Transdermal Drug Delivery Systems (TDDS)
Unit 6 Module 9: Transdermal Drug Delivery Systems (TDDS) & Technologies
Introduction to TDDS
TDDS is a successful and suitable approach for drug delivery due to its advantages over other Drug Delivery Systems (DDS).
Main Advantages: Sustained release, bypassing first-pass metabolism, enhancing patient compliance.
Offers an attractive alternative to oral administration and most parenteral routes.
Limitation: Poor skin permeability.
The skin is composed of several layers through which the drug must pass to enter systemic circulation and exert therapeutic activity.
Factors to Consider for TDDS Effectiveness: Drug properties (molecular weight (MW), solubility, lipophilicity), vehicle composition, and skin characteristics (hydration, temperature, regional permeability), ensuring it is non-irritating.
Learning Objectives
Upon completion of this module, students will be able to:
Explain the physicochemical properties of drugs that determine their suitability for transdermal dosage forms.
Discuss physiological skin factors influencing percutaneous absorption.
Discuss how chemical permeation enhancers and physical methods facilitate percutaneous drug absorption.
Differentiate various transdermal delivery systems.
Discuss the advantages and disadvantages of transdermal drug delivery compared to other routes.
Define and differentiate iontophoresis from phonophoresis.
Various Models Used for In-vivo Studies of TDD
Human Skin
Example: Human skin.
Advantages: Excellent choice, significant species addressable, less intra- and inter-subject variations.
Disadvantages: Less availability, requires ethical and practical reasons; variations can include age, sex, race, plastic surgery, amputation, cadaver.
Animal Model
Pigs, Rats, Rabbits, Guinea Pigs, Hairless Rats, Hairless Mice, Monkeys (Rhesus/Squirrel)
Pigs: Easily available, low cost, almost physiologically related to human skin, hairless species available.
Disadvantages: Very predictive as opposed to in vivo; species extrapolation needed for animal skin.
Monkeys: Relevant animal model, large for serial blood sampling.
Disadvantages: Constrained by price and availability, challenging to manage, requires specialized facilities and skills.
Rabbits: Good choice, epidermis similar to humans.
Disadvantages: Difficult to manage in a lab, requires specific animal facilities, poor vascularization, ethical permission required.
Rats: Excellent animal choice, easily available, rat skin resembles human skin more structurally, easy to handle, inexpensive.
Disadvantages: Ethical permission, changes in physiological variation (age, weight, hair removal), high density of hair follicles leading to higher permeation rates than human skin.
Rabbits (cont.): Reasonable model.
Disadvantages: Permeable and percutaneous absorption variation, high hair follicle density, hair removal is difficult.
Guinea Pigs: Skins of guinea pigs and humans have a very good correlation, hairless species available.
Disadvantages: Ethical permission required, less available, expensive.
Hairless Rat, Hairless Mice, Hairless Guinea Pig: Permeation consistent with human, easily available, inexpensive, similar structure of epidermis, thickness, and blood vessels.
Disadvantages: Inter-subject variation, specific facilities required, lipid content variable, ethical permission, expensive, specific facilities.
Reconstructed Human Skin Models
Examples: Human reconstructed epidermis models (Epiderm™; Episkin™; SkinEthic™), Living skin equivalent models (StrataTest®; Phenion®; Graftskin LSE™).
Advantages: Readily accessible, replicable, standardized, derived from humans, made up of human cells cultured as tissue and matrix substitutes resembling skin.
Disadvantages: High cost, greater consistency in permeability compared to varied human skin (lower predictive value), low stability, transition in diffusion cells.
Artificial Membranes
Examples: Lipid-based membranes (PAMPA, PVPA, SCS).
Advantages: Easily accessible, standardized, reproducible, suitable for basic diffusion mechanism analysis, consistent and homogeneous.
Disadvantages: Technical limitations, no metabolism, not representative of human skin, lack the true lipid bilayers found in biological membranes.
Silicone Model
Examples: Poly(dimethyl siloxane) (PDMS) or silicone membranes.
Advantages: Reproducible, low cost, stable, screening for aqueous dilutions.
