Imidazole Antifungals Against Fungal Pathogens: Resistance Mechanisms and Emerging Delivery Strategies

Abstract

Fungal infections remain a major and growing global health concern, particularly in immunocompromised populations and in settings where antifungal resistance is increasing. Imidazole antifungals continue to play an important role in the treatment of superficial and mucocutaneous mycoses because they inhibit lanosterol 14α-demethylase (CYP51), a key enzyme in ergosterol biosynthesis. This mechanism disrupts fungal membrane integrity and underlies their clinical utility. However, the effectiveness of imidazoles is increasingly limited by resistance mechanisms such as CYP51 mutations, efflux pump overexpression, and biofilm-associated tolerance. In parallel, several biopharmaceutical constraints, including poor aqueous solubility, limited tissue penetration, short residence time, and variable local drug exposure, further reduce therapeutic performance. This review critically examines the medicinal chemistry, mechanism of action, and resistance biology of imidazole antifungals, while also highlighting the role of pharmacokinetic and pharmacodynamic limitations in treatment failure. Particular attention is given to emerging drug delivery approaches, including lipid-based systems, vesicular carriers, nanocarriers, and other advanced topical formulations, which are being developed to improve solubility, enhance tissue retention, and sustain antifungal exposure at the site of infection. By integrating resistance mechanisms with formulation science, the review provides a translational perspective on how imidazole antifungals may be optimized for improved clinical utility and resistance management.

1. Introduction

The burden of fungal infections globally continues to be underestimated, despite many countries having a high rate of infection with over 600 million fungal infections in 100 countries each year, through skin (superficial mycoses) and invasive fungal infections, with a poor prognosis for the immunocompromised and critically ill patients. The increasing rates of antifungal use have increased the incidence of antifungal resistance through empirical use in the healthcare system and also through fungicides utilized by the agriculture industry. As a result, there continues to be an increase in the number of reports of treatment failures due to drug resistance, particularly for the azole fungicides [1].

The azole antifungals are the mainstay of antifungal therapy because of their mode of action. They inhibit the synthesis of ergosterol by inhibiting lanosterol 14α-demethylase, the critical enzyme in ergosterol synthesis. Within the azole class of antifungals, the class of imidazoles has played an important role in the treatment of topical or mucosal infections [2]. Examples of imidazoles include clotrimazole, ketoconazole, and luliconazole, which are widely used for treating dermatophytosis, cutaneous candidiasis, and vulvovaginal infections, respectively. These imidazoles possess a broad spectrum of activity, are inexpensive, and are well tolerated locally; therefore, their use is supported globally.

Despite their widespread clinical use, the therapeutic performance of imidazole antifungals is frequently constrained by significant formulation and delivery-related limitations. Most imidazole compounds exhibit poor aqueous solubility and high lipophilicity, which complicate formulation design and restrict effective drug availability at the site of infection. Conventional topical formulations, such as creams, lotions, and solutions, often provide only short-lived drug exposure due to rapid clearance from the skin or mucosal surfaces [3]. In addition, penetration through biological barriers, including the stratum corneum and nail plate, remains inconsistent and is further reduced in hyperkeratotic or biofilm-associated infections. These factors result in heterogeneous drug distribution and subtherapeutic concentrations in deeper tissue layers. Clinically, such exposure gaps can compromise efficacy and enable the persistence of tolerant fungal populations. Biofilm-associated microenvironments further limit drug diffusion and promote adaptive resistance [4]. Together, these limitations highlight that treatment failure is not solely a function of antifungal potency, but also of inadequate drug delivery, underscoring the need for advanced formulation strategies to improve local exposure and therapeutic outcomes.

These limitations are largely driven by underlying biopharmaceutical constraints rather than insufficient intrinsic antifungal activity. The majority of imidazole-based molecules feature low solubility in water, high lipophilicity, and variable permeability through keratinous or mucosal barriers [3]. Conventional topical formulations such as creams, lotions, and solutions may provide only a short period of contact with the site of infection, resulting in rapid clearance, poor penetration into tissues, and inconsistent distribution within infected tissues. As a result, local concentrations may be less than optimal, especially for infections associated with biofilms or hyperkeratosis.

Pharmacokinetic inconsistencies may occur due to exposure to drug gradients in tissues that have low penetration and structured biofilms. Therefore, the ability of partially tolerant fungal populations to survive drug exposure could result from either the coexistence of differing populations of fungi or resistance mechanisms (such as CYP51 changes, increased expression of efflux pumps, or biofilm-mediated resistance) [4]. Thus, resistance should be considered not only as a molecular issue but also as the result of the inability to effectively deliver antifungal agents to the infected tissue. Consequently, improving the local exposure profile of antifungal agents is a means of complementing molecular drug design (i.e., redesigning antifungal agents) [5].

New advances in both formulation science and nanotechnology can help address many of these challenges, including lipid-based nanoparticles, nanoemulsions, vesicular and polymeric carriers, solid lipid nanoparticles, and others, which have been studied as a means to increase solubility, improve dermal penetration, provide extended residence times, and deliver drugs in a controlled or targeted manner [3,4]. The use of these types of drug delivery platforms might offer a way to enhance therapeutic efficacy by improving drug distribution within the site of infection, while minimizing the extent of systemic exposure and toxicity of the drug. There is still a significant amount of experimental research being conducted to better understand and optimize the clinical translation of bench-scale formulations into actual, clinically relevant products [6,7].

Although previous reviews have reported on the pharmacology of imidazole antifungal drugs and the application of various individual nanocarriers, a complete literature analysis that examines the correlation between the molecular characteristics, biopharmaceutical barrier issues, development of resistance, and rational formulation design is not available [8,9]. In order to establish whether advanced drug delivery systems will be able to successfully extend the therapeutic use of this long-standing class of antifungal drugs, a critical, translational-oriented study is warranted (Figure 1).

The current review evaluates the antifungal imidazole class through the lens of drug delivery. This review is therefore a synthesis of the relevant information related to the medicinal chemistry of imidazoles, the biology of resistance, and the formulation strategies of nanotechnology in order to determine the potential impact of targeted modulation of biopharmaceutical barriers on resistance trajectories and ultimately improve clinical outcomes. As such, this new perspective of consideration may assist in repositioning imidazoles as flexible platforms for contemporary antifungal therapy, rather than legacy agents.

2. Methodology

To conduct this systematic review on imidazole antifungal agents, the authors followed a systematic literature search method and listed all peer-reviewed studies relating to the chemical, pharmacological, resistance mechanisms, pharmacokinetic profiles, and pharmacodynamics of imidazole antifungal agents. The literature search was primarily restricted to studies published between 2000 and 2025 to identify MeSH headings, keyword variations, and terminology related to imidazole antifungals, antifungal resistance, and nanotechnology-based formulations. A complete list of keyword and search term combinations was compiled, including; azole antifungals, azole resistance, azole antifungal agents (e.g., clotrimazole, miconazole, econazole, ketoconazole), mechanism of action (e.g., inhibition of ergosterol biosynthesis), target enzymes, structure-activity relationship (SAR) for azoles, pharmacokinetic properties of azoles, pharmacodynamic properties of azoles, CYP51 mutations, drug efflux pump overexpression, biofilm-mediated antifungal resistance, cross-resistance between different azoles, antifungal delivery by nanocarriers, solid lipid nanoparticles, nano-structured lipid carriers, liposomal antifungals, nano-emulsions, transdermal and transungual delivery, and antifungal stewardship [5,6,7,8]. Earlier studies were included selectively when they provided foundational insights into imidazole pharmacology, mechanism of action, or clinical use. This approach ensured a balanced representation of both historical context and recent developments. Databases included PubMed, Scopus, Web of Science, and Embase. In addition to database searches, the authors screened reference lists of all included articles to identify any potentially relevant studies not captured by their original search.

3. Chemistry of Imidazoles

An imidazole is a five-membered planar ring heterocyclic aromatic compound containing 2 non-adjacent nitrogen atoms (at the 1 and 3 positions). This arrangement confers electron delocalization and aromatic stability, as well as hydrogen bonding abilities due to the presence of an imidazole scaffold that has considerable versatility in medicinal chemistry [10,11,12]. The planarity and electronic density of the ring provide a basis for coordinate bonding between the heme iron of cytochrome P450 enzymes from fungi (particularly CYP51—lanosterol 14α-demethylase) and imidazole compounds such that ergosterol biosynthesis is inhibited [13].

In addition to target binding, the fundamental physicochemical properties of the imidazole nucleus (moderate basicity, lipophilicity, and ability to adapt substitution patterns) significantly affect solubility, membrane interactions, and distribution of imidazole derivatives in biological systems. Functionalizing different positions around an imidazole ring will enable side chains to be added that alter lipophilicity, binding selectivity, and metabolic stability of imidazole derivatives [12]. These imidazole nucleus properties are critical in determining antifungal potency, biopharmaceutical action (dermal permeation, keratin retention), and pharmacodynamic properties of antifungal agents. Therefore, the chemical structure of imidazoles is the basis for pharmacological activity as well as rational formulation design [14].

3.1. Structure-Activity Relationship (SAR)

The actions of imidazole antifungal agents against fungi depend on a variety of factors, including the properties of their substituents (their nature, size, and polarity) and the presence of electron-withdrawing or electron-donating groups on the imidazole nitrogen atom (the nitrogen atom also plays an important role in coordination with CYP51 heme iron). If changes to any one of these properties reduce their ability to coordinate to CYP51 heme such that ergosterol synthesis can be inhibited, then the resulting imidazole will lose its antifungal activity [13].

Imidazole antifungals that contain hydrophobic aryl or halogen-containing aryl side chains exhibit greater membrane permeability and increased hydrophobic interactions with the active site of the enzyme, resulting in enhanced antifungal activity [15,16]. Additionally, the presence of these groups can influence the binding of the imidazoles to the enzyme by increasing or decreasing their binding affinity and selectivity for the fungal CYP51 versus mammalian cytochrome P450 isoforms.

In addition to the presence of substituents and the size of the side chain, the length of the linker connecting the imidazole core to the aromatic substituents is important for determining how well-positioned the compound will be in the active site of the enzyme and how stable the hydrophobic and hydrogen bonding interactions will be during the dosing regimen. Additionally, how the substituents on an imidazole derivative are distributed in space may also affect the metabolic stability of the compound and its susceptibility to resistance. Structural variation of the fungal CYP51 enzyme may also modify drug-enzyme binding interactions, thus influencing how the imidazole derivative will behave metabolically. Taken together, the above-described structure-activity relationships (SAR) provide the foundation on which to rationally design new imidazole derivatives with improved antifungal activity, expanded antifungal activity, and an improved safety profile [17,18].

