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7.1 Introduction

Nanotechnology has gain great interest in many areas of scientific research during last decades due to its potential benefits. The pharmaceutical field has also taken the advantage of nanotechnology, and the advances in that area have led to the optimization of different types of nano-sized materials for various biomedical applications. In this context, nano-drug delivery systems are increasingly being explored to deliver drugs, cosmetic compounds, or vaccines or for therapeutic purposes. Nano-drug carriers have superiorities of improving aqueous solubility of hydrophobic drugs, controlling/prolonging the drug release, decreasing/minimizing side effects of the drugs such as irritation, keeping the drugs away from environmental factors, and targeting of drugs into specific tissues. Therefore, a great range of nanomaterials including colloidal carriers, vesicles, nanocrystalline, and polymeric nanoparticles has been widely investigated, while some of them are already commercially available; there are also some remarkable data which promise a commercialization in the future.

Fungal infections are widely observed and remain as one of the major healthcare problems worldwide. They can be classified as superficial fungal infections which affect the skin, nails, hair, or mucous membranes and systemic infections affecting the whole body. The prevalence and the incidence of either systemic or superficial fungal infections have been increased in the last three decades. Particularly, the treatment of invasive fungal infections has become more difficult in high-risk patient groups such as AIDS patients, organ transplant recipients, and cancer patients undergoing immunosuppressive chemotherapy. Superficial fungal infections have a less tendency to develop to systemic infection, but they could be serious due to the inefficiency of the treatment (Zhang et al. 2007; Kumar et al. 2014).

Overall, it has a great impact to assess the function of the pathogenetic fungi that cause disease in order to choose the most appropriate therapy and antifungal agent in the treatment of fungal infections. Besides, the delivery system of these agents may play a major role for penetration of drugs into target sites of the disease in terms of improving therapeutic aspect and diminishing or preventing the possible adverse effects (Zhang et al. 2007; Kaur and Kakkar 2010).

The antifungal drugs are administered by topical, oral, or parenteral routes. Topical therapy is the most common approach to the management of mucosal and cutaneous fungal infections because of its advantages including targeting of drugs to the site of disease and reducing of systemic side-effect risk of drugs. The conventional dosage formulations including cream, powder, gels, etc. are widely used in the topical treatment of superficial fungal infections. Some adverse reactions may occur at the site of application, but are less than those of systemic agents. However, in some cases topical therapy could lead to side effects like redness, burning, or swelling, which decrease patient compliance. Furthermore, the topical treatment of deep-seated fungal infections like invasive candidiasis could be inefficient due to the low penetration capacity of the drug into the target site and inadequate deposition in the skin, resulting in low topical bioavailability. As well as the barrier characteristics of the skin, the physicochemical properties of the drugs including lipophilic character and low aqueous solubility affect the penetration of compounds across the membranes. Noticeably, almost all of antifungal agents currently available in the market are highly lipophilic, and they have poor aqueous solubility, which lead to low release rate of drugs into the skin (Zhang et al. 2007; Kaur and Kakkar 2010; Güngör et al. 2013). Likewise, in case of fungal infection of nail and eye, conventional formulations may show problem of less bioavailability.

Oral treatment of fungal infections is preferred when the disease shows extensive harmful characteristics. But, the main drawbacks of the oral therapy are the serious adverse effects like hepatotoxicity and drug interactions (Kumar et al. 2014). The parenteral administration of antifungal agents in the treatment of systemic infections may also lead to severe toxicity reactions. For example, amphotericin B, a broad antimycotic agent, is widely used in the very serious systemic infections. However, this drug has limitations due to its severe nephrotoxicity, which may lead to kidney failure. Therefore, liposome formulation of amphotericin B for parenteral administration has been first marketed under the name AmBisome in 1990. Then, other products containing lipidic carriers of amphotericin B have come into market in the commercial names of Abelcet® (lipid complex) and Amphotec® (colloidal lipid dispersion). The toxicity of the antifungal agent has been reduced with these liposome-based and submicronic colloidal systems of amphotericin B (Torrado et al. 2008; Kaur and Kakkar 2010). In this context, the formulation of antifungal agents into a suitable delivery system is crucial for either topical or systemic treatment of fungal infections. The solubility and permeability of drugs, which are affecting parameters for the enhancement of therapeutic efficacy, should be taken into account. The controlling of drug release also has a great impact to minimize systemic absorption and to decrease the toxicity of these agents. Therefore, the development of novel drug delivery systems is a great challenge to overcome the limitations of conventional dosage forms in terms of improving the efficacy and safety of the treatment. For this aim, different nano-sized drug carriers including liposomes, niosomes, ethosomes, microemulsions, nanoparticles, microspheres, and micelles are intensively investigated. Further, they also provide better penetration of drugs into the deep skin to treat invasive fungal infections. Thus, nano-sized carriers could be considered as a promising tool to improve the efficacy and safety of the treatment of fungal infections. Some comprehensive reviews on novel drug delivery approaches for the treatment of fungal infections have already been published (Kaur and Kakkar 2010; Carneiro et al. 2012; Güngör et al. 2013; Madhu et al. 2012). In the present chapter, the limitations of conventional drug carriers of fungal agents are concisely emphasized and the impact of nano-sized carriers in delivering antifungal agents has been addressed paying particular attention toward the studies performed in recent literature.

