Therapeutic Advance in Transdermal Drug Delivery Systems, Enhancing Efficiency Through the Skin

Transdermal drug delivery systems (TDDS) offer a non-invasive route to administer medicines through the skin, combining improved patient compliance with avoidance of first-pass hepatic metabolism and more stable plasma concentrations compared with many oral formulations. TDDS therefore represent an attractive alternative for chronic therapies, pain control, hormone replacement, and vaccination strategies. [1] Despite these advantages, the skin—and in particular the stratum corneum—presents a formidable barrier to most drugs. The stratum corneum’s dense lipid matrix and corneocyte architecture restrict transcutaneous transport of hydrophilic molecules, large biologics, and many small-molecule therapeutics, limiting classical passive patch systems to primarily small, lipophilic drugs. Overcoming this barrier without causing unacceptable irritation or damage is the central technical challenge for modern TDDS. [2] Historically, TDDS progressed through “generations”: first-generation passive patches (e.g., nicotine, nicotine replacement therapy) relied on molecules with suitable physicochemical properties; second-generation approaches incorporated chemical enhancers and controlled-release matrices; and third-generation technologies use physical penetration enhancers or minimally invasive devices to transiently bypass the stratum corneum. Recent years have seen an acceleration beyond these categories, with hybrid strategies combining nanocarriers, microneedles, and physical modalities to expand the druggable space delivered via skin. [3] Two areas driving this expansion are micro-fabricated devices (especially microneedles) and nanocarrier systems. Microneedle arrays create micron-scale conduits that permit rapid, pain-sparing delivery of small molecules, vaccines, peptides, and even nanoparticles; dissolving and polymeric microneedles further allow controlled release and simplified disposal. Systematic reviews show rapid clinical and preclinical growth in microneedle research for both therapeutics and vaccination. [4] Nanocarrier technologies—such as liposomes, ethosomes, niosomes, solid-lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), polymeric nanoparticles and cubosomes—have been exploited to enhance skin permeation, protect labile actives, and achieve sustained release. Ethosomes (ethanol-containing lipid vesicles) and related lipid-based carriers have received particular attention for improving skin deposition and transdermal flux of both hydrophilic and lipophilic drugs. [5] Complementary physical enhancement techniques—iontophoresis, sonophoresis, and thermal/mechanical methods—are increasingly used alone or in combination with carriers to further increase permeability. Low-frequency sonophoresis has emerged as a promising and versatile method to increase drug mobility via cavitation and transient disruption of skin lipids, while iontophoresis can drive charged molecules using mild electric current. Combined modalities can produce synergistic increases in flux for challenging molecules. [6] Beyond simply increasing flux, current TDDS research places strong emphasis on therapeutic efficiency: controlled and sustained release, reduction of systemic side effects via targeted local delivery, preservation of biomolecule activity, and improved patient adherence through comfortable, wearable platforms. Smart, stimuli-responsive patches (temperature, pH, or electrically triggered release), integration with sensors and digital health tools, and advances in materials and manufacturing (including 3D printing and quality-by-design) are shaping the next generation of clinically viable transdermal products. [7]

Types of Transdermal Drug Delivery System:

Table 1: Types of Transdermal Drug Delivery System [8-12]

Benefits Of TDDS:

1. facilitates self-medication.

2. Fewer side effects than with oral administration.

3. Maintains consistent plasma drug levels.

4. Offers a prolonged period of drug effect.

5. Prevents incompatibilities in the digestive tract.

6. Lowers the frequency of administration.

7. is simple to use and remember.

8. Offers a bigger application surface than the buccal and nasal routes.

The Drawbacks of TDDS Include:

1. Potential for skin irritation or allergic responses.

2. Cannot be used with drugs that have a large molecular weight or need a large dosage.

3. Less effective for ionic medications.

4. Before the medicine reaches therapeutic levels, there must be a lag time.                                                                                                                               

1. The Importance of The Transdermal Route:

Transdermal drug delivery systems (TDDS) provide a convincing substitute for traditional modes of delivery. TDDS bypass first-pass metabolism by administering medications directly into the bloodstream through the skin. TDDS deliver controlled and sustained metabolism, bypass gastrointestinal degradation, and eliminate the need for injections, thereby significantly enhancing patient comfort and adherence. [14,1] TDDS are especially beneficial in long-term treatments. TDDS is especially advantageous because of its non-invasive nature, little discomfort, ease of use, and ability to maintain consistent plasma drug levels and lower dosage frequency [1]. for vulnerable groups like youngsters and the elderly. [14, 16]

2. Difficulties of The Skin Barrier:

Transdermal Drug Delivery Systems (TDDS) are constrained by the skin's innate barrier characteristics, despite its benefits. The primary obstacle to drug absorption is the stratum corneum, which is the outermost layer of skin and is composed of densely packed corneocytes in lipid matrices. The viable epidermis and dermis below it, which contain blood vessels and tight connections, provide additional barriers to medication movement. Because of these obstacles, passive diffusion via the skin is only possible for tiny, lipophilic molecules. This limits the range and complexity of medicines that may be administered transdermally [15-16].