3.2. Expanded SAR: Functional Groups, Trade-Offs, and Design Strategies

The antifungal activity of imidazole derivatives is strongly influenced by the nature of their substituent groups, which govern both target binding and biopharmaceutical behavior. Halogenated aryl groups (e.g., dichloro- or fluorophenyl moieties) are frequently incorporated to enhance lipophilicity and strengthen hydrophobic interactions within the CYP51 active site. These groups improve binding affinity and antifungal potency but often reduce aqueous solubility and increase nonspecific tissue retention. Excessive lipophilicity may also promote off-target interactions with mammalian cytochrome P450 enzymes, contributing to safety concerns [13].

Alkyl and aryl side chains play a critical role in modulating membrane permeability and drug distribution. Increased hydrophobic character generally enhances penetration into lipid-rich fungal membranes and keratinized tissues; however, this benefit is counterbalanced by reduced formulation flexibility and variable diffusion across biological barriers. Similarly, heteroaromatic substitutions and electron-withdrawing groups can improve metabolic stability and binding selectivity, but may also alter ionization properties and limit drug release from topical formulations.

The linker region connecting the imidazole core to aromatic substituents is another key determinant of activity. Optimal linker length and flexibility enable proper orientation of the imidazole ring for coordination with the heme iron of CYP51. However, overly rigid or excessively long linkers may reduce binding efficiency or increase metabolic liability [15,16].

Importantly, many of these limitations can be addressed through rational chemical modification without compromising antifungal activity. Strategies such as bioisosteric replacement (e.g., substituting highly lipophilic phenyl rings with heteroaromatic analogues), incorporation of polar functional groups to balance lipophilicity, and optimization of linker flexibility can improve solubility, selectivity, and pharmacokinetic performance. In addition, prodrug approaches and ionizable group modifications may enhance formulation compatibility and local drug delivery. These considerations highlight that effective imidazole design requires balancing target affinity with biopharmaceutical properties to achieve optimal clinical performance [17,18,19]. The structure of various imidazole derivatives is shown in Figure 2.

3.3. Modifications for Enhanced Antifungal Activity

Optimizing imidazole structure to increase the selectivity, membrane interactions, and stability of metabolism of their derivatives has been under research. Increased lipophilicity and greater binding affinity to the fungal enzyme lanosterol 14α-demethylase [19,20] via adding halogenated phenyl types of fluorinated or chlorinated aryl rings is a satisfactory attempt. Additions of alkyl or aryl groups on the side chains improve the pharmacokinetics of the compound, while enabling more appropriate spatial fit to the active site of the enzyme, and are also excellent areas of development. Modifying the linker region between the imidazole nucleus and the aryl substituents provides flexibility in the conformation and orientation of the compound, which may increase the inhibition of the enzyme while still having an optimal selectivity [21,22]. In addition, substituent effects involve electron modification that will affect the interaction with the target as well as the ability to withstand metabolism. Bulky hydrophobic or heteroaromatic substituents have been added to some more advanced analogs that have broadened the anti-fungal activity and may have eliminated the resistance-related changes to the CYP51 enzyme’s structure.

Although the structural modifications have produced potent and therapeutically useful imidazole antifungal agents, they have also increased the compounds’ hydrophobicity and therefore reduced their inherent solubility [23]. Consequently, factors associated with drug delivery are becoming more important than determining the molecular activity of the imidazole at the site of infection and current imidazole drug research emphasizes that imidazoles not only be evaluated on the basis of their intrinsic potency but also by their ability to reach the body tissues, become retained in the local area and inhibit development of resistance to therapy via formulations used to deliver imidazoles [24].

4. Mechanism of Action

4.1. Target Engagement and Inhibition of Lanosterol 14α-Demethylase (CYP51)

Imidazole antifungal agents exert their primary pharmacological effect through the inhibition of lanosterol 14α-demethylase (CYP51), a heme-dependent cytochrome P450 enzyme that catalyzes a key oxidative step in ergosterol biosynthesis. Ergosterol is an essential structural component of fungal cell membranes, governing membrane fluidity, permeability, and the functional integrity of membrane-associated proteins. At the molecular level, the imidazole moiety coordinates directly with the heme iron within the CYP51 active site, forming a stable drug–enzyme complex that interrupts the catalytic demethylation of lanosterol. This coordination blocks the conversion of lanosterol into ergosterol and effectively halts sterol biosynthesis [25]. The efficiency of this interaction is strongly influenced by structural determinants such as lipophilicity, substituent orientation, and the ability of the imidazole ring to achieve optimal positioning within the enzyme active site, as discussed in SAR analyses.

4.2. Disruption of Ergosterol Biosynthesis in Fungal Cell Membranes

Inhibition of CYP51 produces a dual biochemical consequence characterized by depletion of ergosterol and accumulation of aberrant 14α-methylated sterol intermediates. The loss of ergosterol compromises membrane rigidity and organization, while the accumulation of these non-functional sterols disrupts lipid packing and alters the physicochemical properties of the membrane [22,26]. These intermediates fail to support the structural and dynamic requirements of fungal membranes, resulting in impaired membrane permeability and dysfunction of embedded proteins, including transporters and enzymes [24,27]. The resulting sterol imbalance destabilizes essential cellular processes such as nutrient uptake, ion homeostasis, and signal transduction. Importantly, the magnitude of membrane disruption is dependent on both the degree of CYP51 inhibition and the local concentration of the antifungal agent, linking molecular activity directly to pharmacokinetic exposure. Figure 3 shows the inhibition of ergosterol biosynthesis and the consequent downstream destabilization of membranes by imidazole antifungal agents.

4.3. Cellular Consequences: From Growth Arrest to Cell Death

The progressive disruption of membrane structure translates into a cascade of cellular dysfunctions that ultimately determine the antifungal outcome. Increased membrane permeability leads to leakage of intracellular components and dissipation of electrochemical gradients, thereby impairing energy metabolism and biosynthetic pathways. Concurrently, dysfunction of membrane-bound enzymes further compromises cellular viability. At suboptimal concentrations, these effects predominantly result in growth inhibition, reflecting a fungistatic mode of action. However, sustained or higher local drug concentrations can induce irreversible membrane damage and metabolic collapse, resulting in fungicidal activity [26]. This concentration-dependent behavior underscores the importance of maintaining adequate drug levels at the site of infection to achieve complete fungal eradication.

4.4. Selectivity and Off-Target Interactions

The selectivity of imidazole antifungals arises from differences between fungal ergosterol biosynthesis and mammalian cholesterol synthesis pathways, particularly in the structure and binding characteristics of CYP51. Imidazoles generally exhibit higher affinity for fungal CYP51, enabling preferential inhibition of ergosterol production. However, this selectivity is incomplete, as imidazoles can also interact with mammalian cytochrome P450 isoenzymes at higher concentrations. This off-target inhibition contributes to adverse effects such as endocrine disruption and drug–drug interactions, especially with systemic agents like ketoconazole [27,28]. These limitations highlight the importance of localized delivery strategies to maximize antifungal selectivity while minimizing systemic exposure.

4.5. Pharmacodynamic Modulation and Microenvironmental Constraints

The effectiveness of CYP51 inhibition is highly dependent on achieving and maintaining sufficient drug concentrations at the site of infection. In clinical settings, pharmacodynamic outcomes are strongly influenced by tissue penetration, retention, and local microenvironmental conditions. Infections involving hyperkeratotic tissue, nail plates, or biofilms often exhibit heterogeneous drug distribution, leading to spatial variations in antifungal exposure. These gradients result in partial inhibition of ergosterol biosynthesis in certain regions, allowing subpopulations of fungi to persist and adapt. Consequently, the same molecular mechanism may produce different outcomes-fungistatic or fungicidal, depending on local pharmacokinetic conditions. This variability highlights the importance of integrating drug delivery considerations into mechanistic understanding [28].

4.6. Secondary Cellular Responses and Adaptive Pathways

Beyond direct membrane disruption, inhibition of ergosterol biosynthesis triggers a range of secondary cellular responses that influence fungal survival. Alterations in membrane composition can impair vesicular trafficking, protein localization, and cell division, while mitochondrial dysfunction may lead to increased oxidative stress. In response, fungal cells may activate compensatory pathways, including stress response signaling and alternative sterol acquisition mechanisms. Although these adaptations may provide transient protection under subtherapeutic drug exposure, they also facilitate the emergence of tolerant or resistant phenotypes over time. This dynamic interplay between drug action and cellular adaptation further reinforces the need for sustained and adequate antifungal exposure [29,30].

4.7. Integrated Mechanistic Perspective

Taken together, the mechanism of action of imidazole antifungals represents a multi-layered process that extends beyond simple enzyme inhibition. While the primary event is the coordination-based inhibition of CYP51 and subsequent disruption of ergosterol biosynthesis, the ultimate antifungal outcome is determined by a complex interplay of factors, including sterol imbalance, membrane destabilization, pharmacokinetic exposure, and adaptive resistance mechanisms [31]. This integrated perspective highlights that effective antifungal therapy requires not only potent molecular inhibition but also optimized drug delivery to ensure consistent and therapeutically relevant exposure at the site of infection. Such an approach is essential to overcome intrinsic biological barriers and emerging resistance, thereby improving clinical efficacy [23].

5. Clinical and Formulation Landscape of Imidazole Antifungals

5.1. Topical Imidazoles

Topical imidazoles are the most commonly used antifungal medications for treating superficial and mucocutaneous fungal infections. They are broad-spectrum antifungals that have low absorption into the body and a good safety profile. Although they have a common mechanism of action, their clinical effectiveness varies according to their physicochemical properties (i.e., lipophilicity, keratin-binding affinity, and tissue retention).

Clotrimazole and miconazole, two first-generation topical imidazoles, remain among the most commonly used antifungals for dermatophytosis and candidiasis. These medications are well-tolerated and have been found to be effective. Newer topical imidazoles (e.g., sertaconazole, tioconazole) are more lipophilic and have greater tissue retention; thus, they can be dosed less frequently and improve patient compliance [30,31]. The additional imidazoles (e.g., econazole, oxiconazole, bifonazole, fenticonazole, isoconazole, sulconazole, Butoconazole, omoconazole) further extend the clinical utility of topical imidazoles to treat infections caused by dermatophytes, Candida, and Malassezia [10,32].

Despite the structural and therapeutic differences between the various topical imidazoles, they are mostly applied as conventional cream, lotion, powder (vaginal), or solution. Also, many of the formulations used to deliver topical imidazoles have limited penetration through hyperkeratotic skin or nail plates, short residence time (i.e., duration of effectiveness) on mucosal surfaces, and variable release kinetics (i.e., time of release from product). Therefore, the successful treatment of fungal infections with topical imidazoles largely depends upon the frequency with which the drug is applied and the degree of patient compliance rather than the relative antifungal potency of the product [33].