7.2 Fungal Infections and Current Treatment Options

Fungal infections of the hair, skin, and nails form the most numerous and widespread group of all mycoses. Superficial mycoses are most often caused by dermatophytes and yeasts. Dermatophytes require keratin for growth and therefore cause diseases in body sites where keratin is present. These sites include the skin surface, hair, and nail. Treatment of dermatophytosis is often dependent on the clinical setting. Single cutaneous lesions can be adequately treated with a topical antifungal drug, but the treatment of some fungal infections on scalp and nail is often ineffective, and systemic therapy is usually needed to cure these disorders (Ghannoum et al. 2013; Zhang et al. 2007). Yeasts are part of human normal microflora, and invasive infections are observed due to disruption of the barrier or impairment of immune functions. Invasive superficial cutaneous infections include mostly the yeast infections with Candida as the absolutely dominating pathogen (Arendrup 2013; Zhang et al. 2007). Candida albicans (C. albicans) can invade virtually every part of the body including deep organs and tissues as well as superficial sites like skin, nails, and mucous membranes (Randhawa et al. 2015). Most infections due to yeasts respond well to topical treatment, whereas extensive lesions often require oral treatment (Kelly 2012).

Fungal infections of the oral and vaginal mucosa and eyes are also predominantly associated with C. albicans (Melkoumov et al. 2015). A number of effective antifungal agents administered either topically or systemically are available for the management of oral candidiasis. However, antifungal drug resistance and poor patient compliance can impair therapy and lead to chronic relapse of the infections (Munoz et al. 2010). Fungal diseases of vulva and vagina are also superficial infections predominantly caused by C. albicans (vulvovaginal candidiasis) (Kasper et al. 2015; Stock 2010). Most cases are accessible to the treatment with local and systemic antifungal agents, and different conventional vaginal formulations (creams, gels, suppositories, powder, ointment, etc.) are available. But these conventional formulations have limited efficacy due to self-cleansing action of vagina, resulting in diminishing residence time of drug on vaginal epithelium (Johal et al. 2014; Stock 2010). Fungal eye infections are less common as compared to infections caused by bacteria or viruses. Various regions of the eye that are attacked by the fungi are cornea and the interior segment of the eye (Kumar et al. 2014).

The main classes of systemic and topical antifungal treatment modalities include the allylamines, the azoles, the polyenes, and the echinocandins (Munoz et al. 2010; Zhang et al. 2007). A list of antifungal compounds which are approved or under investigation and administrated via oral, intravenous or topical route is given in Table 7.1. The conducted studies using nanocarrier approaches for effective delivery and targeting of these agents are also included.

Table 7.1 Conventional commercial available dosage forms and nano-based delivery carriers of antifungal drugs investigated in literature
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7.2.1 Allylamine Antifungal Agents

Allylamine antifungals act through inhibiting of an essential enzyme (squalene epoxidase) in the ergosterol biosynthesis pathway of cell membrane formation of fungus. The increased cellular permeability and growth inhibition occurred due to alterations in fungal cellular membranes (Güngör et al. 2013; Kelly 2012).

Terbinafine has a broad-spectrum activity against yeast, fungi, molds, and dermatophytes and is indicated for both oral and topical treatment of mycoses. Topical formulations of terbinafine, such as dermal spray, cream, and film-forming solution, are also effective against tinea versicolor, an infection caused by Malassezia sp. Terbinafine is considered the second-line systemic therapy for tinea capitis in children, whereas griseofulvin is considered the first-line systemic therapy (Kelly 2012). Naftifine has been shown to be an effective topical allylamine antifungal for the treatment of superficial dermatophytoses (Ghannoum et al. 2013). Cream, gel, and dermal spray formulations of naftifine are available in the market.

