By David N. Leff

With the upsurge of smokers trying to quit, transdermal nicotine patches are riding the crest of a new market for slow-release skin penetrants.

Other important applications are for nitroglycerin to allay heart attacks, estrogen and testosterone, and analgesics for chronic pain. En route to their various systemic target receptors, all these preparations have to cross one common barrier, the skin’s outermost layer, the stratum corneum.

This impermeable integument — only 10 to 20 microns thick — acts as a kind of reversible raincoat, keeping the body’s tissues from losing moisture, and preventing environmental water from entering. Its resistance to the passage of water makes the stratum corneum (SC) a problem for designers of transdermal patches, who must calibrate the amount of a pharmaceutical that will be absorbed across that waterproof lining.

Thus, a paper in the latest Proceedings of the National Academy of Sciences (PNAS), dated Feb. 18, 1997, recalls: “When CP [4-cyanophenol, a test compound] permeation in man was measured by the ‘classic’ technique of solvent deposition of a (relatively) large dose of radiolabeled chemical, followed by monitoring of radioactive carbon urinary excretion, the . . . variation associated with the cumulative amount absorbed was 13 percent to 50 percent . . . .“

That PNAS paper, by pharmaceutical chemist Richard Guy and his colleagues at the University of California, San Francisco and other centers, bears the title: “Characterization of the permeability barrier of human skin in vivo.“

The project employed an advanced form of spectroscopy to rapidly and non-invasively quantify the uptake of a chemical into the stratum cornea of living subjects.

“It measures the chemical by the vibrations that occur between the molecules,“ explained pharmaceutical chemist Audra Stinchcomb, a co-author of the paper. “It’s important in this method,“ she told BioWorld Today, “to have a chemical that’s different from the skin, because the skin itself has its own spectroscopic absorption spectra. So the 4-cyanophenol we used can be distinguished from the skin spectra.“

Dosed Forearm Skin Tape-Stripped

In their experiments, seven healthy volunteers in their late twenties bared their inner forearms to the test delivery system. This consisted of gauze pads soaked in CP solution, and taped to an area of 20 square centimeters.

After 15 or 60 minutes, (in two separate experiments), the pads were removed, the skin daubed dry, and subjected to a tape-stripping procedure with heavy-duty Scotch tape. “It lifted off the stratum cornea layer cake,“ as Stinchcomb put it, “in about 20 successive peelings.“ Then, after ultra-sensitive weighing, the collected SC fragments were subjected to spectroscopic analysis.

“We could measure the amount of chemical in the skin across the layers in two hours,“ Stinchcomb said, “which really hadn’t been done before with that type of mechanism. Other standard ways used to quantify percutaneous absorption take two days.“

The main focus of the pharmaceutical researchers was less on how to ferry useful drugs across the skin barrier, and more on how to keep out harmful environmental contaminants.

“Soil absorption,“ she observed, “is especially interesting. It’s a new area people haven’t investigated too much.“

“For example,“ Stinchcomb pointed out, “if you go to the beach, and the sand is contaminated with toxic chemicals, absorption from the soil into the skin is really quite substantial. Toxicologists traditionally thought that if a person ingested or inhaled a harmful chemical, that was very dangerous, but the skin wasn’t important. Now we’re finding out that it is a very important route of absorption for toxic chemicals.“

These she defined as “usually very fat-soluble substances, which go through the skin easily. Typical are pesticides, chemicals in paints and varnishes, or anything dissolved in contaminated ground-water — even shower water, if it’s contaminated.“

Its trans-SC systemic effect, she added, “is the same as any drug absorbed by a different route.“

Last November, Stinchcomb left Guy’s laboratory at University of California to take up a faculty position at the Albany College of Pharmacy, in New York state.

“The project I was working on in California,“ she observed, “is supposed to continue in the future, studying absorption of toxic chemicals from volatile solvents. Sometimes,“ she pointed out, “non-toxic solvents are used in topical or transdermal formulations, to enhance absorption. So the drug you might want to deliver through the skin can be measured by our spectroscopy method.“ *