Recent advances in formulation strategies have focused on improving the delivery efficiency of topical imidazole antifungals by addressing limitations such as poor penetration and limited retention (Table 2). Lipid-based systems, including liposomes, ethosomes, solid lipid nanoparticles, and nanoemulsions, are among the most translationally advanced platforms due to their biocompatibility and relative ease of scale-up, with ethosomes showing enhanced permeation across the stratum corneum and nanoemulsions improving drug solubility and dispersion. In contrast, vesicular carriers such as niosomes and transfersomes enable deeper skin penetration through increased deformability but are often limited by stability and manufacturing challenges. Polymeric systems, including nanogels and bioadhesive platforms, provide controlled release and prolonged residence time; however, their complexity and regulatory considerations have largely restricted their development to preclinical stages [34,35,36,37,38]. Film-forming systems improve local retention by creating a drug reservoir at the application site, whereas hybrid approaches such as microneedle-assisted delivery and nanoparticle-loaded hydrogels show promise for enhancing delivery in difficult-to-treat conditions such as onychomycosis, although they remain largely experimental [19,25]. Overall, while these platforms demonstrate clear improvements in local bioavailability, only a limited number show strong clinical translation potential, highlighting a gap between formulation innovation and real-world therapeutic application. The clinical uses and formulation characteristics of the various imidazole derivatives are summarized in

Table 1. Summary of clinical usage, therapeutic applications, and formulation strategies of Topical imidazole derivatives for the treatment of superficial fungal skin infections, with emphasis on their antifungal spectrum, dosing regimens, and clinical advantages.

Imidazole Derivative	Fungal Spectrum	Clinical Usage	Formulation & Dosing	Clinical Advantages	Reference
Clotrimazole	Dermatophytes, Candida, Malassezia	Tinea, cutaneous & mucosal candidiasis	Cream, lotion, powder; twice a day for 4 weeks	Widely available OTC, well tolerated	[32,33]
Econazole	Broader: dermatophytes, Candida, Malassezia, some Aspergillus	Tinea corporis/pedis, pityriasis versicolor, early onychomycosis	1% cream or solution; once daily	Effective against difficult-to-treat pathogens; high tissue penetration	[34,35]
Miconazole	Similar spectrum + mild antibacterial activity	Intertrigo, seborrheic dermatitis, mucocutaneous candidiasis	Cream, powder, gel; twice a day for 2–4 weeks	Useful in mixed infections, good mucosal efficacy	[35,36]
Luliconazole	Broad-spectrum against dermatophytes (e.g., T. rubrum) and yeasts; fungicidal and skin-retentive	Tinea pedis, corporis, cruris; short-course protocols	1% cream, once daily for 1–2 weeks	Rapid cure, high skin retention, comparable or superior to terbinafine	[39,40,41,42,43,44,45]
Sertaconazole	Antifungal + anti-inflammatory/antipruritic action	Inflammatory tinea (corporis/cruris)	2% cream, usually twice a day for 4 weeks	Faster symptom relief than clotrimazole, effective in erythematous lesions	[46,47]
Tioconazole	Lipophilic; prolonged tissue retention	Vaginal candidiasis and superficial keratinized dermatophytosis	Single-dose ovule or nail lacquer	Once-daily dosing, excellent patient adherence	[48]
Bifonazole	Fungicidal, broad action (dermatophytes, Candida, Malassezia)	Tinea infections, pityriasis versicolor	Cream, gel, powder; once daily	Long retention allows short treatment duration and high compliance	[49]
Oxiconazole	Dermatophytes and yeasts	Tinea pedis/corporis/cruris	Cream or lotion; once daily for ~4 weeks	High cure rates (>80%), minimal local irritation	[50]
Sulconazole	Broad yeast and dermatophytes activity	Tinea corporis/cruris/pedis	Cream or solution; once daily	Comparable clinical response, good tolerability	[51,52]
Fenticonazole	Antifungal + mild antibacterial & antitrichomonal action	Cutaneous and vaginal candidiasis	Cream, ovules, powder	Cream, ovules, powder	[53,54]
Isoconazole	Antifungal + antibacterial (e.g., Corynebacterium)	Tinea, candidiasis, erythrasma	Cream, solution, vaginal suppository	Useful in mixed infections due to dual activity	[47,55]
Efinaconazole	Potent against dermatophytes; superior nail penetration	Primarily for onychomycosis; off-label cutaneous dermatophytes	10% topical solution; once daily for~48 weeks (nails)	Greater nail penetration and efficacy vs. ciclopirox; minimal skin irritation	[56,57]

.

5.2. Systemic Imidazoles

Ketoconazole is a systemic imidazole antifungal available for oral administration; however, its clinical use has become limited due to safety concerns, particularly hepatotoxicity and drug–drug interactions arising from inhibition of cytochrome P450 enzymes. Other oral antifungal agents, including triazoles such as fluconazole and itraconazole, as well as the allylamine terbinafine, are more widely used in current clinical practice due to their improved safety profiles and broader therapeutic applicability [44].

In contrast, other imidazoles such as clotrimazole and miconazole exhibit low oral bioavailability and minimal systemic exposure, and are therefore primarily used for topical or mucosal applications [10,58]. Triazoles, including fluconazole and itraconazole, demonstrate improved selectivity toward fungal CYP51 and more favorable pharmacokinetic properties compared to imidazoles, which have established them as the leading agents for systemic antifungal therapy.

The decline in the clinical use of systemic imidazoles highlights an important therapeutic principle: molecular potency alone is insufficient to ensure clinical success in the presence of suboptimal pharmacokinetics or safety limitations. The development trajectory of these agents underscores the need for an integrated approach that combines rational chemical design with optimized pharmacokinetic and drug delivery strategies [59].

5.3. Emerging Formulation Trends of Imidazole Derivatives

Due to the limitations of typical topical products in treating biopharmaceuticals, there have been many recent advances in the formulation of imidazole antifungal drugs. Most topical creams and ointments are quickly removed from the body, do not penetrate well into the deeper layers of skin or nails, and have variable drug release properties.

New advanced delivery systems have been studied for imidazole antifungals such as lipid-based systems (liposomes, ethosomes), solid lipid nanoparticles (SLNs), nanoemulsions (NEs), and polymeric nanogels (PNGs). The benefits of these advanced systems compared to conventional formulations include improved solubility, better dermal absorption, and longer retention at the site of infection [60,61]. Many of these products will provide prolonged therapeutic concentrations within the infected tissue, which will lead to a reduction in the frequency of dosing and lower the risk of resistance development associated with use of subtherapeutic treatment.

Recent studies have used several imidazole antifungals (sertaconazole, tioconazole, bifonazole, oxiconazole, sulconazole, fenticonazole, and isoconazole) to develop vesicular formulations using various nanocarrier systems. These studies demonstrated improved penetration, controlled release, and enhanced antifungal activity [42,62]. All of the studies reviewing formulation technologies for imidazole antifungals are summarized in

Table 2. Advanced topical formulations of imidazole antifungals, highlighting carrier systems, formulation types, and key pharmacotechnical outcomes, compiled from recent peer-reviewed studies.

