Frontiers in Anti-Infective Agents: Volume 5 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Anti-Infective Agents
- Sprache: Englisch
Anti-infective agents are a distinct class of pharmacologically important molecules that have served mankind in different capacities to combat life-threatening pathological conditions. They include antibacterial, antifungal, antiviral, antituberculosis, antimalarial and urinary anti-infective agents. However, evolutionary changes, adaptations and development of new strains of pathogenic microorganisms that have reduced the therapeutic efficacy of existing drugs, thus, limiting their clinical utility over the years.
Frontiers in Anti-Infective Agents Volume 5 is a collection of notable research efforts, successful anti-infective drug development programmes and a comprehensive overview of successful and unsuccessful clinical trials in this domain. The volume covers interesting topics: 1) the treatment of acute wounds with the vikut® formula, 2) anti-infective treatment of ocular diseases and 3) sars-cov vaccine development and antimicrobial therapy for SARS symptoms. A chapter summarizing recent anti-infective approaches rounds up the contents of this volume.
This book is a timely reference for postgraduate scholars and researchers seeking updates in specific areas of anti-infective drug development. Allied healthcare professionals (clinical and public healthcare professionals) can also benefit from the information presented within.
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Veröffentlichungsjahr: 2021
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PREFACE
Bacteria, viruses, fungi, protozoa, or parasites are the causative agents for various infectious diseases and are responsible for morbidity and mortality at large scale worldwide. Although remarkable accomplishments have been achieved in recent years in developing new anti-infectives, the widespread emergence of drug resistance has been the main obstacle and continues to provide a strong stimulus to develop new strategies in drug design and discovery. For instance, despite the exuberant therapeutic success of antibiotics, acute infections are still responsible for 25% of deaths worldwide, killing around 17 million people per year. Apart from de novo drug discovery, the re-positioning, and re-engineering of existing drugs or drug-like molecules with known pharmacokinetics and established target profiles have now become ideal starting points for identifying new chemical entities as new anti-infectives. The quantum of research in this field has shown a tremendous increase in recent years and thus keeping oneself abr/east of recent developments is rather challenging.
The book series “Frontiers in Anti-infective Agents” is aimed to update the scientific community on recent accomplishments and provide critical commentaries on the most exciting developments in the field of anti-infectives. The present volume 5 of the series has six comprehensive reviews, contributed by leading practitioners in these fields. These reviews broadly cover the clinical use of Vikut® for chronic and non-chronic wounds, drug delivery systems for ocular drug targeting, aspects of vaccination against SARS-CoV virus categories, nanotechnological interventions for the diagnosis and treatment of infectious diseases, repurposing and re-engineering of various drugs for targeting SARS-CoV-2 and a bilayer tablet approach for the treatment of sexually transmitted diseases.
The 1st chapter by Durgun et al. explicates ocular drug targeting as one of the most challenging research areas because of the presence of natural barriers of the eye. It discusses in detail the various drug delivery systems approved by USFDA for the treatment of ocular infections wherein the bioavailability is enhanced using micro and nano-carriers. The 2nd chapter by Rani et al. includes the various aspects of vaccination, its importance in the current scenario, and methods of implementation specifically targeting SARS-CoV virus categories.
The 3rd chapter by Lara-Esqueda et al. describes the healing properties of each of the components of Vikut® and the results of its use in the clinical case obtained by healthcare professionals in the treatment of both chronic and non-chronic wounds. Sonia Sethi discussed the nanotechnological interventions for the diagnosis and treatment of infectious diseases, particularly resistant to conventional antibiotics, in the 4th chapter. In particular, the use of nanomaterials with intrinsic anti-infective properties as carriers for targeted and site-specific delivery of potential drugs is discussed in detail.
Mohan and Venugopal, in the 5th chapter, highlight the successful repurposing and re-engineering of various drugs for assessing their activities on SARS-CoV-2 and are in various phases of clinical trials. A particular emphasis was given on protease inhibitors, polymerase inhibitors, antimalarial drugs, rheumatoid drugs, and lipid-lowering statins with promising SARS-CoV-2 activities. The 6th chapter by Gaikwad and Patil delineats a bilayer tablet approach for the treatment of sexually transmitted diseases. The combination of Cefixime and ofloxacin was employed to prepare the bilayered tablets to maintain the peak plasma level of the drug.
