Abstract
Transdermal drug delivery systems (TDDS) represent an innovative and effective method for administering drugs systemically through the skin. These systems offer significant benefits over conventional oral and injectable routes by avoiding hepatic first-pass metabolism and allowing for controlled, sustained drug release. This not only enhances drug bioavailability but also improves patient adherence, particularly in the treatment of chronic conditions. Although the skin’s outermost layer, the stratum corneum, presents a significant barrier, advancements in both passive methods (such as patches) and active techniques (including microneedles, iontophoresis, and electroporation) have broadened the scope of drugs suitable for transdermal delivery. This review examines the core mechanisms involved in transdermal permeation, the anatomy and physiological functions of the skin, and the various pathways through which drugs traverse the dermal layers. It classifies TDDS into passive, active, and emerging hybrid systems, detailing their unique design characteristics, representative examples, and clinical use cases. Additionally, it highlights the major advantages of TDDS, such as user-friendliness, minimized gastrointestinal side effects, and enhanced therapeutic efficiency, while also addressing key challenges like potential skin irritation, limited dosing capacity, and high development expenses. The review concludes by exploring both chemical and physical enhancement strategies that are essential for broadening the applicability of TDDS to a more extensive range of pharmaceutical compounds.
Keywords
Transdermal Drug Delivery System (TDDS), Microneedles, Iontophoresis, Skin Permeation, Drug Absorption, Nanocarriers, Smart Patches.
Introduction
Transdermal drug delivery systems (TDDS) offer a cutting-edge and effective approach for administering medications systemically through the skin, presenting several benefits over traditional oral and injectable methods. By facilitating the transport of drugs directly into the bloodstream via the skin, TDDS provide a non-invasive alternative that bypasses hepatic first-pass metabolism and ensures controlled, sustained drug release [1,2]. This approach enhances patient adherence, particularly in long-term therapies, and supports improved treatment outcomes by maintaining consistent plasma drug concentrations over time [3]. Despite its advantages, the skin serves as a formidable barrier, mainly due to the stratum corneum—the outermost layer—which significantly limits drug permeation [4]. To address this challenge, a variety of delivery strategies have been developed, from passive systems like transdermal patches to active enhancement methods such as iontophoresis, microneedles, electroporation, and ultrasound-assisted delivery [5,6].
Mechanism Of Transdermal Drug Delivery
Transdermal drug delivery (TDD) allows medications to be absorbed through the skin and enter systemic circulation, effectively bypassing the gastrointestinal system and avoiding first-pass liver metabolism. For successful delivery, drugs must penetrate several skin layers, with the stratum corneum acting as the primary barrier to diffusion.
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Fig.No.1: Mechanism of TDDS
Structure Of the Skin
The skin consists of three major layers:
- Epidermis – the outermost layer; includes the stratum corneum.
- Dermis – provides structural support and houses blood vessels.
- Hypodermis – composed of fat and connective tissue.
The stratum corneum is a 10–20 µm thick layer of dead, flattened keratinocytes embedded in a lipid matrix. It is the major rate-limiting barrier to drug permeation [7].
Pathways Of Transdermal Permeation
Drugs can penetrate the skin and enter systemic circulation through three primary pathways:
- Transcellular (Intracellular) Route:
In this route, the drug passes directly through the corneocytes—cells rich in keratin—encountering alternating hydrophilic and lipophilic regions. Successful permeation via this pathway requires the drug to have good solubility in both water and lipids [8].
- Intercellular (Paracellular) Route:
Here, the drug moves between the skin cells, diffusing through the lipid matrix of the stratum corneum. This is the most common route for small, lipophilic molecules, as it generally presents less resistance compared to other pathways [9].
- Appendageal (Shunt) Route:
This pathway involves drug entry through skin appendages, including hair follicles and sweat glands. Although these structures occupy less than 0.1% of the total skin surface, they can play a crucial role in the delivery of larger molecules, ions, and particulate systems [10].
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Fig.No.2: Pathways of Transdermal Permeation
Step-By-Step Mechanism of Drug Transport Through the Skin
- Application on the Skin Surface:
The drug is administered onto the skin using a specific formulation such as a patch, cream, or gel.
