INNOVATIVE DRUG DELIVERY SYSTEMS FOR INFECTIOUS DISEASES OF THE SKIN

Ayyüce Türkmen1image, İmren Esentürk-Güzel1*image, Bilge Ahsen Kara2image

1*Department of Pharmaceutical Technology, Hamidiye Faculty of Pharmacy, University of Health Sciences, Istanbul, Türkiye. 

2Ankara Gazi Mustafa Kemal Occupational and Environmental Diseases Hospital, Ankara, Türkiye.

ABSTRACT 

Introduction: Skin is the organ of the body that is exposed mostly to the microorganisms. Bacteria, fungi, and viruses are usually responsible for the infection of the skin. Due to lack of penetration through the stratum corneum of conventional systems used in infectious diseases of the skin leads to a decrease in bioavailability. For this reason, nanoscale drug delivery systems that could be used in infectious diseases of the skin are currently being investigated. 

Areas covered: In this review, innovative studies conducted over the years are presented. New topical formulations such as nanoparticles, microemulsions, liposomes, nanofibers and micelles etc are widely used and topic of research for many researchers. 

Conclusion:  Studies have shown that the smaller size and control of these delivery systems provide more effective treatment by increasing drug penetration into the skin. It has been found that drug delivery systems provide a better antibacterial effect, especially in resistant infections caused by MRSA. Also the conventional therapy is also investigated.

Keywords: drug delivery systems, modified release dosage forms, Skin infectious diseases, topical.

 

INTRODUCTION

 

In line with the different cell types it has, the skin basically forms a three-layered structure: epidermis, dermis and hypodermis1. The stratum corneum (SC), is a lipid structured layer containing multiple corneocyte layers in the epidermis2 and drug is absorbed through it. Basically it ac as the barriers in transdermal delivery of drugs3. Conventional formulations like gels and creams show poor penetration while passing through the SC. For this reason, it is necessary to develop innovative drug delivery systems4. Innovative drug delivery systems, being nano-sized, penetrate the skin better and increase absorption. Due to localized drug accumulation residence time of drugs gets increased in the skin. It reduces the side effects of the drug by limiting the systemic absorption. It also allows for controlled drug release5. The skin is an organ open to microorganisms, and bacteria, fungi and viruses are among the pathogens that cause skin infections6,7. Due to the limited success of conventional dosage forms in skin infections, intensive studies are carried out on innovative drug delivery systems including microemulsions, liposomes, nanoparticles, nanofibers and micelles8,9.

In this review, studies on infectious diseases of the skin and dosage forms with some innovative systems  for the delivery of drugs are presented with an overview.

 

INFECTIOUS DISEASES 

 

Bacterial Diseases of the Skin

Streptococcus species are responsible for many skin and soft tissue infections. Impetigo is characterized by a superficial, non-purulent, pruritic, vesicular rash that turns into pustules on the face or extremities, followed by golden, honey-colored crusts 10,11. Staphylococcus aureus is responsible for it12. Ecthyma gangrenosum refers to the sepsis state of P. aeruginosa. Localized lesion gets developed rapidly, initially vesiculobullous that transforms within 12-24 hours to ulceronecrotic lesion13. However lesions remains in less number but may multiply in different stages. Acute bacterial folliculitis associated with one or more hair follicles infection. S. aureus is responsible for it.  It is the most common form of superficial folliculitis. It is 'Impetigo of Bockhart' and is caused by S. aureus. Deeper folliculitis in depth may leads to chronic condition11.

An abscess is the condition of pus in the body tissue11. In mostly cases S. aureus is responsible for it14. In case of accessibility to the affected body part, it can be treated by the means of drainage11.

Cellulite is a disease with an orange peel appearance, which occurs as a result of superficial skin edema surrounding the hair follicles14.  This disease can affect lymph tissue and blood. Gram-positive pathogens, specially Streptococci are treated to control it11. Erysipelas is a more superficial form of cellulite. Erysipelas is more common in older age. It is typically caused by group A streptococci, but group C and G streptococci can also cause this disease11.