We are indeed grateful to all the authors of the above-cited articles for their excellent contributions and hope that these contributions will help readers in gaining a better understanding of this field. We would also like to express our gratitude to the entire team of Bentham Science Publishers, particularly Ms. Fariya Zulfiqar (Manager Publications), and Mr. Mahmood Alam (Editorial Director), for the timely production of the 5th volume.
List of Contributors
Anti-Infective Agents in Ocular Treatment and New Approaches
Meltem Ezgi Durgun1,*,Sevgi Güngör1,Yıldız Özsoy1Abstract
Ocular drug targeting is one of the most interesting and challenging research topics due to the presence of natural barriers of the eye that attract pharmaceutical technologists. It is important to treat ocular infections, which are frequently encountered and affect people of all ages, in order to protect the integrity of the eye. For this reason, anti-infective agents used in the treatment of ocular infections are frequently the subject of ocular drug delivery system studies. The ocular bioavailability of anti-infective agents is also increased, thanks to micro and nano-carriers, where the dose strength of drugs and frequency of administration can be reduced. On the other hand, the fact that there are products approved by the USFDA among these delivery systems which have completed clinical phase studies shows that these drug delivery systems are promising in the ocular field.
INTRODUCTION
The eye, the organ of vision, is located in the orbita and is protected by the orbital bones. It is one of the most complex organs in the human body due to its anatomy and physiology and consists of three different layers as fibrous, vascular, and neural structures. Since the eye is in contact with the external environment, it contains natural protective mechanisms. The protective mechanisms known as ocular barriers are tear film, cornea, conjunctiva, sclera, blood-aqueous humor, and blood-retina barrier. They are mainly tasked with minimizing the toxic effects of external agents such as liquids and dissolved molecules on the eyes. However, these protective mechanisms also reduce ocular bioavailability of drugs. Different drug delivery strategies have been developed in order to eliminate the effect of
ocular barriers, which are more effective in topically applied drugs, and thus increase ocular bioavailability. However, most of Ocular drugs are differentiated into conventional dosage forms and drug delivery systems. 90% of commercial products are conventional dosages and are applied topically to the eye. In response to these drugs with low ocular bioavailability, the development of new drug delivery systems is one of the most interesting and challenging areas for scientists. These systems can cross the ocular barriers, accumulate in the target area, show a longer retention time, and do not cause systemic toxicity. Micro and nanoparticles, microemulsions, nanosuspensions, solid lipid nanoparticles, liposomes, cubosomes, dendrimers, niosomes, hydro-gelling systems, ocular lens/inserts/implants, and micelles have been developed as ocular drug delivery systems.
Depending on the anatomical and physiological structure of the eye, any ocular disease or disorder can easily trigger a secondary disease/disorder. In particular, ocular infections can quickly involve other tissues. Also, alterations in tissue because of infection cause activation of opportunistic pathogens and aggravation of infection. To maintain the structural integrity of the eye, it is imperative to treat ocular infection quickly, accurately, and effectively. Otherwise, serious complications such as visual loss or spreading of infection to different organs can be seen. The primary group of commercial ocular products is intended to treat ocular infections. Artificial tears and lens solutions are used for the treatment of dry eye disease. However, both dry eye disease and lenses that are not used or stored properly cause ocular infection. For this reason, we can evaluate artificial tears and lens solutions as prophylactic products against ocular infection.
The development of new dosage forms for the treatment of ocular infections is one of the main topics in pharmaceutical science. The subject of these studies may be anti-infective agents that have been used for a long time in the treatment of ocular diseases, and those the effectiveness of which has been proven byin vivoexperiments. Also, newly developed anti-infective agents that have not yet been studied in the ocular field may be a subject. All studies have the aim of increasing the ocular bioavailability of anti-infective agents with a suitable drug delivery system.