- Partitioning into the Stratum Corneum:
Depending on its solubility, the drug either dissolves in the lipid layers of the stratum corneum or enters through aqueous channels.
- Diffusion Through the Stratum Corneum:
The drug travels across the stratum corneum via one of the three main pathways—transcellular, intercellular, or appendageal. Lipophilic drugs typically diffuse more efficiently through the intercellular route.
- Penetration into the Viable Epidermis:
Once past the stratum corneum, the drug reaches the living layers of the epidermis, where it may interact with various cells or enzymes.
- Migration into the Dermis:
The drug then diffuses into the dermis, a hydrophilic layer containing a dense network of extracellular matrix and blood vessels.
- Absorption into Systemic Circulation:
Upon reaching the dermal capillaries, the drug is absorbed into the bloodstream and begins to exert its therapeutic effect [11].
Factors Affecting Transdermal Drug Delivery [12,13,14]
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Fig.No.3: Factors Affecting TDDS
Types Of Transdermal Drug Delivery Systems
Transdermal drug delivery systems are generally classified into two main types: passive and active, depending on the method employed to transport the drug across the skin. Each system is engineered to enhance drug uptake while addressing the challenges posed by the skin’s natural barrier.
Passive Transdermal Drug Delivery Systems
Passive TDDS rely solely on diffusion across the skin without any external enhancement techniques. The most common form is the transdermal patch.
Membrane-Controlled (Reservoir) Systems
- Feature a liquid or gel drug reservoir separated from the skin by a membrane that regulates the release rate.
- Enable precise, sustained drug delivery over a specific time period.
- Example: Nitroglycerin (Nitro-Dur®) patch [15].
Matrix-Controlled Systems
- The drug is uniformly distributed within a polymer matrix that governs the release rate.
- Known for their straightforward design, flexibility, and reduced risk of sudden drug release.
- Example: Fentanyl (Duragesic®) patch [16].
Adhesive Diffusion-Controlled Systems
- Incorporate the drug directly into the adhesive layer of the patch.
- Offer a streamlined design and maintain effective contact with the skin.
- Example: Nicotine patch [17].
Active Transdermal Drug Delivery Systems:
Active systems employ physical or chemical enhancement methods to improve drug penetration, particularly useful for delivering larger molecules or drugs with low skin permeability.
Iontophoresis
- Involves the application of a low electrical current to propel charged drug molecules across the skin.
- Particularly effective for delivering peptides, proteins, and water-soluble drugs.
- Example: IONSYS® fentanyl system [18].
Sonophoresis (Ultrasound)
- Utilizes ultrasonic energy to temporarily disrupt the stratum corneum, improving drug permeability.
- Suitable for both lipophilic and hydrophilic compounds [19].
Electroporation
- Delivers short bursts of high-voltage electrical pulses to form temporary pores in the skin.
- Effective for the transdermal delivery of large biomolecules such as DNA, vaccines, and insulin [20].
Microneedle Systems
- Use tiny needles to create micro-channels in the skin, enhancing drug delivery.
- Available in various forms: solid, coated, dissolvable, or hollow.
- Commonly used for administering vaccines, hormones, and biological agents.
- Example: Experimental insulin microneedle patches [21].
Thermal And Magnetophoresis Systems
- Thermophoresis: Applies controlled heat to increase skin permeability and promote drug diffusion.
- Magnetophoresis: Employs magnetic fields to assist in drug transport through the skin [22].
Emerging And Hybrid TDDS Technologies
- Development of intelligent patches equipped with sensors for real-time drug monitoring and controlled dosing.
- Use of advanced nanocarriers such as liposomes, transfersomes, and ethosomes to enhance targeted drug delivery.
- Integration of TDDS with wearable devices that combine diagnostics, monitoring, and drug administration capabilities.
Advantages And Limitations of Transdermal Drug Delivery Systems
Transdermal drug delivery systems provide an innovative and patient-friendly method of administering medications. Nevertheless, their broader use is hindered by several limitations.
