A Review on the Role of Transdermal Drug Delivery: Microneedles, Patches, and Nanogels

Transdermal drug delivery provides a non-invasive route for systemic and local therapy while avoiding first-pass metabolism, improving patient compliance, and enabling controlled release. Historically, transdermal delivery succeeded for a narrow set of molecules (e.g., nicotine, fentanyl, estradiol) due to the formidable barrier posed by the stratum corneum (SC). In recent decades, engineering approaches — from chemical permeation enhancers to mechanical and micromechanical methods — have expanded the scope of TDD. Among emerging technologies, microneedles (MNs) and nanogels represent two complementary strategies: MNs temporarily breach the SC to create transport pathways, whereas nanogels can encapsulate a wide variety of payloads and facilitate penetration, controlled release, and targeting. This review focuses on the state-of-the-art in transdermal patches, microneedles, and nanogels, highlighting design principles, comparative advantages, manufacturing and regulatory issues, and clinical translation. [1,2]

Skin structure and barrier properties relevant to TDD

The skin consists of three main layers: epidermis (including the SC), dermis, and hypodermis. The SC — composed of corneocytes embedded in a lipid matrix — is the principal barrier to permeation. Molecular size (rule of thumb: <500 Da), lipophilicity (logP), and polarity influence passive diffusion across SC. For macromolecules, proteins, and hydrophilic drugs, passive permeation is poor; thus, physical strategies (microneedles, iontophoresis, sonophoresis) and carrier-assisted methods (liposomes, nanoparticles, nanogels) are required. Skin appendages (hair follicles, sweat glands) provide auxiliary pathways but account for a small fraction of surface area. [3]

Conventional transdermal patches [4]

Patch components and design [2,3]

Typical patch architecture includes: backing layer, drug reservoir or matrix, rate-controlling membrane (in reservoir-type patches), adhesive, and protective liner. Based on design, patches are classified as matrix-type, reservoir-type, or drug-in-adhesive. Key excipients include pressure-sensitive adhesives, polymers (e.g., acrylics, silicones), plasticizers, and permeation enhancers.

Permeation enhancement strategies

Chemical enhancers (ethanol, DMSO, terpenes, oleic acid) transiently disrupt lipid structures; formulation tactics such as supersaturation and microemulsions increase thermodynamic activity; and physical enhancement (microdermabrasion, tape stripping) are sometimes combined. Patch geometry, drug loading, and occlusion influence flux.

Clinical examples and marketed products

Successful products include nicotine patches, fentanyl patches, transdermal hormone replacement therapies (estradiol, testosterone), clonidine, and scopolamine. Many of these were formulated as matrix or reservoir systems with well-characterized release profiles.

Strengths and limitations

Patches offer convenience, steady-state dosing, and improved adherence. Limitations include restricted candidate drugs (typically low molecular weight and lipophilic), skin irritation/allergy to adhesives, variable absorption due to skin site, and challenges delivering macromolecules.

Structure of a Patch

• Backing layer

• Drug reservoir/matrix

• Rate-controlling membrane (optional)

• Adhesive layer

• Release liner (removed during application)

MECHANISM OF ACTION

Patch applied → Drug dissolves in skin → Penetrates stratum corneum → Diffuses through epidermis → Enters dermal microcirculation → Systemic absorption.

Advantages

• Steady drug release

• Avoids first-pass metabolism

• Improved patient compliance

• Long-acting (up to 7 days)

Disadvantages

• Only suitable for potent drugs

• Skin irritation

• Slow onset of action

Microneedles (MNs) [5,6]

Types and working principles

Microneedles are arrays of micron-scale projections (typically 50–900 µm in length) that painlessly penetrate the SC to create transient microchannels. Major types:

•  Solid MNs: used for ‘‘poke-and-patch’’ approach — create microchannels then apply a drug formulation.

•            Coated MNs: drug coated onto needle surfaces, dissolves upon insertion for bolus delivery.

• Dissolving MNs: composed of water-soluble/biodegradable polymers that encapsulate drug and dissolve in skin, leaving no sharp waste.

•   Hollow MNs: function like microinjections, allowing fluid flow through needles for controlled infusion.

• Hydrogel-forming MNs: swell upon insertion to form conduits from patch reservoir into epidermis/dermis.

Materials and fabrication [7]

Materials include silicon, metals (stainless steel, titanium), ceramics, and polymers (e.g., PVA, PVP, CMC, PLGA). Fabrication methods: micro-molding (popular for polymer MNs), photolithography and etching (silicon), laser cutting, 3D printing (additive manufacturing). Material choice balances mechanical strength, biocompatibility, and manufacturability.

Drug loading and release mechanisms

Coated and dissolving MNs directly deposit drugs into the viable epidermis for rapid release. Dissolving MNs can provide controlled release kinetics via polymer selection and crosslinking. Hydrogel-forming MNs combined with patch reservoirs enable sustained delivery; hollow MNs facilitate infusion of larger volumes or viscous formulations.

Applications: vaccines, biologics, small molecules, cosmetics

MNs have been investigated for vaccine delivery (e.g., influenza, COVID-19 antigens), insulin and other peptides/proteins, local anesthetics, analgesics, and cosmetic actives. MNs enhance immunogenicity due to skin immune cell richness and reduce need for cold chain in some vaccine formats.

Safety, pain, and skin healing [26]

Numerous studies report minimal pain and rapid recovery of barrier function. Infection risk is low when aseptic manufacturing and appropriate dressings are used; dissolving MNs remove sharps waste concerns. Skin irritation and transient erythema are common but usually mild.