Drug	Formulations	Composition and Carrier	Outcomes	Innovation	Advancement to Traditional Formulations	Reference
Clotrimazole	Microemulsion gel	Lemon oil or IPM/Tween-80/n-butanol/water; gelled with Carbopol 940	Enhanced skin retention; improved antifungal activity; thermally stable	Thermodynamically stable nano-sized emulsion system for improved solubilization	Superior permeation and retention vs. cream due to nanoscale droplets and surfactant action	[63]
	Microemulsion gel (eco-friendly)	Clove oil (~15%), Brij-35 (~30%), water, ethanol or 1-propanol; gelled with CMC (~2 wt%)	Nanodroplets~60 nm; >98% release within 6 h; improved permeation, indicates the sustained release of CTZ	Green surfactant-based nanoemulsion system	Enhanced localized delivery with reduced irritation vs. conventional formulations	[64]
	Emulgel (Pemulen polymer)	Pemulen TR1/TR2 + jojoba oil or IPM base	Higher release rate than cream; stable, Emulgel dosage form based on Pemulen polymeric emulsifier is a promising vehicle for topical delivery of Clotrimazole	Polymeric emulsifier-based hybrid system	Improved transdermal delivery vs. marketed cream	[65]
	Ufosomes vesicular system	Cholesterol + sodium oleate vesicles (ufosomes)	Lipid-based fatty acid vesicles; enhanced epidermal deposition and retention; economical to prepare	Fatty acid–based vesicular alternative to liposomes	Improved skin bioavailability with simpler formulation vs. cream	[66]
	Electrospun microemulsion nanofiber mat	CZ-loaded microemulsion blended into PVA/Chitosan nanofibers (~106–126 nm)	EE~73–98%; release ~65–74% at 4 h; rapid antifungal action; mucoadhesive potential, potential to be promising candidates for oral candidiasis applications	Nanofiber-based drug reservoir system	Faster onset and improved mucosal retention vs. topical formulations	[67]
Miconazole nitrate	Transfersomal gel	Transfersomes by thin-film hydration; Carbopol 934 gel	Particle size 63–85 nm; EE 68–91%; flux 85.97 µg/cm2/h vs. 72.49 µg/cm2/h for cream; larger zone of inhibition	Ultra-deformable vesicular carrier	Enhanced penetration and faster clinical response vs. cream	[68]
Sertaconazole nitrate	Vesicular gel (liposomes, glycerosomes, transfersomes, ethosomes)	Soy phospholipid (~3%) + sodium deoxycholate (~0.15%); gel base	Highest flux in transferosomal system; deep epidermal penetration	Multi-vesicular flexible delivery systems	Improved dermal targeting and efficacy vs. cream	[69]
	Microemulsion hydrogel (HSM-4)	Oleic acid (8.75%), Tween 80 (33.35%), propylene glycol (33.35%), water (24.55%); Carbopol 940 gel	Skin retention ~3× vs. commercial cream; inhibition zone~23.5 mm vs. 16.5 mm; no irritation in rabbits	Penetration-enhancing nanoemulsion hydrogel	Reduced dose requirement with enhanced efficacy vs. cream	[70]
	Microemulsion + microneedles	Microemulsion + dissolving or silicon microneedles (PVP-based)	Combined ME + solid MN increased skin deposition 4.6 times vs. ME alone; combination of solid silicon MNs and biocompatible ME favored more SN skin accumulation, preferable in the treatment of skin fungal infections	Hybrid physical + chemical enhancement system	Markedly improved drug localization vs. conventional topical systems	[71]
Luliconazole	Solid Lipid Nanoparticle (SLN) Gel	SLN (≈344 nm, PDI ≈ 0.17, zeta ≈ 18.8 mV), Carbopol 934 (1.5%) gel	Entrapment ≈ 92%, sustained release ~80% over 24 h, strong Candida albicans zone, luliconazole loaded SLN G3 gel formulation containing 1.5% w/v carbopol 934 suitable for topical application and have strong anti-fungal activity	Lipid matrix-controlled release system	Prolonged drug action vs. immediate-release creams	[72]
	Niosomal gel	Niosomes encapsulating luliconazole	Improved skin retention & antifungal activity, niosomal luliconazole may enhance the activity of luliconazole against Candida albicans (C. albicans).	Surfactant-based vesicular carrier	Enhanced skin targeting vs. conventional gel	[73]
	Nanosponge gel	Polymer-based nanosponges in gel	Enhanced solubility, controlled release, strong inhibition zones, developed nanosponges hydrogel stable and high rate of permeation with better retention	Porous polymeric drug reservoir	Sustained delivery and higher retention vs. standard gel	[74]
	Microemulgel	Microemulsion (linseed oil, surfactant, sodium alginate gel)	In vitro permeation ~63% at 5 h; zone of inhibition~38 mm; no skin irritation, effective for topical antifungal treatment	Hybrid nanoemulsion–gel system	Improved permeation and efficacy vs. conventional gel	[75]
	Nanoemulgel (peppermint oil)	Peppermint-oil-based nanoemulgel (formulation specifics)	Improved solubility and skin permeation vs. basic gel, developed nanoemulgels as vehicles for topical dosage form effective for the transportation of luliconazole	Nano-sized oil droplet delivery	Better drug transport vs. basic gel systems	[76]
	Invasome gel	Invasomes (ethanol/phospholipid/carrier vesicles)	Improved bioavailability	Ethanol-assisted flexible vesicles	Improved penetration vs. conventional gel	[77]
	Cubosomal emulgel	Cubosomes dispersed in emulgel matrix	Gel-based cubosomes with improved solubility and skin delivery; excipient-optimized dosage form, cubosomes Emulgel is favourable approach for the topical delivery of luliconazole for the treatment of fungal infections	Liquid crystalline nanostructures	Enhanced dermal delivery vs. cream	[78]
Luliconazole	Herbal ethosomal gel	Ethosomal vesicles capped with neem extract in Carbopol gel	Particle size & PDI optimized; improved entrapment; natural antioxidant and antifungal synergy, indicates that ethosomal formulation with luliconazole and neem extract show synergistic effect thereby, expressing excellent result against the treatment of fungal infection	Phytochemical-integrated nanocarrier	Enhanced efficacy with added antioxidant effect vs. conventional formulations	[79]
	Elastic lipogel & Ethogel	Elastic liposomes or ethosomes in gel; EE~92–93%, size ~nanometric	2.5–3 times potency vs. marketed cream; enhanced deposition; non-irritant in vivo, demonstrate d elastic liposomes and ethosomes, as a carrier are an attractive approach for enhanced topical delivery of Luliconazole	Ultra-flexible vesicular carriers	Higher potency and retention vs. marketed cream	[79]
	Film-forming nanoparticle gel (FFG)	Ethyl cellulose nanoparticles, EC:PVP:PVA matrix; ~125 nm; ~83% EE	92% release over 24 h; antifungal efficacy; film forms in ~5 min, the optimized FFG formulation FFG4 showed the shortest film-forming time of 5.06 min (min), percentage Cumulative drug release of 92.18% after 24 h, and promising in vitro antifungal activity	In situ film-forming nanocarrier system	Prolonged residence and sustained release vs. conventional gel	[80]
	Spanlastic (elastic vesicle) gel	Span:edge activator vesicles, nano-size, EE 77–88%	In-vitro permeation study revealed the flux value obtained for luliconazole entrapped in the vesicular spanlastics found to be higher than that of the marketed and conventional gel. The results revealed that spanlastics could be a potential nanocarrier for well controlled delivery thus providing new opportunities for dermal treatment	Highly deformable vesicles	Improved dermal targeting vs. marketed formulations	[81]
Ketoconazole	Cubosome-based topical hydrogel	Ketoconazole cubosomes (~198 nm; EE~45%) in gel	67% release in 24 h; ~92% ex vivo permeation; sustained skin delivery, the particle size of ketoconazole loaded cubosomes was 198 nm with 45% ketoconazole entrapment efficiency, can be used for topical drug delivery	Liquid crystalline lipid carriers	Enhanced penetration vs. cream	[82,83]
	PAMAM dendrimer hydrogel	KET + PAMAM-NH2 G2/G3 in Carbopol hydrogel	Increased zones of inhibition vs. pure KET; improved solubility and penetration, improvement of solubility and the higher KET release from hydrogels seems to be a very significant factor affecting antifungal activity of KET in hydrogels containing PAMAM dendrimers	Nanoscale branched polymer system	Overcomes solubility limitation of conventional formulations	[84]
	Microemulsion-loaded hydrogel (with Nigella oil)	Capryol (2:1) oil, Transcutol/PG, ~few µm; gel base	Sustained release up to 10 h; enhanced permeation & antifungal activity vs. marketed cream, the microemulsion-loaded hydrogel exhibited a 10 h sustained release profile as compared to the marketed cream	Nanoemulsion-based delivery	Enhanced antifungal efficacy vs. marketed cream	[85]
	Niosomal gel via Span/CHO vesicles	Niosomes size~5–7 µm, EE 55–79%, Carbopol gel	Prolonged release vs. plain gel; superior antifungal activity, Gel formulation containing niosomes loaded with Ketoconazole showed prolonged action than formulations containing Ketoconazole in non-niosomal form and it can be employed successfully to improve the antifungal activity	Vesicular encapsulation system	Sustained drug action vs. plain gel	[86]
	Liposome-encapsulated lotion	soya lecithin, Liposomes~179 nm, EE~75–80%, zeta −5 mV	Better anti-fungal activity against Candida sp. in comparison to other preparations, indicating its potential as a promising topical drug delivery system	Phospholipid vesicular system	Better antifungal activity vs. control formulations	[87]
Ketoconazole	Hyaluronic acid gel with NLCs	NLCs in HA gel (emulsion sonication)	Prolonged in vitro release (~5 h); enhanced antifungal activity ketoconazole, NLCs loaded HA modified gel provides prolonged release, excellent drug diffusion and antifungal activity, a promising carrier for topical delivery of ketoconazole	Hybrid lipid-polymer system	Enhanced retention and activity vs. marketed gel	[88]
	HA gel with selenium & KZ nanoparticles	KZ NPs~121 nm in HA gel; selenium NPs ~51 nm	Enhanced permeation and combined antifungal/anti-inflammatory effect for seborrheic dermatitis, optimized hydrogel with ketoconazole and selenium in nanotemplate offer a potential strategy for the treatment of SD	Multi-functional nanocomposite	Superior therapeutic effect vs. monotherapy	[89]
	ZnO nanoparticle-loaded gel with honey	KZ-ZnO NPs~70–75 nm; ethyl cellulose + honey gel, dextrose as an intermediate compound, carbopol, methylparaben, propyl paraben and propylene glycol	High drug loading (~65%), ~96% releases in 12 h; greater inhibition zone vs. controls in veterinary model, results indicated that the semi-solid gel preparations influenced the penetration and also favored the accumulation into the skin membrane, veterinary clinical studies indicated highly suitable for treatment of Malassezia	Inorganic-organic hybrid system	Enhanced antimicrobial synergy vs. conventional gel	[90]
	β-Cyclodextrin nanosponges hydrogel	KTZ-loaded nanosponges (274–367 nm) crosslinked with diphenyl carbonate; in Carbopol gel	Controlled release up to 8 h; improved skin retention & antifungal efficacy vs. commercial cream, results indicate controlled drug release, potential of skin targeting with enhanced antifungal activity	Inclusion complex nanocarrier	Enhanced bioavailability vs. cream	[91]
	Microsponges gel	Eudragit S-100/L-100 microsponges loaded with KTZ; incorporated into Carbopol 934 gel	Sustained release over ~8 h; enhanced drug delivery and skin bioavailability, microsponges improved drug delivery	Porous polymer system	Improved bioavailability vs. conventional gel	[92]
Econazole Nitrate	Nanosponges in gel	β-Cyclodextrin-based nanosponges + Carbopol 934 gel	~421 nm particle size, improved permeation, sustained release	Cyclodextrin-based nanocarrier	Better control of infection vs. marketed product	[93]
	Transfersomal Gel	Phospholipids + Tween/Sodium Cholate vesicles (~0.3–0.7 µm) + Carbopol	Flexible vesicles; enhanced skin penetration; improved antifungal effect, result showed the antifungal activity of the EN-loaded TFs was significantly higher than the marketed product, EN loaded transferosomal gel has the ability to penetrate the skin, overcoming the stratum corneum barrier	Deformable vesicular system	Superior antifungal efficacy vs. cream	[94]
	Co-crystal Gel	Econazole–succinic acid co-crystal (600–1000 nm) in Carbopol gel	Enhanced dissolution, permeation & antifungal zones vs. standard gel, formulated optimized co-crystal gel showed good potential of hydrogen, Viscosity, Zone of inhibition, drug content. ECZN co-crystal showed good in-vitro dissolution. Selected formulation of ECZN co-crystal loaded topical gel showed good ex-vivo permeability on topical skin and antifungal activity against C. albicans.	Crystal engineering approach	Enhanced solubility vs. standard gel	[95]
	Oleic Acid Vesicles Gel	Fatty acid vesicles with econazole	Developed oleic acid vesicle gel formulation significantly enhanced skin penetration	Lipid-based vesicular system	Enhanced therapeutic performance vs. cream	[96]
Econazole Nitrate	Chitosan Nanoparticles	Chitosan crosslinked with TPP	Improved drug delivery and skin retention	Biopolymer nanocarrier	Better delivery vs. conventional systems	[97]
Sertaconazole	Microemulsion-loaded hydrogel (HSM-4)	Oleic acid, Tween 80, propylene glycol, Carbopol 940	The permeation rate of STZL from optimized formulation (HSM-4), composed with oleic acid (8.75%, w/w), tween 80 (33.35%, w/w), propylene glycol (33.35%, w/w) and water (24.55%, w/w) observed higher in compare with other HSMs and commercial cream. HSM-4 stable	Mucoadhesive polymer system	Enhanced retention vs. standard gel	[96,97]
	Topical bioadhesive gel (TPA)	1% Carbopol 934 + 1% NaCMC polymer blend	On the basis of product characteristics viscosity, bioadhesiveness, permeation study, in-vitro release, in-vivo studies, TPA and spreadability it can be concluded that the best batch of topical bioadhesive gel of Sertaconazole nitrate would be with 1% Carbopol 934 and 1% NaCMC	Mucoadhesive polymer system	Enhanced retention vs. standard gel	[98]
	Flexisome-embedded hydrogel	Phospholipid + edge activator—flexisomes in hydrogel	STZN loaded STZN-FS shows high flexibility and enhanced antifungal activity, found to be potential carriers for drug deposition in skin layers without disturbing their integrity	Elastic vesicular system	Improved skin targeting vs. conventional gel	[99]
	Proniosomal gel	Non-ionic surfactants + cholesterol (proniosomes)	Formulation shown highest skin deposition and lower flux of sertaconazole nitrate through the rat skin	Pro-vesicular delivery system	Improved stability and delivery vs. niosomes	[100]
	Mucoadhesive Liposomal Gel (vaginal)	Cationic DDAB liposomes coated with pectin + gel base	High entrapment, prolonged mucosal retention, effective vaginal antifungal activity	Mucoadhesive liposomal system	Enhanced vaginal delivery vs. conventional dosage forms	[101]
	Thermosensitive NLC in situ gel (ocular)	Nanostructured lipid carriers (NLCs) + Pluronic F127/HPMC hydrogel	Sertaconazole-NLCs showed a higher antifungal activity and permeation through the bovine cornea compared to the free drug and the in situ gel formulation, prepared nanocomposite system may have potential for treatment of fungal keratitis	Stimuli-responsive nanocarrier	Improved bioavailability vs. free drug	[102]
	Glycerosomes Hydrogel	Glycerol-rich vesicular system	Deep skin penetration and high local skin accumulation efficiency for the effective treatment of fungal infections	Hydration-enhanced vesicular system	Improved dermal delivery vs. cream	[103]
Tioconazole	Pickering Emulsions (PE)	Tioconazole + silica nanoparticles + tea tree oil	Enhanced antifungal activity vs. conventional formulations in onychomycosis	Surfactant-free nanoparticle-stabilized system	Improved stability and efficacy vs. conventional emulsions	[104]
	Emulgel	Carbopol-934, Xanthan gum or combinations; oil-in-water emulsion	Tioconazole emulgel provide the better platform for delivery of hydrophobic drug for topical route and able to produce better patient compliance	Hybrid gel-emulsion system	Better delivery of hydrophobic drug vs. cream	[105]
	Transferosomal Hydrogel (TEs)	Ethanol, phospholipid, edge activator (e.g., Tween)	Ultra-deformable vesicles (~170 nm, EE~94%); enhanced flux (~48 µg/cm2/h); sustained release for 24 h; effective in dermatitis	Ultra-deformable vesicles	Enhanced penetration and sustained delivery vs. cream	[106]
	Transethosomal Gel	Ethanol, phospholipid, edge activator, Carbopol (DOE optimized)	Ultrafine vesicles (~170 nm), EE~94%, high flux, effective dermatitis model efficacy	Hybrid vesicular system	Superior delivery vs. conventional gel
Efinaconazole	Spanlastic nanovesicles	Elastic vesicles (Span + edge activator)	The optimized efinaconazole-loaded spanlastic vesicles had a particle size of 197 nm, transparency of 91%, relative deformability of 12.5 min, and dissolution efficiency of 81.23%. The spanlastic formulation was incorporated into a gel and explored ex vivo for transungual delivery	Elastic vesicular system	Enhanced transungual delivery vs. topical solution	[107]
	Microemulsion-based gel	Capmul® MCM oil, Labrasol® surfactant, Transcutol® P cosurfactant; Carbopol gel	Efinaconazole loaded microemulsion formulations could be considered as an effective therapy in the treatment of onychomycosis	Nanoemulsion-based system	More effective therapy vs. conventional formulations	[108]
	Iontophoretic hydrogel (transungual)	Ethanol, Labrasol, Tween 80, PEG 400, PVP K30, antioxidants; hydrogel matrix	Antifungal studies further substantiate the release data and have shown remarkable inhibition of Trichophyton mentagrophyte	Active transungual delivery system	Significantly improved nail penetration vs. passive delivery	[109]

