PRIN CIPLES OF PERCUTANEOUS ABSORPTION 397

Reservoir fun ction

As a direct consequence of the barrier function in healthy (and , in part, in diseased)

skin, the greater part ofthe applied drug remains on the skin surface and in the horny

layer, even when the applied quantity is I mg ointment cm-2 or less. This surplus

represents a reservoir of the drug , permitting a steady and slow flow into deeper

layers. The reservoir funct ion ofthe horny layer is the reverse of its barrier function .

Th is reservoir can be regarded as the consequence ofthe adherence ofthe preparation

to the skin surface and its presence in wrinkles and folds, as weil as the result of the

amount which has been taken up by the corneocytes ofthe horny layer by swelling.

20

5

Number of strippings

c'",Q

e

..'"c

'iij 5

Ci

Q

><

N

E

u 15 ..

Q.

::>

c

E

:!:. 10

Figure 2 Distribution of radioactivity in homy material of psoriatic skin after topical

application ofa labelIed steroid(triamcinolone acetonide)in vivo.

Distribution in the epidermis and dermis

In the steady state of diffusion (mostly after 100-300 minutes), the distribution ofthe

drug in the epidermis and upper dermis is represented by a rather steep concentration

gradient, which in a half logarithmic plot rarely appears linear (Figure 3); equal

distribution in all layers has never been achieved. This is a consequence of the fact

that the underlying dermal tissue is ten times thicker than the epiderrnis, representing

a relative1y large distribution volume with little restriction to diffusion in and out of

the tissue, while diffusion into the epidermis is limited by the barrier function of the

horny layer. Thus a three-step flux gradient pertains: the flux through the horny layer

is slowest with highest concentrations in this layer, in the epidermis flux is faster

establishing medium grade concentrations whereas in the dermis flux is almost as fast

as free diffusion in water, with respectively low concentrations because of the

resorption of the substances by the capillary and Iymph systerns , and /or further

diffusion into the subcutaneous fat.

398 H. SCHAEFER, W. SCHALLA, J. GAZITH, G. STÜTTG EN & E. BAUER

These two processes are illustrated in Figure 4. After 100 min penetration time,

high molar concentrations are achieved in the skin; however, 24 h later these

concentrations have largely disappeared and, in addition, a small increase in

concentrations is observed in the transition region from dermis to the subcutaneous

fat. In terms of pharmacological action, significant amounts are reached in most

cases as early as 30 min after application . In both epidermis and dermis, the

N

5

:;; . a. Horny Layer

'"

c:

.g 103

'"

.,

oe

'in

Ci

5 10 15

Numbers of

strips

40 200 600 1000 1400 1800 2200 2600 160 400 800 1200 1600 2000 2400

Depth of layer (/Lm)

Flgure 3 Distribution of triamcinolone acetonide in psoriatic skin in vivo after topical

application.

Irradiated with UVA

(O.3 J cm-2 after 100 min)

0

S

e

.2

'§

" 10- 6 .,

u

c:

0

u

"

.,

ö

(; • '"

a. • >- • " 10- 0 7

;:

.,

::0 • I

CD

• • 10- 8

900 1500

Depth of skin (/Lm)

Figure 4 Distribution of 8-methoxypsoralen in normal human skin 100 min and 24h after

topical application in vivo.

PRINCIPLES OF PERCUTANEOUS ABSORPTION 399

concentration changes slowly with most substances, since a steady flow from the

reservoir maintains it nearly constant. This type of topical skin pharmacokinetics is

distinctly different from that of systemically applied drugs . The drug depot

sometimes desired in oral therapy, with the resulting even bioavailability, is nearly

always automatically achieved in topical therapy and remains so for periods that can

often extend up to 16h or longer.

As long as the reservoir on and in the horny layer is still present, penetration is a

one way process and back diffusion can be neglected , even under steady state

conditions. In consequence, the total amount of substance which overcomes the

horny layer barrier and enters into the epidermis and dermis will be, sooner or later,

resorbed by the vessels.

After extended penetration periods (one day or more), the concentrations in the

living skin layers decrease via this resorption, without the horny layer reservoir being

exhausted (see Figure 4, lower curve). The remainder in the horny layer is then

depleted by the proliferation ofthe skin, which results in thedesquamation - together

with the substance - of about one layer per day. This means that in a first approach

the total quantity of a substance which penetrates into the living organism, can be

estimated in vitro by exposing skin sampies for prolonged periods (ca 1000 min) to the

substance, discarding the horny layer by stripping with adhesive tape and measuring

the amount in the epidermis, dermis and in saline below the skin sampie.