Necrotizing fasciitis is a serious picture in which the infection starts with changes such as erythema on the skin surface and extends to the fascia layer14. The disease caused by the synergistic association of aerobic or anaerobic bacteria is defined as type I. Type II necrotizing fasciitis, which is monomicrobial, is also called “streptococcal gangrenous cellulitis”13. Streptococcus pyogenes is the most common pathogen. This is followed by other β-hemolytic streptococci such as newly emerging Streptococcus dysgalactiae. MRSA, Clostridium spp., Vibrio vulnicifus, and S. aureus, including other gram-negative bacilli, are rare causes of type II infection15.

Fournier's gangrene is considered a variant of necrotizing fasciitis with an initial and specific location in the genital or perianal region. It runs in the superficial and deep planes of the urogenital and anogenital fascia. The most common infectious agent is Escherichia coli13.

Viral Diseases of the Skin

Human papillomavirus (HPV) and herpes simplex virus (HSV) are two common viral venereal diseases. HPV infections are characterized by anogenital warts and less frequently premalignant or malignant lesions. HSV infections classically present as grouped vesicles on an erythematous base and are accompanied by burning or pain16. Condylomata acuminata are warts that appear in the anogenital area as a result of sexually transmitted HPV. Condylomata acuminata is present in the anogenital region as single or multiple flat, papillae, hyperpigmented, pink or tan, well-circumscribed papules or plaques16. Anogenital herpes is an infection of the external genitalia and anus with HSV type 1 or type 2 that classically presents as grouped vesicles on an erythematous base. Similar to HPV, HSV is transmitted by skin contact or contact with vesicular fluid16. Common warts (Verruca vulgaris) are clinically characterized by exophytic papules with a rough, papillomatous surface. The most affected areas are the hands and fingers. In addition, stalked and filiform lesions can be seen, especially in the periorificial face areas. In dermoscopic examination, vascular papillomatous areas with thrombosis can be seen in each papilla center17.

Flat Warts (Verruca plana) are characterized by the presence of normochromic pinkish or brown papules with a flat, smooth surface. They are most seen on the back of the hands, upper extremities, or face. Dermoscopy reveals evenly distributed punctate or globular vessels on a yellowish-brown background17.

Palmoplantar warts are endophytic, hyperkeratotic, and often painful lesions. When they occur more superficially with lesions that coalesce into large plaques, they are called mosaic warts or mirmecia17.

Molluscum contagiosum is a skin infection caused by the molluscum contagiosum virus from the poxvirus family. Atypical presentations such as solitary or giant lesions mimicking warts and epidermal cysts may also be seen. It often shows a white-yellowish polylobular structure, and a central pore or navel surrounded by crown-shaped peripheral vessels. Transmission occurs through direct contact with infected skin17. Eruptive pseudoangiomatosis is a self-limiting condition characterized by the appearance of erythematous papules with a halo of vasoconstriction. Lesions are presumed to be triggered by insect bites or viral conditions, including echovirus, Epstein-Barr virus, or cytomegalovirus17.

Fungal Diseases of the Skin

While most fungal infections are superficial, some types of fungi can cause life-threatening infections18,19,20. Dermatophytes are a group of keratinophilic filamentous fungi that cause superficial infections in keratinized tissues and affect 20-25% of the world's population. They are known to invade the SC, causing onychomycosis, tinea cruris, tinea corporis, and tinea capitis. T. rubrum is the most common pathogen causing dermatophytosis, and the emerging dominance of the T. mentagrophytes complex has also been noted recently21. Onychomycosis represents 50% of all nail diseases with a worldwide prevalence ranging from 2% to 8%. It can be caused by different species: dermatophyte fungi, non-dermatophyte fungi and leveduriform fungi. About 90% of all hallux onychomycosis are caused by dermatophytes. The clinical aspects of onychomycosis are mainly onycholysis, changes in nail color and subungual hyperkeratosis17. Tinea capitis is an infection characterized by presenting a single plaque, which can be of microsporic type, caused by dermatophyte fungi that affect the scalp and hair follicles. Trichosporon type transmitted by human-to-human contact, usually showing multiple lesions; The favus type or Kerion celsi type is an inflammatory form with the presence of pustules and micro-abscesses. Clinically, areas of hair loss are observed with toned hair shafts associated with the presence of scaling, inflammation, and pustules17. Tinea nigra is a superficial mycosis caused by the dematiaea fungus Hortaeawerneckii that occurs predominantly in tropical and subtropical climates. Clinically, it presents as an irregularly pigmented brownish or blackish macula that classically occurs on the palms and soles17. Mucormycosis has become the third life-threatening fungal infection worldwide, after candidiasis and aspergillosis. According to clinical findings, it is divided into cutaneous and soft tissue, rhino-orbito-cerebral, gastrointestinal, renal, abdominal, bones and joints mucormycosis. Abscess, necrosis, dry ulcers, skin swelling and eschars are characteristic signs21. Candidiasis, (Candida spp.) is a commensal organism of human skin that can go into pathogenic mode to cause mucosal or disseminated candidiasis. It is a unique type of candidiasis characterized by severe, recurrent or persistent infections of the skin, nails and mucosa by Candida organisms21.