. The development of these new formulations is indicative of a shift away from traditional topical therapies towards more barrier and retention-oriented product designs. As there is a pharmacological variety between imidazole derivatives, the therapeutic efficacy is determined increasingly by formulation engineering as opposed to only molecular structure.

Translational and comparative assessments of nanocarrier systems for imidazole antifungals are summarized in

Table 3. Translational status and comparative assessment of nanocarrier systems for imidazole antifungals.

Nanocarrier System	Key Strength	Primary Limitation	Translational Status	Reference
Liposomes	Biocompatible; improved penetration	Stability issues	Early clinical/translational	[101]
Ethosomes	Enhanced skin permeation	Ethanol-related irritation	Advanced preclinical/emerging clinical	[78,79]
Nanoemulsions	Improved solubility and dispersion	Limited drug loading	Advanced preclinical	[75,102]
Transfersomes	Deep skin penetration	Formulation instability	Preclinical	[99,106]
Niosomes	Better stability than liposomes	Scale-up challenges	Preclinical	[73,86]
Polymeric nanogels	Controlled release; prolonged retention	Regulatory and formulation complexity	Early-stage research	[81,82]
Hybrid systems (e.g., microneedles)	Enhanced delivery across barriers	Device complexity	Experimental/early clinical	[102]

.

5.4. Emerging Analogues and Next-Generation Derivatives

Extensive efforts to improve imidazole-based compounds have been made to reduce their dependence on classical imidazoles by reducing their propensity to be developed as resistant targets due to their inappropriate pharmacokinetic profiles, systemic toxicity, and poor molecular binding to the lanosterol 14α-demethylase (CYP51) enzyme [110]. An example is the focus on new molecular structural modifications that include a higher degree of lipophilicity or substituents that affect the side chain and enhance binding affinity to CYP51 enzymes.

Molecular design advances through the incorporation of both enantioselective stereoisomers and the precise physicochemical properties of a compound (i.e., optimizing logP, controlling pKa, and appropriate salt form) have led to improve in vivo performance of these compounds for topical application. Additional improvements can be attributed to the incorporation of membrane-affine moieties such as dichloro-substituted aromatic or benzothiophene groups, which enhance the ability of these compounds to be retained in tissue and have also been demonstrated in some cases to provide additional anti-inflammatory and membrane-interactive effects [111,112]. At the same time, extensive efforts have been made with respect to the chemistry associated with the design of compounds to reduce unwanted effects associated with the off-target inhibition of mammalian cytochrome P450 (CYP450) isoenzyme activity, improving photostability and reducing the extent of excessive keratin binding for the management of conditions affecting the nail [113].

Among advances that have been clinically verified, including luliconazole, are new and innovative drugs; there has been low MIC against T. rubrum and C. albicans sources, as evidenced from both experimental laboratory and clinical studies demonstrating rapid and long-lasting antifungal actions [114,115]. As a result, a once daily short course dosing frequency is indicative of how the optimized, modified molecular design translates into greater patient compliance and more effective pharmacologic treatment. In addition, when comparing lanoconazole and flutrimazole with previous imidazole-based medications, they have demonstrated significantly higher drug retention in the skin, resulting in improved clinical outcomes. These examples represent that slight changes or adjustments made to the structure of a drug molecule can have a major impact upon local pharmacology, therapeutic response [116,117,118].

Most recently, the ketoconazole ionic liquid system was developed in 2023; by utilizing lower doses of the drug ketoconazole as compared to previously manufactured products, patients were shown to achieve better medical results when the drug was provided to them via a LI delivery methodology [119,120]. Research studies are currently being undertaken on the use of novel hybrid scaffolds containing azole-thiazole, imidazole-triazole, and quinolines that are linked to one another, for the purpose of developing azole-based compounds with a higher metabolic half-life and overcoming the challenge of resistance-associated alterations to the cytochrome P450-51 enzyme [120,121].

The imidazole compounds fused to lipids outside or on the surface, as well as attached to nanoparticles, are being developed to enable deeper penetration into the dermal and subungual layers of the skin in relation to long-standing barriers associated with onychomycosis and chronic skin infections [122]. Such strategies reflect the increased potential for using structure-based design combined with innovative delivery technologies. The current state of innovation in the imidazole class is no longer strictly limited to potency alone but is now characterized by the combination of computational modeling, rationally derived structural modifications, and delivery techniques to prolong efficacy while minimizing resistance development. Recent patent (

Table 4. Patents of key imidazole antifungal agents, highlighting antifungal modifications and application for targeted dermal delivery.

Patent No.	Year	Derivative	Modifications	Applications	Company
US3660577A	1972	N-trityl-imidazoles	Novel imidazole derivatives with broad-spectrum antifungal activity (Candida, dermatophytes)	Experimental; early antifungal scaffolds	-
US4402968	1983	Benzofuranyl-imidazole compounds	Antifungal agents active against Candida, dermatophytes, systemic fungi	Demonstrated in vivo/in vitro efficacy, preclinical	-
US4925953	1990	Novel imidazole derivatives	Strong antifungal and antibacterial activity; new substituents for broader spectrum	Patent granted, investigative compounds	SS Pharmaceutical Co., Ltd.
US4912124	1990	Imidazole-formulated topical solution	Solvent-based preparation applicable for topical fungal infections	Applied to cream/ointment formulations	-
US5071540A	1992	Clotrimazole manufacturing process	High-yield synthesis from trityl intermediate	Improved production method	Erregierre Chimica S.p.A.
US5571831A	1996	Imidazole derivative formula	Inhibition of fungal CYP450, broad antifungal and antifungal/aromatase dual use	Basis for future pharmaceutical derivatives	Japanese origin inventors
US5514698A	1996	Vaginal cream formulation	Viscous, long-lasting imidazole cream with stable viscosity at 37 °C	Marketed vaginal formulations	-
US5711954A	1998	Powder imidazole antifungal	Stable powder formulation for dermatological/dispenser use	Market deployable dry formulation	-
WO2003068770A1	2003	Sertaconazole mononitrate	Enantiomerically pure R-(−)-sertaconazole synthesis, reduced toxicity	Formulated as Ertaczo® topical antifungal cream	Ferrer Internacional S.A.
US5135943 (EP family)	2003	Sertaconazole nitrate	Cream composition with improved formulation consistency and feel	Topical cream for tinea pedis/corporis/cruris	Ferrer Internacional S.A.
WO2009010986A1	2009	Topical cream formulations	Improved cream base with reduced wax content for better skin feel	Improved Ertaczo® formulation	Ferrer/generic manufacturer
WO2010079373A1	2010	Vaginal suppository formulation	Suppository with dissolved + suspended imidazole for prolonged efficacy	Delivery optimization	-
WO2011121604A2	2011	Vaginal liquid spray	Spray combining imidazole + lactic acid/lactobacilli for vaginal health	Alternative vaginal fungal therapy	Johnson & Johnson et al.
US10703744B2	2015	Purification of luliconazole	Crystallization process yielding high-purity, stable luliconazole hydrochloride	Commercial-scale stability improvement	Nihon Nohyaku Co., Ltd.
US11285148B1	2022	Ketoconazole ophthalmic gel	Trans-ethosomal nanoparticle gel for deep ocular fungal infections	Preclinical/clinical development	King Abdulaziz University
WO2023131969A1	2023	Process for luliconazole synthesis	Novel intermediate (methanesulfonate salt) enables cost-effective, high-yield production	Industrial manufacturing process	Nihon Nohyaku Co., Ltd.
CN102389421A	2012	Oxiconazole nitrate formulations	Diverse forms (gels, ointments, suppositories) enhancing convenience and compliance	Enhanced topical dosage forms	China-based pharm developer
EP0573492B1	1986	Oxiconazole and corticosteroid	Combination cream (fluticasone propionate  +  oxiconazole) for inflammatory fungal dermatoses	Used in combination topical therapy	Siegfried AG/pharma partners
EP1698336A1	2006	Sertaconazole and hydrocortisone/quinolone	Combination topical formulation for fungal-inflammation co-infections	Improved symptom relief and compliance	Ferrer/co-developers
US20170290810A1	2017	Imidazole in hybrid nail formulation	Combination of allylamine, triazole, and imidazole antifungals with penetration enhancers	For onychomycosis; formulation stage	Imprimis Pharmaceuticals Inc.
WO1994016710A1	1994	Ketoconazole and glucocorticoid	Physicochemically stable co-formulation of ketoconazole and steroid for skin infections	Market product for dermatitis/fungal co-treatment	Janssen/collaborators
WO1996006613A1	1996	Ketoconazole emulsions	Ketoconazole emulsions lacking irritant sulfite, improved shelf-life and tolerability	Stable topical formulations for dermatitis & tinea	Janssen Pharmaceuticals
WO2002015936A1	2002	Ketoconazole cream compositions	Low-viscosity alcohol-based solution for enhanced skin permeation	Novel gel/solution forms for topical ketoconazole	Janssen Pharmaceuticals
US20190358329	2019	Stable efinaconazole topical formulation	Use of BHT, EDTA and citric acid to maintain color/stability over time	Improves patient acceptability and shelf life	Valeant/Bausch Health
US20210007355A1	2021	Imidazole + activated creatinine combo	Fungicidal and antibacterial combo formulations targeting resistant infections	Patent application; preclinical stage	-
US20230226033A1	2023	Efinaconazole stable formulation	Acidifying agent (e.g., α-ketoglutaric acid) prevents oxidation, enhances purity	Improved topical solution stability	Valeant/Bausch Health (US)
WO2022146007A1	2022	Efinaconazole oral co-crystal	Efinaconazole–PEG co-crystal with superior oral bioavailability and stability	Preclinical oral antifungal formulations	South Korean pharma entity

