Nicotine patch
The nicotine patch is a transdermal medication that delivers a controlled dose of nicotine through the skin into the bloodstream to help individuals quit smoking by reducing nicotine withdrawal symptoms such as cravings, irritability, and anxiety.[1] It is available over-the-counter for adults aged 18 and older in various strengths, typically ranging from 7 mg to 21 mg per 24 hours, and is applied once daily to clean, dry, non-hairy skin on areas like the upper arm, chest, or hip.[2] The patch is worn for 16 to 24 hours before removal, often as part of a stepped program where dosage decreases over 8 to 12 weeks to gradually wean users off nicotine entirely.[3] Developed in the mid-1980s as a form of nicotine replacement therapy (NRT), the nicotine patch emerged from early research demonstrating transdermal nicotine absorption could suppress smoking urges, with key patents filed in 1986 and 1989 for delivery systems using adhesive matrices or reservoirs.[4] The U.S. Food and Drug Administration (FDA) approved the first nicotine patches in late 1991 and early 1992, including brands like Habitrol, Prostep, Nicoderm, and Nicotrol, marking a significant advancement in smoking cessation aids following the earlier approval of nicotine gum in 1984.[4] By 1996, these patches became available without a prescription, broadening access and contributing to their widespread use, with sales exceeding $1 billion in the U.S. shortly after market entry.[4] As the simplest and most compliant form of NRT due to its continuous delivery without user action beyond application, the nicotine patch increases the likelihood of successful quitting by 50% to 70% compared to placebo, particularly when combined with behavioral counseling or other therapies like bupropion.[3] It works by stimulating nicotinic acetylcholine receptors in the brain to release dopamine, thereby mimicking the rewarding effects of smoking while avoiding exposure to tobacco's carcinogens and toxins.[3] Common side effects include skin irritation or redness at the application site, headache, and nausea, though serious reactions like allergic responses or cardiovascular symptoms are rare and require medical attention.[2] Precautions include avoiding use in non-smokers, pregnant individuals, or those with recent heart conditions, and patches should be kept away from children and pets to prevent accidental poisoning.[1]Design and Mechanism
Composition and Formulation
The nicotine patch is a transdermal delivery system with nicotine serving as the primary active ingredient, formulated in its free base form to enhance skin permeability and ensure stable release.[5] This form of nicotine, rather than a salt, is preferred due to its lipophilic properties, which support diffusion across the stratum corneum without ionization barriers.[5] Nicotine patches typically feature a multilayer construction designed for controlled release. The outermost layer is an occlusive backing, commonly composed of impermeable materials such as high-density polyethylene, polyester, or aluminized polyester to prevent drug loss through evaporation or external exposure.[6] Beneath this lies the drug reservoir or matrix layer, which incorporates the nicotine alongside pressure-sensitive adhesives and optional penetration enhancers; a protective release liner, often silicone- or paper-based, covers the adhesive side and is peeled off prior to application.[6] Formulations vary between reservoir and matrix types. In reservoir patches, nicotine is contained within a gel or liquid compartment bounded by a rate-controlling membrane (e.g., ethylene vinyl acetate copolymer), allowing precise dosing as seen in products like NicoDerm CQ.[6] Matrix patches, more prevalent in contemporary designs such as Habitrol or Nicorette, disperse nicotine uniformly throughout an adhesive polymer matrix (e.g., acrylate or polyisobutylene-based) for simpler manufacturing and even distribution without a separate membrane.[6][7] Inactive ingredients play crucial roles in stability, adhesion, and release modulation. Common adhesives include acrylate copolymers or silicone polymers to secure the patch to the skin; penetration enhancers such as ethanol may be added to the reservoir or matrix to improve flux rates; and stabilizers like antioxidants prevent nicotine oxidation during storage.[6] For instance, NicoDerm CQ includes ethylene vinyl acetate-copolymer, polyisobutylene, and high-density polyethylene as key excipients.[8] These components collectively enable the patch's role in sustained transdermal delivery.[6]Transdermal Delivery
The transdermal delivery of nicotine from patches operates through passive diffusion, whereby nicotine molecules migrate from a high-concentration reservoir within the patch across the skin to the lower-concentration systemic circulation, driven by a concentration gradient. This mechanism adheres to Fick's first law of diffusion, mathematically represented asJ = -D \frac{dc}{dx},
where J represents the diffusion flux, D is the diffusion coefficient of nicotine through the skin, and \frac{dc}{dx} denotes the concentration gradient across the barrier. The patch design maintains a constant nicotine concentration gradient, resulting in a predictable flux rate of approximately 29–69 μg·cm⁻²·h⁻¹ in vivo.[5] The primary barrier to nicotine absorption is the stratum corneum, the outermost layer of the epidermis, which limits permeation due to its lipophilic structure and compact keratin-filled corneocytes. To overcome this, certain nicotine patch formulations incorporate permeation enhancers, such as ethanol, which disrupt the intercellular lipids of the stratum corneum, thereby increasing nicotine solubility and diffusivity. Following application, nicotine penetrates the stratum corneum, diffuses through the viable epidermis and dermis, and enters the dermal capillaries for systemic distribution, with steady-state plasma levels generally achieved after several hours.[5][9] Pharmacokinetically, transdermally absorbed nicotine exhibits an elimination half-life of about 2 hours, reflecting rapid hepatic metabolism primarily via CYP2A6 to cotinine. For a representative 21 mg/24-hour patch, steady-state plasma concentrations typically range from 10 to 20 ng/mL, delivering nicotine at a sustained rate that approximates the average levels observed in smokers but avoids the rapid spikes and toxic byproducts associated with cigarette combustion. This controlled release maintains therapeutic plasma levels without the need for frequent dosing.[10][11] The patch ensures a constant release rate of nicotine over its intended duration, commonly 16 to 24 hours depending on the system design, such as matrix or reservoir types, thereby providing prolonged and stable systemic exposure throughout the application period.[5]