Fig 1: Skin barrier [21]

3. Justification for Reviewing Recent Advances: -

1) Scientists have created a variety of methods to get around the skin barrier:

Physical techniques:

* Micro-needle

* Iontophoresis

* Sonophoresis

* Electroporation

* These either break lipid structures or create microchannels to improve drug penetration.

• Nanotechnological Approaches:

* Liposomes

* Niosomes

* Robust lipid nanoparticles

* Transferosomes

* These enhance the regulated release, stability, and solubility of medications.

• Hybrid Systems: They are more efficient since they combine physical and nanobased approaches.

2) A Comprehensive Evaluation of These Strategies Will:

• Show their therapeutic benefits.
• Serve as a guide for future innovations.
• Assist in overcoming obstacles to clinical translation [1,14,16,17,18]

4. Review's Goals and Scope:

The Review's Scope

The review offers a thorough overview of Transdermal Drug Delivery Systems (TDDS), including:

1) The fundamentals of how drugs permeate the skin.

2) The benefits and drawbacks of TDDS in comparison to traditional medication delivery methods.

3) The skin's functional and structural anatomy as it relates to medication administration.

4) The main components and manufacturing techniques of transdermal patches.

5) Indicators used to assess the safety and effectiveness of patches.

6) The most recent innovations and cutting-edge technologies include iontophoresis, electroporation, microneedles, ultrasound methods, and needle-free injections.

7) Possible and developing prospects for increasing the effectiveness and therapeutic scope of TDDS.

Review Goals

This review aims to accomplish the following:

1. Describe the clinical significance and scientific underpinning of TDDS.

2. Emphasize the benefits of TDDS, such as regulated medication delivery, increased patient adherence, and avoidance of hepatic first-pass metabolism.

3. List the drawbacks and difficulties of TDDS, such as skin irritation, low permeability, and dosage restrictions.

4. Provide a thorough explanation of the ingredients of the composition, such as polymers, adhesives, backing layers, and permeation enhancers.

5. To guarantee the quality, safety, and efficiency of patches, go through evaluation procedures.

6. Investigate the latest technological advancements and how they might help us get around current limitations and broaden the use of TDDS.

7. Encourage more research and development to improve drug delivery through the skin and improve patient care outcomes.                                                

Skin Structure & Barrier Function

1] Detailed Anatomy of The Skin Relevant To TDDS:

1. Epidermis

* Primarily keratinocytes make up the outermost layer of skin.

* Divided into:

Stratum corneum (SC):

1) 10–20 layers of flat, dead keratinocytes in a lipid matrix.

2) Thickness: between 10 and 15 µm.

3) The main factor limiting the rate of drug penetration. The stratum granulosum, spinosum, and basale are the layers.

1) Renew and provide structural support for the skin.

Barrier Functions:

1) Molecules larger than 500 Da are prohibited by the SC.

2) Paracellular transport is controlled by tight junctions in the granular layer.

2. Dermis

• Composed of connective tissue, ranging in thickness from 0.6 to 3 mm.
• Packed with nerves, lymphatics, blood vessels, elastin, and collagen.

Functions:

* Provides the epidermis with oxygen and nutrients.

* The last place a drug is absorbed before entering the bloodstream.

Role in TDDS: The rate of systemic absorption is determined by blood flow and skin hydration.

3. Hypodermis, or subcutaneous tissue

1) Primarily adipose tissue, with larger blood arteries and nerves.

2) Offers energy storage, insulation, and cushioning.

3) Relevance to TDDS: Influences the diffusion of medications into systemic circulation and functions as a drug store for lipophilic medicines.

4. Skin Appendages

1) Hair follicles: May serve as conduits for medication penetration because they reach deep into the dermis.

2) Sweat glands and sebaceous glands: Alternative pathways for nanoparticles, ions, and hydrophilic medicines.

3) Appendageal route = small surface area (~0.1%), but vital for targeted delivery and macromolecules.