Disadvantages: Nonbiodegradable, low skin permeability, no general mixture model available.
Factors Responsible for the Transdermal System
Pharmacokinetics
Availability of drug at site of action.
Half-life.
Distribution process.
Excretion process.
Plasma concentration factor.
Physiological/Biological Factors
Application site.
Skin permeability.
Skin metabolism.
Skin conditions (allergies, disease).
Physicochemical Properties
Solubility.
Molecular Weight.
Crystallinity.
Melting Point.
Mechanism of Drug Penetration Pathways
Transepidermal Routes
Intracellular route: Through the cells of the epidermis.
Intercellular route: Between the cells of the epidermis.
Transappendageal Routes
Through hair follicles.
Through sweat glands.
Strategies for TDD
TDDS can replace medications unsuitable for parenteral and oral delivery.
They reduce drug dosage frequency while achieving therapeutic response, especially with carefully acting patches.
General Development of TDDS
A TDDS should possess the following characteristics:
Non-irritating to the skin.
Suitable permeation into the skin.
Adequate solubility and compatibility.
Suitable pharmacokinetic response.
Secure the enzymatic metabolism of the skin.
Permeation Enhancers
Definition: Substances used to improve the absorption of therapeutic substances through diffusion via the stratum corneum and epidermis of the skin.
Also known as accelerants or sorption enhancers.
They enhance drug transport across skin layers, reducing the resistance of the stratum corneum to drug permeation via diffusion.
Characteristics of Permeation Enhancers
Nontoxic, nonallergenic, nonirritating, and therapeutic in nature.
Should act quickly, with predictable and repeatable duration.
Should have desired qualities to penetrate various skin layers and be compatible with therapeutic molecules, while maintaining physiological state (body fluids, electrolytes, endogenous materials).
After removal, it should allow the skin to restore its barrier qualities.
Compatible with other excipients and molecules.
Transdermal Patches
Popularly known as 'patches'.
Dosage forms designed to deliver a therapeutically effective amount of drug from outside the skin, through its layers, into the bloodstream.
Advantages of Transdermal Drug Delivery
Avoids the stomach environment.
No Gastrointestinal (GI) distress or other physiological contraindications of the oral route.
Easy to use, increasing patient compliance and potentially decreasing medical costs.
Avoids the first-pass effect; non-invasive, avoiding inconvenience of parenteral therapy.
Can decrease medical waste and healthcare costs if used instead of needles.
Allows effective use of drugs with short biological half-lives.
Provides extended therapy with a single application, improving compliance over other dosage forms requiring frequent dosing.
Allows administration of drugs with narrow therapeutic windows.
Drug therapy can be terminated by removal of the application.
Easily and rapidly used in emergencies.
Provides steady plasma levels of highly potent drugs.
Disadvantages of Transdermal Drug Delivery
Drugs requiring high blood levels cannot be administered.
Adhesive may not adhere well to all skin types.
Drug or drug formulation may cause skin irritation or sensitization.
Patches can be uncomfortable to the wearer.
System may not be economical in the long run for some patients.
Only relatively potent drugs are suitable candidates due to natural limits of drug entry imposed by skin's impermeability.
Adverse Events
TDDSs, despite popularity, can cause side effects like dermatitis and contact allergic reactions.
The FDA (2005) announced that fentanyl transdermal patches caused narcotic overdose and deaths.
Cause: Manufacturing defect allowed gel-containing medication to leak out of its pouch too quickly.
Improvement: Use of a matrix/adhesive suspension where medication is blended with the adhesive instead of being held in a separate pouch with a porous membrane.
