Transdermal Drug Delivery Notes

Transdermal Drug Delivery (TDD)

Learning Outcomes

• Discuss the rationale for transdermal drug delivery (TDD).
• Recall advantages and limitations of TDD.
• Describe the important features of skin structure as a barrier, with particular reference to Stratum Corneum.
• Recall the different types of transdermal patches and their limitations.
• Recall the different penetration enhancement techniques in TDD, their mechanisms, and applications.

Overview

• Transdermal drug delivery (TDD).
• Advantages & limitations of transdermal delivery.
• Skin anatomy.
• Transdermal patches.
• TDD: penetration enhancement techniques.
• Iontophoresis
• Electroporation
• Sonophoresis
• Micro needles

Transdermal Drug Delivery (TDD) Definition

• Delivery of drugs through the skin into blood (systemic) circulation.
• Different from dermal delivery, which is delivery into the skin.
• The skin is the largest organ of the human body, made of water, protein, fats, and minerals.
• Nerves in the skin help you feel sensations like hot and cold.

Advantages and Limitations of Transdermal Drug Delivery

• First-pass effect:
  • Drug is taken orally.
  • Liver is responsible for metabolizing any drugs.
  • Active drug absorbed from stomach and small intestines.
  • High blood concentration of drug is in hepatic portal vein.

Advantages of Transdermal Delivery

• Can reduce first-pass drug degradation (metabolism) effect.
  • Some drugs are so extensively metabolized by the liver that only a small amount of unchanged drug may enter the general blood (systemic) circulation.
• Can reduce drug side effects.
  • Estradiol patches do not cause liver damage, in contrast to oral formulations.
  • Clonidine, nitroglycerin, and fentanyl patches are also associated with fewer adverse effects.
• Sustained delivery of drugs.
  • Drugs require a steady plasma concentration.
  • Patches can last from 1 to 7 days.
• Drug reservoir remains outside the body.
  • Difficult to stop the effects of a drug after oral administration.
  • Allows removal of drug source.
• Non-invasive (no needles or injections).
  • Permits self-administration & improves patient compliance.

Disadvantages of Transdermal Delivery

• Potential skin irritation.
• Variability of dosing due to:
  • Different levels of skin hydration.
  • Thickness of stratum corneum found at different anatomical sites.
  • Variation between patients in temperature, skin type, skin of different aged patients, diseased skin…
• Poor diffusion of large (high molecular weight) molecules.
  • Number of drugs that can be administered using conventional patches is very limited.

Summary of Advantages and Disadvantages

Skin Anatomy

• Main features of the skin:
  • Prevent flux of toxins in the body.
  • Minimize water loss.
  • Has natural very low permeability to penetration of foreign molecules.
  • A 15 mm thick layer (stratum corneum) is responsible for these barrier properties.
• One inch of your skin has approximately 19 million skin cells and 60,000 melanocytes (cells that make melanin or skin pigment). It also contains 1,000 nerve endings and 20 blood vessels.

The Anatomy of Human Skin

• Epidermis: (other sub-layer): viable tissue, devoid of blood vessels, 50-100$mm$
• Dermis: lower living portion of the skin, contains blood vessels, sweat glands and hair follicles, 1-2$mm$
• Stratum corneum: upper dead sub-layer of the epidermis 10-20$mm$

The Anatomy of Human Skin: Stratum Corneum

• Vertically-stacked, corneocytes surrounded by a lipid-rich matrix.
  • Corneocytes: comprise crosslinked keratin fibers (structural protein); devoid of lipids.
  • Lipid-rich matrix: serves the primary barrier function of the stratum corneum.
  • Layer of lipids immediately adjacent to each corneocyte is covalently bound to it.

The Anatomy of Human Skin: Stratum Corneum Lipids

• Represent approximately 20% of SC volume.
• Assembled into multi-lamellar bilayers.
• Major lipid by mass:
  • Ceramides 50%
  • Cholesterol (sulfate) 25%
  • Fatty Acids (& triglycerides) 10-20%
• Transdermal transport of solutes is largely controlled by SC lipid bilayers ~intercellular pathway.

