Permeation through the skin involves the drug passing through various layers:
1. Stratum Corneum: The outermost layer, composed of dead keratinized cells, acts as the primary barrier.
2. Epidermis: Below the stratum corneum, containing living cells and blood vessels.
3. Dermis: The deeper layer housing nerves, glands, and connective tissue.
4. Subcutaneous Tissue: The innermost layer with fat and connective tissue.
For effective permeation, drugs must navigate these layers, primarily traversing the stratum corneum via intercellular (between cells), intracellular (through cells), or transappendageal (through hair follicles and sweat glands) pathways.
Anatomy of the Skin (Permeation through skin)
The skin, the body’s largest organ, performs vital functions such as protection, sensation, temperature regulation, and vitamin D synthesis.
It consists of three main layers:
Epidermis
Function: Protection
Sub-layers:
Stratum Corneum: Outermost layer of dead, keratin-filled cells; primary barrier to drug permeation.
Stratum Lucidum: Thin layer found only in palms and soles.
Stratum Granulosum: Produces keratin for skin strength.
Stratum Spinosum: Contains immune cells to fight infections.
Stratum Basale: Site of new skin cell formation and melanin production.
Dermis
Function: Structural integrity
Components:
Collagen and elastin fibers for strength and elasticity
Blood and lymph vessels for nourishment and immune responses
Nerve endings for sensation
Sweat and sebaceous glands for temperature regulation and skin hydration
Hair follicles.
Hypodermis (Subcutaneous Layer)
Note: Not technically part of the skin
Components:
Adipose tissue for insulation and cushioning
Larger blood vessels
Connective tissues.
Accessory Structures
Hair: Protection, sensory input, thermoregulation
Nails: Protect fingertips and aid in manipulation
Sweat Glands: Eccrine (cooling) and apocrine (thicker sweat)
Sebaceous Glands: Produce sebum to moisturize skin and hair
Specialized Cells
Keratinocytes: Produce keratin
Melanocytes: Produce melanin for UV protection
Merkel Cells: Light touch sensation
Mast Cells: Involved in inflammation
Lymphatic Vessels: Aid immune responses
Functions of the Skin
Protection: Against mechanical impact, pathogens, UV radiation
Sensation: Detects temperature, touch, vibration, pain
Thermoregulation: Through sweat and blood vessel adjustments
Metabolic Functions: Vitamin D synthesis
Immune Defense: Detects and fights pathogens
Mechanism of Drug Transport Across the Skin
Primary Mechanisms
Passive Diffusion
Movement from high to low concentration
No energy required
Active Transport
Uses carrier proteins or pumps
Requires energy
Electrophoresis and Iontophoresis
Utilize electrical currents to move charged molecules
Layers Involved
Stratum Corneum: Main barrier; drugs must penetrate this layer first
Epidermis (Excluding Stratum Corneum): Continuation of diffusion
Dermis: Absorption into systemic circulation
Factors Affecting Permeation
Molecular Size: Smaller molecules penetrate more easily
Lipophilicity: Lipophilic drugs permeate better through lipid-rich layers
Permeation Enhancers: Chemicals that disrupt the stratum corneum to facilitate drug passage.
Routes of Skin Penetration
Transcellular Route
Through cells of the stratum corneum and epidermis
Challenging due to hydrophobic barriers
Intercellular Route
Between the cells through lipid-rich domains.
Favored by lipophilic drugs but hindered by the tortuous path
Transappendageal (Shunt) Route
Through hair follicles, sweat, and sebaceous glands
Useful for certain drugs, especially macromolecules
Subcutaneous Route
Direct delivery into subcutaneous tissue via injections
Bypasses skin barriers, not typically used in TDDS