Transdermal Drug Delivery

Transdermal drug delivery (TDD) involves the application of drugs to the skin surface for absorption into the systemic circulation. It is an important route for both local cutaneous therapy and systemic drug administration.

The Skin Barrier

The primary obstacle to transdermal absorption is the stratum corneum (10–20 microns thick) — a densely packed layer of keratin-filled corneocytes embedded in a lipid matrix. Beneath it lies the viable epidermis (50–100 microns) and dermis (1–2 mm), the latter containing the superficial capillaries that provide systemic uptake.

Conventional TDD is a passive process governed by Fick's Law: flux (J) is proportional to the concentration gradient across the barrier.

J = Kp × Cv

where Kp is the permeability coefficient (dependent on diffusivity D, partition coefficient Km, and path length L), and Cv is the drug concentration in the vehicle.

Pathways of Skin Penetration

Pathways into the skin for transdermal drug delivery

Four major pathways exist:

Pathway	Description
A — Intercellular (tortuous lipid)	Winding path through extracellular lipids of the stratum corneum; used by most passive and chemical-enhancer methods
B — Follicular/appendageal	Through hair follicles and sweat ducts; enhanced by iontophoresis and some particle formulations
C — Transcellular (electroporation)	Direct crossing of corneocytes; enabled by electroporation
D — Microchannel	Physical disruption (microneedles, ablation, abrasion, fractional photothermolysis) creates pores bypassing the stratum corneum

— Dermatology 2-Volume Set, 5e

Theoretical Advantages

Compared to oral or injectable routes, transdermal delivery offers:

Avoids first-pass hepatic metabolism — oral drugs are often heavily metabolised before reaching systemic circulation
Avoids GI degradation and side effects
Eliminates peak-and-valley fluctuations — maintains near-steady-state plasma levels (as shown above), reducing toxicity and sub-therapeutic troughs
Reduced dosing frequency — long-acting patches can last days to weeks
Improved patient adherence
Avoids painful injections
Targeted local therapy — for dermatological diseases, drug reaches the site directly

— Dermatology 2-Volume Set, 5e

Physicochemical Requirements for Transdermal Drugs

Not all drugs are suitable. FDA-approved transdermal drugs share these properties:

Low molecular weight (<400 Da)
Lipophilic (octanol-water partition coefficient up to 10,000)
Low dose requirement (typically <10 mg/day)

Drugs Available as Transdermal Patches

Buprenorphine, clonidine, estradiol, fentanyl, granisetron, glyceryl trinitrate (nitroglycerin), levonorgestrel, lidocaine, methylphenidate, methyl salicylate, nicotine, norelgestromin, norethindrone acetate, oxybutynin, rivastigmine, rotigotine, scopolamine, selegiline, sumatriptan, testosterone

— Dermatology 2-Volume Set, 5e

Strategies to Enhance Transdermal Delivery

Fewer than two dozen drugs have been FDA-approved for transdermal administration due to the barrier's efficiency. Two broad categories of enhancement strategies exist:

1. Chemical Enhancement

Agent	Mechanism
Water (occlusion)	Hydration swells corneocytes and distends intercellular spaces, creating "pores"; 24–48 hrs of occlusion needed
Solvents (ethanol, acetone, chloroform)	Extract barrier lipids and disrupt lamellar bilayers
Surfactants (e.g., sodium lauryl sulfate)	Extract lipids and expand lacunar domains
Penetration enhancers (azone, sulfoxides, fatty acids, urea)	Extract lipids AND alter lipid phase organization
Liposomes / nanoparticles	Carrier-mediated delivery through follicular route
Ionic liquids	Newer approach for enhanced drug solubilisation and delivery
Peptides	Cell-penetrating peptides acting as carrier vectors

2. Physical Enhancement

Method	Mechanism
Iontophoresis	Electrical current drives ionised drug through follicles/sweat ducts
Electroporation	High-voltage pulses create transient pores directly across corneocytes
Ultrasound (sonophoresis)	Cavitational/thermal effects disrupt lipid bilayers
Microneedles	Arrays of micron-scale needles physically breach the stratum corneum without reaching nerve endings
Mechanical abrasion / stripping	Remove outer layers of stratum corneum
Thermal ablation / fractional photothermolysis	Laser or heat creates microchannels through the stratum corneum
STAR particles	Star-shaped particles that physically disrupt the barrier

— Dermatology 2-Volume Set, 5e

Conventional Patch Design

Transdermal patches consist of several layers:

Backing layer — impermeable, protects drug from environment
Drug reservoir or drug-in-matrix layer — controls release rate
Rate-controlling membrane (in reservoir-type systems) — governs flux
Adhesive layer — maintains skin contact
Release liner — peeled off before application

Clinical Pharmacokinetic Considerations

Onset of action is slower than oral or IV routes due to diffusion lag time through skin
A depot effect exists in the stratum corneum; drug levels persist after patch removal
Site selection matters: skin thickness, hair follicle density, hydration, and local blood flow vary by body region
Example: Transdermal fentanyl avoids hepatic first-pass metabolism but has a slow onset and an inability to rapidly adjust dosing — important in analgesia management — Morgan & Mikhail's Clinical Anesthesiology, 7e
Testosterone gels and patches provide more stable serum testosterone levels than IM injections of esters — Goodman & Gilman's Pharmacological Basis of Therapeutics

Limitations

Only suitable for potent, low-dose, small, lipophilic molecules
Local skin reactions (contact dermatitis, irritation)
Slow onset — not suited for acute conditions
Drug absorption varies with skin condition (age, disease, anatomical site)
Risk of dose dumping if patch is damaged or exposed to heat

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