Transdermal Delivery Across Intact Skin, Penetrating The Stratum Corneum

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Targeted local application, rather than systemic

🧠 Key Rule: "500 Dalton Rule"

  1. Drugs with molecular weight ≤ 500 Da have a better chance of penetrating the stratum corneum.
  2. Penetration is still influenced by:
    1. LogP (lipophilicity) – ideal range: 1–3
    2. Aqueous solubility
    3. Charge – neutral molecules penetrate better

e.g: Rapamycin is (~914 Da) while Tadalafil (Cialis) has a molecular weight of approximately 389.4 g/mol. (Dalton (Da) = grams per mole (g/mol))

🥇 1. Ethosomes in Hydrogel/Cream (Best for passive delivery)

  • Ethosomes are lipid vesicles with high ethanol content, which fluidizes the stratum corneum and carries the drug deep into the skin.
    1. 🔬 Ingredients:
    2. Phospholipid (e.g., soy lecithin)
    3. Ethanol (20–40%)
    4. Water
    5. Drug (the molecule)
    6. Hydrogel base (e.g., Carbopol or HPMC for gel; cetostearyl alcohol/cream base for cream)

🧪 Process:

    1. Dissolve lipid in ethanol with stirring (lipid phase).
    2. Dissolve drug in water (aqueous phase), if water-soluble. If not, add to lipid phase.
    3. Slowly add aqueous phase to lipid/ethanol phase under stirring → ethosome vesicles form spontaneously.
    4. Sonicate for 5–10 minutes to reduce vesicle size (optional).
    5. Mix ethosomes into pre-prepared gel or cream base.

🥈 2. Transfersomes in Hydrogel/Cream

  • Transfersomes are deformable liposomes containing edge activators (like Tween 80) that let them squeeze through tight skin pores.
    1. 🔬 Ingredients:
    2. Phospholipid
    3. Edge activator (e.g., sodium cholate, Tween 80)
    4. Water
    5. Drug
    6. Gel/Cream base

🧪 Process:

    1. Dissolve lipid and edge activator in ethanol or chloroform.
    2. Evaporate solvent → thin lipid film forms.
    3. Hydrate with drug-containing water solution → vesicles form.
    4. Sonicate or extrude to control size.
    5. Mix with gel/cream base.

🥉 3. Ethanol-Based Gel + Penetration Enhancers

  • Ethanol disrupts lipid packing in the stratum corneum. Combined with enhancers (e.g., oleic acid, menthol), it increases permeability.
    1. 🔬 Ingredients:
    2. Ethanol (30–70%)
    3. Penetration enhancer (e.g., oleic acid, DMSO, menthol, limonene)
    4. Carbopol gel base
    5. Drug

🧪 Process:

    1. Dissolve drug in ethanol + penetration enhancer.
    2. Prepare Carbopol gel in water and neutralize (e.g., with triethanolamine).
    3. Mix drug solution into gel base under slow stirring.

⚠️ Notes:

    1. Good for rapid delivery.
    2. Can irritate skin with prolonged use.
    3. Less sustained release.

🏅 4. Solid Lipid Nanoparticles (SLNs) – For extended release (lower penetration but better retention)

  • SLNs provide a drug reservoir in skin layers but penetrate less deeply.
    1. 🔬 Ingredients:
    2. Solid lipid (e.g., stearic acid, glyceryl monostearate)
    3. Surfactant (e.g., Tween 80, Poloxamer)
    4. Drug
    5. Water

🧪 Process:

    1. Melt solid lipid (~70°C), dissolve drug into it.
    2. Heat aqueous surfactant solution to same temp.
    3. Add lipid to aqueous phase under high-speed homogenization.
    4. Rapidly cool → solid lipid nanoparticles form.
    5. Add to gel/cream base if desired.



✅ Summary: Best-to-Worst for Skin Penetration


Rank	Strategy	Penetration	Retention	Irritation Risk	Complexity


🥇 1	Ethosomes in hydrogel/cream	⭐⭐⭐⭐	⭐⭐⭐	Moderate	Medium


🥈 2	Transfersomes in hydrogel/cream	⭐⭐⭐	⭐⭐⭐	Low	High


🥉 3	Ethanol gel + enhancers	⭐⭐⭐	⭐	High	Low


🏅 4	SLNs	⭐	⭐⭐⭐⭐	Low	High

See also:

  • PLO gel (Pluronic Lecithin Organogel) – popular in compounding pharmacies for transdermal delivery.
  • Methyl Salicylate - penetration enhancer - ✅ Very Good - Penetrates skin well; can carry small actives with it. Proven to penetrate deeply and often used to carry NSAIDs through skin.
  

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