Transdermal Drug Delivery Optimization

• Strategies exist for improved drug permeability for optimizing transdermal drug delivery

Optimizing Transdermal Drug Delivery Strategies

• Includes drug/vehicle interactions, vesicles & particles, stratum corneum modification or bypassing, and electrically assisted methods.

Drug Vehicle Interactions: Prodrugs

• Partition coefficients is a critical factor for drug absorption
• Prodrug approach helps enhance the transdermal delivery of drugs with unfavorable partition coefficients.
• Prodrug design includes adding a pro-moiety to increase the partition coefficient and solubility, enhancing drug transport in the stratum corneum.
• Once prodrugs reach the viable epidermis, esterase releases the active drug via hydrolysis, optimizing its concentration in the epidermis

Drug Vehicle Interactions: Ion-Pairs

• Charged drug molecules do not readily partition into or permeate through human skin, and lipophilic ion-pairs increase stratum corneum penetration.
• Ion-pair strategy involves adding an oppositely charged species to a charged drug, neutralizing the charges to allow complex partitioning and permeation through the stratum corneum.
• The ion-pair dissociates in the aqueous viable epidermis, releasing the parent charged drug that can diffuse within the epidermal and dermal tissues.

Vesicles and Particles: High Velocity Particles

• Needle-free jet injectors are used for high velocity particles.

Advantages of High Velocity Particles

• Pain-free delivery because particles are too small to trigger pain receptors
• Improved efficacy and bioavailability
• Targeted delivery to specific tissues like vaccine delivery to epidermal cells
• Accurate dosing eliminating needle phobia
• Device avoids skin damage/infection from needles or body fluid splashback.
• PowderJect system fires solid particles (20–100µm) through the stratum corneum into lower skin layers, using a supersonic shock wave of helium gas.
• Intraject is a vaccine gun development designed to deliver liquids through skin without needles.

Stratum Corneum Modification: Chemical Permeation Enhancers

• Chemicals increase permeability of the epithelial barrier by modifying its structure.
• Chemical permeation enhancers are also called accelerants or sorption promoters that enhance drug flux

Characteristics of Ideal Penetration Enhancers

• Non-toxic, non-irritating, and non-allergenic
• Immediate onset of increased permeability
• Immediate and reversible recovery of normal barrier properties upon removal
• Physical and chemical compatibility with a wide range of drugs

Mechanism of Action for Percutaneous Absorption Enhancers

• Reduce the resistance of the stratum corneum
• Alter the hydration of the stratum corneum
• Affect a change in the structure of the lipids and lipoproteins in the cellular channels through denaturation
• Carrier mechanism involved in the transport of ionizable drugs

Chemical Penetration Enhancers

• Materials hydrate the stratum corneum to enhance absorption.
• Natural moisturizing factors (NMF) help the skin cells bind more water, e.g. urea, free fatty acids, sodium, potassium, and calcium lactate.
• Urea can be a transdermal chemical enhancer and a keratolytic agent
• Water opens up the compact horny layer
• Moisturizing factors, occlusive films, hydrophobic ointments and transdermal patches all enhance skin hydration and bioavailability.

Chemical Penetration Enhancers That Alter Lipids

• Solvents like ethanol, acetone, polyethylene glycol, glycerol, propylene glycol, dimethyl sulfoxide, dimethylacetamide, and dimethylformamide
• Surfactants such as Brij30, brij72, Span 20, Tween 80, sodium lauryl sulphate, or Pluronic or poloxamer
• Azones such as N-Acyl hexahydro-2-oxo-1H-azepines, N-Alkylmorpholine-2,3-diones
• Terpenes like limonene and carvone
• Fatty alcohols, such as lauryl alcohol, capric acid, oleic acid, and lauric acid.
• Miscellaneous substances such as lecithin, sodium deoxycholate, L-amino acid, phosphatase, phospholipase & calonase

Stratum Corneum Bypassed or Removed: Microneedle Array

• Microneedles are typically applied via small arrays that range from a few to several hundred needles attached to an applicator or patch.
• Microneedles are constructed via photolithographic processes or micromolding, involving the etching microscopic structures into resin or silicon.
• Microneedles are made from a variety of materials like silicon, titanium, stainless steel, and polymers.
• Some microneedles are drug delivery systems shaped like needles for skin penetration.
• Microneedles vary in size, shape, and function, serving as an alternative to hypodermic needles or injection apparatus

Key aspects of microneedle Arrary

• Penetrates the skin's stratum corneum (10-15µm).
• Arrays are applied to the skin for effective drug administration.
• Physicians require less training for microneedle application because they are not as hazardous as other needles
• Microneedles offer a safer and less painful drug administration method, avoiding infection risks, hazardous waste, and high costs of drug delivery.

Stratum Corneum Ablation: Thermal Ablation

• Thermal Approaches (Lasers and Radio-Frequency Heating)
• Thermal ablation delivers drugs by heating the skin surface, depleting the stratum corneum selectively at the heating site
• Laser and radiofrequency are used to cause thermal ablation.
• Heat exposure should be of short exposure/duration, so that the temperature gradient across the stratum corneum is high enough to keep the skin surface extremely hot without significantly increasing the temperature of the viable epidermis.