Malassezia is the most common fungus on mammalian skin and >90% of all skin fungi belong to this genus. Malassezia has the potential to invade SC and interact with the host immune system, either directly or through chemical mediators. Therefore, Malassezia can be associated with a variety of skin disorders, from chronic to severe. It is estimated to affect more than 140 million people worldwide each year21. Sporotrichosis is a skin infection caused by the fungus Sporothrixschenckii and its transmission is usually by direct inoculation into the skin and subcutaneous tissue. The most common cutaneous manifestation is lymphocutaneous, where verrucous papules or nodules develop at the site of inoculation with further spread following the lymphatic pathways17.

Chromomycosis, also known as chromoblastomycosis, is a chronic fungal infection most caused by traumatic inoculation of dermatozoa fungi of the genus Fonsecaeaor Cladophialophora. In chromomycosis, dermoscopy reveals a pinkish-white background, yellow-orange oval structures, polymorphic vessels, scaling and crusting17. Eumycetoma or mycetoma is a chronic fungal infection that affects the skin and subcutaneous tissue. Several species of hyaline and dematiaceous fungi may be causative pathogens; but the main ones are Madurella mycetomatis, Nigrograna mackinnonii, Trematosphaeria grisea, Falciformispora senegalensis, Scedosporium apiospermum and Acremonium falciforme. Infection typically occurs by inoculation and affects the distal parts of the lower extremities. It is characterized by the formation of a tumor area, fistula tracts and macroscopic granules. Depending on the fungus involved, the granules may be black or yellowish-white17.

Histoplasmosis is an infection caused by inhalation of the fungus histoplasma capsulatum. Most infections are asymptomatic or self-limited, but some individuals may have serious or widespread conditions. Skin lesions occur in disseminated histoplasmosis and have a wide range of clinical presentations17. Blastomycosis is an infection caused by inhalation of the fungus blastomyces dermatitidis, which can cause an asymptomatic condition or pulmonary and extrapulmonary manifestations that are endemic in parts of North America. The skin is the second most affected organ, after the lung and usually after hematogenous spread, but rarely traumatic grafting may also occur17. Talaromycosis, talaromycesmar-neffei, is an important thermal dimorphic fungus in tropical countries of South and Southeast Asia. The characteristic lesions are papules with central necrosis, but other symptoms may also occur, including papules and ulcers21.

Parasitic Diseases of the Skin

Epidermal parasitic skin diseases include scabies, pediculosis, cutaneous larva migrans, myiasis, and tungiasis22,23. Head lice are obligate human parasites that spend their entire life cycle on the scalp and feed on blood every few hours. Female lice live ≤30 days and lay about 10 eggs per day. Itching, papular urticaria, excoriations, and cervical/occipital lymphadenopathy may occur. Diagnosis is made by direct observation of lice or nits on hair shafts. Head lice can carry and transmit Staphylococcus aureus and Streptococcus pyogenes23. Tungiasis is an ectoparasitic disease caused by the skin of the female Tunga penetrans or, less commonly, Tunga trimamillata flea. Lesions predominantly affect the feet. Typically, after a painless introduction to the feet, embedded fleas mature after a few weeks. The early-stage lesion is a 1 mm red-brown macula that transforms into a central dark punctal nodule. Flea blockage after egg production causes swelling, erythema, itching and pain23. Scabies is a disease caused by sarcoptesscabiei, an obligate microscopic parasitic mite that lives in the human epidermis, where female mites enter the SC and cause a cutaneous hypersensitivity reaction to its products. In classical scabies, prolonged skin-to-skin contact, including sexual contact, is the primary mode of transmission, and fomite-mediated transmission is rare24.