7.2.2 Azole Antifungal Agents

Azole antifungals act through selectively inhibiting the synthesis of fungal cell ergosterol, and they alter the permeability of cell membrane by binding with the phospholipids in the fungal cell membrane. The azole antifungal drugs used in the treatment composed of either two or three nitrogens in the azole ring and are thereby classified as imidazoles (e.g., ketoconazole and miconazole, clotrimazole) or triazoles (e.g., itraconazole and fluconazole), respectively (Thompson et al. 2009). Triazoles have a broad range of applications in the treatment of both superficial and systemic fungal infections, and they became standard therapy for invasive candidiasis in the late 1980s (Güngör et al. 2013; Lewis 2010; Sheehan et al. 1999).

The reader is referred to the table to see the conventional dosage formulations of azole antifungals that are currently in therapy. There are a number of licensed azole antifungal drugs; however, fluconazole, itraconazole, posaconazole, and voriconazole are the most frequently used ones in a clinical setting for treatment of systemic fungal infections (Brüggemann et al. 2009).

7.2.3 Polyene Antifungal Agents

The polyene antifungal agents exert their antifungal activity by binding irreversibly to cell membrane ergosterol of fungus. Therefore, the polyenes are fungicidal and have the broadest spectrum of antifungal activity of any of the clinically available agents. These antifungal agents are of amphipathic nature and chemically instable (Flückiger et al. 2006; Güngör et al. 2013; Lewis 2010).

Amphotericin B is the first polyene macrolide antifungal that has been successfully developed into a systemic antifungal agent for the treatment of invasive fungal infections (Adler-Moore and Proffitt 2004). Even though its clinical use is limited by its toxic side effects, amphotericin B remains an important treatment option due to the drug’s broad spectrum and minimal cross-resistance with other antifungals. The therapy options already in use include intravenous infusion, lipid complex, colloidal dispersion, and liposomal dispersion of the drug. Parenteral liposomal amphotericin B (Ambiosome) is on the market since 1990, and it has been shown that this preparation demonstrates less nephrotoxicity when compared to amphotericin B lipid complex (Abelcet®) (Kumar et al. 2014). Amphotericin B has very limited aqueous solubility, thus the development of its novel formulations and administration strategies, which take advantage of the drug's unique pharmacokinetic and pharmacodynamic profile, will open new opportunities for safer and more effective uses of this polyene antifungal (Lewis 2010).

Nystatin is a polyene antifungal drug that has been used in the treatment of cutaneous, vaginal, and oral mucosal fungal infections since the 1950s (El-Ridy et al. 2011). Nystatin has exhibited broad antifungal activity in treating mucocutaneous fungal infections, and its conventional formulations include oral suspension, vaginal ovules, and ointment. The most common adverse effect reported with topical nystatin is allergic contact dermatitis.

7.2.4 Echinocandin Antifungal Agents

Echinocandins destabilize fungal cell walls due to inhibiting of the 1,3-β-glucan synthase complex. They are active against a broad range of Candida and Aspergillus species (Sable et al. 2008). The Infectious Diseases Society of America has published in 2009 a guideline recommending the use of three echinocandin compounds, namely, caspofungin, micafungin, and anidulafungin as initial therapy for the treatment of candidemia in adults, whereas in Europe only caspofungin and micafungin are indicated for candidemia in pediatric and adult patients (Munoz et al. 2010).

7.2.5 Others (Ciclopirox and Griseofulvin)

Ciclopirox is a synthetic hydroxypyridone derivative having antifungal, antibacterial, and anti-inflammatory activities. Ciclopirox inhibits essential enzymes interfering with fungal mitochondrial electron transport processes and energy production. It is active against many fungi including dermatophytes and yeast (Güngör et al. 2013). The conventional formulations of ciclopirox are dermal and vaginal creams and dermal solutions and sprays.

Griseofulvin is the first agent with antifungal activity and was isolated in 1939 (Sheehan et al. 1999). It is an orally administered antifungal drug and is active against all common dermatophytes and shows fungistatic effect in humans. Griseofulvin is accepted as a safe medication and its adverse effects are common, but mild, including nausea, headache, and urticaria (Kelly 2012).