Stratum Corneum Ablation: Laser Thermal Ablation

• Laser ablation removes the stratum corneum without damaging deeper tissues to enhance lipophilic and hydrophilic drug delivery.
• Lasers cause ablation to create microchannels or micropores in the skin.
• The degree of barrier disruption achieved is controlled by wavelength, pulse length, tissue thickness, pulse energy, tissue absorption coefficient, pulse number, duration of laser exposure and pulse repetition rate
• Pre-treatment with laser followed by lidocaine cream was found to reduce the onset of lidocaine action to 3-5 min in human volunteers.
• Structural changes from laser usage at may enhance the transport of large molecular weight therapeutics

Electrically Assisted Methods: Ultrasound (Phonophoresis / Sonophoresis)

• Used in physiotherapy and sports medicine; a preparation is applied topically and massaged with an ultrasound source.
• Ultrasonic energy (at low frequency) disturbs the lipid packing in the stratum corneum via cavitation.
• Sonicators operating at frequencies between 20kHz to 10 MHz are available for Sonophoresis.
• Therapeutic ultrasound has low-frequency (1-3MHz)
• For massage very low-frequency is used: ultrasound (23-40kHz)
• In dentistry, high-frequency ultrasound is applied (3-10 MHz)
• Ultrasound is also used for diagnostic purposes.

Electrically Assisted Methods: Iontophoresis

• Electrically drives charged (ionized) molecules into tissue, and passes a small direct current (0.5 mA/cm²) through a drug-containing electrode in contact with the skin.
• The eletrodes are based on by the silver/silver chloride redox couple.
• Enhancement by iontophoresis is due to electrical transport of the molecules:
• Charged species are driven primarily by electrical repulsion from the driving electrode.
• Electric current flow may increase skin permeability.
• Electroosmosis may affect uncharged molecules and large polar peptides.
• Limitations includes possilbe hair follicle damage

Electrically Assisted Methods: Electroporation

• Electroporation (electro-permeabilization) creates aqueous pores in the lipid by applying high voltage electrical pulses (100-1000 V/Cm) for short times (milliseconds;. Pores act as the pathway for drug penetration straight through the horny layer.
• Electroporation increases skin permeability of molecules with diverse lipophilicity and size, including larger biopharmaceuticals over 7kDA.

Mechanisms of Action for Transdermal Penetration Enhancers

• Chemical enhancers reduce skin impedance, size selectivity, and increase enhancer delivery, possibly synergizing with iontophoresis, electrophoresis, electroosmosis, or lipid disruption.
• Cavitation increases, pores enlarge, and enhancer delivery increases, synergizing with skin impedance, electrophoresis, and size selectivity reduction.
• Ultrasound leads to lipid disruption, diffusion enhancement, and convection, potentially decreasing skin impedance and size selectivity, while increasing convection.

Basic Components of TDDS

• Drug (with more lipophilicity)
• Polymer matrix or reservoir
• Penetration enhancers
• Other Excipients: Rate controlling membrane, Adhesive, Release liner, Backing membrane

Types of TDDS

• Includes adhesive device, monolithic device, and reservoir device.

Transdermal Matrix (Monolithic) Systems

• Initially releases the drug rapidly, then less over time
• The rate of release is proportional to the square root of time.
• The drug permeation rate is low
• Polymers employed for matrix systems may be hydrophilic or lipophilic.
• First category contains a drug dissolved in the polymer matrix and the other a drug dispersed within the matrix.
• Advantages are that they are sleek and thinner for daily or multiple-day applications.
• Matrix systems are best for drugs that penetrate readily, have low dosage requirements, or have large therapeutic indices

Transdermal Reservoir (Membrane Controlled) Systems

• Are used when matrix systems cannot penetrate skin; drugs require significant penetration enhancement and/or high dosage levels.
• Are suitable for drugs with low therapeutic indices.
• Drug release membranes are made of polyethylene, with microporous structure

Release Liners

• Substrate carries a very thin release coating
• Protects the skin-contacting adhesive during storage
• Provides low energy surface for ease of removal
• Can be made of polyester or polystyrene based films (hydrophobic or hydrophllic)

Backing Material in TDDS

• Contains formulation throughout shelf life and wear period
• Has laminated structure
• Is compatible with the formulation (non adsorptive)
• Is occlusive and completely water impermeable
• Can be made of: Poly urethane films, Ethyl vinyl acetate, Poly olefins, Polypropylene, polyethylene. (hydrophobic or hydrophllic)

Adhesive Layer

• Can be acrylic copolymers, polyisobutylene and polysiloxane (hydrophobic)
• Polybutyl acrylate is commonly used as the adhesive in TDDSs

Evaluation of TDDS

• Includes assessments of content, content uniformity
• In vitro release Vs Ex vivo permeation of active and penetration enhancer (diffusion cells).
• Evaluation of residual solvent, residual monomer
• Evaluation of release liner peel and adhesion
• Assessments of mechanical properties
• Assessments of moisture absorption & moisture loss
• Must undergo microbiological testing

Franz Diffusion Cell

• Is used with rat abdominal, rabbit, porcine, and human cadaver skin for testing.

Evaluation of a TDDS' Mechanical Properties

• Are measured by ultra-tester using tensile strength and elongation.
• Tensile strength (Kg.mm²) = Force at break (Kg) / Initial cross sectional area of the sample (mm²)
• Elongation at break (% mm²) = Increase in length (mm) / Original length (mm) X 100 / Cross sectional area (mm²)

Evaluation of a TDDS' Moisture Absorption

• Is tested with a saturated solution of AlCl3(79.50% RH)/ 3 days.
• Percentage moisture absorbed = Final weight - Initial weight / Initial weight X 100.

Evaluation of a TDDS' Moisture Loss

• Is tested by placing patches in a desiccator containing CaCl₂ at 40°C/24 hr.