Cutaneous larva migrans (CLM), also called creeping eruption, is a parasitic infestation produced by burrowing the larva of Ancylostomabraziliense. The larva enters intact or eroded skin after contact with fecal-contaminated soil. Solitary tracts involving the feet, hands, hips, and genitals are frequently encountered25. Myiasis is the infestation of the larvae of dipterous (biwinged) flies of vertebrates, including humans. It is traditionally classified according to the site of invasion (cutaneous myiasis, nasopharyngeal myiasis, ocular myiasis, auditory myiasis, urogenital myiasis, and intestinal myiasis)26.

 

TOPICAL DRUG CARRIER SYSTEMS

 

The impact of skin morphology between body sites and individuals is to determine which drug candidates can be absorbed through the skin, how quickly, and if potent enough, they can be useful in topical products. Only small (molecular weight <500 Daltons), soluble (usually low melting point) and moderately lipophilic (log P value between 0-5) compounds with few hydrogen bonds easily pass SC unless some form of skin penetration enhancement technology is used. A larger and more lipophilic drug has more difficulty in passing into the more hydrated living epidermis due to its poor water solubility27,28. Due to the disadvantages of conventional formulations, exploration of potential applications of new carriers such as vesicles, lipidic particles and nano-sized carriers has become an integral part of the development of topical skin disease therapy8. On the other hand, polymer-based nanocarriers can easily pass through the hair follicle29. Solid-lipid nanoparticles, liposomes, niosomes, microemulsion, nanoemulsion etc. New topical systems such as nanocarriers are among the frequently used nanocarrier systems9. Literature examples of innovative drug delivery systems used in infectious diseases of the skin are summarized in Table 1.

Nanoparticles

Nanoparticulate drug delivery systems can be used in the treatment of various diseases through their unique physicochemical properties and their ability to deliver therapeutic agents to desired areas in the body at a predetermined speed and time. There are various nanoparticulate release systems that have been studied as potential drug carriers for the treatment of many diseases30.

Solid Lipid Nanoparticles

They are nano-lipid carriers in which the active therapeutic agent is dispersed in a lipid core matrix. Solid lipid nanoparticles can be prepared using high homogenization or by microemulsion. Solid Lipid Nanoparticles (SLN) are S/Y type emulsions containing solid lipids as oil phase9.

Liquid Crystal Nanoparticles

Liquid crystal nanoparticles (LCNPs) or lyotropic liquid crystals (LLCs) are self-assembled mesophases that exhibit properties of both ordered solids and isotropic liquids. They are also called mesophase, showing that it has a unique structure between the ordered solid phase and the true liquid phase. Liquid crystals are divided into three types: metallotropic, thermotropic and lyotropic. Lyotropic and thermotropic liquid crystals consist mainly of organic molecules31.

Polymer Based Nanoparticles

Polymeric systems are popular as they are more biocompatible and biodegradable. Various polymers and natural protein polymers such as poly lactic acid (PLA), poly glycolic acid (PGA), poly lactide co-glycolide (PLGA), poly caprolactone (PCL), and poly cyanoacrylate (PCA) are used for the preparation of polymeric drug delivery systems. PLA, PGA, PLGA, PCL and PCA polymers are FDA approved for human use due to their high biocompatibility. Mannose-linked and AmB-encapsulated PLGA nanoparticles showed specific targeting on macrophage receptors, thus increasing the efficacy of the drug32.