7.3 Nanocarriers of Antifungal Agents

Numerous types of nano-drug carriers have been developed for the treatment of fungal infections. Overview of novel drug delivery approaches of antifungal agents is briefly shown in Fig. 7.1. The research studies focused on nano-sized carriers as a challenge for the effective treatment of fungal infections have been summarized below.

Fig. 7.1
figure 1

Novel drug delivery technologies of antifungal agents

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Vesicular carriers such as liposomes, niosomes, and transfersomes have also been intensively explored for delivering fungal agents in either topical or systemic treatment. Vesicular systems have the advantages of controlling release rate of the active compound and providing localization of topical delivered drugs in dermal layers. Besides, vesicular systems help to carry drug molecules into systemic circulation to decrease toxicity of drugs (Cevc 1996; Akhtar 2014). At the end of the 1980s, the first liposome dermatological product of econazole nitrate (Pevaryl® Lipogel) had been approved by regulatory authorities, and it was introduced in various countries (Korting et al. 1997). Niosomes are liposomes prepared with nonionic surfactants. They have a potential to overcome the barrier characteristic of skin with the effect of high amount of surfactant in their content (Mahale et al. 2012; Marianecci et al. 2014). Transfersomes are defined as elastic vesicles that can be highly deformed. Classical liposomes have a diameter varying from 200 to 400 nm, which is too large to pass through the skin. On the other hand, transfersomes reach deeper dermal tissues and even the systemic circulation with their elastic and highly deformable characteristics (Benson 2009). Ethosomes contain phospholipids like classical liposomes; however, they contain high concentrations of alcohol in their structure. These carriers improve drug permeation due to the high alcohol content which acts as penetration enhancer as well as disruption of the structure of skin by the phospholipids in their content (Ainbinder et al. 2010; Mbah et al. 2014).

Microemulsions are one of the colloidal carriers studied intensively during the last decades by many scientists to enhance delivery of topical antifungal agents into targeted skin sites. They are thermodynamically stable, optically isotropic, colloidal nanocarriers with a dynamic microstructure that form spontaneously by combining oil, water, surfactant, and a cosurfactant. Microemulsions basically offer increased drug-solubilizing capacity and enhanced drug release and skin penetration. They can modify the diffusional barrier of the skin, which is resulted in enhancement of drug penetration into deeper skin layers compared to conventional formulations. The internal phase of microemulsions can act as a drug reservoir resulting in controlled and sustained drug release (Santos et al. 2008; Neubert 2011; Güngör et al. 2015a, b).

Solid lipid nanoparticle and nanostructured lipid carrier formulations have also been investigated intensively for the topical treatment of fungal skin infections due to their ability to enhance skin penetration of loaded drugs. While solid lipid nanoparticles are water-in-oil emulsions composed of solids as oil phase and are prepared from solid lipids or from blends of these lipids, nanostructured lipid carriers are new generation lipid particles, and they contain mixtures of different solid lipids blended with liquid oils. The principal advantage of these carriers is their low risk of toxicity (Iqbal et al. 2012; Scalia et al. 2015).

Micelles are colloidal carriers; they are composed of amphiphilic block polymers and characterized by core-shell morphology in nanoscale size. They have been investigated to facilitate the penetration of antifungal drugs for topical delivery via skin. Cutaneous delivery of drugs into micellar carriers, particularly for the treatment of skin diseases, would benefit in terms of improving aqueous solubility of hydrophobic drugs, targeting of drugs into skin layers (Güngör et al. 2015a, b).

The nano-sized carriers reported in current literature to improve delivery of antifungal drugs are summarized in Table 7.1.

7.3.1 Nanocarriers of Allylamine Antifungal Agents

Hydrogels and microemulsion-based gel formulations of terbinafine have been studied to evaluate the efficacy of these formulations for the treatment of fungal infections. In vitro examination of antifungal activity revealed that the Natrosol®-based hydrogel was a good candidate for the topical delivery of terbinafine (Çelebi et al. 2015). In another study, Barot et al. developed a microemulsion-based gel of terbinafine for the treatment of onychomycosis. They have indicated that the developed microemulsion-based gel formulation enhanced penetration and retention of terbinafine into the human cadaver skin as compared to its commercial cream. This gel formulation of terbinafine showed better activity against C. albicans and Trichophyton rubrum than the commercial cream (Barot et al. 2012a, b).

