The wall called the stratum corneum
Transdermal delivery means getting a drug through the skin and into the bloodstream for a whole-body effect. The obstacle is the stratum corneum — the outermost layer of dead, flattened cells embedded in lipid, often pictured as a brick wall with greasy mortar. It is barely a tenth of a millimetre thick, yet it is the single greatest barrier to drug entry anywhere on the body. Evolution built it to stop water leaving and chemicals entering; a formulator has to outwit it.
Because the mortar is fatty, the drugs that cross best are small and moderately lipophilic — roughly a log P between 1 and 3 and a molecular weight under about 500. They also need to be potent, because the skin only lets a trickle through. Nicotine, fentanyl, oestradiol and scopolamine fit this profile, which is why they were among the first patch drugs.
Fick's law sets the speed limit
The drug crosses by passive diffusion, and the rate obeys [[ficks-first-law|Fick's first law]]: flux is proportional to the concentration difference across the skin, the area of contact, and how easily the drug dissolves in and moves through the skin. The neat consequence is that if a patch keeps the drug concentration at its surface roughly constant, the flux is roughly constant too — giving the steady, zero-order-like delivery that makes patches so useful for round-the-clock dosing.
Fick's first law for transdermal flux
J = (D · K · ΔC) / h
J = flux per unit area (amount crossing per cm² per hour)
D = diffusion coefficient of drug in stratum corneum
K = partition coefficient (skin vs. vehicle)
ΔC = concentration difference across the membrane
h = thickness of the barrier
Worked estimate (round numbers):
D = 1e-7 cm²/h (slow — the barrier is dense)
K = 2 (drug prefers skin lipid 2:1)
ΔC = 10 mg/cm³ (saturated reservoir at the surface)
h = 0.002 cm (20 µm stratum corneum)
J = (1e-7 × 2 × 10) / 0.002
= 2e-6 / 0.002
= 1e-3 mg/cm²/h = 1 µg/cm²/h
To deliver 0.5 mg/h (a typical patch target):
area = 0.5 mg/h ÷ 1 µg/cm²/h = 500 cm² → too big!
Fix: add a permeation enhancer to raise D (and K), or pick
a more potent drug needing less per hour. Doubling D·K to
4 µg/cm²/h shrinks the patch to a wearable ~125 cm².Two ways to build a patch
Patches come in two main designs. A [[reservoir-system|reservoir]] patch holds the drug as a liquid or gel behind a rate-controlling membrane: the membrane, not the skin, sets the delivery rate, so it can be very precise. A [[matrix-system|matrix]] patch dissolves the drug in an adhesive polymer layer; it is thinner, simpler and harder to abuse, but the release rate drifts as the matrix empties. Most modern patches are matrix or drug-in-adhesive designs for exactly these practical reasons.