Metal Nanoparticles

It is a cluster of small metal atoms with a size range of 10-100 nm. In a recent study by Andrade et al.30, chitosan nanoparticles loaded with a new active compound called N'-(5-nitrofuran-2-yl)methylene)-2-benzhydrazide were developed against multidrug resistant diseases. The optimized charged nanoparticles were found to be spherical and regular, with an average diameter of 321 nm, a polydispersity index of 0.18, a zeta potential of +37 mV, and a retention efficiency of 44%. Hasan et al.31 investigated the potential of polymeric nanoparticles (PNP) as a promising therapeutic alternative for skin infections. Mixed PNPs based on PLGA/PEI with loaded clindamycin, a semi-synthetic antibiotic derived from lincomycin, effective against aerobic gram-positive cocci and anaerobic gram-negative bacilli were developed.

Takahashi et al.32 evaluated the potential of PNPs as a new carrier system against S. epidermis biofilm skin infections. Imidazolium cations are loaded into PLGA as the active compound. In the study of Boge et al.33, the use of cubosomes for topical delivery of antimicrobial peptide (AMP) LL-37 was investigated. In the study of Thorn et al.34, liquid crystals that respond to Pseudomonas infection were developed for the combination of glycoside hydrolase and antibiotics. The enzyme glycoside hydrolase (alginate lyase) and antibiotic (gentamicin) are loaded into infection-susceptible liquid crystals to treat Pseudomonas biofilms. Mussin et al.35 prepared silver nanoparticles (AgNP) using the A. australe plant used in skin and soft tissue infections. The antimicrobial activity of AgNPs was tested against 298 fungi and bacteria that cause skin and soft tissue infections..

Emulsions

Emulsions are metastable colloidal systems consisting of droplets of one liquid dispersed in another immiscible liquid. In general, there are three main types of emulsion systems: Macroemulsions, nanoemulsions, and microemulsions65.

Microemulsions

They are stable, translucent, and isotropic oil dispersions in water stabilized by surfactants and co-surfactants for topical and transdermal application of drugs with a droplet size of 0.1-1.0 µm. The presence of oils and surfactants in the microemulsion formulation facilitates drug permeability throughout SC9.

In the study of Erdal et al.36 physicochemical characterization was carried out by preparing microemulsions containing oleic acid (oil phase), Kolliphor EL or Kolliphor RH40 (surfactant), Transkutol (common surfactant) and water. C. albicans ATCC 10231 and C. parapsilosis were used to evaluate the antifungal susceptibility of naftifine loaded microemulsions. Itraconazole is an antifungal agent used in the treatment of ringworm infection. It shows lower permeability when applied topically. Therefore, Patel et al.37 prepared a microemulsion to increase the permeability of itraconazole through the skin. The microemulsion was prepared using eucalyptus oil, tween 20 and methanol as oil phase, surfactant and co-surfactant, respectively. Chhibber et al.38 prepared a microemulsion-based topical application system containing histidine-coated silver nanoparticles to treat murine wound infection induced by K. pneumoniae, a bacterial species that spreads easily in the hospital environment and shows high resistance to antibiotics. Qurt et al.39 designed a microemulsion formulation to increase the permeability of both voriconazole and sertaconazole to the skin due to its high solubility and permeability enhancing properties. oleic acid (oil), tween 80 (surfactant) and ethanol (co-surfactant) based microemulsion systems have been developed. Antifungal activity was evaluated against Candida species.

Nanoemulsions

Nanoemulsions (NE) are Y/S, S/Y dispersions of two immiscible liquids stabilized using a suitable surfactant. The resulting mean droplet diameter is usually < 500 nm. During the preparation of NE, a suitable emulsifier or emulsifier combination is added to achieve long-term stability. 

Lewinska et al. 40 designed NE stabilized with N-oxide surfactants for topical application. Curcumin, derived from Curcuma longa L., has traditionally been used as an antimicrobial phytochemical. Hussain et al.41 prepared a NE gel for topical application of AmB and evaluation of antifungal activity. A series of NEs were prepared using cefsol 218 oil, Tween 80 and Transcutol P by slow spontaneous titration. Antifungal activity against three fungal strains was investigated using the in vitro well agar diffusion method. Danielli et al.42 analyzed the chemical composition of the essential oil of Stenachaeniummegapotamicum to evaluate the antifungal activity of pure oil and NE. NE was obtained by self-emulsification and exhibited a translucent appearance, pH 5.14, particle diameter of 210 nm, and polydispersity of 0.369. Significantly reduced minimum inhibitory concentration and minimum fungicide concentration were observed in NE containing the essential oil of S. megapotamicum. Coelho et al.43 prepared chalcone-containing NE for the development of molecules with leishmanicidal activity. Trans chalcone nanoemulsion and 3'-(trifluoromethyl)-chalcone were prepared using a spontaneous emulsification method. All formulations contain medium chain triglycerides, soybean lecithin, glycerol, ethanol, poloxamer, and water in the aqueous phase as the oily core in the organic phase.