To resolve problems of long treatment durations and frequent administration in conventional therapy, solid lipid nanoparticles of terbinafine were developed. The skin of nude mice was used as a barrier membrane, and penetration levels of terbinafine of the formulations designed and its commercial product in the stratum corneum, viable epidermis, and dermis were measured. It was concluded that the application of terbinafine solid lipid particles for 12 h might have an efficacy comparable to that of the commercial topical product (Chen et al. 2012).

The skin permeation of ethosomes, binary ethosomes, and transfersomes of terbinafine was compared under nonocclusive conditions. The results indicated that the binary ethosomes most effectively permitted drug penetration through skin, whereas transfersomes made it easier for the drug to accumulate in the skin. Ethosomes had greater improvement in skin permeation of terbinafine than that of its skin deposition (Zhang et al. 2012).

Nails are skin appendages susceptible to fungal attack, and it is difficult to treat fungal infection of nail by conventional formulations because of the very low permeability of the nail plate (Kumar et al. 2014). Tanrıverdi and Özer prepared terbinafine hydrochloride-loaded liposome and ethosome formulations and performed nail characterization studies to examine the effect of formulations on nail surface. They concluded that vesicular carriers could be served as efficient formulations for ungual application of terbinafine hydrochloride (Tanrıverdi and Özer 2013).

In addition to these studies, liposomal gel formulations of terbinafine and an alcohol-free niosome gel containing naftifine hydrochloride were developed and characterized by various researchers (Barakat et al. 2009; Koutsoulas et al. 2014; Sudhakar et al. 2014).

7.3.2 Nanocarriers of Azole Antifungal Agents

Azole antifungal drugs show numerous drug-drug interactions (Brüggemann et al. 2009). The most significant common drug interactions are drug elevations of cyclosporine, tacrolimus and sirolimus due to most calcium channel blockers and benzodiazepines, many statins and steroids, and warfarin and rifabutin (Zonios and Bennett 2008). Furthermore, the increase in antifungal drug resistance, particularly to azoles, created a strong need for the identification of novel antifungal therapies and drug targets. Several novel vehicles, e.g., microemulsions, vesicular carriers, and lipid particles, have been proposed for the topical application of azole antifungal agents.

7.3.2.1 Imidazoles

Clotrimazole

Clotrimazole was first synthesized in the late 1960s and was introduced to markets in 1973. This drug is accepted worldwide for the treatment of common fungal diseases such as vaginal yeast infections and athlete’s foot. Microemulsions, ethosomes, and ultradeformable liposomes were formulated and evaluated by various researchers as clotrimazole nanocarriers for dermal, transdermal, vaginal, and ocular delivery (Basha et al. 2013; Maheshwari et al. 2012; Vanić and Škalko-Basnet 2013). The efficacy and tolerability of clotrimazole microemulsion in the treatment of various topical fungal infections were evaluated clinically (Hashem et al. 2011). Ultradeformable carriers showed prolonged ocular delivery of clotrimazole, and their antifungal activity against C. albicans was higher than niosomal formulation as well as the drug suspension (Basha et al. 2013). Clotrimazole-loaded solid lipid nanoparticles and nanostructured lipid carriers were prepared by the hot high-pressure homogenization technique to assess the physical stability of these particles, as well as the loading capacity and in vitro release pattern. The results obtained demonstrated the use of the lipid nanoparticles as modified release formulations for clotrimazole (Souto et al. 2004). Aqueous micelle solutions of several azole antifungals (clotrimazole, econazole nitrate, and fluconazole) were prepared using amphiphilic methoxy-poly(ethylene glycol)-hexyl substituted polylactide block copolymers. The significant increase in skin deposition demonstrated the ability of micelle-type carrier systems to improve cutaneous antifungal drug bioavailability (Bachhav et al. 2011).

Ketoconazole

Ketoconazole is a broad-spectrum, systemic antifungal agent. Lipid vesicular systems including conventional liposomes, ethosomes, deformable liposomes, and ethanol-containing deformable liposomes were prepared as nanocarriers for ketoconazole, respectively. Characterization of the vesicles was based on particle size, zeta potential, entrapment efficiency, and transmission electron microscopy. The results demonstrated that ethanol-containing deformable liposomes improved both in vitro and in vivo skin deposition of ketoconazole (Guo et al. 2015). Microemulsion formulations of ketoconazole enhanced percutaneous absorption of the drug, and it has been shown that a microemulsion and cyclodextrin combination enhanced the antifungal activity of the drug in vitro against Candida parapsilosis test (Che et al. 2015; Patel et al. 2011).

