Pharmaceutics II: Chemical Penetration Enhancers

Chemical Penetration Enhancers

• Terminology: Penetration refers to crossing the stratum corneum (SC), permeation refers to crossing the epidermis, and absorption refers to entering the blood supply.
• Passive Chemical Penetration Enhancement: Uses a chemical mediator to interact with skin cells and clear the way for the drug.

Ideal Chemical Penetration Enhancer

• Inert: Does not react with the skin or drug.
• GRAS (Generally Regarded as Safe): Considered safe for use.
• Fast in Action: Quickly exerts its effect on the skin barrier.
• Reversible Effect: The effect on the skin barrier is reversible.
• Compatibility: Compatible with drugs and excipients.
• Economic: Cost-effective.
• Acceptable: Acceptable to patients in terms of odor, color, and other factors.

Chemical Skin Penetration Enhancers

• Types: Water, natural moisturizing factors, fatty acids, alcohols, surfactants, dimethyl sulfoxide, and azone.

Water

• Natural Skin Plasticizer: Renders the skin lipid content less rigid by fluidizing the lipid crystalline structure.
• Mechanism of Action: Acts as a solvent for polar molecules, increasing drug solubility and partitioning through the skin.
• Hydration Effect: Increases skin water content, making it more permeable to drugs.
• Moisturizing Effect: Indirectly increases skin water content through humectants, occlusive agents, and other means.

Natural Moisturizing Factors (NMFs)

• Definition: Natural moisturizing factors that bind water to skin cells, increasing drug penetration through the skin.
• Hydrating Agent: Produces hydrophilic diffusion channels through the SC.
• Prevents TEWL (Trans Epidermal Water Loss): Retains moisture within corneocytes.

Fatty Acids

• Mechanism of Action: Modifies the orientation of lipid domains in the SC, causing lipid fluidization and allowing the drug to penetrate more easily.
• Oleic Acid: Has a superior skin permeation effect due to its molecular structure, which leads to increased SC lipids fluidity.

Alcohols

• Best Concentration Range: 1-10% for optimal skin permeation.
• Mechanism of Action: Solubilizes the drug, extracts lipid fraction from the skin, and increases thermodynamic activity of the drug.
• Ethanol: Most commonly used chemical permeation enhancer in transdermal formulations.
• Butanol: Most effective alcohol for skin permeation.

Surfactants

• Definition: Decreases surface tension between the formulation and skin.
• Mechanism of Action: Solubilizes the lipophilic API and solubilizes lipids within the SC.
• Non-Ionic Surfactants: Safest option, e.g., Polysorbate 80.
• Anionic Surfactants: Most active, e.g., Na lauryl sulphate.

Dimethyl Sulfoxide (DMSO)

• Universal Solvent: Facilitates drug partitioning from the formulation to the skin.
• Mechanism of Action: Enhances permeation of both hydrophobic and hydrophilic molecules across cell membranes.
• Concentration Effect: Induces membrane thinning and fluidity at low concentrations, and forms transient water pores at high concentrations.

Azone

• Highly Lipophilic Synthetic Molecule: With a log P value of 6.2.
• Mechanism of Action: Interacts with the lipid domains of the SC, disrupting their packing arrangement and fluidizing the lipids.
• Effective Concentration Range: 0.1-5%.

Summary of Passive Chemical Enhancement

• Mechanisms: Interaction with extracellular lipid matrix, alteration of SC solvent nature, interaction with proteins, and formulation modification.
• Enhancers: Humectants, NMFs, ethanol, surfactants, sulfoxides, and azone work through a combination of these mechanisms to improve drug delivery.