Rajpoot et al.44 developed an acyclovir-loaded nanoemulsion-based organogel (NEOG) system for the effective treatment of HSV infection via topical application. The NEOG system of acyclovir was developed using an oil (isopropyl myristate), surfactants (Span 60/Tween 80) and doubly distilled water as the aqueous phase..

Liposomes

In 1965, Bangham A first discovered that phospholipid molecules can spontaneously form closed bilayer vesicles in water. Shortly thereafter, liposomes ranging in size from 5 to 200 nm were reported to encapsulate hydrophilic or lipophilic drugs in the aqueous phase or bilayer membrane phase using the affinity of different segments of the vesicles. Potential instability issues of liposomes typically relate to oxidation and/or hydrolysis of lipids, drug leakage, aggregate formation, and liposomal fusion45. Naeini et al.46 aimed to evaluate the efficacy of a combination of liposomal and oral azithromycin against CL as the first clinical trial. Liposomes were prepared by a hydration dehydration method. In conclusion, the combination of topical liposomal and oral azithromycin has shown success in the treatment of CL due to its biodegradability, biocompatibility, non-toxic, non-immunogenic nature and prolonged release capability of liposome-loaded azithromycin. Meghana et al.47 developed a liposomal gel containing the antifungal tolnaftate for the treatment of topical fungal infections. Preparation of liposomes with soy lecithin containing tolnaftate was accomplished by dried thin film hydration. Prepared liposomes were added to carbopol gel under stirring to obtain 1% tolnaftate liposomal gel. Ternullo et al.48 developed an effective liposomal formulation intended for transdermal delivery of curcumin for the treatment of inflamed and infected wounds..

Nanofibers

Semnani et al.49 investigated the possibility of using fluconazole locally and as a carrier with the help of polymeric nano and micro fibers in the treatment of infections caused by Candida albicans. Asgari et al.51 produced AmB-loaded core-shell nanofibers using PVA, chitosan, AmB as cores and PEO and gelatin as shell-forming components to minimize AmB side effects. After the solutions were prepared, they were transferred to syringes and placed in pumps. The distance to the collector was set as 14 cm and a voltage of 22 kV was applied between them. Fathi et al.52 prepared vancomycin loaded nanofibers to reduce the toxicity of vancomycin used in the treatment of MRSA skin infections. The nanofibers were prepared by electrospinning. Certain amounts of sodium alginate and PEO were separately dissolved in distilled water under magnetic stirring for 48 hours to ensure complete dissolution. In a study conducted at Isfahan University of Medical Sciences28, two drug formulations (acyclovir nanofiber patch and acyclovir cream) were compared in the treatment of recurrent diseases. As a result of the study, it was observed that acyclovir nanofiber patch and routine acyclovir formulation did not have a significant effect on the healing or crusting time of HSV lesions53. 

Micelles

Polymeric micelles are nano-sized drug release systems characterized by a core-shell structure resulting from the self-assembly of amphiphilic block copolymers in aqueous solution. In the diluted aqueous solution, the amphiphilic molecules exist separately, and the amphiphiles work as surfactants, reducing the surface tension at the air-water interface. The hydrophobic segment can be made from polyesters such as poly(propylene oxide) or poly(ɛ-caprolactone) or polymers and copolymers of glycolic and lactic acids54,55. Bachhav et al.56 investigated the antifungal activity of new aqueous micelle dispersions of different antifungal drugs clotrimazole, econazole nitrate and fluconazole. Micelles were developed using new amphiphilic block copolymers (methoxy poly(ethylene glycol)-hexyl substituted polylactide).  Albayaty et al.53 investigated the delivery of chlorhexidine to S. aureus, MRSA and S. epidermidis biofilms with both single and mixed micelle systems based on polyvinyl caprolactam (PCL)-PEG copolymers. Chlorhexidine along with the polymers was dissolved in 1 mL of acetone, then the organic solution was dispersed into the aqueous phase. He et al.54 developed a charge-convertible quaternary ammonium salt-based micelle system for in vivo bacterial disinfection. It is formed by combining two amphiphiles with opposite charges and shell crosslinking strategy.