In this chapter, anti-infective agents used in the treatment of ocular infections, commercial products, and new approaches to anti-infective therapies will be examined. Also, the anatomy and physiology of the eye will be discussed with the aspects that affect the ocular bioavailability of drugs and should be considered in the development of new ocular drugs. This chapter will be informative for people
working on drug delivery systems for ocular targeted drugs and anti-infective agents. It will also provide insight for clinicians who follow promising new approaches among treatment options and participate in clinical trials.
ANATOMY, PHYSIOLOGY, AND PHARMACOKINETIC OF EYE
The eye, the organ of vision, is located in the orbita and is protected by the orbital bones. The lens divides the eye into two as anterior and posterior segments. The eyeball consists of three layers, from the outside to the inside, the tunica fibrosa bulbi, the tunica vasculosa bulbi, and the tunica interna bulbi [1]. Inside the eyeball limited by these three layers, the corpus vitreum, lens, and aqueous humor are located. Tunicae Fibrosa Bulbi (Corneal-Scleral Layer) is the fibrous layer of the eyeball. Tunica vasculosa bulbi is the vascular layer, and tunica interna bulbi is the innermost neural layer [2]. The anatomy and segments of the eye are shown in Fig. (1).
Fig. (1)) Anatomy of the eye and ocular drug administration routes.The eye contains natural barriers that limit the passage of liquids or dissolved substances into the anterior and posterior segments of the eye, depending on its anatomy and physiology. These barriers also affect the ocular absorption and the bioavailability of drugs. These barriers are in an anatomical order; tear film, cornea, conjunctiva, sclera, blood-aqueous humor or iris-ciliary body, lens, and blood-retinal barriers. While tear film acts as the first barrier for the drugs applied, it dilutes the drugs due to continuous production of tear fluid and nasolacrimal drainage. The cornea has a lipophilic and hydrophilic character at the same time due to tight junctions and collagen fibers in its structure. For this reason, the corneal epithelium acts as a barrier for hydrophilic drugs, while the stroma prevents the passage of lipophilic drugs to internal tissues. The sclera also acts as a barrier to lipophilic drugs with the collagen fibers it contains [3-6]. Besides, the pores of the cornea and sclera affect the passage of drugs to internal tissues. Drugs with particle size smaller than 100 nm and particle sizes in the range of 20-80 nm, respectively, can pass through the cornea and sclera [7, 8].
Drugs are administrated to the eye with different methods in order to increase bioavailability in the presence of ocular barriers. In addition to topical application, subconjunctival, scleral, and intravitreal injection are other ocular drug administration routes. However, the difficulty of applying these methods and possible complications limit their use.
OCULAR İNFECTİONS
Keratitis
Keratitis is one of the most common causes of visual impairment among adults. It is a rapidly progressing disease. Corneal opacification due to keratitis is the fourth underlying cause of blindness [9]. Contact lenses, ocular surgery, physical or chemical injury, diabetes, immunosuppressive diseases, topical steroids and agricultural activities in developing societies may be the predisposing factors of keratitis formation. The type of microorganism that causes keratitis depends on the geographical location and climate of the region where the person lives. Keratitis is divided into three main groups as infectious, interstitial, and non-infectious, as shown in Table 1 [10-15].
Conjunctivitis
Conjunctivitis is an infection of the conjunctiva due to bacteria, viruses, irritant substances, or allergens. It is a common ocular disease that affects people of all ages and socio-economic segments. The fact that 70% of acute conjunctivitis cases present to primary care centers or emergency services instead of an ophthalmologist is one of the data showing the prevalence of the disease [20-23].
Fungi species do not play a role in the development of conjunctivitis. However, conjunctival involvement can also be seen in allergic conjunctivitis or in cases of fungal keratitis and/or scleritis [24-26]. Depending on the pathogen type, topical drugs are preferred in the treatment.