) also indicates an ongoing interest from industry in hybrid scaffold types and optimized formulations that have been developed to improve local site distribution and therapeutic benefit [122,123,124,125,126,127,128].

6. Pharmacokinetics and Pharmacodynamics of Imidazole Antifungals

Topical imidazoles (Econazole, Clotrimazole, and Miconazole) can be very effective in treating superficial fungal infections due to their strong local pharmacodynamics and minimal systemic exposure [65,68,96]. They are primarily absorbed in the stratum corneum and upper layers of the epidermis when applied topically. Therefore, high local concentrations of these drugs are present at the site of infection, while no measurable plasma levels are evident. This pharmacokinetic profile leads to safe drugs; however, this profile limits the utility of topical imidazoles in the treatment of other mycoses that are deep or systemic [129].

Systemic imidazoles (Ketoconazole) have an acceptable oral bioavailability when ingested under acidic conditions in the gastrointestinal tract, and after ingestion, they attain clinically relevant plasma concentrations. However, the oral bioavailability of systemic imidazoles is very dependent on the pH; thus, being given acid-suppressive medications may significantly lower the absorption of systemic imidazoles [130,131,132]. Systemically exposed to imidazoles may carry risks of hepatitis, endocrine disturbances, and drug-drug interactions, all due to the inhibition of mammalian drug metabolizing enzymes (aka P450).

Once absorbed systemically, imidazoles are widely distributed in tissues and exhibit a high degree of protein binding. Accumulation of imidazoles in the keratinized skin, nails, vaginal mucosa, and oily sebum also supports their use in dermatological infections [133]. However, systemic imidazoles only penetrate the central nervous system to a limited degree, which restricts their use against neuroinvasive fungal diseases. Therefore, systemic administration of imidazoles allows for a larger spread, but increased safety concerns and variability in pharmacokinetics accompany systemic administration.

The pharmacodynamics of imidazoles show fungistatic or fungicidal action based on the concentration of the active ingredients localized around the minimum inhibitory concentration (MIC) [134]. Topical formulations are advantageous due to their avoidance of being metabolized before reaching the site of infection and allowing for drug concentrations within superficial tissues that remain well above the MIC. However, there are variable penetration rates through hyperkeratotic skin, thickened nails, or biofilms housing the fungal organisms that could result in localities that are sub-therapeutically adequate. The development of concentration gradients can create incomplete eradication and may also allow the development of resistance as the fungi are re-exposed to the imidazole [135].

Conventional topical imidazoles allow for an effective safety-efficacy balance when treating superficial infections; however, pharmacokinetic limitations (limited penetration into tissues, variability regarding retention, and limited systemic applicability) indicate that new and improved delivery strategies are required. Optimized vehicles with the ability to enhance the dermal deposition of the drug, sustain the levels necessary for therapeutic effect, as well as overcome anatomical barriers, may provide more consistent pharmacodynamics while reducing systemic toxicity [136]. As shown in Figure 4, topical imidazoles achieve localized drug accumulation within the skin layers, whereas systemic agents undergo absorption and distribution prior to exerting antifungal effects.

7. Clinical Applications & Spectrum of Activity

Due to their strong antifungal activity, extensive antifungal coverage, and their good safety record, topical imidazole antifungals continue to be a mainstay for treating skin fungal infections. The topical imidazole antifungals (Clotrimazole, Miconazole, Econazole, and Tioconazole) are commonly used to treat skin fungal infections such as cutaneous candidiasis, vulvovaginal candidiasis, pityriasis versicolor, and dermatophyte infections such as Tinea Corporis, Tinea Cruris, and Tinea Pedis [137]. Because of their lipophilic qualities, topical imidazole antifungals have the ability to remain in the stratum corneum, making it possible for them to produce high drug concentrations locally while having very low systemic absorption. The general use of imidazole antifungals across the dermatophyte infections is illustrated in Figure 5.

7.1. Superficial Cutaneous and Nail Infections

Imidazoles demonstrate low MICs for is Dermatophyte infections (T. rubrum, T. mentagrophytes, and E. floccosum); 0.03–0.5 µg/mL with good clinical results [131,132]. Therefore, the high affinity of the Imidazole class of compounds for Keratinized tissue makes them effective against Tinea infections, although prolonged duration of treatment may be required for hyperkeratotic or occluded lesions [138,139].

For Onychomycosis, moderate efficacy has been demonstrated for topical formulations (e.g., Tioconazole or Econazole Nail Lacquers) in mild to moderate cases. However, limited nail plate penetration is the primary barrier to adequate treatment, suggesting that penetration-enhancing and nanoparticle-based delivery systems should be developed to increase the performance of topical Antifungal agents [140].

7.2. Vulvovaginal and Oropharyngeal Candidiasis

In the case of vulvovaginal candidiasis (VVC), which is usually caused by the yeast species Candida albicans, intravaginal clotrimazole, miconazole, econazole, and tioconazole have very good clinical and mycological cure rates. They have flexible dosing options (1–7 days), and they produce very low systemic absorption; therefore, they are the first-line treatment for women with VVC, including in uncomplicated cases during pregnancy [141,142].

Tioconazole is of particular interest because of its ability to remain in tissue for a long period of time, making it ideal for effective single-dose treatment. The availability of these products over the counter and their excellent safety profiles further solidify their position as important antifungals for mucosal infections [143].

In treating oropharyngeal infection caused by Candida albicans, the local antifungal activity of clotrimazole troches and miconazole oral gel can provide a long-term effective antifungal therapy in a person with mild disease and who is immunocompromised and is being treated in an outpatient setting [144].

7.3. Activity Against Yeasts and Emerging Resistance

The activity of imidazoles against Candida albicans, Candida tropicalis, and Candida parapsilosis shows potent antimicrobial activity with a MIC of between 0.03–2 µg/mL against these organisms. A growing concern, however, is the development of resistance among non-albicans species, especially in the following: C. glabrata and C. auris [145,146,147]. This is a particular concern for patients with immuno-compromising conditions and with recurrent infections. The development of resistance to imidazoles has been attributed to several factors, such as the use of azoles at subtherapeutic low doses, biofilm formation, and the repeated use of azoles. Therefore, there is a great need for local delivery of imidazoles capable of providing sustained concentrations above the MIC threshold [148].

7.4. Limited Mold Coverage

Ketoconazole was the first imidazole approved for systemic use and was developed almost 40 years ago. Ketoconazole can produce dose-dependent hepatotoxicity and endocrine suppression (i.e., decreased cortisol and testosterone production) and CYP3A4-mediated drug interactions, which now limit its systemic use to very specific indications (i.e., cancer) and are subject to very strict monitoring. Ketoconazole is still widely used topically and is well-tolerated for the treatment of non-invasive superficial fungal infections [149].

7.5. Systemic Use and Clinical Limitations

Ketoconazole is the first systemic agent approved for therapeutic use. However, it carries significant risks of hepatotoxicity, hormone suppression (cortisol, testosterone), and CYP3A4-mediated drug interactions that place restrictions on its use in the systemic context. Current indications for its use are highly selective and monitored closely, whereas topical ketoconazole remains available for use and is tolerated in patients with superficial infections [150].

7.6. Combination Therapy

Combining topical imidazoles with corticosteroids (i.e., hydrocortisone, betamethasone) is a common practice when treating patients with inflammatory dermatomycoses to mitigate or eliminate symptoms (pruritus, erythema) without compromising antifungal effect [151]. Additionally, combining topical imidazoles with antibacterial agents (like neomycin) can also be performed when there is a mixed infection caused by multiple pathogens. Systemic combination therapy is infrequently utilized and primarily reserved for patients with refractory infections because of concerns regarding the cumulative toxicity of the agents and the potential for drug interactions via pharmacokinetic mechanisms [152].

8. Biopharmaceutical Barriers in Cutaneous and Nail Fungal Therapy

While there is a significant level of intrinsic antifungal activity among imidazole compounds, their clinical treatment potential is often hindered by various anatomical and physicochemical obstacles that affect drug penetration, retention, and pharmacodynamic variability, especially with regard to chronic and recalcitrant infections [153,154]. The knowledge of these obstacles is important for the rational design of advanced delivery systems, as illustrated in Figure 6.

8.1. Stratum Corneum Barrier

The stratum corneum represents the most significant barrier to topical antifungal therapy. The stratum corneum is a lipid-protein matrix that contains densely packed corneocytes held within ceramide, cholesterol, and free fatty acids. As a result, the “brick and mortar” structure provided by these components restricts the diffusion of hydrophilic and very lipophilic molecules into the viable deeper layers of the epidermis (i.e., the stratum corneum) beneath the skin surface [155,156]. Therefore, although imidazoles are moderately lipophilic, excessive lipophilicity will likely result in the sequestration of the drug within the superficial layers without sufficient diffusion into the deeper layers of the viable epidermis, while insufficient lipophilicity creates difficulties with respect to the drug’s partitioning through membranes. Therefore, achieving an optimal log P value remains crucial. The presence of hyperkeratosis, scaling, and inflammation changes the barrier properties further and will create heterogeneity with respect to penetration profiles and variability in therapeutic success [157,158,159].

