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DISCUSSION
Method.-The procedure developed in this in-
vestigation eliminates certain variables inherent in
previous methods for studying percutaneous absom-
tion, which may, in part, be responsible for the
nnmerous contradictory statements regarding drug
absorption to be found in the literature. For ex-
ample, inunction of the ointment base, which is
commonly employed in absorption studies, was
avoided in this investigation since it is obviously diffi-
cult to control adequately the force of application
and surface area involved.
Following a study of dermal permeability in
chronically heat- and humidity-stressed rats, Clay
and Kelson (3)suggested that the dermal permeabil-
ity of drugs may be altered by stress. To minimize
the Occurrence of a situation which might possibly be
considered as stressful, in this study all animals were
conditioned t o the experimental routine twice weekly
1 1 I I for a period of one month prior to performance of the
0 2 4 6 8 actual experiments and were not, a t any time, placed
TIME IN HOURS in a restraining device.
Fig. 3.-The effect of the type of ointment base on Previously reported quantitative methods for
the percutaneous absorption of salicylic acid. 0, studying percutaneous absorption have generally
hydrophilic ointment ; A, hydrophilic petrolatum consisted of a one-point determination of test com-
with water; 0, petrolatum; A, polyethylene glycol pound in either urine or blood collected at a specified
ointment. interval after application of the ointment. The
technique employed in this investigation, whereby
blond salicylate concentration was determined at
hourly intervals for an extended period of time fol-
lowing application of the ointment, was thought to
enable a more valid comparison of the extent of per-
cutaneous absorption of medicament from various
ointment bases.
Solubility of Drugs.---With the ointment bases
utilized in this stady it was found that salicylic acid,
a pi edorninantly oil-soluble drug, was substantially
absorbed through the skin and was absorbed to a
U i I /
much greater extent than sodium salicylate, a prg-
dominantly water-soluble compound.
I t is the opinion of many investigators in this field
that oil-soluble substances are absorbed through the
skin, whereas water-soluble or oil-insoluble sub-
0 2 4 6 8 stances are not or only poorly absorbed, since the
TIME IN HOURS skin is largely impermeable to water and therefore
to water-soluble compounds.
Fig. 4.-The effect of the type of ointment base on The percutaneous absorption of oil-soluble sub-
the percutaneous absorption of sodium salicylate. stances is often quite rapid and the extent of absorp-
0,hydrophilic ointment; 0 , hydrophilic petrola- tion appears to increase in those cases where the
tum with water; A, petrolatum; A, polyethylene
glycol ointment. compound possesses a degree of water solubility in
addition to oil solubility. Despite extensive reports
in regard to the influence of oil and water solubility
recognized that the blood salicylate level a t any on percutaneous absorption (4-7). it has not been
given time represents a complex interaction of such established that the percutaneous absorption of com-
factors as absorption, storage, biotransformation. pounds is a function of their distribution coefficients
and excretion. (i. e., oil solubility/water solubility).
Sodium salicylate was found t o be absorbed Bischler, et al. (8). refute the necessity of water
through tbe skin to a measurable degree when in- solubility in regard to the absorption of compounds
corporated in hydrophilic ointment. although the ex- through the skin. They demonstrated excellent
tent of absorption was considerably less than that ob- percutaneous absorption of oleates of certain alka-
served with salicylic acid ointments prepared with loids which they state to be insoluble in water.
March 1960 EDITION
SCIENTIFIC 147
On the other hand, it has been shown by the use of tistically significant blood salicylate levels. The
immunologic procedures that oil-insoluble antigens possibility remains, however, that some degree of
are absorbed from either ointments or wet-packs sodium salicylate absorption did occur from the lat-
(9-12), although the degree of absorption is ad- ter three ointments, which could not be detected on
mittedly small. the basis of blood salicylate level. Evidence for this
Considerable emphasis has been placed on the im- assumption may be based on the known biologic
portance of oil solubility, since i t is believed that this properties of salicylates, and the indicative but not
property tends to enhance percutaneous absorption statistically significant blood salicylate concentra-
by the transfollicular route (13). In contrast, rela- tions obtained with petrolatum and hydrophilic pe-
tively little attention has been directed to the trolatum ointments.
influence of the solubility of the drug in the ointment Since the literature in regard to percutaneous ab-
vehicle on the extent of percutaneous absorption. sorption of sodium salicylate is meager, it was not
This factor will be considered in a subsequent publi- possible t o corroborate the results obtained in this
cation. study. However, Kionka (20) and Miyazaki (21) re-
It remains equivocal as t o whether sodium ported the absorption through the skin of sodium
salicylate is absorbed through the intact skin as such salicylate incorporated in lanolin, a water-in-oil
or only after conversion to salicylic acid. A study emulsion type base, and petrolatum containing olive
by Schwenkenbecher (14) in 1904 indicated that oil. These authors did not note any significant dif-
salicylates per se were not absorbed percutaneously. ference in the extent of absorption from the two
This conclusion was drawn from an experiment in types of ointment bases. Valette and Cesar (22)
which salicylate but not lithium ion was found in a demonstrated the superiority of an oil-in-water type
urine sample collected twenty-four hours after the base to other liquid vehicles with respect to the per-
topical application of a 2% lithium salicylate solu- cutaneous absorption of sodium salicylate.
tion. Schwenkenbecher, thereFore hypothesized
that salicylate salts were converted in the skin to
salicylic acid which was subsequently absorbed and SUMMARY
excreted in the urine. More recent renal excretion
studies (15) indicate, however, that the lithium ion 1. A procedure, utilizing t h e intact rabbit
does not appear in the urine until two to three days skin, is described for the study of percutaneous
after the oral ingestion of lithium chloride. absorption of drugs.
Aqueous solutions of sodium salicylate (6.95%),as 2. The relative extent of percutaneous absorp-
well as sodium salicylate ointments having a con- tion of salicylic acid and sodium salicylate from
tinuous aqueous phase, were found to have a p H
range of 6.2 to 6.5. The pH of the skin of the rabbit four different physical types of ointment bases
was determined t o range from 6.0 t o 7.4, values was investigated.
which are in agreement with tbose previously re- 3. The influence of the type of ointment base
ported (16). Therefore, it is doubtful that the con- on the absorption of salicylic acid and sodium
centration of free salicylic acid present at such p H
values could account for the amounts detected in the salicylate through t h e skin is considered.
blood of rabbits examined during this investigation.
Effect of Type of Ointment Base.-The results ob- REFERENCES
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(20) Kionka, H., K l m . Wochschr.. 10, 1570(1931).
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ethylene glycol ointment, was not followed by sta- lG(1948).