SL32112-Lecture 18/19 - Transdermal drug delivery - 1&2

Primary rationale for developing TDD systems, comparing them to oral delivery.

To achieve sustained systemic concentrations over long periods in therapeutic window, control delivery, reduce dosing frequency (improving compliance), and bypass hepatic first-pass metabolism (reducing dose and toxicity).

Describe the typical Cp​ profile of a drug given orally vs. transdermally.

Oral: Rapid increase to a high Cmax​, followed by a quick decay determined by elimination kinetics.

Transdermal: Slow, sustained increase leading to a stable, plateaued Cp​ maintained near zero-order kinetics.

How TDD systems overcome the limitations of classic topical formulations (ointments/gels).

Classic topical applications are inefficient and lack predictive control.

TDS (Transdermal Delivery Systems) aim to deliver drugs to the systemic circulation at a controlled and predictive rate via specialized device design.

• only small potent molecules

• lipophilic drugs

• area of patch < 100cm as this ideal for body surface area

• not locally irritating or sensitising

The primary barrier and rate-limiting step for drug absorption in TDD.

The Stratum Corneum (SC). This acidic, lipid-rich layer provides high resistance to transport, making skin permeability, rather than device release, the typical rate-limiting step for the overall PK profile.

Key difference between Adhesive TDS, Layered TDS, and Reservoir TDS.

Adhesive: Drug is directly dispersed within the pressure-sensitive adhesive layer (simplest).

Layered/Matrix: Drug is dispersed within a polymer matrix layer (often acrylic or silicone).

Reservoir: Drug is contained within a liquid/gel compartment separated from the skin by a rate-controlling membrane.

The role of Polymers (e.g., Acrylates, Silicones) in TDD patch construction.

They form the pressure-sensitive adhesives (for matrix/adhesive systems) or the rate-controlling membrane (for reservoir systems) and the backing laminates (e.g., polycarbonates, PVC).

Why is Patch Area considered more important for TDD rate control than drug loading (for skin-controlled systems)?

If the skin controls the rate (most common scenario), the flux (J) is proportional to the area (A).

Therefore, varying the patch size is the most direct way to control the dose and systemic input rate.

PK comparison: TDD vs. Oral (Barrier, Resistance, Delivery Surface, Duration).

TDD: SC barrier, High resistance, Same delivery surface (static/occlusive), 0.5-7 day duration.

Oral: GI epithelium, Low resistance, Variable/large surface, 6-18 hr duration.

Primary clinical application and dosing strategy for Nitroglycerin (GTN) TDS.

Used for angina. Patches must be applied using an intermittent dosing mode (e.g., 12 hrs on, 12 hrs off) to prevent the development of nitrate tolerance.

sublingual: quickly eliminated, short half life, requires multiple doses

spray: uses skin as rate control membrane, prolonged absorption, sustained effect

The TDD drug significant for being the first drug developed from the outset for transdermal delivery.

Rotigotine (Neupro patch), used for Parkinson's disease. Its development was TDD-first, unlike most other patches which target existing oral drugs.

PK benefit of using TDD for Oxybutynin (Oxytrol) to treat overactive bladder.

Oral oxybutynin undergoes extensive first-pass metabolism (CYP3A4), producing active and potentially toxic metabolites. TDD avoids this, offering a reduced daily dose and reduced side-effects.

The key PK benefit of using the Selegiline (EMSAM) patch over oral Selegiline.

TDD avoids first-pass metabolism, significantly changing the parent/metabolite ratio. This reduces L-amphetamine and methamphetamine metabolites, leading to reduced side-effects (e.g., less insomnia).

Clinical and design characteristics of the Methylphenidate (Daytrana) patch for ADHD.

It's an adhesive patch worn for a controlled period (e.g., 9 hours) then removed to stop delivery. This allows for situational dosing to manage symptoms during the day and prevent nighttime insomnia.

The design of the Rivastigmine (Exelon) patch and its clinical use.

A layered/matrix adhesive system (acrylic/silicone) used to treat mild to moderate dementia (Parkinson's/Alzheimer's). It offers greater compliance and a smoother PK profile than oral dosing.

Key design features and delivery duration of the Fentanyl patch (Durogesic).

Fentanyl is a highly potent opioid (transdermal due to potency). The patch is typically a reservoir or layered system designed for sustained delivery over 72 hours (3 days) for chronic pain management.

Clinical use and patch duration for Granisetron (Sancuso).

A 5-HT3​ receptor antagonist used for prevention of chemotherapy-induced nausea and vomiting (CINV). The patch delivers drug over 24 hours but can be worn for up to 7 days for multi-day chemotherapy cycles.

Mechanism of the original Estradiol reservoir patch and the shift in TDD design.

Original was a reservoir system (often containing ethanol) designed for 3-4 day wear. Patches now favour adhesive or layered matrix designs for simplicity and improved wearability.

System design and major problem with the Clonidine (Catapres-TTS) patch.

A reservoir patch for hypertension, worn for 7 days. The main problem is achieving reliable adhesion for the full 7-day period, along with potential sensitization (skin irritation).

Name the two hormones in the EVRA contraceptive patch and its wear schedule.

Hormones: Norelgestromin and Ethinyl Estradiol.

Schedule: Worn for 3 weeks (patch changed once a week) followed by a 1-week patch-free interval.

Why is limited drug loading (25-75% delivered) a necessary consideration in TDD patch design?

Drug loading must be high enough to maintain the concentration gradient driving the drug out of the patch (thermodynamic activity), but ideally close to the delivered amount for safety and efficiency.

Clinical use of the Donepezil TDD system.

It is an acetylcholinesterase inhibitor used for the treatment of Alzheimer's disease (dementia).

Define the required occlusivity of a TDD system.

The patch must be occlusive (static/non-breathable) to ensure maximum thermodynamic activity of the drug is maintained against the skin barrier, driving the passive diffusion process.

TDD is predominantly used for drugs with which physicochemical property?

Drugs that are potent (low dose required) and possess an appropriate balance of lipophilicity (log P values typically around 1-3 or 4) to partition into the SC and the viability layer.

What is the basis for proving bioequivalence of TDD patches?

Bioequivalence is based on systemic Cp​ levels (Area Under the Curve (AUC) and Cmax​) achieved in clinical trials, not solely on the drug content or in vitro release rate.

What are the two major local dermatological concerns associated with TDD patches?

Skin Irritation (Erythema/Redness) and Sensitization (allergic reaction, often due to drug, excipients, or adhesive materials).