Transdermal Drug Delivery Strategies

• Strategies for enhancing drug permeability aim to optimize transdermal drug delivery.

Optimizing Transdermal Drug Delivery

• Different approaches include drug/vehicle interactions, vesicles and particles, stratum corneum modification, bypassing/removing stratum corneum, and electrically assisted methods.
• Drug/Prodrug, Ion Pairs/Coacervates, Eutectic Systems, Liposomes & Analogues, High Velocity Particles, Chemical Enhancers, Microneedle Array, Ablation, Follicular Delivery, Ultrasound, Iontophoresis, Electroporation, Magnetophoresis, and Photomechanical Wave

Drug Vehicle Interactions: Prodrugs

• For drug absorption, partition coefficients serve as the most vital factor.
• Prodrugs are utilized to improve transdermal drug delivery when drugs show unfavorable partition coefficients.
• Prodrug design involves adding a pro-moiety to improve the partition coefficient, increasing both the solubility and transport of the drug through the stratum corneum.
• Esterase releases the active drug via hydrolysis upon reaching the viable epidermis, enhancing its concentration in the epidermis.

Drug Vehicle Interactions: Ion-Pairs

• Charged drug molecules do not readily partition into or permeate through human skin.
• Formulation of lipophilic ion-pairs raises stratum corneum penetration of charged species.
• This strategy involves adding an oppositely charged species to the charged drug, creates an ion-pair with neutralized charges, allowing the complex to partition and permeate through the stratum corneum.
• The ion-pair dissociates in the aqueous viable epidermis, releasing a parent charged drug that can diffuse within the epidermal and dermal tissues.

Vesicles & Particles

• Uses high velocity particles and needle free jet injectors

High Velocity Particles: Advantages

• Particles are too small to trigger pain receptors on the skin for Pain-free delivery.
• Results in improved efficacy and bioavailability.
• Can target specific tissues, such as vaccine delivery to epidermal cells.
• Allows accurate dosing and overcomes needle phobia.
• The device avoids skin damage/infection from needles and splash back of body fluids and it safe.
• The PowderJect system utilizes a supersonic shock wave of helium gas to fire solid particles (20–100µm) through the stratum corneum into lower skin layers.
• The development of vaccine gun, Intraject delivers liquids through without using needles.

Stratum Corneum Modification Via Chemical Enhancers

• Increases the permeability of the epithelial barrier by modifying its structure and enhances drug flux.
• Ideal penetration enhancers should be non-toxic, non-irritating, and non-allergenic.
• Should provide an immediate onset of increased permeability.
• Should allow an immediate recovery of normal barrier properties upon removal (reversible).
• Should be physically and chemically compatible with a wide range of drugs.

Percutaneous Absorption Enhancers: Mechanism of Action

• Reduces the resistance of the stratum corneum.
• Alters the hydration of the stratum corneum.
• Effects changes in the structure of lipids and lipoproteins in the cellular channels, through denaturation.
• Carrier mechanism for the transport of ionizable drugs.

Chemical Penetration Enhancers

• Materials enhance absorption by hydrating the stratum corneum.
• Natural moisturizing factors (NMF) increase water content in skin cells via urea, free fatty acids, sodium, potassium, and calcium lactate.
• Urea acts as a transdermal chemical enhancer and a keratolytic agent.
• Water can open up the horny layer.
• Factors like moisturizing agents, occlusive films, hydrophobic ointments, and transdermal patches supports skin hydration and bioavailability.

