Transdermal & Topical Drug Delivery

Transdermal and topical drug delivery routes offer significant advantages over oral administration for selected drugs, including first-pass avoidance, sustained drug release, and localised therapy with reduced systemic effects. However, the skin presents formidable barriers to drug permeation that must be understood and overcome for effective formulation design.

Skin Structure and Permeability Barriers

The skin is the largest organ of the body, comprising approximately 1.8 m² of surface area in adults. It acts as a highly effective barrier against the external environment while maintaining internal homeostasis.

Layers of the Skin

1. *Epidermis*: Outermost, avascular layer. Subdivided into:

- Stratum corneum (SC): ~10–20 layers of dead, corneocyte-filled cells embedded in a lipid matrix (ceramides, cholesterol, free fatty acids). The SC is the principal barrier to drug permeation. Average thickness 10–15 μm on most body surfaces; up to 400–600 μm on the palms and soles.

- Stratum granulosum, stratum spinosum, stratum basale (living cell layers): Transit zone and melanocyte layer.

1. *Dermis*: Collagen-rich, highly vascularised layer containing nerves, sweat glands, hair follicles, and lymphatics. Once a drug reaches the papillary dermis, systemic absorption occurs via the rich capillary network.
2. *Hypodermis (subcutaneous tissue)*: Fat and connective tissue; reservoir for depot preparations.

Routes of Permeation Through Skin

• *Transcellular (intracellular)*: Through corneocytes; requires drug to partition repeatedly between lipid and protein domains. Rare.
• *Intercellular (paracellular — lipid)*: Through the continuous lipid bilayer lamellae between corneocytes. The predominant route for most drugs. Requires lipophilic properties.
• *Appendageal (shunt)*: Via hair follicles and sweat ducts; bypasses SC; important for polar drugs, nanoparticles, and early drug permeation before steady state; accounts for <1% of skin surface area.

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Fick's Law of Diffusion

Drug permeation across the skin follows Fick's first law of diffusion:

J = D · K · (Cd − Ca) / h

Where:

• J = flux (drug permeation rate, μg/cm²/h)
• D = diffusion coefficient of drug in the SC
• K = partition coefficient (SC/vehicle)
• Cd = drug concentration in the donor vehicle
• Ca = drug concentration at the receptor site (≈ 0 for sink conditions)
• h = thickness of the diffusion membrane (SC thickness)

Implications for Formulation Design

• Increasing K (lipophilicity): Lipophilic drugs partition favourably into SC; however, if too lipophilic (log P > 4), they may become trapped in the SC and not diffuse into the aqueous dermis.
• Optimal log P for transdermal delivery: 1–3 (e.g., fentanyl log P ≈ 4, estradiol log P ≈ 4, nitroglycerin log P ≈ 2).
• MW < 500 Da: High molecular weight compounds permeate poorly (Lipinski-like limitation for skin).
• Melting point: Lower melting point drugs tend to have higher thermodynamic activity in a vehicle → higher permeation.
• Vehicle concentration: Higher drug concentration in vehicle increases Cd and hence flux.

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Penetration Enhancers

Penetration enhancers are excipients that reversibly reduce SC barrier resistance, increasing drug flux without causing lasting skin damage.

Mechanism Categories

1. *Lipid fluidisation*: Fatty acids (especially oleic acid, C18:1 cis) and alcohols intercalate into the SC lipid bilayers, disrupting their ordered arrangement and increasing fluidity. Oleic acid is one of the most studied and effective SC enhancers, used in many transdermal formulations.
2. *Protein modification*: Surfactants can disrupt corneocyte keratin structure. High concentrations of surfactants (SDS) cause irritation; low concentrations of non-ionic surfactants (polysorbate 80) are used safely.
3. *Solvent extraction*: DMSO (dimethyl sulfoxide) removes SC lipids and proteins, dramatically increasing permeation. DMSO causes skin irritation, garlic odour (metabolised to dimethyl sulfide), and systemic effects; its use in humans is restricted (primarily veterinary and industrial applications, though used in some clinical DMSO preparations for musculoskeletal conditions).
4. *Water uptake (hydration)*: Occluded skin (e.g., under an occlusive dressing or patch) hydrates the SC, swelling corneocytes and creating aqueous channels. Skin hydration increases drug permeation 5–10-fold.