Endophthalmitis
It is an infection of the intraocular cavities, the aqueous humor, and the vitreous humor that fills these cavities. It is basically divided into two groups as infective and non-infective. The infection seen in infective endophthalmitis is usually of bacteria or fungus origin. The development of viral or parasitic infections is not a common condition [27].
Infectious endophthalmitis is divided into exogenous and endogenous endophthalmitis. Exogenous endophthalmitis is a type of endophthalmitis that occurs after eye surgery or trauma. Possible contamination in sterile equipments and solutions used during intravitreal injection and surgical procedure, the risk of contamination from the personnel of the surgery, and the flora of the eyelid or conjunctiva may be factors in the development of infection [27-30]. Endogenous Endophthalmitis accounts for 5-15% of total endophthalmitis cases. The infectious agent is bacteria or fungal. It occurs when a possible infectious agent in any tissue reaches the eye. Gram positive bacteria such as S. aureus, streptococci and Gram negative bacteria such as Pseudomonas and E. coli [28]. Infectious endophthalmitis is treated with antibiotics or anti-fungal agents, depending on the type of pathogen. These drugs are the same as the active ingredient used in the treatment of infectious keratitis and are applied topically, systemically, or intravitreally [28].
Non-infectious endophthalmitis is an uncommon type of endophthalmitis seen with infection caused by an allergen substance independent of any microorganism infection. Corticosteroids are used in their treatment [31, 32].
Uveitis
Uveitis is the infection of the uvea, or vascular layer of the eye due to various reasons. Although it is defined as ocular infection, it is actually a multidisciplinary disease since it may develop due to another underlying disease. Determining the agent by performing a detailed examination in an individual diagnosed with uveitis can enable the diagnosis of another disease [33-35]. It is thought that more than 2 million people in the world are affected with uveitis and 10% of blindness worldwide is due to uveitis. The incidence in the age range of 16-65, defined as the working population, is higher than in other age groups [35-39].
The International Uveitis Working Group (IUSG) classifies uveitis clinically into infectious, non-infectious, and masked uveitis [40]. In some sources, endophthalmitis is considered uveitis [35, 41].
Infectious uveitis is a type of uveitis that develops due to bacterial, viral, protozoal, fungal, helminthic, or intestinal worms. Its incidence is 50% more common in less developed and / or tropical countries than in developed countries. It is seen in the USA and European countries with a rate of 13-21%. While varicella-zoster, herpes simplex, or toxoplasma are the main factors in the USA and European countries, mycobacterium leprae, Mycobacterium tuberculosis, toxoplasma, and onchocerciasis causing river blindness are the main factors in tropical and/or underdeveloped countries [35 ,42]. Infectious uveitis is generally seen in the posterior segment. Therefore, the main drug administration method in treatment is intravitreal injection. It is extremely important to determine the pathogen type to choose the correct active ingredient. Ganciclovir and foscarnet as anti-virals, vancomycin, gentamicin, ceftazidime, moxifloxacin, and amikacin as anti-bacterials, clindamycin, and Trimethoprim/sulfamethoxazole as an antiprotozoal, AMB and VRC as anti-fungal are preferred [35].
Non-infectious uveitis is associated with systemic disease [40]. In the absence of systemic disease, uveitis may develop due to trauma, an ocular surgical procedure, idiopathic diseases, and the use of drugs such as cidofovir or rifabutin. Diseases such as sarcoidosis, juvenile idiopathic arthritis, and Behçet's disease are given as examples of uveitis due to systemic diseases [35]. Treatment in non-infectious uveitis is generally performed with corticosteroids or alternative agents that will suppress the immune system [35].
Masked uveitis is a type of uveitis that develops due to cancer. It is divided into neoplastic or non-neoplastic [40].
Scleritis
Scleritis is a type of ocular infection that is centered in the sclera and can often involve adjacent tissues such as the episclera, cornea, and uvea. It is a rare ocular disease with severe pain and blinding potential [43-45].