Currently Available Drugs Used as TDDS in the US
1979
Drug: Scopolamine
Indication: Motion sickness
Product Name: Transderm-Scop
1981
Drug: Nitroglycerin
Indication: Angina pectoris
Product Name: Transderm-Nitro
1984
Drug: Clonidine
Indication: Hypertension
Product Name: Catapres-TTS
1986
Drug: Estradiol
Indication: Menopausal symptoms
Product Name: Estraderm
1990
Drug: Fentanyl
Indication: Chronic pain
Product Name: Duragesic
1991
Drug: Nicotine
Indication: Smoking cessation
Product Name: Nicoderm, Habitrol, ProStep
1993
Drug: Testosterone
Indication: Testosterone deficiency
Product Name: Testoderm
1995
Drug: Lidocaine/Epinephrine (iontophoresis)
Indication: Local dermal analgesia
Product Name: Iontocaine
1998
Drug: Estradiol/Norethidrone
Indication: Menopausal symptoms
Product Name: Combipatch
1999
Drug: Lidocaine
Indication: Post-herpetic neuralgia pain
Product Name: Lidoderm
2001
Drug: Ethinyl estradiol/Norelgestromin
Indication: Contraception
Product Name: Ortho Evra
2003
Drug: Estradiol/Levonorgestrel
Indication: Menopausal symptoms
Product Name: Climara Pro
2003
Drug: Oxybutynin
Indication: Overactive bladder
Product Name: Oxytrol
2004
Drug: Lidocaine (ultrasound)
Indication: Local dermal anesthesia
Product Name: SonoPrep
2005
Drug: Lidocaine/Tetracaine
Indication: Local dermal anesthesia
Product Name: Synera
2006
Drug: Fentanyl HCl (iontophoresis)
Indication: Acute postoperative pain
Product Name: Ionsys
2006
Drug: Methylphenidate
Indication: Attention deficit hyperactivity disorder
Product Name: Daytrana
2006
Drug: Selegiline
Indication: Major depressive disorder
Product Name: Emsam
2007
Drug: Rotigotine
Indication: Parkinson's disease
Product Name: Neupro
2007
Drug: Rivastigmine
Indication: Dementia
Product Name: Exelon
Skin Site for TDD
Human skin is a readily accessible surface for this delivery system.
Average adult body skin covers approximately 2 \text{ cubic meters} and receives about 1/3 of the blood circulating through the body.
The principal mechanism is passive diffusion of the drug through the skin.
Macro-routes: Transepidermal pathway and transfollicular pathway.
Human skin layers: Epidermis, Dermis, Subcutaneous fatty tissue.
Components of Transdermal Patches
Backing
Drug
Membrane
Adhesive
Liner
Generations of TDDS
1st Generation TDDS
Goal: Deliver small, lipophilic molecules.
Liquid Reservoir System: Patch consists of a protective and adhesive backing material, a liquid drug reservoir, and a release membrane.
Example: The first commercially available Rx patch, scopolamine for motion sickness (approved 1979 by US FDA).
Also used for forms of estrogen to treat menopausal symptoms.
Adhesive Matrix System: Adhesive and drug are combined in the same layer, resulting in three layers: backing layer, drug and adhesive layer, and protective layer.
Most currently available patches use this design.
2nd Generation TDDS
Goal: Deliver organic molecules by reversibly disrupting the stratum corneum barrier function to provide a driving force for molecule movement, avoiding skin injury.
Limitation: Enhancement techniques are limited to small, lipophilic molecules and have little effect on larger or hydrophilic molecules.
Enhancement Techniques:
Chemical Penetration Enhancers:
Mechanism: Increase skin permeability by reversibly damaging or altering the physicochemical nature of the stratum corneum, reducing its diffusional resistance. This involves:
Increased hydration of the stratum corneum.
Changes in structure of lipids and lipoproteins in intercellular channels through solvent action or denaturation, or both.
Examples: Acetone, dimethylacetamide, ethanol, menthol, dimethyl sulfoxide, oleic acid, polyethylene glycol, propylene glycol, sodium lauryl sulfate.
Heat as a Penetration Enhancer:
Increases skin permeability.
Controlled Heat-Assisted Drug Delivery (CHADD) system: A safe method.
Example: Lidocaine/Tetracaine patch system (Synera patch) numbs small skin areas for medical procedures (biopsy, minor surgery, IV insertion).
Iontophoresis:
Uses a tiny electric current to promote flow of charged drugs through the skin.
A powered drug delivery system for local administration of ionic drug solutions, serving as an alternative to injections.
Wireless Patches: Self-contained, ultra-thin battery technology. Clinician-applied, allowing patients daily activities while receiving time-released iontophoresis. A charged drug delivery electrode (negative) repels drug ions into underlying tissue.