Common Enhancers and Their Applications

| Enhancer | Concentration | Drugs Enhanced | Notes |

|----------|--------------|----------------|-------|

| Oleic acid | 1–10% | Piroxicam, diclofenac | Best for lipophilic drugs |

| Propylene glycol | 40–80% | Many (often combined) | Co-solvent + enhancer |

| Ethanol | 30–80% | Oestradiol, testosterone | Volatile; evaporation increases concentration |

| DMSO | 10–100% | Wide range | Irritant; limited clinical use |

| Azone (laurocapram) | 1–5% | Many | Potent; minimal toxicity |

| Sodium lauryl sulfate | <1% | Polar drugs | Irritant at higher concentrations |

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Transdermal Patch Systems

Matrix Patches

In matrix-type patches, the drug is homogeneously dispersed or dissolved within a polymer matrix layer that is in direct contact with the skin. Drug release is controlled by diffusion through the matrix and subsequent permeation through the SC. Rate is governed by the matrix polymer properties and drug loading.

Advantages: Thinner and more flexible; skin contact adhesive often incorporated into drug layer; lower risk of dose dumping.

Reservoir Patches

In reservoir patches, the drug is contained in a separate liquid or gel reservoir, separated from the skin by a rate-controlling membrane (typically a porous polyethylene or ethylene-vinyl acetate membrane). The membrane controls the rate of drug delivery, making release more predictable and dose-independent of remaining drug load.

Advantages: More predictable zero-order release; can contain high drug load.

Disadvantages: Risk of dose dumping if membrane is breached or cut; bulkier; must not be cut.

Examples of Transdermal Patches in NZ Clinical Use

| Drug | Brand | Indication | Patch Type | Dosing Interval |

|------|-------|-----------|-----------|----------------|

| Fentanyl | Durogesic | Chronic cancer/non-cancer pain | Reservoir | 72 hours |

| Buprenorphine | Norspan | Chronic pain | Matrix | 7 days |

| Estradiol | Estradot | HRT | Matrix | 3–4 days |

| Testosterone | Androderm | Male hypogonadism | Reservoir | Daily |

| Nicotine | Nicorette Invisi | Smoking cessation | Matrix | 24 hours |

| Glyceryl trinitrate | Transiderm-Nitro | Angina | Reservoir | Daily, nitrate-free interval |

Counselling Points for Patches

• Application site rotation to prevent skin irritation and local tolerance (especially GTN and nicotine).
• Avoid heat (electric blankets, saunas, fever): Increases skin blood flow and drug absorption → potential toxicity (fentanyl patches and heat are a key safety issue; HDC/CARM cases in NZ).
• Do not cut matrix patches (uncontrolled dose); NEVER cut reservoir patches (dose dumping).
• Used patches must be folded sticky-side to sticky-side and disposed of safely (child and pet poisoning hazard — residual fentanyl in used patches remains lethal).

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Topical Dosage Forms: Creams vs Ointments vs Gels

Creams

Creams are semi-solid emulsions. Oil-in-water (O/W) creams are cosmetically elegant, non-greasy, and washable; they promote drug penetration into the aqueous dermis but have lower occlusion and hydration of SC. Water-in-oil (W/O) creams (e.g., cold cream) are more occlusive. Preservatives are required due to aqueous content.

Ointments

Ointments are single-phase systems, most commonly anhydrous (petrolatum-based). They are highly occlusive, significantly hydrating the SC and enhancing drug permeation. Drug release from ointments is typically slower and more sustained. Ointments are preferred for chronic, dry, or lichenified skin conditions. They do not require preservatives.

Gels

Gels are semi-solid systems based on hydrophilic polymers (carbomer, hydroxypropyl methylcellulose) dispersed in water or water-ethanol systems. They are non-occlusive, leave no greasy residue, and are cosmetically acceptable. Ethanol-based gels enhance drug permeation (e.g., diclofenac sodium 1% gel — Voltaren Emulgel). Gels are not suitable for very dry or cracked skin.