Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow-226028, INDIA.
The ideal medication delivery system is as practical and user-friendly for the patient as oral solid dose forms, but it has a bioavailability similar to parenteral dosage forms. Transdermal drug delivery (TDD), a non-invasive delivery method, has drawn more attention in recent years. technique that is often seen to be simple to administer to more vulnerable age groups, such as elderly and pediatric patients, while avoiding some bioavailability issues that come with oral drug delivery because of poor metabolism and absorbability. Nevertheless, TDD is still limited to a small number of medications despite its many advantages. The evolution of the TDDS from first-generation to fourth-generation systems is summarized in this work, along with the features of each carrier with regard to mechanism composition, penetration technique, mechanism of action, and current preclinical research. We also examined the major obstacles faced during the TDDS's development and the vital importance of clinical trials. Nonsteroidal anti-inflammatory medications (NSAIDs) have revolutionized the treatment of pain, inflammation, and skin disorders through the use of topical and transdermal drug delivery systems. The topical and transdermal uses of ibuprofen, ketoprofen, and flurbiprofen are highlighted in this analysis, emphasizing their superior skin permeability and localized pain management, as well as an assessment of their security in such uses. They are excellent candidates for skin research and targeted therapy due to their broad use in commercial goods, compatibility with a variety of formulations, and low systemic adverse effects.
The skin, the body’s largest organ, acts as a protective barrier and maintains homeostasis [1,2]. It consists of the epidermis, dermis, and hypodermis, with the stratum corneum (10–20 µm thick) following a “brick and mortar” structure of corneocytes within lipid matrices [3,4]. Transdermal drug delivery (TDD) offers advantages like controlled dosing and improved compliance, while oral delivery is limited by poor solubility, degradation, and first-pass metabolism, and parenteral delivery is used for drugs with low bioavailability[5–9].
Wounds are classified by depth and duration, and healing occurs in inflammation, proliferation, and remodeling phases [10–14]. Microneedles are a recent advancement that create microchannels for delivering large molecules with minimal invasiveness and better targeting, though challenges like scalability and safety remain [15–17].Lipid-based nanocarriers (SLNs, NLCs, nanoemulsions, transfersomes, ethosomes, invasomes) enhance solubility, retention, and controlled release while reducing irritation [18–20]. Ultra-deformable vesicles improve penetration, and invasomes enable deeper delivery[20,21]. Physical methods like sonophoresis and iontophoresis enhance drug permeation but need more clinical validation. Targeting appendageal pathways, especially hair follicles, supports localized and sustained drug delivery, particularly when combined with nanocarriers or microneedles [22].
BARRIERS TO DRUG DELIVERY TO LOCAL SKIN
Drugs vary in molecular size, with micromolecules generally penetrating the skin more easily, while macromolecules require specialized delivery methods[23,24]. Drug permeation occurs through three main pathways: appendageal, transcellular, and intercellular routes [25–27]. The appendageal pathway allows uptake via sweat glands and hair follicles, the transcellular route involves direct passage through cells, and the intercellular pathway facilitates diffusion between cells, especially for lipophilic drugs. Effective therapy requires delivering drugs to the target subcutaneous site at appropriate concentration and dosage [28].
The stratum corneum (SC) is the main mechanical barrier of the skin and is essential for drug absorption via passive diffusion. It consists of corneocytes embedded in lipid matrices, connected by corneodesmosomes and tight junction remnants. Corneocytes are terminally differentiated cells with a rigid envelope and keratin filaments cross-linked by proteins such as involucrin, loricrin, and filaggrin[29–31].Corneodesmosomes regulate epidermal turnover through protease-mediated degradation, controlled by factors like LEKTI, pH, and cholesterol sulfate, while tight junction remnants limit protease access[29–31]. The extracellular space contains lipid lamellae (ceramides, cholesterol, fatty acids) arranged in structured phases that determine permeability, with ceramides playing a key role in barrier integrity[31–35].Disruption of the SC increases transepidermal water loss and enhances drug absorption [36,37]. Techniques such as laser ablation, electroporation, sonophoresis, iontophoresis, microneedles, and jet injectors improve delivery by altering this barrier[38–40]. Chemical enhancers (e.g., sodium lauryl sulphate, oleic acid, linoleic acid) further increase permeability by disrupting or modifying SC lipids [41–44].