Sertaconazole

Sertaconazole is a broad-spectrum third-generation imidazole derivative that is effective and safe to cure superficial mycoses, such as tineas, candidiasis, and pityriasis versicolor. Microemulsion-based hydrogels for cutaneous delivery of sertaconazole were studied with an objective to increase the solubility and skin permeability of the drug. The results indicated that the microemulsion-based hydrogel studied provided higher antifungal activity against C. albicans when compared with commercial cream of sertaconazole (Sahoo et al. 2014a, b).

Bifonazole

Bifonazole is a substituted imidazole antifungal agent possessing a broad spectrum of activity in vitro against dermatophytes, molds, and yeasts. It is an effective and well-tolerated treatment for superficial fungal infections of the skin. It has been reported that microemulsion-based hydrogel of bifonazole provided sustained drug release cutaneous application (Sabale and Vora 2012).

Miconazole

Propylene glycol phospholipid vesicles and ultraflexible liposomes have been advocated as deformable lipid carriers for enhanced skin delivery of broad-spectrum imidazole antifungal agent miconazole. The results provided evidence of controlled drug delivery, higher rate of drug transfer across the skin, enhanced skin deposition of miconazole, and better antifungal activity as compared to traditional liposomes and plain drug solution (Elmoslemany et al. 2012; Pandit et al. 2014). Miconazole possesses only slight water solubility, which limits its bioavailability and antifungal efficacy. To increase the dissolution rate of miconazole and itraconazole, the particle size of these compounds was scaled down into nano-size by media milling, respectively. The nanosuspensions obtained had a mean particle size of 210 nm and showed enhanced in vitro performance (Cerdeira et al. 2013).

Econazole

Solid lipid nanoparticles and nanostructured lipid carriers of econazole were designed for the treatment of deep-seated fungal infections. In vivo studies demonstrated that solid lipid nanoparticles promoted a rapid penetration of econazole through the stratum corneum and improved the diffusion of the drug in the deeper skin layers (Keshri and Pathak 2013; Sanna et al. 2007). Polymeric nanosponges were prepared as an alternative carrier for targeting econazole to the skin through topical hydrogel formulation (Sharma and Pathak 2011).

7.3.2.2 Triazoles

Fluconazole

Fluconazole is a semisynthetic triazole, which is active against numerous yeasts. It remains one of mostly prescribed triazoles due to its good bioavailability and substantially fewer drug-drug interactions than other triazole compounds. However, systemic treatment with fluconazole can cause adverse effects, including hepatic enzyme elevation and drug interactions (Melkoumov et al. 2015). Microemulsions were investigated for topical delivery of fluconazole and some promising results have been achieved (Hoeller et al. 2008; Brito Oliveira et al. 2015; Patel et al. 2009). One of the major drawbacks of using microemulsions for topical delivery is their liquid nature and their consequently low residence time on the application site. Therefore microemulsion-based hydrogels have gained interest to improve the viscosity of different formulations. Microemulsion-based hydrogels were evaluated as fluconazole delivery systems for the treatment of cutaneous and vaginal mycoses. The small-scale clinical studies indicated that the microemulsion-based gel developed for the vaginal delivery of fluconazole showed faster onset of action than commercial preparation (Bachhav and Patravale 2009; Coneac et al. 2015; Salerno et al. 2010).

Fluconazole-entrapped liposomes and niosomes were prepared and evaluated in terms of in vitro skin permeation and skin retention. Cutaneous accumulation of fluconazole was affected by components and size of the vesicles. Physical stability studies showed superior potentials of lyophilized fluconazole liposomes after reconstitution in comparison with those of a solution product (El-Nesr et al. 2010; Gupta et al. 2011; Schwarz et al. 2011). To improve the stability and overall applicability of the formulations, fluconazole-loaded liposomes and niosomes have been further incorporated into polymer gels. The studies performed in vivo showed that liposomal gel could produce significantly higher drug, a localization in viable skin, compared with its plain gel. The antifungal study also confirmed the maximum therapeutic efficacy of liposomal gel showing its potential for topical delivery of fluconazole with increased accumulation of drug in the skin (Gupta et al. 2010). Bhalaria et al. prepared fluconazole-encapsulated ethosomes and incorporated in a dermatological base to assess the comparative clinical efficacy in the treatment of candidiasis patients. From the clinical evaluation, the novel delivery system developed demonstrated high antifungal activity in comparison to liposomal formulation, marketed formulation, and hydroethanolic solution of the drug (Bhalaria et al. 2009).