Chemical Penetration Enhancers: Altering Lipid/Lipoprotein Structure

• They alter the structure of lipids and lipoproteins in intercellular channels(paracellular).
• Solvents: Includes ethanol, acetone, polyethylene glycol, glycerol, propylene glycol, dimethyl sulfoxide, dimethylacetamide, and dimethylformamide.
• Surfactants: Such as Brij30, brij72, Span 20, Tween 80, Sodium lauryl sulfate, and Pluronic or poloxamer (polyoxyethelene-polyoxypropylene-polyoxyethelene).
• Azones(-NH2 or -NH- with ketone): Includes N-Acyl hexahydro-2-oxo-1H-azepines and N-Alkylmorpholine-2,3-diones.
• Terpenes: e.g. Limonene and Carvone.
• Fatty Alcohols and Acids: e.g. Lauryl alcohol, capric acid, oleic acid, and lauric acid.
• Miscellaneous: Includes Lecithin, sodium deoxycholate, L-amino acid, phosphatase, phospholipase & calonase.

Stratum Corneum Bypassed or Removed

Microneedle Array

• Microneedles are applied through small arrays and the collection of them on the arrays range from a few to several hundred.
• Microneedles are constructed through photolithographic processes or micromolding, involving etching microscopic structures into resin or silicon.
• Microneedles made from a range of materials including silicon, titanium, stainless steel, and polymers.
• Some microneedles are composed of drug to be delivered and shaped to penetrate the skin.
• Microneedles differ in size, shape, and function, used as alternatives to conventional hypodermic needles or other injection apparatus.
• The main goal of microneedle design is to penetrate the stratum corneum (10-15µm).
• Arrays are applied to patients and timed with effective drug administration.
• These needles are easier for physicians due to less training needed, less hazardous than other needles, safer and less painful administration, and avoids drawbacks of other drug delivery like infection risk, hazardous waste or cost.

Stratum Corneum Ablation

• The stratum corneum can be ablated for drug delivery

Thermal Ablation

• Utilizing laser and radio-frequency heating.
• Used to deliver drugs systemically through the skin, by heating the surface and depleting the stratum corneum selectively without damaging deeper tissues.
• Thermal ablation is achieved via laser, radiofrequency, or electrical heating elements.
• Short thermal exposure generates high temperatures to ablate stratum corneum without damaging epidermis, thus maintaining a high temperature gradient.

Laser Thermal Ablation

• Laser thermal ablation selectively removes the stratum corneum without damage and enhances the delivery of lipophilic and hydrophilic drugs.
• Lasers cause evaporation of water and formation of microchannels or micropores via deposition of optical energy.
• Barrier disruption 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 reduces the onset of lidocaine action (3-5 min) in human volunteers.
• Structural changes in skin, need assessment, especially at higher laser intensities for transporting large molecular weight therapeutics.

Electrically Assisted Methods

Physical Permeation Enhancer: Ultrasound (Phonophoresis / Sonophoresis)

• Preparation applied topically and massaged using an ultrasound source, originally from physiotherapy and sports medicine
• Ultrasonic energy (at low frequency) disturbs lipid packing in the stratum corneum through cavitation.
• Commercial sonicators operate between 20kHz to 10 MHz for Sonophoresis.
• Low-frequency (1-3MHz) ultrasound offer therapeutic uses.
• Massage utilizes very low-frequency ultrasound (23-40kHz).
• High-frequency ultrasound (3-10 MHz) is used in dentistry.
• Can be used for diagnostic purposes.

Electrically Assisted Methods: Iontophoresis

• The electrical driving of charged (ionized) molecules into tissue is performed by small direct current (approximately 0.5 mA/cm²) via a drug containing electrode in contact with the skin.
• The most popular electrodes are based on the silver/silver chloride redox couple.
• Three mechanisms enhance molecular transport: Charged species repulsion, increased skin permeability from electric current, and electroosmosis effects on uncharged molecules/large polar peptides.
• Limitations: Possible hair follicle damage.

Electrically Assisted Methods: Electroporation

• Electroporation (electro-permeabilization) of skin creates transient aqueous pores in the lipid via high voltage application of electrical pulses of approximately 100-1000 V/Cm for short time(milliseconds).
• The pores provide pathways for drug penetration that travel straight through the horny layer.
• It enhances skin permeability for molecules with differing lipophilicity including biopharmaceuticals >7kDA.