Tight junctions (TJs) in the stratum granulosum act as a second barrier, restricting molecular penetration and regulating charge-selective paracellular transport of ions like calcium, sodium, and chloride[45,46]. They are composed of claudins, TJ-associated proteins (occludin, tricellulin), and junctional adhesion molecules, with claudin-1 and claudin-4 being critical for barrier integrity (47). Scaffold proteins such as ZO-1, ZO-2, and cingulin support TJ structure and signaling [48].Claudin-1 deficiency increases permeability, causes water loss, and disrupts skin barrier function, as seen in animal models and human NISCH syndrome[49–55]. Modulating TJs can enhance drug delivery; agents like cCPE, peptides (m19, AT1002), antibodies (7A5, 3B11), and sodium caprate increase permeability by disrupting TJ integrity and reducing TEER[56–59]. Thus, targeting TJs is a promising strategy for improving transdermal delivery, though unintended alterations by drugs and carriers must be considered.
The basement membrane (BM) is located at the dermo-epidermal junction beneath the stratum basale and is composed of carbohydrates and matrix proteins such as laminins, collagens, proteoglycans (e.g., perlecan), and hyaluronic acid. These components form a cross-linked, mat-like structure essential for epidermal development and barrier formation [60]. Autoantibodies against laminin cause blistering pemphigoid disorders[61,62], and BM thickness is reduced in atopic dermatitis[63]. The BM’s role as a barrier remains debated. Its mesh structure suggests limited material exchange, yet proteins up to 40 kDa (HRP) are not restricted in transport [64]. In contrast, absorption of 8 nm particles is significantly reduced(65,66), and it blocks viral spread such as herpes simplex virus [67]. Additionally, due to its negative charge, the BM may act as a charge-selective barrier for larger molecules (~450 kDa) [68].
The skin’s vasculature acts as the “last barrier,” where a one-cell-thick endothelial layer connects skin tissue to circulation at the papillary loops near the dermo-epidermal junction. This endothelium responds to stimuli such as pressure, heat, osmolarity, chemokines, and cytokines by adjusting permeability and regulating vasodilation or constriction[69]. Beyond inflammatory responses, skin vessels can open normally closed vascular loops, playing a key role in thermoregulation. Skin perfusion ranges from 0.05 L/min in cold stress to about 0.25 L/min at rest and exceeds 5.00 L/min during hyperthermia [70]. These changes influence both thermoregulation and the movement of substances across the skin barrier[71,72]. Clinical trials show that increased temperature enhances systemic absorption of transdermal drugs such as nicotine, fentanyl [73], clonidine [74], and testosterone[75]. Overall, the skin’s vascular system is a crucial component of its barrier function alongside the epidermis.
DEVELOPMENT AND EVOLUTION OF TDDS
Transdermal penetration in TDDS is influenced by factors such as the stratum corneum, drug properties, carrier systems, temperature, and pH, which can reduce its effectiveness. To address this, researchers have focused on improving carrier systems to enhance permeation efficiency. Since their introduction in 1981, TDDS has evolved through four generations [76]. First-generation systems use patch-based delivery with basic permeation strategies. Second-generation systems incorporate techniques like iontophoresis, sonophoresis, prodrugs, and chemical enhancers, though they may cause physiological damage. Third-generation TDDS emphasizes methods such as electroporation and microneedles. The latest generation focuses on nanocarriers, the most extensively studied systems, which enhance the delivery of hydrophilic biomolecules across the skin and improve drug penetration into deeper layers[77].
Iontophoresis, a second-generation TDDS, uses low-voltage current (≤10 V) to enhance drug delivery across the stratum corneum into systemic circulation[78]. Its mechanisms include electro-repulsion (movement of similarly charged molecules) and electro-osmosis (transport of charged and uncharged molecules via current-driven flow) [79–82]. Drug transport mainly occurs through skin appendages and intercellular pathways, enabling targeted delivery.It serves as a noninvasive alternative to injections, improving patient compliance and enabling delivery of large molecules[83,84]. Studies show enhanced efficacy, including better outcomes than intradermal injections and improved drug penetration, especially in damaged skin [85,86]. Controlled drug release is achieved by adjusting current intensity and application area [86].Despite advancements, only a few FDA-approved products exist, with limited availability [87]. Safety concerns remain, as high current intensity or prolonged use may cause skin irritation, erythema, itching, and tingling.