As shown by Blank & Scheuplein (1964), rapidly penetrating substances diffuse

mainly through the cells of the stratum corneum (corneocytes). Slowly penetrating

substances (that is, electrolytes) may initially diffuse through the shunts (hair follicles

and sweat glands) but later on the direct diffusion through the horny layer will

become predominant, since the area ofthe shunts represents only 0.1% ofthe surface

ofhuman skin.

Penetration in diseased skin

In most skin diseases, the integrity of the horny layer is disturbed and its bar~ier

function weakened (though not abolished), so that larger amounts ~f drugs (or forelg.n

material in general) can migrate into the living layers of the skin (Table 1). This

provides topical therapy with a considerable ~dvantage ~ela~ive to o~al therapy of

skin diseases: with appropriate dosage and a suitable application techmque, the drug

will enter almost exclusively into damaged areas in relevant amounts. In oral

therapy, on the other hand, the drug is distributed in the whole skin and in the whole

body as weil, though only defmed skin areas need to be treated. Fur~her~ore, sm~1I

amounts of a topically applied drug may represent high concentrations In the skin

because of its thinness, as mentioned in the introduction, but when percutaneously

resorbed, these amounts are diluted by the whole body volume.

If, however, the total skin surface is treated, (that is, about 20,000 cm-),

percutaneous penetration can become very significant (Table 2). If, for example, an

erythrodermic psoriasis of the entire body is treated by ~teroid ointment? the

percutaneous resorption rate can equal or surpass the rate whIch would be achieved

by oral treatment. It has to be remembered, however, that percutaneous resorption

proceeds very slowly and that in comparison to oral or intravenous therapy, the

serum concentrations after this resorption remain very low, if renal function is

normal.

Besides the status of the horny layer, the localization of contact to drugs or other

foreign material is of major importance for the penetration rates.Up to hundredfold

higher penetration rates were observed in scrotum skin in comparison to back skin

(Feldmann & Maibach, 1967).

Table 1 Penetration ofdesoximetasone into normal and diseased skin in vivo(100-300 min penetration period)

o

o

Hornylayer Epiderm is Derm is

Patient Concentration Applied quantity

(%) ofointment %

%

%

la 0.05 100 mg 25 cm-2 13.7 0.27 1.88 0.038 0.48 0.0095

Ib 0.25 93 mg 28 cm-2 14.4 1.2 0.57 0.048 0.21 0.0175

2a 0.05 60 mg 12cm-2 Near basalioma, 0.58 0.014 0.34 0.084

2b 0.25 60 mg 12 crrr-' homy layer not evaluated 0.32 0.040 0.19 0.023

3a 0.05 70 rng lz crrr-' 13.0 0.31 1.30 0.031 0.039 0.0094

3b 0.25 70 mg 12 crrr-' 3.77 0.55 0.24 0.035 0.061 0.0089

4 0.05 46 mg 12 cm-2 12.4 0.24 7.56 0.145 6.22 0.12

5 0.25 60 mg 15 cm-2 9.0 0.90 4.96 0.496 1.81 0.181

6 0.25 30 mg 7 cm-2 0.88 0.042 1.62 0.078 1.05 0.051

Patient I: Tattoo, normal skin

Patient 2: Near basalioma, normal skin appearance

Patient 3: Tattoo, normal skin

Patient 4: Psoriatic lesion

Patient 5: Psoriatic lesion, homy layer=2xlO lJI1l slices

Patient 6: Temple, normal skin near melanoma

Patients 1-3: Two experiments performed simultaneously

with 0.0 5% (a) and 0.25% (b) ointment

Thickness ofhomy layer dH: 20 IJm

Th ickness ofepiderm is dE: 160 IJm

Th ickness of derm is dc: 30x40 IJm(la)

34x40 IJm(lb)

18x40 IJm(2a)

23x40 IJm(2b)

32x40 IJm(3a)

28x40 IJm(3b)

25x40 IJm(4)

18x40 IJm(5)

28x40 IJm(6)

:t

1'l

:t

>- rn

;::J

1"

1'l

:t

>-

rr-

?

:-

o

>-

N

::j

.:t

P

CI)

-I

C :

rn

Z

ll:<>

rn

ce

>-

C

m

'"

PRINCIPLES OF PERCUTANEOUS ABSORPTION 401

Table 2 Total exeretion of 8-methoxypsoralen in the urine within 72h after its topical

applieation to the upper thigh in two patients. Penetration time was 1000min.

Oral dosage" Percentageofapplied 8-methoxypsoralen

quantityexcreted excreted ....