Itraconazole

Itraconazole is a triazole antifungal agent which may be given orally or intravenously. A microemulsion-based gel of itraconazole was developed for overcoming the shortcomings and adverse effects of currently used therapies. The in vivo evaluation indicated the superiority of microemulsion hydrogel formulation for treating superficial fungal infections than those of its conventional approaches (Kumar and Shishu 2015). Microemulsion-based itraconazole gel was also evaluated for effective treatment of onychomycosis. Ex vivo permeation studies indicated better penetration and retention of itraconazole into nail plate and nail bed models (Barot et al. 2012a, b). Chudasama et al. determined in vitro itraconazole permeation from microemulsion gels across excised rat skin. In vitro antimycotic inhibitory activity of the gels was evaluated with agar cup method and C. albicans as a test organism. The results indicated that the microemulsion gel studied showed the widest zone of inhibition and therefore may be a promising vehicle for topical delivery of itraconazole (Chudasama et al. 2011). Deformable liposomes containing hydroxypropyl-β-cyclodextrin enhanced the amount of itraconazole in stratum corneum and deeper skin layers compared to conventional liposomes (Alomrani et al. 2014). Nanosuspensions formulated by ultrasound treatment improved the dissolution behavior of itraconazole (da Fonseca Antunes et al. 2013).

Voriconazole

Voriconazole is a second-generation triazole available in both intravenous and oral formulations (Sable et al. 2008). It has revolutionized the treatment of aspergillosis in severely immunocompromised patients, but the use of voriconazole is compromised by complicated pharmacokinetics, notable drug interactions, and relatively significant adverse events (Zonios and Bennett 2008). Microemulsions as vehicles for topical administration of voriconazole were investigated, and drug-loaded microemulsions were evaluated for their physicochemical characteristics and in vitro permeation studies using guinea pig skin. The presence of permeation enhancers in the formulation favored transdermal rather than dermal delivery of voriconazole (El-Hadidy et al. 2012).

Transethosomes composed of phospholipid, ethanol, water, and edge activator (surfactants) or penetration enhancer (oleic acid) were developed and evaluated for enhanced skin delivery of voriconazole. Transethosomes enhanced both in vitro and in vivo skin deposition of voriconazole in the dermis/epidermis region compared to conventional liposomes, ethosomes, and transfersomes (Song et al. 2012). In order to develop topical preparations of voriconazole for the treatment of mycotic infections of the skin, a nanostructured lipid carrier-based hydrogel formulation was developed and its physical characteristics, in vitro skin permeation, and retention profiles were examined. The in vitro skin permeation study showed that the nanostructured lipid carrier-based hydrogel was superior to conventional cream and microemulsion-based gel formulations of voriconazole. In addition, the formulation developed led to markedly greater accumulation of voriconazole in deeper skin layers as compared with the reference formulations (Song et al. 2014).

Posaconazole

Posaconazole, a lipophilic second-generation antifungal triazole, has a significant role for the prophylaxis of invasive fungal infections in severely immunocompromised patients with extended antifungal spectrum, significant activity against the zygomycetes, and apparently, optimal safety profile. Posaconazole is only available as an oral formulation (Brüggemann et al. 2009). Multiple daily dosing, the need for fatty foods for absorption, and the absence of an intravenous formulation restrict its use to selected populations (Zonios and Bennett 2008). There has been consideration of a potential enhancement in solubility with decreasing of the particle size of drugs into nanometer size range. To enhance solubility and the rate of dissolution, posaconazole was nano-sized using wet media milling technology. The mean particle size of the processed crystals had a narrow distribution profile with a mean size of 185 nm (Merisko-Liversidge and Liversidge. 2011).

7.3.3 Nanocarriers of Polyene Antifungal Agents

The activity of nano-sized amphotericin B against the growth of C. albicans was investigated, and the conventional micro-sized amphotericin B was converted into nano-size (5–20 nm) using a ball milling machine. The results revealed that the antifungal activity of nano-sized drug was two to four times greater than the micro-counterpart. Nano-sized amphotericin B showed an enhanced surface activity by interacting with the walls of Candida yeasts (Randhawa et al. 2015). Kang et al. formulated amphotericin B-loaded cationic liposome gels for topical application and have found this thermosensitive gel to be more stable and less toxic than free amphotericin B for vaginal delivery (Kang et al. 2010).