5. Obstacle structures outside SC

1) Basement membrane: The layer of cross-linked proteins (collagen, laminin) that divides the epidermis and dermis. Serves as a supplementary barrier

2) Endothelial cells of the dermal blood vessels: regulate drug entry into the bloodstream.

Fig 2: Skin anatomy [20]

2] Role of Stratum Corneum As A Primary Barrier: -

• Stratum Corneum: Structure & Barrier Function

• Outermost layer of epidermis (~10–15 μm thick).
• Composed of 15–20 layers of flattened, dead keratinocytes (corneocytes) embedded in a lipid matrix (ceramides, cholesterol, fatty acids).
• Functions like a “brick-and-mortar” model:
• Bricks = corneocytes (protein-rich, keratin-filled).
• Mortar = intercellular lipids that seal gaps.

Barrier Role In TDDS

1. Primary Rate-Limiting Barrier Controls the diffusion of drugs from transdermal patches. Highly resistant to penetration, allowing only small, moderately lipophilic molecules (<500 Da).

2. Hydrophobic Shield The lipid matrix makes SC impermeable to hydrophilic and large molecules. Maintains body’s water balance and prevents entry of toxins/microbes.

3. Pathways for Drug Penetration Intercellular route: Between lipid domains (main route for most drugs).

Transcellular route: Across corneocytes (difficult due to keratin density).

Appendageal route: Through sweat glands & hair follicles (minor, but useful for ions & macromolecules).

4. Barrier Tightness

SC renewal (desquamation) ensures continuous defense. Tight lipid packing and keratin density are the main resistances to drug diffusion.

3] Pathways Of Drug Permeation: -

Primary Pathways of Drug Permeation

 1. Intercellular Pathway (Between Cells)

1. Most common and important route.
2. Drug molecules diffuse between corneocytes via the lipid matrix.
3. Favored by lipophilic drugs due to lipid-rich environment.

2. Transcellular (Intracellular) Pathway (Through Cells)

1. Drug penetrates directly across corneocytes.
2. Less common, as corneocytes are densely packed with keratin and water.
3. Requires drug molecules to repeatedly cross hydrophilic (cytoplasm) and lipophilic (lipid membrane) domains.

3. Appendageal (Trans-appendageal) Pathway

1. Drug penetrates via hair follicles, sweat glands, and sebaceous glands.
2. Contributes only ~0.1% of skin surface area but important for:

• Hydrophilic drugs.
• Macromolecules.
• Nanoparticles/liposomes.

Steps in Transdermal Permeation

1. Drug release from patch (matrix or reservoir).

2. Penetration of stratum corneum (rate-limiting step).

3. Passage through viable epidermis and dermis.

4. Uptake into dermal microcirculation, leading to systemic absorption.

Evolution of Transdermal Drug Delivery Systems (TDDS)

1. First Generation – Simple Patches

Based on passive diffusion through the skin. Drugs had to be small, lipophilic, and potent to pass the stratum corneum.

Example: Nitroglycerin patches for angina.

2. Second Generation – Chemical Enhancers

Focused on improving skin permeability using chemical penetration enhancers. Substances like ethanol, fatty acids, surfactants temporarily disrupted the stratum corneum barrier. Helped more drugs enter, but irritation and variability were issues.

3. Third Generation – Advanced Technologies

Targeted the stratum corneum barrier more precisely without major damage.

Used physical methods such as:

Microneedles (tiny needles creating microchannels). Iontophoresis (electric current pushing charged drugs). Sonophoresis (ultrasound) to enhance penetration. Laser  ablation & electroporation to make temporary pores in skin. [13]

Recent Advances in Transdermal Technologies

1. Physical Enhancers: Microneedles, iontophoresis, sonophoresis, electroporation, laser.
2. Chemical Enhancers: Alcohols, fatty acids, surfactants, terpenes, pyrrolidones.
3. Nanotechnology: Liposomes, transferosomes, ethosomes, nanoparticles, dendrimers, nanogels.
4. Smart TDDS: Stimuli-responsive systems (responding to pH, temperature, enzymes, or light), and smart patches linked with biosensors or IoT.

5. Newer Systems

1. Macroflux: Microneedle arrays for painless delivery of proteins and vaccines.
2. Metered-dose transdermal spray (MDTS): Sprayable drug film with adjustable dosing.
3. Biodegradable microneedles: Deliver drug then dissolve in the skin.

5. Market and Applications

1. FDA-approved patches include contraceptive (Ortho Evra), fentanyl, rivastigmine, rotigotine etc.
2. Market size is growing fast due to demand for painless, long-acting, and patient-friendly drug delivery.
3. New patches for Alzheimer’s, Parkinson’s, contraception, and chronic pain are already launched. [22]

Therapeutic Application: -

1. Microneedles
   • Tiny needle patches that painlessly pierce the skin barrier.
   • Used for vaccines (like influenza, polio, rotavirus).
   • Help deliver drugs that normally cannot pass through the skin (proteins, peptides).