Considering the etiology, the incidence of the systemic disease has been reported to be 39-50% in individuals with scleritis [46-48]. Posterior scleritis is more likely to be associated with anterior scleritis in an individual with underlying systemic disease [46]. Infection, autoimmune diseases, surgical interventions, intraocular tumors such as melanomas, conjunctival tumors, lymphoma, trauma, congenital erythropoietic porphyria after allogeneic bone marrow transplantation, rare systemic diseases such as graft- versus -host disease can cause scleritis [43, 49,50].
Infection is a rare cause of scleritis (5-10%). However, it is a common belief that infected scleritis begins with an autoimmune basis and appears with a progressively worsening condition and has worse results than autoimmune scleritis. Although the reason for this is not known exactly, it is thought to be caused by the late diagnosis or the aggressiveness of the pathogens causing the infection. Bacteria, protozoa, fungus, coinfections are the most common causes of scleritis due to infection. Many pathogenic organisms have been shown to be among the possible causes of scleritis in cases seen over the years [43,44]. Fungal scleritis generally gives worse results than bacterial or viral scleritis [ 51]. Studies showed that despite the treatment, rapid cataract, serous retinal or choroidal detachments, or endophthalmitis were observed in many patients [43].
Surgery (pterygium, cataract, glaucoma, vitroretinal or conjunctival tumor surgery) [45], immunosuppressants [52,53], traumas, Mitomycin C, and radiation use [54-59] are among the most common infectious scleritis factors.
Watson and Hayreh classified the scleritis by anatomy. This classification system is considered to be the most common predisposing factors of infectious scleritis. Table 2 includes the agents used in this classification and treatment [45].
ANTI-INFECTIVE AGENTS USED IN OCULAR TREATMENT
The eye is separated from other organs due to its unique anatomy and physiology. It has a small size and volume but has rich vascular and neural networks. On the other hand, tear, aqueous humor, and vitreous humor turnover are rapid. Due to this unique anatomy and physiology, it is common for an infection that begins in any ocular tissue to spread to other ocular tissues. Also, as ocular immunity is suppressed by infection, the eye becomes suitable for the activation of other opportunistic pathogens. Therefore, the treatment of ocular infections should be done quickly with a suitable agent. Anti-bacterial, anti-viral, anti-fungal, and anti-parasitic drugs are used in the treatment of ocular infections. The anti-infective agent should be selected according to the type of pathogens that caused the infection. For this reason, it is very important to be able to isolate the strain that is the cause of infection. Anti-infective agents used in ocular infection, approved by the USFDA, are listed in Table 3.
Most of the commercial products used in the treatment of any disease are in a conventional dosage form. 90% of the products in the treatment of ocular diseases are also included in this group. Conventional dosage forms applied to the eyes are solutions, suspensions, ointments, and gels (4-6). These dosage forms, also known as traditional medicines, generally target the anterior segment of the eye and do not show much effect on a possible disease in the posterior segment. On the other hand, the ocular bioavailability of these drugs is low due to the ocular barriers. Because of their low bioavailability, the dose frequency during the day is high, and this reduces patient compliance. Also, the fact that gels and ointments cause blurry vision is another factor that reduces patient compliance. To address these issues, drug delivery systems targeting ocular tissues have been developed.
OCULAR DRUG DELIVERY SYSTEMS
Microparticles and Nanoparticles
Microparticles and nanoparticles are colloidal drug delivery systems with particle sizes between 1-10 µm and 10-1000 nm, respectively [66, 67]. They are often preferred for ocular drug targeting. Prolonged drug release and slow ocular drainage due to particle size are important advantages compared to conventional dosage forms. Because the particle size of microparticles is larger than nanoparticles, their ocular tolerability is less than nanoparticles [68-70].
Cortesi et al prepared acyclovir loaded microparticles using different Eudragit types. It was found that the prepared microparticles had an extended release for 8 hours, and their anti-viral activity was similar to that of acyclovir solution [71]. Gavini et al. produced ciprofloxacin loaded microparticles using chondroitin 6-sulfate or lambda-carrageenan. Also, they examined the mucoadhesion properties by adding carbomer (Carbopol 934P®) to the microparticles. They reported that the microparticles were suitable for ocular application in terms of particle size, and high mucoadhesion was seen in all formulations, although it was higher in those with carbomer added [72].
