14 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

Transdermal Drug Delivery (TDD)

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

Brief History of TDD

• First transdermal drug delivery system approved.

Advantages and Limitations of Transdermal Drug Delivery

First-Pass Effect

• Oral drug administration leads to metabolism by the liver before entering systemic circulation.
• This can result in low blood levels of the drug.

Advantages of Transdermal Delivery

• Can reduce the first-pass drug degradation (metabolism) effect.
• Some drugs are extensively metabolized by the liver, resulting in only a small amount of unchanged drug entering the systemic circulation.
• Can reduce drug side effects.
  • Example: estradiol patches do not cause liver damage, unlike oral formulations.
  • Clonidine, nitroglycerin, and fentanyl patches are associated with fewer adverse effects.
• Sustained delivery of drugs.
  • Drugs require a steady plasma concentration which TDD can provide.
  • Patches can last from 1 to 7 days.
• Drug reservoir remains outside the body.
  • Allows removal of drug source.
  • Difficult to stop the effects of a drug after oral administration.
• 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 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.
  • The 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 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:
  • 50-100mm
  • Viable tissue, devoid of blood vessels.
• Dermis:
  • 1-2 mm
  • Lower living portion of the skin, contains blood vessels, sweat glands, and hair follicles.
• Stratum corneum:
  • 10-20mm
  • Upper dead sub-layer of the epidermis

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.
  • The 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 is 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 the 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 ð nicotine (162)
    • Largest drug ð oxybutinin (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

1. 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 (e.g., ethanol, propylene glycol)

Penetration enhancement techniques How does it work?

• 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

2. Physical Approaches

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

Iontophoresis

• Low voltage electric current, applied for several minutes (e.g., ~30 min)
• Example: 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 the skin by 2 different mechanisms (charged molecules / uncharged molecules)

Iontophoresis: Mechanisms

• Electrophoretic driving force: charged molecules move away from the electrode of like charge.
• 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 a 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…
• The 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
  • (e.g., 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 the 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 the treatment of psoriasis.
• Reduced side-effects (nausea and vomiting).
• Improved efficacy compared to oral administration or other conventional TDD approaches.