8.2. Nail Plate Barrier (Onychomycosis)

The nail plate serves as one of the most substantial obstacles for drug delivery in dermatology. The nail plate is made from tightly packed keratin fibres that are cross-linked together, and keratin contains very little fat or lipids, so the amount of passive diffusion of the majority of antifungal agents through the nail plate is limited [160]. Topical antifungal agents, imidazole formulations such as Tioconazole and Econazole, are available as nail lacquer but provide only limited effectiveness for treating mild to moderate onychomycosis. The limited permeability of the nail plate, the slow growth of nails, and the presence of subungual fungal biofilms contribute to the length of time needed for treatment as well as to the high rates of recurrence seen with onychomycosis. These factors have spurred research efforts into developing penetration enhancers, keratolytic agents, nano-carriers, and Iontophoresis [161,162].

8.3. Fungal Biofilms and Microenvironmental Factors

The impact of biofilms formed by dermatophytes and Candida on the treatment of onychomycosis has not been fully appreciated. Biofilms provide a protective environment around fungal cells, which results in reduced metabolic activity, altered gene expression, and increased efflux pump activity of fungal cells, thereby reducing the susceptibility of fungal cells to treatment with antifungals such as azoles [163]. The local physicochemical environment within a biofilm, such as pH, moisture, and the presence of keratin debris, may also lead to the creation of locations within the biofilm where drug concentrations are below therapeutic levels, creating a drug gradient within the biofilm [164]. Once exposed to drug concentrations below MIC, fungal cells may develop adaptive mechanisms that can confer resistant phenotypes to antifungal treatment, especially among non-albican species of Candida, such as Candida glabrata and Candida auris. The maintenance of drug concentrations above the mutant prevention concentration is therefore a key design consideration when developing treatment strategies for onychomycosis [165].

8.4. Pharmacokinetic Variability and Retention Limitations

Topical dosage forms (creams and ointments) suffer from a high degree of pharmacokinetic instability after application because of their removability from the skin. After application, drug removal from the skin surface occurs quickly due to perspiration, physical abrasion (i.e., friction), cleansing, and the natural turnover of skin. Since mucous membranes naturally produce large amounts of exudate, they have both a rapid clearance rate of the drug from the applied site, as well as relatively poor adhesion to the drug, therefore requiring repeat applications to maintain the required drug concentration for therapeutic effectiveness [166]. In the case of chronic infections such as dermatophytosis or recurrent candidiasis, variance in patient adherence to prescribed treatment regimens contributes to fluctuations in the concentration of the drug available for therapeutic use. From a formulation point of view, semisolid formulations that partially crystallize may lead to reduced thermodynamic activity of the drug within the dosage form and, thus, altered kinetic performance characteristics over an extended period of time [167]. In addition, because imidazoles demonstrate pH-dependent solubility and ionization, they may also impact the ability of imidazoles to partition into underlying infected tissues, particularly if those tissues demonstrate signs of inflammation or contain biofilm. Individually or in combination, the above factors can create unpredictable pharmacodynamic profiles with heterogeneous areas of subtherapeutic concentrations for certain imidazole compounds, leading to a higher risk of failure to eradicate all fungal organisms and potential for reinfection [168].

8.5. Systemic Exposure and Toxicity Constraints

Systemic administration adds another layer of complexity to pharmacokinetics. For example, ketoconazole is highly dependent on gastric acidity for oral absorption; therefore, patients receiving acid-reducing medications have reduced bioavailability because their stomachs will have lower acidity than those who are not taking acid-reducing medications. Additionally, when drugs are administered via the systemic route, they undergo extensive first-pass metabolism in the liver, which significantly limits the ability to predict systemic concentrations for systemic administration of most drugs due to their high level of hepatic metabolism before reaching systemic circulation [169]. Likewise, due to their high level of plasma protein binding, very little, if any, will actually reach the free form of the drug. Additionally, inhibition of cytochrome P450 isoenzymes results in drug–drug interactions with clinical significance and can result in dose-dependent effects on liver toxicity and endocrine disruption. Overall, the significant limitations imposed by pharmacokinetics and safety issues associated with systemic administration of imidazoles have significantly reduced their use in clinical practice and emphasize the need for localized targeted drug delivery systems that will maximize the drug concentration within the tissue while eliminating unnecessary amounts of drug from the body through systemic administration [170,171].

8.6. Translational Implications for Advanced Delivery

These biopharmaceutical limitations show that simply being able to kill yeast cannot guarantee you the ability to cure yeast infections. Even if one develops new imidazole analogues that are very effective at killing yeast, there are many potential reasons for their failure, including poor penetration into the target tissue, a lack of sufficient drug retention, or the concentration gradient across the local tissue being less than the level at which the drug is effective. The problem of inconsistent drug exposure is further exacerbated by the presence of biofilm-associated resistance mechanisms [172]. Therefore, the advanced drug delivery systems being investigated may include all the above: lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, ionic liquid platforms, mucoadhesive systems, and hybrid polymeric carriers. However, these should not be perceived as simply being incremental improvements to the formulation of drugs; rather, they represent strategic technology interventions to overcome known physiological barriers to drug delivery [173,174]. These delivery technologies are expected to provide benefits through enhancing dermal deposition, increasing nail permeation, extending the time a drug remains in a mucosal tissue, and providing a stable, controlled release profile for the drug. Ultimately, all these delivery technologies are expected to result in better harmony between pharmacokinetic properties and pharmacodynamic requirements of the drug and a reduced risk of developing drug resistance [175,176].

9. Resistance Patterns and Mechanisms

Resistance to the imidazole antifungals represents a significant concern clinically, particularly when the drug is used over an extended period of time, when there are recurrent infections, or when there is sub-therapeutic dosing. The imidazole antifungals still have good efficacy against the majority of superficial mycoses; however, adapted fungal responses may negatively affect their potency by patterns of molecular and phenotypical alterations [177,178]. Many of the principal pathways shown in Figure 7 lead to loss of efficacy by way of alterations to the target enzyme, increased expression of efflux transporters, and tolerance while within a biofilm, and cross-resistance among different azole classes.

9.1. Alterations in Target Enzyme: CYP51A1 Mutations

The most common mechanism of azole antifungal resistance is the presence of mutations in the CYP51 gene that encodes lanosterol 14α-demethylase. Structural alterations to this enzyme alter the binding pocket of the azole and decrease the affinity of the azole to the heme iron core, which is necessary for the azole’s inhibitory activity. As a consequence, the biosynthesis of ergosterol can proceed despite exposure of the fungus to the drug, and the membrane integrity and viability of the fungus may be restored. Many of the clinically relevant resistance-associated mutations found in isolate strains include Y132H, K143R, and G54E of A. fumigatus, C. albicans, and C. glabrata; these mutants are often associated with chronic azole exposure in immunocompromised individuals or in settings with inadequate drug exposure [179].

The changes to CYP51 frequently result in resistance to all classes of azoles since all classes of azoles target this same enzyme. The change to the CYP51 enzyme will also limit the efficacy of other azoles since they have a similar structure. As a result, these patients may require transition to the use of other antifungal classes like echinocandins or amphotericin B. Therefore, molecular surveillance of CYP51 mutations and their patterns will be critical to inform appropriate antifungal stewardship and treatment decision-making.

9.2. Efflux Pump Overexpression: ABC Transporters

A second major mechanism of azole resistance is the overexpression of efflux pumps. Currently, all efflux pumps are characterized as either an efflux pump/ATP-binding cassette (ABC) transporter. These efflux pumps actively export azole compounds from fungal cells, thereby reducing the concentration of azole inside fungal cells below the level needed to inhibit or kill yeast and fungi [180]. Resistance to azoles in the most clinically significant Candida species, namely Candida albicans and Candida glabrata, is highly correlated with the upregulation of ABC efflux pumps CDR1 and CDR2 and is regulated by factors including but not limited to transcription factors such as TAC1 [181]. Prolonged exposure to azoles can lead to sustained overexpression of these transport systems. Efflux-mediated azoles will pose problems to the treatment of patients since patients who exhibit efflux-mediated azole resistance using one azole will demonstrate resistance to multiple azole compounds. Thus, patients with active efflux transport systems may demonstrate broad resistance to both triazoles and imidazoles [182]. In strains that form biofilms, the activity of efflux systems can be further exacerbated and complicate treatment failure. The development of organic efflux pump inhibitors and other treatment strategies to prevent resistance has recently gained interest, but has not yet been established clinically.

9.3. Biofilm Formation and Tolerance

Biofilms are a type of structural and metabolic adaptation that reduces the susceptibility of fungi to imidazole antifungals significantly. Biofilms consist of organized communities containing three-dimensional structures within an extracellular matrix produced by organisms that are bound to host tissue or medical devices [183]. The extracellular matrix formed by the organisms acts as a barrier for diffusion and limits drug penetration into the biofilm, creating gradients in terms of the concentration of the antifungal drug that exists between the biofilm architecture.

In addition to creating a physical barrier, biofilm-associated cells have a different pattern of gene expression, have more activated stress response pathways [184], and increased expression of efflux pumps, in general (CDR1, MDR1). Furthermore, biofilm-associated cells that are metabolically quiescent are less responsive to agents that target ergosterol synthesis, which are an active form of the drug. The combination of all these characteristics results in an antifungal tolerance status rather than traditionally defined resistance.

Infections associated with biofilms tend to be recurrent and persistent. Candidiasis of the Vagina, denture stomatitis, candidiasis of the oral cavity, and infections associated with the use of catheters have all been shown to be associated with the presence of biofilms and antifungal tolerance. Therefore, in order to combat the antifungal tolerance exhibited by biofilms, most of the time it requires prolonged periods of therapy, higher local concentrations of antifungal drugs, and other therapeutic interventions such as removal of the medical device and matrix disruptive strategies [185].

9.4. Cross-Resistance with Other Azoles

Therapeutic concerns can arise due to increasing cross-resistance in azoles. For example, as both imidazoles (ketoconazole) and triazoles (fluconazole) target lanosterol 14α-demethylase, developing CYP51 mutations or excessive use of efflux pumps may lead to lower susceptibility of multiple agents to one agent. This may be a problem for the use of itraconazole, voriconazole, or posaconazole after developing resistance whilst receiving treatment with either food or ketoconazole [177]. Other examples of patients treated with azole were also resistant to azole, most notably in azole-resistant A. fumigatus and C. albicans spp., who were also presented with limited options for further drug treatment. Most of the time, azole-resistant strains will be developed after prolonged or misused azole exposure. Therefore, demonstrates the need for developing reliable antifungal susceptibility, rational dosage, and antifungal stewardship programs (178).

9.5. Translational Implications

While some articles state that resistance is fundamentally a genetic basis to resistance, it is also tightly connected to drug delivery and pharmacokinetic features. Suboptimal tissue exposure and poor penetration and variability within the drug film, and lack of consistency with drug administration, create selection pressure in a way sensitive to materials that carry resistant organisms [180]. Thus, the evolution of resistance cannot be viewed as something separate from a drug delivery system that performs well. The use of advanced drug delivery systems designed to maintain drug levels above therapeutic levels for an extended period of time, enhance the ability to penetrate keratinized tissue, and replicate and hold up concentration gradients probably not only enhances efficacy but also reduces the emergence of resistance. Thus, from this perspective, formulations have a genetic impact and should therefore be treated in a complementary approach to antifungal stewardship rather than as a technology by itself [184].