Liu et al prepared cyclosporin A loaded poly-lactic acid (PLA) nanoparticles and compared them with Restasis®, which is used to treat dry eye disease. It has been observed that nanoparticles have a longer retention time with ocular tissues than Restasis® thanks to their mucoadhesion feature and significantly reduces the dose of cyclosporine A to be used (50- to 100-fold). Although Restasis® is normally used twice a day, it was determined that nanoparticles were applied once a week to eliminate infection. In addition, it has been reported that goblet cells regenerate within one month in the treatment applied with nanoparticles, and this regeneration is not seen in the treatment with Restasis® [73]. Poly(lactic-co-glycolic acid) (PLGA) is a copolymer commonly used in the preparation of ocular delivery systems [74]. Gupta et al. produced levofloxacin loaded PLGA nanoparticles and compared with a commercial product. It has been determined that the nanoparticles remain in the pre-corneal area for 24 hours and their efficiency is better than the commercial product in in vivo rabbit model [75]. In another ocular study with PLGA, acyclovir loaded nanoparticles were produced using PLGA combined with TPGS. Alkholief et al. reported that AUC0-24h, t1/2 (h), and MRT0-24h values of nanoparticles were 2.78-fold, 1.71-fold, and 2.2-fold higher, respectively, compared to acyclovir solution [76]. Clarithromycin is another anti-infective agent studied with PLGA. In anti-fungal activity studies, the minimum inhibitory concentration (MIC) of nanoparticles on S.aureus was 8-fold lower than clarithromycin solution. Although this study was not conducted with direct ocular drug targeting, Mohammadi et al. underlined that the nanoparticles were suitable for ocular application due to their particle size (in the range of 180-280 nm) [77].
Solid Lipid Microparticles and Nanoparticles
Despite the advantages of micro and nanoparticles, their use is limited because of the long-term potential toxicity of the polymers used in their preparation. Solid lipid microparticles (SLM) and solid lipid nanoparticles (SLN) are drug delivery systems developed in the 1990s as an alternative to the emulsion, polymeric nanoparticles, and liposomes. Their lipid part formed by the liquid lipid (oil) has been substituted by a solid lipid. While SLNs have smaller diameters than 1 µm, SLMs have a larger particle size [78, 79].
SLM or SLN are often preferred for ocular targeting of anti-bacterial drugs. Wolska et al. prepared SLMs of cyclosporine A using Compritol 888 ATO and Tween 80, and emulsions of cyclosporine A using soybean oil or castor oil for comparison. In the studies, the concentration of cyclosporin A in the precorneal tissues in the SLM groups was found to be higher than the therapeutic value and emulsion groups [80]. Gökçe et al. also developed SLN drug delivery systems containing cyclosporine A. It has been shown that the cumulative corneal permeation value of cyclosporin A of these formulations was higher 2-fold than the cyclosporin A solution, and the formulations were not cytotoxic and did not cause irritation in cell culture studies [81]. In studies conducted with another antibiotic ofloxacin, it was observed that SLNs had extended release for 8 hours, and in vivo corneal permeation of SLNs in rabbit eyes after 24 hours were 2.5-fold higher than commercial eye drops (Oflox®) [82]. In the study done by Pignatello et al. with ciprofloxacin, it was reported that SLNs have anti-bacterial effects on different strains, even nine months after their production [83].
Tobramycin is an antibiotic with commercial ocular drops, suspension, and ointment [84]. Chetoni et al. applied the tobramycin SLNs they developed both topically to the eye and intravenously to two separate groups. In these in vivo rabbit studies, it has been observed that tobramycin SLNs accumulate in the retina, regardless of the route of administration. It was also reported that SLNs show more bactericidal activity against Pseudomonas aeruginosa compared to tobramycin solution [85].