Suggested Mechanisms for Actions of Transdermal Penetration Enhancers

• Chemical enhancers work through lipid disruption, protein interaction, and partitioning promotion.
• Ultrasound enhances diffusion and convection by causing lipid disruption.
• Electroporation enhances pore formation.
• Cavitation increases, which increases enhancer delivery of the agent/drug.
• Iontophoresis, electrophoresis, and electroosmosis are examples
• Skin impedance increases due to size selectivity and increased enhancer delivery.

Basic Components of TDDS (Transdermal Drug Delivery System)

• Drug (with a high level of lipophilicity)
• Polymer matrix or reservoir.
• Rate controlling membranes
• Other Excipients: Adhesive, Release liner, and Backing membrane.

Types of TDDS

• Adhesive Device
• Monolithic Device
• Reservoir Device

Transdermal Matrix (Monolithic) System

• Factors affecting drug release include drug concentration in polymer matrix, chemical nature of the polymer matrix and the geometry of the device.
• Rate controlling factors include the stratum corneum.
• A drug is initially released rapidly and declines as a matrix is depleted.
• This is the result of the rate of release being proportional to the square root of time.
• Polymers have hydrophilic or lipophilic types of devices that the matrix contains, with the 1st type the drug dissolved and 2nd the drug dispersed.
• Advantages: Sleeker and thinner, daily or multiple-day applications.
• Appropriate for drugs that penetrate readily and/or have low dosage requirements or large therapeutic indices.

Transdermal Reservoir (Membrane Controlled) System

• Rate controlling factors include Membrane thickness and Membrane permeability
• Advantages: Used when matrix systems cannot penetrate skin, and when drugs require significant penetration enhancement and/or high dosage levels, also suitable for drugs with low therapeutic indices.
• Release membranes commonly use polyethylene, with microporous structures of varying pore sizes to fit specifications.

Transdermal Patches: Release liners

• Substrate carries a very thin release coating.
• Protects the skin-contacting adhesive during storage.
• Provides low energy surface for ease of removal.
• e.g.: polyester or polystyrene based films that are hydrophobic or hydrophllic

Transdermal Patches: Backing material

• Contains formulation throughout shelf life and during wear period.
• They have laminate structure
• They are non adsorptive/compatible with the formulation.
• They are occlusive and completely water impermeable in nature.
• e.g.: Poly urethane films, Ethyl vinyl acetate, Poly olefins, Polypropylene, and polyethylene that are hydrophobic or hydrophllic.

Transdermal Patches: Adhesive layer

• Acrylic copolymers, polyisobutylene and polysiloxane (hydrophobic).
• Polybutyl acrylate is commonly used as an adhesive.

Evaluation Techniques for TDDS

• Includes content, content uniformity, In vitro and Ex vivo permeation and penetration.
• Residual solvent, residual monomer, Release liner peel, adhesion, Mechanical properties and Moisture absorption/loss, Microbiology.

Franz Diffusion Cell

• Used to test skin from Rat abdomen, Rabbit, Porcine or Human
• Has a flat ground joint connected to a sampling port, water jacket connected to heater or circulator connected to a stir bar.

Mechanical Properties are evaluated using an ultra tester

Moisture Studies

• Done under moisture absorption and moisture loss.
• Moisture absorption uses Saturated solution of AlCl3(79.50% RH)/ 3 days.
• Moisture loss involves a desiccator containing CaCl₂at 40°C/24 hr.

Transdermal Patches Available in the Market

• Includes but not limited to: scopolamine, nitroglycerin, nicotine, testosterone, estrogen and clonidine.
• The first drug used for TDDS was scopolamine.

Marketed Products of Modified Transdermal Drug Delivery Technologies

• Enhanced via Macroflux, Microprojection, Ultrasound , E-Trans Drug product available or under consideration.
• Includes but not limited to therapeutic or Vaccines, Proteins and Peptides.