Transdermal Patches

• Two different designs:
  1. Reservoir type
     • Drug in a solution or gel.
     • Drug delivery controlled by a rate-controlling membrane.
     • Good control of delivery rate.
     • Greater design complexity.
  2. Matrix type
     • Combine drug and adhesive.
     • No rate-controlling membrane: skin permeability controls rate of drug delivery.
     • Simpler design.
     • Less control on delivery rate.

Transdermal Patches Limitations

• Main constraining characteristics of drugs administered using transdermal patches:
  • Low molecular weight (Mw) (< 500 D).
    • Smallest drug ðnicotine (162)
    • Largest drug ðoxybutinin (359)
  • Small required dose.
    • < 50 mg per day (ideally < 10 mg)
  • Melting point lower than 100 oC.
  • Good water & lipid solubility.
  • Neutral rather than ionic drugs.

Penetration Enhancement Techniques

• Chemical
• Physical

Penetration Enhancement Techniques: Chemical Approaches

• Chemical additives: used as penetration enhancers; they are combined with the drug in transdermal patches.
• Surfactants (Surface active agents)
  • Usually organic compounds that are amphipathic, meaning they contain both hydrophobic groups (hate water) and hydrophilic groups (love water).
    • Fatty acids/esters
    • Solvents (eg., ethanol, propylene glycol)
• Can increase skin permeability by various mechanisms:
  • Enhancing drug solubility.
  • Fluidizing structure of stratum corneum.
  • Dissolution of stratum corneum lipids.
• Potent irritants to the skin.

Penetration Enhancement Techniques: Physical Approaches

• Allow delivery of protein-based and DNA-based therapeutic macromolecules.
• Improve efficiency of traditional TDD systems.
• Iontophoresis
• Electroporation
• Sonophoresis
• Microneedles

Iontophoresis

• Low voltage electric current, applied for several minutes (eg., ~30 min).
• e.g., delivery of anti-inflammatory agents, local anesthetic…
• Uses an electric field to move both charged and uncharged species across the skin.
• Can also be used in the reverse direction to draw a molecule such as glucose through the skin.

Iontophoresis: Advantages

• Increases skin permeability upon exposure to an electric field.
• Enhances transport across skin by 2 different mechanisms (charged molecules / uncharged molecules).

Iontophoresis: Mechanisms

1. Electrophoretic driving force: charged molecules move away from electrode of like charge.
2. Electro-osmotic driving force:
   • Small cationic ions such as $Na^+$ are highly mobile.
   • Cations move from the anode to the cathode.
   • Cations are solvated (associated with layer of water).
   • Cations flux induces a solvent (water) flow.
   • Uncharged molecules are dragged by electrically induced solvent flow.

Electroporation

• Creation of aqueous pores in lipid bilayers by the application of a short (microseconds to milliseconds) high voltage (tens to hundreds of volts) electric pulse.
• Large macromolecules can be delivered, including proteins, vaccines, DNA…
• Electric field induces pore formation by disrupting lipid bilayers and provides electrophoretic driving force.

Sonophoresis

• Forms microscopic aqueous channels in the lipid bilayers of the intercellular space of the stratum corneum by application of ultrasonic waves.
• Result in the formation of bubbles in or next to the skin.
• Ultrasound at frequencies in the range of 20kHz-16MHz.
• Can be used to transport high-molecular mass drugs.
• (eg., Cyclosporin, immunosuppressant drug, with Mw of 1203).

Microneedles

• Needles of micron dimensions.
  • Pierce skin surface to create holes large enough for molecules to enter.
  • Holes small enough to avoid pain and skin damage.
  • Do not penetrate to the depth of nerve endings (dermis).
• Used as:
  • Pretreatment before application of a patch.
  • Microneedles coated with drug.
• Can increase permeability by orders of magnitude for small drugs, large macromolecules, and even nanoparticles.

Example of Microneedle Use in TDD

• Transdermal delivery of methotrexate for treatment of psoriasis.
• Reduced side-effects (nausea and vomiting).
• Improved efficacy compared to oral administration or other conventional TDD approaches.