Advantages
- Avoidance of First-Pass Metabolism
- TDDS bypasses the hepatic first-pass effect, which can significantly increase the bioavailability of certain drugs [23].
- Improved Patient Compliance
- Non-invasive, painless application with less frequent dosing makes TDDS particularly suitable for chronic therapy [24].
- Controlled and Sustained Release
- TDDS allows for the controlled release of drugs over an extended period, maintaining steady plasma drug concentrations and reducing dosing frequency [25].
- Reduced Gastrointestinal Side Effects
- Since the drug is not ingested, TDDS minimizes gastric irritation and degradation by digestive enzymes [26].
- Easy Termination of Therapy
- Drug administration can be quickly discontinued by removing the patch if adverse effects occur [27].
- Convenience and Self-Administration
- Transdermal systems are user-friendly and can be applied without medical assistance, increasing independence for patients [28].
- Improved Efficacy for Lipophilic and Potent Drugs
- Ideal for delivering potent drugs with low oral bioavailability and short half-lives [29].
Limitations
- Barrier Properties of the Stratum Corneum
- The skin’s outermost layer limits the permeation of most drugs, especially large, hydrophilic, or ionic molecules [30].
- Limited Number of Suitable Drugs
- Only drugs with specific characteristics—low molecular weight, lipophilicity, and potency—are suitable for transdermal delivery [31].
- Skin Irritation and Allergic Reactions
- Prolonged application of patches or use of enhancers may cause irritation, sensitization, or contact dermatitis in some patients [32].
- Inconsistent Drug Absorption
- Absorption can vary based on skin condition, hydration, temperature, application site, and individual variability [33].
- Risk of Dose Dumping
- Damage to the patch or external conditions (e.g., heat) can lead to uncontrolled drug release and toxicity [34].
- Limited Dose Capacity
- Transdermal systems are generally suitable for low-dose drugs (≤10 mg/day), which limits their use for high-dosage medications [35].
- High Development and Manufacturing Costs
- Advanced TDDS technologies (e.g., microneedles, iontophoresis) may require complex design and costly production processes [36].
Enhancement Techniques for Transdermal Drug Delivery
To expand the variety of drugs suitable for transdermal delivery, several enhancement methods have been devised. These approaches aim to boost skin permeability and enhance drug absorption efficiency.
Chemical Enhancers
These are substances that interact with skin components (mainly lipids and proteins) to temporarily reduce barrier resistance and enhance drug permeation.
- Examples: Ethanol, oleic acid, DMSO, azones, surfactants
- Mechanism: Disrupt stratum corneum lipids, denature proteins, increase drug partitioning [37].
Physical Enhancers
These techniques physically disrupt or bypass the stratum corneum to facilitate drug transport.
Microneedles
- Create microchannels in the skin without reaching nerves or blood vessels.
- Types: Solid, coated, dissolving, hollow microneedles [38].
Iontophoresis
- Applies low electric current to drive charged drugs into the skin.
- Useful for peptides, insulin, and small hydrophilic molecules [39].
Sonophoresis (Ultrasound)
- Uses high-frequency sound waves to increase skin permeability.
- Often combined with other enhancers for better effect [40].
Electroporation
- Delivers short, high-voltage pulses to form reversible pores in the skin.
- Effective for large molecules and gene delivery [41].
Thermal Ablation
- Applies localized heat to remove the outer skin layer.
- Facilitates passive drug diffusion through the exposed skin [42].
Vesicular Systems
These are lipid-based carriers designed to enhance drug solubility and permeation.
- Types: Liposomes, niosomes, transfersomes, ethosomes
- Function: Fuse with skin lipids, increase drug residence time, and act as penetration enhancers [43].
Nanocarriers
Nano-sized delivery systems offer targeted and sustained delivery through the skin.
- Examples: Solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions, dendrimers
- Advantages: High drug loading, controlled release, and improved penetration of difficult drugs [44].
Recent Advances and Applications Of TDDS
With the growing demand for painless, effective, and patient-friendly drug administration methods, transdermal delivery has seen significant innovation. The recent developments in materials science, nanotechnology, and device engineering have expanded the scope of TDDS beyond traditional patches.