Deng et al.55 prepared ketoconazole with loaded Y-shaped monomethoxy poly(ethylene glycol)-block-poly(ɛ-caprolactone) micelles by thin-film hydration method to improve its water solubility. Hydrophobic ketoconazole could be embedded in a hydrophobic core through its hydrophobic interaction with the poly(ε-caprolactone) chain, while hydration of the hydrophilic polyethylene glycol shell resulted in increased water solubility of ketoconazole. 

Niosomes

It is a kind of spherical lipid vesicles prepared by nonionic surfactants. By interacting with SC, they cause a decrease in transepidermal water loss. Its absorption into the skin depends on the type of surfactant, the properties of the drug used, and the morphological characteristics of the niosomal formulations. Niosomes have proven to be an effective system for antifungal drugs22. 

Microsponge Gel

It is a unique drug delivery system consisting of microporous pellets with a size range of 10-25 μm, providing control of the release of encapsulated drugs. Fluconazole has excellent antifungal activity but is not clinically preferred due to skin irritation following topical application. Fluconazole loaded microsponge formulation was developed by liquid-liquid suspension polymerization using different polymers (styrene and methyl methacrylate). Microsponge has proven to be an excellent formulation for the controlled release of fluconazole9. Shamshina et al.57 found in their study that ebercanazol nitrate-loaded microsponge in ethyl cellulose gel showed controlled drug release, no signs of skin irritation, and higher antifungal potential compared to commercial creams.

Film Forming Systems

As an alternative approach to drug delivery systems, polymeric film forming systems (FFSs) have been developed that are applied directly to the skin and form a thin, cosmetically acceptable, and transparent film as the solvent evaporates. Film-forming formulations can lead to sustained drug release via two mechanisms 

Bocxlaer et al.58 investigated film-forming systems for the delivery of DNDI-0690, a nitroimidazole compound with potent activity against Leishmania causing CL. The efficacy of FFSs was evaluated in vivo in the L. major BALB/c mouse experimental model of CL. 

Polymeric Microneedle Systems

Polymeric microneedle mediated sustained release systems (MN@SRS) is a system that combines the advantages of polymeric MNs and the sustained release technique. MN@SRS is minimally invasive, significantly preventing needle stick injuries and pain caused by subcutaneous injections. Dual continuous release MNs is the third strategy of MN@SRS. These MNs load long-acting packaged drugs into sustained release MNs to achieve a longer sustained release period59.

Nanogel

Nanogel is defined as nanoparticles composed of cross-linked hydrophilic structures. Their size varies between 20-200 nm. Oral, topical, vaginal, ocular etc. they can be applied in different ways. They show better skin permeability due to their smaller size and soft material, and diffusion-based swelling allows for the desired drug release behavior. In general, they have excellent biocompatibility and high hydrophilic drug load9. 

 

CONCLUSION

 

Infectious diseases of the skin are a group of diseases that are difficult to treat and highly contagious. Innovative drug delivery systems have been developed due to the inadequacy of formulations such as creams, ointments and gels used in the treatment of these diseases. These systems are generally nano-sized structures and exhibit superior efficacy in the treatment by being better absorbed into the skin. Nanoparticles, liposomes, microemulsions, nanoemulsions, liposomes, micelles, nanofibers can be given as examples of these systems. Various nanoparticles have been designed for use in resistant skin infections. As a result of these studies, it was observed that antibacterial activity increased and tissue regeneration accelerated in wounds and burns. At the same time, nanoparticles do not cause any irritation to the skin. However, due to the toxicity risk of nanoparticles, cytotoxicity tests should be emphasized in studies to be carried out.

 

CONFLICT OF INTEREST

No conflict of interest associated with this work.

 

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