Baig et al developed SLNs of levofloxacin using the Box-Behnken experimental design. In comparative studies with levofloxacin commercial eye drops, levofloxacin SLNs have been reported to provide extended release for 12 hours. It has also been observed that SLNs, whose anti-fungal activity is similar to eye drops, were not toxic with the hen's egg-chorioallantoic membrane test (HET-CAM test) [86]. Khames et al. also made a different SLN study using the Box-Behnken experimental design. They produced natamycin SLNs with different lipid types and chose the most appropriate formulation using the Box-Behnken experimental design. It was shown that the final natamycin SLN had extended release over 10 hours, and the anti-fungal activity of SLNs was 2.5-fold higher than the natamycin suspension [87].
Valacyclovir is an anti-viral drug. ex vivo corneal permeation and ocular bioavailability of valacyclovir SLNs were found to be 7-fold and 2-fold higher, respectively, compared to valacyclovir solution. Also, HETCAM analysis was demonstrated that the developed SLNs were non-toxic [88].
Although tuberculosis is a disease that generally affects the lungs, orbital and external eye infections were detected in 15% of 6.3 million tuberculosis cases in 2016 [89]. Isoniazid is used in the treatment of tuberculosis caused by Mycobacterium tuberculosis. Singh et al. prepared SLNs of isoniazid considering this situation. Compared to isoniazid solution, SLNs with extended release for 48 hours increased ex vivo corneal permeability and ocular bioavailability of isoniazid 1.6-fold and 4.2-fold, respectively. The MIC value was also five-fold lower than isoniazid solution [90].
Microemulsions and Nanoemulsions
Micro and nanoemulsions are systems that are created by means of an aqueous phase, an oily phase, one or more surfactants. Despite the different definitions in the literature, microemulsions generally define systems with a droplet size of less than 100 nm and nanoemulsions with a droplet size higher than 100 nm. However, there is still a use of the definition of nanoemulsion for systems smaller than 100 nm. Microemulsions are thermodynamically more stable than nanoemulsions [91].
Seyfoddin et al reported that the acyclovir nanoemulsions increased the anti-viral activity of acyclovir 3.5-fold after 24 hours. It was observed that nanoemulsions increase the bioavailability of acyclovir by 4.5-fold in comparative in vivo rabbit studies performed with commercial acyclovir ophthalmic ointment [92].
Bharti et al showed that the moxifloxacin microemulsions remained stable for three months. Microemulsions were found to be more effective than commercial moxifloxacin eye drops in in vivo rabbit studies [93].
Kumar et al examined the voriconazole microemulsions in terms of toxicity and ocular permeability. It was found that the microemulsions developed are suitable for ocular use, and ex vivo corneal permeation is higher than voriconazole suspension. Also, in vivo studies showed that microemulsions had less nasolacrimal drainage than suspension [94].
Nanosuspensions
Nanosuspensions are colloidal systems formed by suspending poorly soluble or insoluble drugs in a suitable dispersion medium. Their stability is provided by surface-active agents. They do not show the potential irritant properties of microemulsions, as their size is smaller than 1 μm [69, 95, 96].
Mugdil et al compared their moxifloxacin nanosuspensions with commercial eye drops. It has been observed that the nanosuspension structure increases the corneal permeability of moxifloxacin in vitro by almost 2-fold compared to commercial eye drops. Also, the anti-bacterial activity of nanosuspensions was also found to be high [97]. Ambhore et al. prepared nanosuspensions of sparfloxacin using hydroxypropylmethylcellulose (HPMC) or chitosan. It has been observed that chitosan nanosuspension had sustained drug released for 9 hours, while HPMC nanosuspensions had 6 hours. The effectiveness of nanosuspensions, which were well tolerated by ocular tissues, were proven by in vivo rabbit studies [98]. When the cyclosporine A nanosuspension developed by Kim et al. was compared with the commercial eye product in terms of toxicity, both products were found to be irritating in the Draize test, while in the Schirmer tear test, the nanosuspension was found to be safer than the commercial product [99].