Sonophoresis, a second-generation TDDS, uses ultrasound to enhance drug penetration into the skin, particularly for hydrophilic and macromolecular drugs. It increases skin permeability through micro-vibrations, especially at low frequencies (20 kHz–16 MHz), which allow deeper penetration with minimal energy loss[88–90]. It has clinical use in applications like lidocaine delivery, reducing anesthesia onset time [91,92]. It is classified into preprocessed (enhancing permeability before drug application) and simultaneous (enhancing transport during ultrasound exposure). The main mechanism is cavitation, along with thermal, mechanical, and convective effects[93]. Despite its benefits, sonophoresis alone is less effective for large molecules, may cause irritation, and is time-consuming. Challenges include limited penetration efficiency, equipment cost, and safety concerns. However, it remains useful for delivering low-bioavailability drugs, vaccines, and genes, especially when combined with other methods, with advanced techniques like dual-frequency ultrasound offering improved outcomes[94].
Chemical penetration enhancers (CPEs) are widely used in second-generation TDDSs due to their easy application, noninvasive nature, compatibility, and low cost [95–99]. Their concentration significantly influences drug penetration, viscosity, and adhesion of formulations[100]. CPEs improve permeation by increasing diffusion, fluidizing the stratum corneum, enhancing drug thermodynamic activity, and altering partition coefficients. However, disruption of the skin barrier may lead to irritation, allergies, and inflammation, especially at higher concentrations, requiring careful balance between safety and efficacy [101]. Optimizing compatibility and combining CPEs can enhance penetration and reduce risks. Although newer CPEs improve performance, including macromolecule delivery, concerns like toxicity, hypersensitivity, and sensitization limit their wider use, highlighting the need for further research[102].
The stratum corneum limits TDDS, and electroporation, a third-generation method, enhances drug permeation by creating temporary pores using high-voltage pulses (50–500 V), especially for macromolecules like DNA and insulin. It disrupts the lipid bilayer to form transient pathways, with effectiveness influenced by pulse parameters and drug properties.Electroporation produces reversible pores with permeability lasting over 12 hours, allowing controlled delivery with minimal lasting damage and improved transport of hydrophilic and high-molecular-weight drugs[103,104] . The mechanism involves structural disruption of the stratum corneum. It is used clinically in electrochemotherapy for skin cancers such as malignant melanoma, but limitations like lower efficiency than iontophoresis and insufficient long-term safety data restrict its wider application, though it remains a promising approach[105].
Third-generation TDDSs include microneedling and microneedle patches [106]. Microneedling creates controlled microinjuries using devices like dermarollers to enhance skin texture and collagen production, with drugs applied afterward through microchannels [107–109].In contrast, microneedle patches consist of micron-sized needles that directly deliver drugs into the skin and are classified as solid, coated, dissolving, hollow, and hydrogel-forming types [110,111]. They enable precise dosing and targeted delivery to specific skin layers[112].Microneedle patches offer advantages such as reduced pain, improved patient compliance, and self-administration, with applications in insulin, vaccines, and other macromolecules [112,113]. Thus, microneedling enhances topical drug absorption, while microneedle patches act as direct delivery systems.
Solid microneedles enhance skin permeability by creating microchannels for passive drug diffusion, which must close quickly to prevent microbial entry[114]. Advanced designs improve delivery efficiency, reduce leakage, and enable multi-drug delivery [115]. However, they require a two-step process, increasing complexity. They can be made from polymers, with successful drug delivery demonstrated using tilapia-derived microneedles [116]. Studies show enhanced delivery of drugs like verapamil, amlodipine, captopril, and metoprolol using microneedle systems[117,118].They also show superior vaccine delivery compared to intramuscular injections, producing stronger and longer-lasting immune responses.
Dissolving microneedles enable “one-step” drug delivery by puncturing the skin and dissolving to release encapsulated drugs. They are typically fabricated by micromolding under mild conditions, suitable for heat-sensitive drugs and vaccines [112,119,120]. Applications include PVA microneedles enhancing boron neutron capture therapy with strong anti-melanoma effects[121], and hyaluronic acid-based microneedles improving melanin inhibition and localized drug delivery[122]. Nanocarriers, a fourth-generation TDDS, enhance drug penetration with minimal skin damage, particularly for hydrophilic biomolecules that are otherwise difficult to deliver transdermally.