10. Advanced Drug Delivery Strategies for Imidazole Antifungals

The traditional limitations of imidazole treatment, such as poor tissue penetration, inconsistent retention, biofilm-related tolerance, and the development of resistance to imidazoles, have prompted the creation of novel drug delivery systems capable of overcoming various anatomical and pharmacokinetic barriers [171,172]. Current approaches seek not only to reformulate existing compounds but also to provide optimized targeting of tissue areas while maintaining concentrations above the necessary thresholds and minimizing patient exposure to systemic drug absorption. These drug delivery systems represent a combination of pharmaceutical engineering, material science, and antifungal pharmacodynamics [173,185]. Along with providing increased penetration and retention, new generation drug delivery systems also work towards reducing systemic exposure and dose-dependent toxicity resulting from the total systemic administration of imidazole antifungals, as shown in Figure 8.

10.1. Lipid-Based Nanocarriers

Delivery systems that utilize lipids have also emerged as an area of great potential for improving dermal and mucosal delivery of imidazole antifungals, specifically clotrimazole, miconazole, and ketoconazole.

10.1.1. Liposomes and Ethosomes

Liposomes encapsulating lipophilic imidazoles in a phospholipid bilayer structure can improve solubility as well as facilitate interaction with stratum corneum lipids. Ethosomes containing an increased concentration of ethanol can enhance the fluidity of skin lipids, thereby allowing the drug to penetrate deeper into the skin. As a result, these systems have demonstrated improved delivery of the drug to viable epidermal cells whilst minimizing systemic absorption [186].

10.1.2. Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs)

Controlled release and improved stability are provided by SLNs and NLCs. Their smaller particle size helps create a larger surface area that comes into contact with the skin surface and also creates occlusive properties that improve hydration and permeability. Compared to SLNs, NLCs also exhibit a greater ability to provide sustained delivery over time by reducing drug loss, or excipients, during storage and allowing for higher drug loading capacity than SLNs. Lipid nanoparticles have demonstrated improved subungual permeability and prolonged retention for treating both onychomycosis and chronic dermatophytosis [187]. Further, lipid nanocarriers provide a dual benefit of delivering drugs to penetrate and maintain prolonged exposure by providing uniform drug distribution and, as a result, uniform drug concentration levels over time. This may help reduce the occurrence of drug resistance due to continuous drug concentration fluctuation [159].

10.2. Nanoemulsions and Microemulsions

Nanoemulsions and microemulsions have improved the solubilization of poorly soluble imidazoles and increased thermodynamic activity at the treatment site through enhanced microscopic particle sizes, improving the homogeneity of drug distribution and increasing the permeation of drug and excipients across the lipid domains of the stratum corneum. This is particularly beneficial for treating fungal infections in the scalp and seborrheic dermatitis by targeting hair follicles for improved antifungal response. Additionally, the increased distribution and cosmetic acceptability may help improve patient compliance, indirectly assisting with drug resistance mitigation [166,188].

10.3. Ionic Liquid-Based Systems

Recent developments in ionic liquid formulations have led to increased interest as an alternative medium for solubilizing and enhancing penetration through the skin. By forming drug-ionic liquid complexes, the amount of drug required for transdermal transport can be reduced due to increased flux through the skin. Ketoconazole-based IL formulations have been shown to improve therapeutic efficacy at lower doses, indicating improved delivery of the drug to tissues with increased bioavailability [189]. ILs have the potential to offer a range of physicochemical characteristics that can be tailored to create systems that provide optimal viscosity, polarity, and release kinetics. Because of this versatility, IL-based systems may also offer a potential solution for treating difficult-to-treat infections such as onychomycosis [172].

10.4. Mucoadhesive and In Situ Gelling Systems

For vulvovaginal and oropharyngeal candidiasis, clearance from mucosal surfaces occurs rapidly, resulting in inconsistencies with drug therapy. Mucoadhesive polymers and in situ gel-forming systems extend the residence time of the drug, allowing for a longer duration of local effect. The use of thermosensitive and pH-responsive gels changes the state of the material from liquid to gel when administered, enhancing retention and reducing leakage of the drug from the application site. As such, these systems will increase the contact between the drug and the infected epithelium, maintaining drug concentrations above the MIC for the treated infection and thereby reducing the potential for recurrent infections [190].

10.5. Polymeric Nanoparticles and Hybrid Platforms

Functionalized polymeric nanoparticles made from biodegradable polymers (such as PLGA polymeric nanoparticles) provide controlled release and protect imidazoles from degradation [175]. Hybrid systems with both lipid and polymeric components optimize drug loading and release. These types of systems may also enhance penetration of the drug into biofilm matrices and keratinized tissue. Furthermore, drug release profile stabilization helps to maintain therapeutic concentration within the therapeutic range; hence, these systems may reduce the evolutionary pressure that contributes to adaptive resistance to imidazole-based antifungal drugs [171,191].

10.6. Nail-Targeted and Transungual Delivery Technologies

Transungual delivery represents a formidable barrier to successfully treating patients with onychomycosis due to the very dense keratinized structure of the nail plate, and the limited lipid content associated with it will significantly inhibit passive diffusion of imidazole-based antifungals (primarily voriconazole and ketoconazole), leading to subtherapeutic drug levels at the site of infection. Several new and novel advances have been developed so as to increase the drug permeation rate while providing persistent local exposure to the drug [153]. Two such advances include incorporating lipid or polymeric nanocarriers into film-forming systems (nail lacquer) to achieve sustained drug release (increased time and depth penetration into keratinized tissue) and using rational formulation design to modulate keratin binding to decrease the degree of drug sequestrated in superficial keratin and promote diffusion towards the nail bed. Chemical penetration enhancers can be used to transiently disrupt the integrity of the keratin network to enhance drug permeation through the nail plate [154,155].

Alternatively, some scientists have explored physical enhancement techniques (microneedle-assisted delivery and iontophoresis) to bypass the barrier or actively drive drug molecules through the nail plate. These techniques have the goal of overcoming the low permeability of the nail and maintaining therapeutic levels within the nail bed chronically without increasing the level of exposure to the whole body.

10.7. Delivery Strategies as Resistance-Mitigation Tools

In addition to pharmacokinetics, advanced delivery systems also may have a direct effect on resistance dynamics. Sustained-release platforms reduce concentration variability to a minimum in the mutant selection window of time; improved biofilm penetration and tissue retention reduce the chances of establishing persistent subpopulations. Therefore, formulation engineering is now considered to be part of antifungal stewardship [162]. By optimizing the pharmacokinetics of an advanced delivery system with the associated pharmacodynamics, recurrence rates, duration of therapy, and the potential for resistance development will be significantly reduced.

11. Recent Developments and Future Perspectives

The latest developments in antifungal research using imidazole-type compounds illustrate a dual-pronged approach, refining structural characteristics of their active components (pharmacophores) and developing more sophisticated ways of delivering them (using “advanced” delivery technologies). The main thrust of molecular optimization is aimed at adding bioisosteres, heterocyclic frameworks, and halogenated aryl substituents, with the goals of increasing the potency, metabolism stability, and selectively targeting fungal CYP51 while reducing off-target side effects. Several new-generation analogs have also exhibited substantial improvements against resistant strains of Aspergillus and Candida (including strains that have some reduced susceptibility to azole medicines) [192,193]. Some hybrid analogs have added multiple forms of bioactivity to their design to provide both inhibition of ergosterol biosynthesis and other actions, such as modulating efflux pumps or inducing oxidative stress, thereby trying to improve both the overall antifungal effect and decrease the opportunity to develop cross-resistance within the azole class [116,194].

As molecular innovation continues, advances in the area of formulation science are also helping to redefine the therapeutic environment. The use of lipid-based nanocarriers, which include solid lipid nanoparticles (SLNs), liposomes, and nanostructured lipid carriers (NLCs), will potentially improve dermal and mucosal absorption, provide longer sustained release profiles, and reduce the potential for local irritation at the site of application [165,166]. These types of delivery systems hold particular promise in treating difficult-to-resolve conditions, such as onychomycosis and biofilm-associated infections, where conventional semi-solid formulations are often ineffective. Moreover, these systems optimize the pharmacokinetic performance of pharmaceuticals to re-align with their pharmacologic requirements by improving target tissue delivery while minimizing systemic exposure [195].

It is anticipated that in future studies, integration of design strategies such as concurrent development of molecular engineering and delivery systems will continue to emphasize the use of structural analysis, structure-based drug design, and prediction platforms for the rational optimization of imidazole derivatives engineered for incorporation into nanocarriers [196]. The development of biofilm-penetrating delivery systems, as well as the use of stimuli-responsive formulations, provides the basis for developing new therapeutic approaches to the treatment of persistent and recurrent fungal infections. Furthermore, imidazoles are likely to remain an essential component of antifungal stewardship, due to their continued importance in the treatment of mild to moderate superficial mycoses, the availability of topical and over-the-counter forms allowing for early treatment intervention, and the fact that their continued use will permit the preservation of systemic triazoles and echinocandins for severe cases [197,198]. As new therapeutic approaches and the development of delivery systems continue to be realized through advances in structural chemistry and targeted delivery, imidazoles are positioned to remain an important, affordable option within the global strategy to reduce antifungal resistance and improve patient outcomes. Figure 9 outlines the overall evolution of the therapeutic paradigm and future innovation landscape.

12. Conclusions

Imidazole antifungals remain a cornerstone in the management of superficial fungal infections, primarily due to their well-established mechanism of action involving inhibition of fungal CYP51 and disruption of ergosterol biosynthesis. Despite strong molecular activity, their clinical performance is largely determined by pharmacokinetic factors, particularly local drug retention, tissue penetration, and exposure duration. This has led to a clear preference for topical delivery systems, while the use of systemic imidazoles has declined due to safety and pharmacokinetic limitations.

Recent advances in formulation science, including lipid-based carriers, vesicular systems, and film-forming technologies, have significantly improved the delivery efficiency of imidazole antifungals by enhancing local bioavailability and overcoming barrier-related limitations. These approaches demonstrate the importance of integrating drug design with delivery strategies to achieve optimal therapeutic outcomes.

However, several challenges remain. Limited penetration in keratinized tissues and biofilm-associated infections continues to restrict efficacy in certain clinical settings. In addition, variability in local drug exposure and incomplete target inhibition may contribute to suboptimal outcomes. Future research should therefore focus on developing retention-driven and barrier-targeted delivery systems for improving transungual and transdermal penetration while establishing more predictive pharmacokinetic–pharmacodynamic relationships. Addressing these gaps will be critical to enhancing the clinical effectiveness of imidazole antifungals and extending their therapeutic utility. The continued optimization of the molecules and formulation-driven improvements to the delivery systems make imidazoles a clinically and strategically important class of antifungal therapies in the modern world.