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
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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.

🔬 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).
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