Liposomes, with particle sizes of 50–1000 nm, are among the most widely used nanocarriers and one of the few nanoformulations applied clinically. Their lipid bilayer structure allows encapsulation of water-soluble drugs in the core and lipid-soluble drugs within the bilayer [123–125]. Due to their amphiphilic, biocompatible, and biodegradable nature, they are especially useful for delivering traditional Chinese medicines. Liposomes enhance therapeutic efficacy by improving bioavailability, enabling sustained release, and supporting targeted drug delivery, thereby increasing safety [112].
Solid lipid nanoparticles (SLNs) and polymer nanoparticles (PNPs) are key nanocarriers in TDDSs. SLNs, typically 50–1000 nm in size, are composed of solid natural or synthetic lipids and are valued for high drug-loading capacity, controlled release, stability, and good biosafety[126,127]. PNPs, with sizes ranging from 10–1000 nm, are made from biocompatible and biodegradable polymers. They offer simple fabrication, targeted delivery, enhanced therapeutic efficacy, improved safety, and reduced side effects[128]. An example includes tacrolimus-loaded liquid crystal nanoparticles, which enhance skin barrier penetration and improve therapeutic outcomes in psoriasis[129].
CLINICAL APPLICATION OF TDDS
Inflammatory skin diseases affect 20–25% of the population and arise from infections or immune dysfunction involving skin barrier, innate, and adaptive immunity, with cytokines regulating T cell activity and inflammation[130–132].Prevalence varies across populations and increases with age, affecting about one-eighth of individuals over 50, with regional and disease-specific differences such as higher adult incidence of seborrheic dermatitis and early onset of atopic dermatitis[130,133–135]. Psoriasis is often linked to comorbidities like diabetes, cardiovascular disease, and depression [136].Treatment includes vitamin D analogs, corticosteroids, calmodulin inhibitors, emollients, antihistamines, and biologics[137–139]. However, limited skin penetration (10–20%) and long-term use may cause side effects like skin thinning, immunosuppression, and metabolic complications[140,141]. Common conditions include acne, psoriasis, and atopic dermatitis.
Psoriasis thickens the stratum corneum, reducing drug penetration. Transdermal patches using polymers like CMC-Na and HPMC enhance mechanical strength, controlled release, and drug absorption, with methotrexate-loaded patches effectively reducing inflammation [142,143]. Advanced approaches include HA-based microneedle patches delivering methotrexate nanoparticles, which decrease inflammation, skin thickness, and cytokines with fewer side effects [144]. Thermoresponsive hydrogels with ionic liquid microemulsions improve solubility, permeability, adhesion, and sustained release while maintaining biocompatibility[145].Nanocarrier systems further enhance therapy, including TQ-Arg-PA nanocapsules and aloe vera-based patches improving drug delivery[146] . Combined nano-systems (TCeO? with 9-ol) reduce ROS and inflammation, while transdermal parthenolide shows superior anti-inflammatory effects via IL-36 targeting[147,148]. ROS-responsive nanomicelles delivering calcipotriol improve solubility and reduce keratinocyte proliferation [149]. Additional innovations include AP-PTPP conjugates, dissolving microneedles, and ROS-regulating systems that enhance delivery and improve the psoriatic microenvironment[150–152].
A P407/CMCS thermosensitive hydrogel enhances drug release and skin hydration for atopic dermatitis by improving porosity and modulating sol–gel transition without altering its properties, making it an effective dual-function TDDS [153]. A conductive TDDS (cTDS) enables electrically controlled, on-demand drug release, improving delivery and reducing inflammation while supporting smart and biosensor-integrated systems[154]. Low-temperature atmospheric pressure plasma (LTAPP) improves delivery of Jaun ointment, reducing cytokines, eosinophils, and inflammation without tissue damage via NF-κB modulation[155]. Triptolide nano-lotion gel enhances skin absorption and reduces systemic side effects, offering effective and low-toxicity treatment for dermatitis [156].
Acne affects about 85% of individuals aged 11–30 and is associated with androgens, keratinocyte proliferation, sebum production, and oxidative stress caused by reactive oxygen species (ROS)[157,158]. A TDDS using a transfer gel of mulberry leaf extract demonstrated strong antioxidant activity and enhanced skin permeability for acne treatment [159]. Additionally, a high molecular weight hyaluronic acid-based microneedle system loaded with eugenol and combined with photothermal therapy showed effective drug delivery, antibacterial activity, reduced inflammation, sebaceous gland shrinkage, and improved skin healing[160].