Sonophoresis / Phonophoresis:
Sonophoresis: Use of high-frequency ultrasound to enhance TDD (still being studied).
Phonophoresis: Use of ultrasound to enhance the delivery of topically applied drugs (e.g., analgesics and anti-inflammatory agents).
3rd Generation TDDS
Goal: Severely disrupt the stratum corneum to allow large molecules to pass into circulation.
Enhancement Techniques:
Iontophoresis (3rd Gen):
Example: Gonadotropin-releasing hormone (GnRH), an oligopeptide, is being developed for transdermal delivery. The GnRH Smart Patch iontophoretic technology (Vyteris) is in Phase 2 clinical trials for female infertility.
Thermal Ablation:
Severely disrupts the stratum corneum using hundreds of degrees for very short periods (micro- to milliseconds).
Forms painless, reversible microchannels in the stratum corneum without damaging underlying tissue.
Ultrasound as a Penetration Enhancer:
Similar to phonophoresis, but often refers to higher energy/focused applications for deeper/larger molecule permeation.
Microneedles:
Microneedle array consists of chips used for administering therapeutic proteins and vaccines.
Method: Poke and patch.
Hollow Micro-Needle Array Example: Intanza, a seasonal flu vaccine approved in Europe since 2009.
Microneedle-Based Patches
Several types with unique features.
Four Major Types:
Solid Microneedles: Simplest type, consisting of solid needles that penetrate skin to create tiny channels. Commonly used for drug delivery and cosmetic treatments.
Hollow Microneedles: Have a hollow core for delivering fluids or drugs into the skin. Often used for transdermal drug delivery and sampling interstitial fluid.
Coated Microneedles: Have a coating that dissolves upon skin penetration, releasing drugs or other substances. Used for transdermal drug delivery.
Dissolving Microneedles: Made of materials that dissolve in the skin, allowing controlled release of drugs. Often used for vaccines and other drug delivery applications.
Dissolving/Degradable Patches
Designed to dissolve on the skin, eliminating the need for removal and disposal.
Made from biodegradable materials absorbed by the body.
Research Example (2019): Successful administration of the antibiotic gentamicin via a dissolving patch in a mouse model of bacterial infection.
Insulin Delivery: Dissolving microneedles (MNs) show high efficiency for poorly permeable drugs and vaccines.
A two-step injection and centrifugation process localized insulin to the needle.
Achieved efficient transdermal delivery of insulin with satisfactory relative bioavailability (RBA) compared to conventional subcutaneous injection.
Demonstrates effectiveness of dissolving patches for diabetes treatment.
Transdermal Patch for Transdermal DDS (Overview)
An alternative revolutionary method for drug delivery via the skin layer.
Medicated patches that deliver drugs directly into the bloodstream through skin layers at a prescribed rate.
Come in different sizes and contain multiple ingredients.
Active ingredients enter systemic circulation via diffusion processes.
Contain high doses of active substances that remain on the skin for an extended period.
Often use a rate-controlling ethylene vinyl acetate membrane.
Sites of Application and Drug Release Duration of Patches
Site of application: Varies by therapeutic category.
Nitroglycerin: Around the chest.
Estradiol: Around the buttocks or abdomen.
Duration of drug release: Varies from shortest (up to 9 hours) to longest (up to 9 days).
Advantages | Disadvantages |
|---|---|
Continuous dosing, multi-day treatment | Limited type of medication |
Bypass the digestive system | Skin irritation |
Avoid first-pass metabolism | Inconsistent absorption |
Can be terminated anytime | Patch failure |
Less invasive | Limited dosing option |
Types of Transdermal Patches (Commercial Categories)
Most are categorized as reservoir or matrix systems. Four main types are:
Drug-in-Adhesive System:
Simplest form of membrane permeation control.
Adhesive layer contains drugs and glues layers together.
Drug mixture is sandwiched between liner and backing.
Reservoir System:
Drug reservoir is held between the backing layer and a rate-controlling membrane.
Drug is released through a microporous rate-controlling membrane.
Drug can be in solution, suspension, gel, or dispersed in a solid polymer matrix within the reservoir chamber.