2. Vesicular Nanocarriers (Liposomes, Ethosomes, Niosomes, Transfersomes)

• Deliver drugs for skin diseases like acne, psoriasis, fungal infections.
• Ethosomes (with ethanol) improve drug solubility and penetration.
• Useful in cancer therapy and chronic skin conditions.

3. Polymeric Nanocarriers

• Encapsulate poorly soluble drugs (like indomethacin, resveratrol).
• Reduce side effects and improve targeted delivery.
• Applied in anti-inflammatory treatment, skin disorders, and wound healing.

4. Lipid-based Nanocarriers (SLNs, NLCs, Liposomes)

• Provide controlled release and higher stability.
• Suitable for proteins and macromolecules.
• Used in long-term therapies, pain management, and dermatology.

5. Metallic Nanocarriers (Gold, Silver, Zinc Nanoparticles)

5. Have anti-cancer, antimicrobial, and anti-inflammatory applications.
5. Example: Zinc oxide nanoparticles with antibiotics used in skin cancer treatment.

6. Nanoemulsions

• Improve drug absorption and stability.
• Used in antifungal therapy, cancer, and hydrophobic drug delivery.
• Example: Miconazole nanoemulsion for candidiasis.

7. Nanofibers / Microfibers

• Provide localized and sustained drug release.
• Applied in wound healing, infections, and skin cancers (e.g., melanoma).

Challenges & Limitations Of Transdermal Drug Delivery Systems (TDDS)

1. Limited Drug Permeability

• The stratum corneum is a strong barrier.
• Only small, lipophilic drugs (<500 Da, low dose) can efficiently cross the skin.
• Many hydrophilic and large molecules cannot be delivered this way.

2. Skin Irritation & Allergic Reactions

• Long-term use of patches or adhesives may cause redness, itching, rashes, or dermatitis.
• Some patients develop hypersensitivity to enhancers or excipients.

3. Slow Onset of Action

• TDDS is unsuitable for emergencies (like heart attack or severe pain).
• It may take hours to reach therapeutic blood levels.

4. Variability in Drug Absorption

• Absorption differs due to skin thickness, hydration, age, ethnicity, temperature, and skin condition.
• Oily, dry, or diseased skin (eczema, psoriasis) alters permeability.

5. High Cost of Formulation

• Advanced TDDS (microneedles, nanocarriers, iontophoresis) need specialized technology.
• More expensive than oral dosage forms.

6. Limited Drug Dose Capacity

• Not suitable for drugs requiring >50 mg/day.
• Skin cannot absorb very high-dose medications.

7. Adhesion Issues

• Patches must stick well to ensure consistent drug release.
• Sweat, body movement, or oily skin can reduce adhesion.

8. Clinical & Regulatory Challenges

• Difficulties in proving bioequivalence with oral drugs.
• Requires extensive trials to test safety, irritation, and long-term stability.

FUTURE PERSPECTIVES OF TDDS: -

1. Overcoming Skin Permeability Challenges

The stratum corneum remains a major barrier. Future research is focused on advanced permeation strategies such as microneedles, nanoparticles, iontophoresis, electroporation, and sonophoresis to improve drug absorption and efficiency.

2. Nanotechnology Integration

Nanoparticles, liposomes, and nanoemulsions are being developed to provide targeted, sustained, and efficient drug release, improving therapeutic outcomes and reducing side effects.

3. Microneedle Patches

These are gaining attention for painless, self-administrable delivery of drugs such as insulin. They hold promise for chronic conditions, improving compliance, minimizing dosing errors, and offering localized therapy.

4. Personalized Medicine

Smart TDDS with biosensors can adjust drug release according to patient-specific needs (e.g., glucose-responsive insulin patches), aligning with the move toward individualized therapy.

5. Combination Therapies & Localized Relief

TDDS are being engineered for combination drug delivery and targeted pain relief (e.g., analgesic patches), offering sustained and site-specific treatment.

6. Improved Patient Comfort & Compliance

Future TDDS are designed to be more convenient, non-invasive, and self-administrable, reducing the need for frequent dosing and mitigating gastrointestinal or hepatic side effects.

7. Clinical Expansion

Beyond pain management and hormone therapy, future TDDS could be applied in neurology, oncology, cardiovascular disease, and vaccines, broadening their therapeutic scope.