RECENT ADVANCES IN TDDS FOR INFLAMMATORY SKIN DISORDERS
|
Study |
Technique |
Type of ISD |
Drug |
Key Outcome |
|
Rana Obaidat et al., 2022 |
Nanofiber microcarrier system |
Various inflammatory skin conditions |
Pioglitazone |
Improved drug retention in skin layers and enhanced local delivery with minimal systemic exposure. |
|
Ji Heun Jeong et al., 2019 |
Pullulan hydrogel with plant extract |
Atopic dermatitis |
Rhus verniciflua extract |
Provided both physical skin protection and therapeutic anti?inflammatory action. |
|
Wenyi Wang et al., 2016 |
Thermosensitive composite hydrogel |
Atopic dermatitis |
P407/CMCS hydrogel |
Enhanced drug diffusion due to porous structure and improved storage stability. |
|
Yuan Yang et al., 2022 |
Conductive transdermal system |
Inflammation?related dermatitis |
Multiple drugs |
Enabled electrically controlled drug release and personalized therapy. |
|
Jeong Hae Choi et al., 2017 |
Plasma?treated herbal ointment |
Atopic dermatitis |
Jaun ointment |
Improved penetration and regulated inflammatory signaling. |
|
Muhammad Shahid Latif et al., 2022 |
CMC?based patch |
Psoriasis inflammation |
Methotrexate |
Improved drug retention and reduced toxicity. |
|
Huaji Wang et al., 2021 |
Microneedle patch |
Psoriasis |
Methotrexate nanoparticles |
Lowered inflammatory markers and improved therapeutic effectiveness. |
LIMITATIONS AND FUTURE PROSPECTS
The stratum corneum is the primary barrier limiting penetration of hydrophilic drugs and macromolecules, leading to restricted drug selection, low bioavailability, and delayed onset in TDDS(161). Skin irritation and toxicity may occur with chemical enhancers and physical methods like iontophoresis and electroporation [162].
Advanced systems such as microneedles and nanocarriers face challenges including safety concerns, stability issues, potential skin damage, and long-term toxicity[163]. High manufacturing costs, formulation complexity, and limited clinical translation due to regulatory and safety constraints further restrict their use[161,164]. Patient variability also affects drug absorption and efficacy.
Nanocarriers (liposomes, SLNs, PNPs) improve solubility, stability, and targeted delivery with fewer side effects[165], while microneedles enable painless and controlled delivery of macromolecules[163]. Hybrid approaches enhance permeation efficiency[161], and smart systems like stimuli-responsive hydrogels and biosensor-based patches support personalized therapy. Emerging technologies such as 4D bioprinting may improve formulation design, with future research focusing on safety, cost reduction, and clinical translation for effective non-invasive treatment[165].
CONCLUSION
The skin as the major protective tissue of the body represents a challenging target tissue with regards to drug delivery because of the unique structure of the skin, notably the stratum corneum. Traditional routes of drug delivery such as oral and parenteral routes exhibit limitations such as poor bioavailability, adverse systemic effects, and low patient compliance.
Drug delivery through transdermal drug delivery systems (TDDS) presents promising alternative options for drug delivery with regard to providing local, minimal-invasive, and regulated drug delivery. Recent advances in drug delivery approaches include the use of microneedles, electroporation, iontophoresis, and liposomes. These strategies have greatly enhanced permeation rates, leading to successful delivery of complex drug molecules, even biologicals.
In addition, liposomal nanocarriers coupled with microneedle technology have helped enhance the delivery of drugs to target skin inflammatory diseases, such as psoriasis, acne, and atopic dermatitis. Nonetheless, these developments face some limitations, including lack of clinical applications, limited safety profiles, and insufficient evidence.
In conclusion, there is an ever-growing advancement in TDDS, which holds great potential to revolutionize dermal drug delivery.
REFERENCES
Sailesh Kumar, Vishakha Jaiswal, Emerging Transdermal Drug Delivery Technologies & Their Clinical Use in Inflammatory Skin Disorder, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 4, 2512-2531, https://doi.org/10.5281/zenodo.19606260
10.5281/zenodo.19606260