Matrix System:
Drugs are uniformly dispersed in hydrophilic or lipophilic polymer matrices.
Resulting drug-containing polymer is affixed to drug-containing discs of controlled thickness and surface area.
Micro-Reservoir System:
Combination of reservoir and matrix dispersion system.
Drug solids are first suspended in an aqueous solution of water-soluble liquid polymer.
Solution is then uniformly dispersed in a lipophilic polymer to create thousands of non-leaching microscopic drug reservoirs.
Recent Advancement of Transdermal Patch
Traditional patches primarily serve for drug storage and release, with challenges like limited dosage or low release.
Novel patches feature new designs capable of sensing and accurately releasing drugs.
Offer higher loading, enhanced penetration, and improved drug release.
The field of transdermal drug delivery is an active area of research and development.
Smart Patches
Equipped with sensors and technologies to monitor patient conditions and adjust drug delivery.
Developed in 2014.
Microneedle-based "smart" patch sensor platform for painless, continuous intradermal glucose measurement for diabetics:
Uses a conducting polymer like poly(3,4–ethylenedioxythiophene) [PEDOT] as an electrical mediator for glucose detection.
Acts as an immobilizing agent for the glucose-specific enzyme glucose oxidase (GOx).
Smart insulin-releasing patch:
Consists of 121 microneedles containing nanoparticles.
Painless penetration into interstitial fluid between subcutaneous skin cells.
Nanoparticles in each needle contain insulin and the glucose-sensing enzyme glucose oxidase.
GOx converts glucose into gluconate.
These molecules are surrounded by hypoxia-responsive polymers.
Increased GOx activity (due to increased glucose) creates an oxygen-depleted environment within nanoparticles.
This hypoxia is sensed by the hypoxia-responsive polymer, triggering nanoparticle degradation and insulin release.
Painless paper patch test for glucose levels using microneedles.
Bendable sensors for wound healing management and monitoring:
Inexpensive, flexible, fully printed smart patch on skin to measure changes in wound pH and fluid volume.
Easily incorporated into wound dressings.
Consists of various electrodes printed on a polydimethylsiloxane (PDMS) substrate for pH and humidity measurements.
Sensitivity of 7.1 \text{ ohm/pH} to the wound pH value.
Smart patch to monitor and treat diabetic foot ulcers (DFU):
Fabricated from conductive hydrogel patches with an ultra-high transparency polymer network.
Uses: Visually monitor wound healing status, promote hemostasis, improve cell-to-cell communication, prevent wound infection, promote collagen deposition, improve vascularity, promote angiogenesis.
Achieves indirect blood glucose monitoring by detecting glucose levels in wounds.
Timely detects movements of various sizes of human bodies.
Monitors chronic wound dressings and treats wounds simultaneously.
Smart patches for delivering natural compounds (e.g., curcumin):
Material consists of paraffin wax and polypropylene glycol as a phase change material (PCM).
Combined with graphene-based heating elements obtained by laser scribing of polyimide films.
Allows electronically-controlled release for repeated dosing.
Emission induced and terminated by controlled heating of the PCM, not relying on passive diffusion.
Permeation only occurs when PCM transitions from solid to liquid.
Curcumin delivery yields were found to be good and satisfactory.
Curcumin: Effective in treating chronic conditions like rheumatoid arthritis, inflammatory bowel disease, Alzheimer’s, and common malignancies (colon, stomach, lung, breast, skin cancers). Considered an age-old anti-inflammatory and anti-neoplastic agent.
Conclusion
Transdermal patch technology is a valuable drug delivery method with many advantages over other routes.
Patches bypass the digestive system and first-pass metabolism, providing continuous dosing over an extended period.
Commonly used for chronic pain, motion sickness, and hormone replacement therapy.
Recent advancements include smart, dissolving/biodegradable, high-loading/release, and 3D-printed patches.
TDDS has potential for convenient and effective drug delivery for various ailments.
Challenges: Possibility of self-inflicted toxicity due to improper dosing, poor adhesion, low drug penetration, potential skin irritation, or patch failure.
Further research and development are warranted to optimize the safety and efficacy of this delivery system.