Lipophilie Hydrophilie Lipophilie Lipophilic

w/o-ointrnent o/w-ointmcnt w/o-ointrnent w/o-ointrnent

40mg 9.60% 4.84% 28.1mg 12.7mg

* Administered in psoriasis therapy, approximate oral dose per treatment

** Calculated on the basis of one square metre body surface, treated with approximately 30g

ointment.

Influence 0/vehicle on penetration

The form of preparation can drastically affect the pharmacokinetic behaviour ofthe

drug. As a carrier, the physical and chemical properties ofthe vehicle will determine

to what extent the drug can migrate into a different phase like the skin. The

composition of the vehicle may affect the barrier function and thereby greatly

influence the diffusion pattern. Thus the antipsoriatic agent dithranol shows

excellent penetration into the skin in a vaseline ointment preparation, whereas from

polyethyleneglycol as vehicle, it penetrates to a far lesser degree . (Kammerau, Zesch

& Schaefer, 1975; Zesch & Schaefer, 1973; Zesch & Schaefer, 1975).

Topical versus systemic application

Essential differences in skin pharmacokinetics are to be expected between these two

routes. I) Topical treatment will achieve far higher concentrations in the skin than

systemic treatment even if less drug is applied, since it enters the target organ before ,

not after systemic distribution. 2) As mentioned, there is a principal difference in the

time course. Figure 5 shows human serum concentrations of8-methoxypsoralen after

oral or topical application, in a logarithmic timescale (Kammerau, Klebe, Zesch &

Schaefer, 1976; Schalla, Schaefer, Kammerau & Zesch , 1976; Gazith & Schaefer,

1977). After oral intake, the excretion is terminated after 7.5 h. After topical application, the excretion takes up to 26 hand more. 3) The distribution pattern will be

different in the skin . Though it has not been demonstrated up to now, the distribution

ofa drug in the skin after systemic application will most probably resemble an equal

0.5

of 40mg

/

/

/

I

,

,

I

I

,

I

I

I

I

I

I

o'::-/.,...,.---'-.J..r.Ju..uJ_-'----L...J...CLL.ll"'::-":>..L.Q-J...J..JJ~=-'--L::"-l..I-':J:ll=_=

0.1 10 100

Time after dosage (h )

Figure 5 Serum levels of 8-methoxypsoralen (8-MOP) after oral applieation

eompared to topieal application ofa 0.15%emulsion to the skin ofthe back.

402 H. SCHAEFER, W. SCHALLA,J. GAZITH, G. STÜTTGEN & E. BAUER

distribution in the dermis, or at least the lowcr epidermis. This pattern is, however,

distinctly different from that after topical application ofthe same drug (see Figure 4),

where the epidermal concentrations are by far higher than those in the dermis. The

consequence of these observations for the local versus systemic treatments of

dermatoses have neither been evaluated nor even discussed.

Percutaneous treatment ofsystemic disorders

With growing knowledge ofthe principles ofpercutaneous absorption the possibility

of treatment of systemic disorders via topical application becomes increasingly

attractive. Two facts are in favour ofthis concept:

I) From the view of the blood system percutaneous absorption resembles a slow

intravenous infusion with prolonged steady state features. Serum levels remain low,

however. In consequence this mode of application is suitable for drugs which are

accumulated to a certain extent at the target site.

2) The first pass effect of the liver can be bypassed. Cutaneous mctabolism plays

hardly any role since the metabolizing tissue (mainly the epidermis) is thin and even

a high metabolie capacity per volume unit can be easily overloaded by most

substances.

Among others, those preconditions have to be fulfilled for topical application of

drugs for systemic diseases: I) The drug has to be innocuous to the skin since every

adverse skin reaction changes the pharmacokinetic behaviour dramatically. 2) It

should have a high specific pharmacological action (response intensity/drug

quantity) because normal skin permits only limited quantities to permeate.

Permeation rates in the range oflOO mg daily are difficult to achieve in healthy skin,

even when treating the entire body surface. 3) The substance should be lipophilic but

not nonpolar. Electrolytes - and paraffins - hardly permeate the skin since they are

insoluble in one ofthe two (hydrophilie and lipophilic) phases ofthe horny layer.

Acknowledgements

This work was supported by a grant ofthe Deutsche Forschungsgemeinschaft, Bonn -

Bad Godesberg.

References

Blank,!. H. & Scheuplein, R. J. (1964) Pereutaneous absorption and the epidermal barrier. In

Progress in the Biological Seiences in relation to Dermatology. Vol. 2, ed. Rook A. F. &

Champion, R. p. 247. Cambridge:Cambridge University Press.