Scale-up and manufacturing considerations

Polymeric micromolding offers scalability; however, batch uniformity, drug loading consistency, sterility assurance, and mechanical robustness are manufacturing challenges. Regulatory expectations include validation of dose delivered, residuals, and sterility.

Clinical status and case studies [8,9]

Several MN products have progressed to clinical trials and a few to market (primarily cosmetic or small-volume products). Regulatory approvals are evolving; design controls, biocompatibility, and clinical endpoints are critical for approval.

Mechanism of Action.

Micropuncture → Disrupt stratum corneum barrier → Create aqueous microchannels → Drug enters epidermis/dermis → Diffuses into blood vessels → Systemic circulation.

Advantages

• Painless and minimally invasive

• Self-administrable

• Suitable for vaccines, peptides, insulin

• Improved drug bioavailability

Limitations

• Limited dose capacity

• Possible skin irritation

• Fabrication complexity

Nanogels for transdermal delivery [10,11,12]

Definition and design principles

Nanogels are crosslinked polymeric networks in the nanoscale range (typically 20–200 nm) capable of swelling and encapsulating hydrophilic and hydrophobic drugs. Their high-water content and soft nature make them attractive for dermal and transdermal applications.

 Characteristics

• Size: 20–200 nm

• Composed of cross-linked polymer networks

• High water content

• Capable of loading hydrophilic and hydrophobic drugs

Mechanism of Action [14]

Nanogel applied → Hydrates stratum corneum → Enhances skin permeation → Controlled drug release → Penetrates into deeper skin layers → Enters systemic circulation or acts locally.

Advantages

• Excellent biocompatibility

• High drug loading

• Controlled/targeted delivery

• Enhanced penetration through hydrated skin

Limitations

• Long-term stability issues

• Complex manufacturing

• Limited regulatory approval

Stimuli-responsive nanogels

Nanogels can be designed to respond to pH, temperature, redox potential, enzymes, or external triggers (light, magnetic field). For skin applications, thermoresponsive and pH-responsive behaviors have been exploited for on-demand release.

Synthesis and characterization

Synthesis routes include emulsion polymerization, inverse microemulsion, free radical crosslinking, and click-chemistry approaches. Characterization typically assesses size (DLS, TEM), swelling ratio, drug loading and encapsulation efficiency, release kinetics, and rheology for gel-like behavior.

Skin penetration mechanisms and enhancement [15,16]

Nanogels enhance penetration via several mechanisms: (1) interacting with skin lipids to disrupt SC; (2) follicular accumulation and gradual release; (3) acting as reservoirs that maintain high thermodynamic activity at the skin surface; (4) being combined with permeation enhancers or physical methods (microneedles, iontophoresis) to reach viable layers.

Therapeutic applications and preclinical/clinical evidence [24,25]

Nanogels have been investigated for analgesics, anti-inflammatory drugs, anticancer agents for topical cancer therapy, antimicrobials, and vaccines (as adjuvant/antigen carriers). Preclinical studies show enhanced skin retention and therapeutic outcomes; clinical translation is still emerging with a few formulations entering human studies.

Stability, toxicity, and regulatory considerations

Nanogels may suffer from aggregation, premature release, or stability issues under storage. Safety depends on polymer chemistry and residual monomers or crosslinkers. Regulatory assessment requires thorough characterization, safety testing (dermal toxicity, sensitization), and clear understanding of degradation products.

Hybrid systems: Combining microneedles, patches, and nanogels

Nanogel-loaded microneedles [17,18,19]

Embedding nanogels within dissolving microneedles or coating MNs with nanogel layers allows localized deposition of nanoparticulate reservoirs in the epidermis/dermis, improving sustained release and protection of labile molecules.

Patch-nanogel composites and reservoir systems

Patches containing a nanogel reservoir coupled with a rate-controlling membrane or hydrogel- forming MN arrays enable controlled, long-duration release. Such systems aim to combine the convenience of patches with enhanced payload range.

Smart/sensing patches with responsive release

Integration of sensors (e.g., glucose sensors) with responsive nanogel reservoirs can create closed-loop systems where detected biomarkers trigger drug release — a promising direction for chronic disease management.

Comparative analysis and selection criteria

Selection between patches, MNs, and nanogels depends on drug properties (molecular weight, stability), desired release profile (bolus vs sustained), patient factors, manufacturing feasibility, and regulatory pathway. Table-like comparison (qualitative):

• Patches: best for small, lipophilic drugs; established regulatory pathways; easy to use.

• Microneedles: enable macromolecule delivery, vaccines; moderate complexity; potential for rapid clinical adoption.

• Nanogels: versatile carriers for diverse payloads; enable stimuli-responsive release; need combination with enhancers or MNs for deep delivery.

Regulatory landscape and quality considerations [20,21,]

Regulatory evaluation depends on product classification: drug/device combination, biologic- device, or medical device. Key CMC considerations include: polymer/excipient safety, leachables, batch-to-batch consistency, sterility/bioburden control, dose uniformity, and stability. For combination products, coordinated review between drug and device centers may be required. Guidance documents from FDA/EMA continue to evolve for microneedles and novel nanocarriers.

Key challenges and future perspectives

Challenges include: scalability and cost-effective manufacturing, ensuring long-term stability of labile biologics, robust and reproducible dosing (especially for MNs and nanogel-loaded devices), regulatory clarity, and user acceptance. Future directions:

•  Long-acting polymeric MNs for sustained systemic therapy.

• Theranostic patches integrating sensing and closed-loop release.

• Personalized patches/MNs via 3D printing for patient-specific dosing.

•  Green manufacturing and biodegradable materials to reduce environmental impact.

• Clinical translation of nanogel systems with focus