Maged et al produced a series of nanosuspensions of econazole nitrate using different surfactants. It was observed that the nanosuspension containing hydroxypropyl-β-cyclodextrin and Tween 80 was stable for one year at room temperature. This selected formulation was suspended in chitosan HCl to improve bioavailability by increasing mucoadhesion. In in vivo studies, the AUC values of econazole nanosuspension and nanosuspension added to chitosan HCL were 2.5-fold and 5-fold higher, respectively, than econazole suspension [100]. Voriconazole was used in another nanosuspension study with anti-fungal agents. It was observed that the nanosuspension increased the anti-fungal effect of voriconazole and produced more inhibition in less concentration on the Candida albicans strain. Also, nanosuspensions showed better ocular permeability than commercial voriconazole injection in both in vitro and in vivo studies [101].
Micelles
Micelles are another nanocarrier frequently used in ocular drug targeting. Micelles are self-emulsifying systems containing amphiphilic copolymer or surfactant. The hydrophobic core and hydrophilic shell of micelles provide an advantage for targeting hydrophobic drugs to hydrophilic environments. Therefore, the lipophilic property of micelles made them pass through the corneal epithelium more easily [102].
Micelles are easy to manufacture and scale-up. For this reason, micellar carrier systems are very likely to turn into commercial products. Cequa® is one of the most recent examples of this. Phase III studies of cyclosporine A loaded micellar eye drops developed by Mandal et al have also been successfully completed. USFDA approved Cequa® in the treatment of dry eye disease [103-105]. Apart from Cequa®, cyclosporine A emulsions are also used in the treatment of dry eye disease [84]. For this reason, many micellar carrier system studies have been conducted with cyclosporine A for the treatment of dry eye disease. It has been reported that the corneal permeation of the lyophilized cyclosporine A micelles developed by Yu et al. was better than the cyclosporine A emulsion and the micelle structure reduces the elimination of cyclosporine A [106]. Luschmann et al. examined the effectiveness of cyclosporine A loaded micelles in an in situ porcine model. It has been reported that micellar structure increases cyclosporine A uptake 3.5-fold and 3-fold, respectively, compared to cyclosporin A in olive oil and Restasis® (cyclosporine nanoemulsion) [107]. The micelles developed by Li et al. increased the corneal penetration of cyclosporine A in vitro and in vivo mice model [108].
Kanoujia et al developed a micellar ocular delivery system with another anti-bacterial drug, gatifloxacin. They have shown that micelles increase corneal permeation of gatifloxacin compared to commercial eye drops and gatifloxacin solution [109]. In a study conducted with Neomycin B, Kanamycin B, and DNA aptamers, it has been shown that micelles increase corneal permeation and inhibit bacterial growth. Willem de Vries et al. reported that micelles could be applied to the human eye [110].
Micelles are also suitable carrier systems for anti-fungal drugs. Triazole group anti-fungal agents, which are used as the first choice in the treatment of fungal infections [111], may be the subject of ocular targeted micellar drug delivery systems. Sertaconazole nitrate loaded micelles developed by Younes et al increased corneal permeation and corneal uptake of sertaconazole 2-fold compared to sertaconazole suspension [112]. Posaconazole, which has a similar chemical structure to itraconazole and has the most penetrating spectrum of triazole agents, is used off-label in cases of severe keratitis and sclerokeratitis [10, 113, 114]. Durgun et al reported that optimized posaconazole loaded micelles that had extended drug release in simulated tear fluid for 8 hours and increased the total amount of drug released 30-fold to 110-fold compared to posaconazole suspension [115]. Terbinafine is an anti-fungal agent not included in the triazole group. Terbinafine hydrochloride loaded micelles developed by Zhou et al increased corneal permeation compared to oily terbinafine hydrochloride. However, it has been reported that the micelle structure did not change the ocular bioavailability of terbinafine [116].
Aciclovir, ganciclovir, famciclovir, valaciclovir, and trifluorothymidine are drugs used in the treatment of viral ocular infections [117]. Varela-Garcia et al reported that acyclovir loaded micelles and acyclovir solution were similar to corneal permeation coefficients, but micelles significantly shortened the permeation lag time through the cornea. In ex vivo
