Transdermal Delivery Across Intact Skin, Penetrating The Stratum Corneum

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'''Targeted local application, rather than systemic''' 🧠 Key Rule: "500 Dalton Rule" # Drugs with molecular weight ≤ 500 Da have a better chance of penetrating the stratum corneum. # Penetration is still influenced by: ## LogP (lipophilicity) – ideal range: 1–3 ## Aqueous solubility ## 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. ## 🔬 Ingredients: ## Phospholipid (e.g., soy lecithin) ## Ethanol (20–40%) ## Water ## Drug (the molecule) ## Hydrogel base (e.g., Carbopol or HPMC for gel; cetostearyl alcohol/cream base for cream) 🧪 Process: ## Dissolve lipid in ethanol with stirring (lipid phase). ## Dissolve drug in water (aqueous phase), if water-soluble. If not, add to lipid phase. ## Slowly add aqueous phase to lipid/ethanol phase under stirring → ethosome vesicles form spontaneously. ## Sonicate for 5–10 minutes to reduce vesicle size (optional). ## 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. ## 🔬 Ingredients: ## Phospholipid ## Edge activator (e.g., sodium cholate, Tween 80) ## Water ## Drug ## Gel/Cream base 🧪 Process: ## Dissolve lipid and edge activator in ethanol or chloroform. ## Evaporate solvent → thin lipid film forms. ## Hydrate with drug-containing water solution → vesicles form. ## Sonicate or extrude to control size. ## 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. ## 🔬 Ingredients: ## Ethanol (30–70%) ## Penetration enhancer (e.g., oleic acid, DMSO, menthol, limonene) ## Carbopol gel base ## Drug 🧪 Process: ## Dissolve drug in ethanol + penetration enhancer. ## Prepare Carbopol gel in water and neutralize (e.g., with triethanolamine). ## Mix drug solution into gel base under slow stirring. ⚠️ Notes: ## Good for rapid delivery. ## Can irritate skin with prolonged use. ## 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. ## 🔬 Ingredients: ## Solid lipid (e.g., stearic acid, glyceryl monostearate) ## Surfactant (e.g., Tween 80, Poloxamer) ## Drug ## Water 🧪 Process: ## Melt solid lipid (~70°C), dissolve drug into it. ## Heat aqueous surfactant solution to same temp. ## Add lipid to aqueous phase under high-speed homogenization. ## Rapidly cool → solid lipid nanoparticles form. ## Add to gel/cream base if desired. {pre} ✅ 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 {/pre} 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. {pre} 🔬 Comparison Chart: Topical Vasodilators & Blood Flow Enhancers Compound Vasodilation Strength Speed Depth Notes Methyl Nicotinate ✅ Strong Fast (minutes) Shallow–moderate One of the most potent OTC topical vasodilators. Causes visible flushing. Methyl Salicylate ⚠️ Mild–Moderate Medium Shallow Mostly a counterirritant; blood flow increase is a reflex response. Capsicum (Capsaicin) ✅ Strong Slow onset, long-lasting Moderate Strong heat and localized vasodilation. May desensitize nerves over time. Cinnamon Leaf Oil ⚠️ Mild Medium Shallow Mild irritant effect. Less consistent than others. Menthol (not in your list) ⚠️ Weak–Moderate Fast Shallow Produces a cooling sensation but can enhance penetration and blood flow reflexively. Niacin (Nicotinic Acid) ✅✅ Very Strong (oral or transdermal) Fast Systemic Taken orally or applied transdermally → intense flushing and systemic vasodilation. DMSO (Dimethyl Sulfoxide) ❌ Not a vasodilator N/A N/A Not a vasodilator itself, but helps carry other compounds deep into the skin. Minoxidil (Rogaine) ✅ Strong (medical) Gradual Moderate–deep True vasodilator used for hair regrowth, sometimes compounded for circulation. Nitroglycerin (Rx only) ✅✅✅ Very Strong Fast Systemic Medical-grade vasodilator for angina; used in patches for transdermal delivery. PDE-5 inhibitors (e.g., topical sildenafil) ✅✅✅ Very Strong Medium Moderate Experimental use in increasing localized blood flow (e.g., ED or muscle pumps). {/pre}
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