valerate lower than 0.05% in a cream base?

It would have been very interesting to have seen an attempt to produce vasoconstriction with hydrocortisone in a vehicle without the penerrant solvents in an attempt to produce a similar dose response curve as is shown in Tables I and II, and thereby attempting to calculate a potency ratio for hydrocortisone in a vehicle with, and without, solvents.

THE LECTURER: We tried 1% hydrocortisone in the pharmocopaeal cream and ointment bases, and got no response at all; we were therefore unable to tackle this problem.

A MEMBER OF TH AUDieNCE: In page 488 you state that some substances will pass through the skin without eliciting an untoward reaction whilst others will produce skin reactions by penetrating only the upper layers of the stratum corneum. Would you like to expand a little on this statement; could you say what types of materials you have in mind?

THE LECTURER: I was concerned here with the various groups of irritant response i.e. those materials that only damage cells in the stratum corneum, not necessarily producing damage any further down in the skin, e.g. dilute acids and alkalis. {49) McKenzie, A.W. and Atkinson, R. M. Arch. Dermatol., 89 741 (1964).

skin penetration

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