Recent Advances
Smart and Wearable TDDS
- Smart patches integrate microelectronics to monitor patient vitals and deliver drugs accordingly.
- Example: Digital patches for insulin or hormone release triggered by glucose or circadian rhythms [45].
Microneedle Arrays
- Biodegradable and dissolvable microneedles enable painless administration of vaccines and biologics.
- Clinical trials have shown promising results in delivering influenza, insulin, and mRNA vaccines [46].
Nanocarrier-Integrated TDDS
- Incorporation of nanoparticles, lipid carriers, and dendrimers enhances drug loading, targeting, and permeation.
- Applied in cancer therapy and localized drug delivery [47].
Bio-responsive Systems
- Systems that release drugs in response to stimuli like pH, enzymes, temperature, or glucose.
- Offers on-demand drug release with minimal side effects [48].
3D-Printed TDDS
- Customizable, layered patches fabricated using 3D printing technologies for personalized medicine.
- Allows precise control over dose, release profile, and patch shape [49].
Clinical And Therapeutic Applications [50].
- Pain Management: Fentanyl, buprenorphine, and lidocaine patches are widely used for chronic pain conditions
- Hormone Replacement Therapy: Estradiol and testosterone patches offer steady hormone levels without hepatic metabolism.
- Smoking Cessation: Nicotine patches are among the most well-known TDDS products and are key in smoking cessation programs.
- Cardiovascular Diseases: Nitroglycerin patches help manage angina by offering sustained vasodilator action.
- Neurological Disorders: Rivastigmine patches for Alzheimer’s disease minimize gastrointestinal side effects and improve compliance.
- Diabetes and Vaccination: Investigational microneedle patches for insulin, GLP-1 analogs, and influenza vaccines are under development or clinical evaluation.
Future Perspectives
The field of transdermal drug delivery is rapidly evolving, driven by advances in materials science, nanotechnology, and biomedical engineering. Despite the current limitations, ongoing research is opening new avenues for expanding the range of deliverable drugs, improving delivery efficiency, and integrating digital health technologies.
- Expanded Drug Library: Future TDDS are expected to accommodate a broader spectrum of drugs, including macromolecules like peptides, proteins, and nucleic acids, through the use of advanced enhancers and hybrid systems [51].
- Personalized TDDS: Integration with 3D printing and biosensors will enable patient-specific drug formulations and real-time dose adjustments, particularly beneficial for chronic conditions such as diabetes and hypertension [52].
- Self-Powered and Smart Systems: Future patches may be equipped with microbatteries, responsive materials, and feedback loops to enable closed-loop therapy — for instance, glucose-sensing insulin patches that deliver insulin as needed
- Vaccine and Biologic Delivery: Microneedle platforms will likely become mainstream for needle-free vaccination, offering a painless, safe, and effective alternative to conventional injections
- Regulatory and Manufacturing Evolution: As novel TDDS become more complex, regulatory frameworks and quality assurance methods must evolve to ensure safety, efficacy, and scalability [53].
CONCLUSION
Transdermal drug delivery systems represent a promising approach for non-invasive, controlled, and sustained drug administration. Their advantages over traditional dosage forms such as bypassing first-pass metabolism, enhancing patient compliance, and allowing self-administration make them highly suitable for chronic therapy. However, challenges like limited permeability, drug selection criteria, and formulation stability must be addressed through continued research and innovation. Emerging technologies such as microneedles, nanocarriers, and smart patches are expected to significantly expand the scope and effectiveness of TDDS. As interdisciplinary collaboration between pharmaceutical sciences, bioengineering, and digital health continues to grow, the future of transdermal delivery is likely to shift toward personalized, responsive, and minimally invasive healthcare solutions.
ACKNOWLEDGEMENT
The authors sincerely acknowledge the support and resources provided which were instrumental in the successful completion of this review. We are deeply grateful to our mentors and colleagues for their insightful guidance and ongoing encouragement throughout the development of this manuscript. We also extend our appreciation to the library and laboratory personnel for their prompt assistance in obtaining essential literature and technical data.
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