Nystatin nanoemulsions have been evaluated for topical application. A faster pharmacokinetic release from the nanoemulsion formulation has been recorded than commercial nystatin ointment, and the amount of drug retained in the skin was sufficient to ensure an effective antifungal effect (Fernandez-Campos et al. 2012). In another study performing a comparative evaluation, a nanoparticulate nystatin formulation against a commercial nystatin preparation showed that nanonization of nystatin provides a novel approach to enhancing the efficacy of drug in the treatment of oral candidiasis (Melkoumov et al. 2015).

El-Ridy et al. have been encapsulated nystatin in niosomes to obtain a safe and effective formulation administered parenterally for neutropenic patients. Nystatin niosomes exerted less nephrotoxicity and hepatotoxicity in vivo, showed higher level of drug in significant organs, and improved efficacy in elimination of the fungal burden in experimental animals infected with C. albicans compared with those treated with free nystatin (El-Ridy et al. 2011).

7.3.4 Nanocarriers of Echinocandins

Caspofungin, micafungin, and anidulafungin exist in intravenous form (lyophilized powder for infusion) and are indicated in the management of invasive fungal infections such as esophageal candidiasis and candidemia (Sable et al. 2008). Currently there hasn’t been any study published about nano-sized delivery systems of echinocandin antifungal agents. This fact might be due to the relatively big molecular weight of echinocandins (>1000 Da) when compared to conventional small-molecule drug compounds.

7.3.5 Nanocarriers of Ciclopirox and Griseofulvin

Aggarwal et al. developed a microemulsion formulation of griseofulvin intended for the treatment of dermatophytosis. The dermatopharmacokinetics and antifungal activity of the formulation were evaluated on guinea pig model. Treatment of guinea pigs with griseofulvin microemulsion resulted in a complete clinical and mycological cure in 7 days. The formulation was observed to be histopathologically safe and stable (Aggarwal et al. 2013).

Griseofulvin was encapsulated in the deformable membrane vesicles for dermal delivery. The optimized vesicles illustrated remarkably higher drug permeation and skin retention when compared with conventional liposomes. The results indicated that the topical deformable vesicles of griseofulvin could be considered as an alternative to reduce the obstacle of conventional oral formulations (Aggarwal and Goindi 2012). The same researchers optimized griseofulvin-loaded solid lipid nanoparticles by hot microemulsion technique. The cumulative amount of drug permeated through excised mice skin from solid lipid nanoparticles was more than fivefolds as compared to permeation from conventional cream base (Aggarwal and Goindi 2013).

Niosomal vesicular carriers were investigated for dermal delivery of ciclopirox olamine. Deposition of drug into rat skin from niosomal dispersion and niosomal gel formulation was significantly higher than that of solution formulation of ciclopirox olamine and its commercial product. Obtained niosomes possessed sufficient stability on storage (Shaikh et al. 2010). Karimunnisa and Atmaram investigated mucoadhesive liposomal ciclopiroxolamine gel for vaginal use. The gel exhibited good mucoadhesivity to sheep vaginal tissue, and furthermore liposome-entrapped drug displayed good antifungal activity (Karimunnisa and Atmaram 2013).

7.4 Conclusion

Delivery of antifungal agents used for the treatment of superficial and systemic infections has a great impact in terms of both therapeutic aspect and safety. In particular, treatment of deep-seated fungal infections could be inefficient due to poor penetration of drugs into targeted sites, resulting in unsatisfactory bioavailability. In addition, the controlling of drug release is also important to minimize systemic absorption and to decrease the toxicity of these agents. Therefore, novel drug delivery systems play a key role to overcome the limitations of conventional dosage forms to improve the efficacy and to ensure safety of the treatment. So far, optimization of different types of nanocarriers such as liposomes, niosomes, micelles, and transfersomes have been intensively investigated to improve efficiency and safety of antifungal agents. Some liposomal products of antifungal agents are already commercially available. At the end of the 1980s, the first liposome dermatological product (Pevaryl®Lipogel) has come into market. Liposome formulation of amphotericin B for parenteral administration has been first marketed under the name AmBisome in 1990. Still there is a great effort to optimize novel carriers of antifungal agents. In this context, a considerable amount of research focused on the development of nanocarriers of antifungal drugs, to some extent, has been published.