Microemulsion as Novel Drug Delivery for Fungal Eye Infection

Neha Mandle^1*

¹Shri Shankaracharya College of Pharmaceutical Sciences, A constituent college of Shri Shankaracharya Professional University, Bhilai

Abstract:  The cornea, orbit, and other ocular tissues may get infected by fungi. Ophthalmic mycoses, often known as ocular fungal infections, are a significant cause of morbidity and blindness. For fungus infections, a brand-new azole derivative has been authorized. New immunological techniques would also be beneficial in the future for enhancing patient outcomes. Treatment of ocular illnesses presents a significant barrier in terms of getting medications into the eyes using traditional drug delivery methods, such as solutions. The main barriers are those between blood and the eyes, between lachrymal fluid and the eyes, and between medication losses from the ocular surface brought on by lachrymal fluid secretion. To increase the bioavailability and lengthen the residence duration of medications administered topically to the eye, a variety of ocular drug delivery carriers have been developed. The microemulsion is created using the PHASE TITRATION METHOD. Due to the dual hydrophilic and lipophilic properties of microemulsions, the loaded medications can diffuse passively and become significantly partitioned in the varying lipophilic-hydrophilic ocular barrier. This abstract will provide details on the microemulsions used to treat fungal infections of the eyes.

Keywords: Microemulsion, Eye infection, Azole derivatives, Fungal infections, Bacterial infection, Eye drops.

Introduction:

Every year, over 1 million people in the US are affected by ocular fungal diseases like fungal and bacterial keratitis (1-4). The eye has complex anatomical and physiological barriers that make drug delivery difficult (5). 90% of commercially available ophthalmic formulations are delivered via conventional methods, like eye drop solutions, ointments, and suspensions (6). However, due to pre-corneal clearance mechanisms as tear turnover, nasolacrimal drainage, reflex blinking, and induced lacrimation, traditional ophthalmic formulations exhibit relatively low bioavailability (7). Additionally, the stroma prevents the flow of hydrophobic medicines whereas the corneal epithelium serves as a barrier for these substances (8). For hydrophobic medicines, the ocular bioavailability varies from 1% to 5% (9). Due to its simplicity of administration, topical instillation continues to be the most favored method despite these drawbacks (10). Inflammation of the cornea, conjunctiva, and eyelids are characteristics of ocular infections, which are typically chronic in nature. Conjunctivitis, blepharitis, keratitis, and keratoconjunctivitis are examples of common ocular infections. To prevent any severe visual consequences, the management of anterior segment ocular infection and inflammation necessitates quick identification and treatment (11). More specifically, the structure, physiology, and biochemistry of the human eye make it such a complex organ that it is almost immune to foreign molecules, including medications. (12-14) The eye's distinctive structure and physiology play a role in its strong defense, which limits medication penetration at the site of action. (15). The eye has three primary layers, with the sclera and cornea making up the outermost part (16).  the inner layer of photoreceptors and neurons known as the nervous tunic, which is composed of the retina; the middle layer responsible for nutrition, known as a vascular tunic, which comprises of the iris, the choroid, and the ciliary body. The conjunctiva, which is made up of the stroma behind the outer epithelium, contributes to the tear film's composition by secreting mucins, fluid, and electrolytes (17). The cornea, which has 5 layers total—the epithelium, Bowman's membrane, lamellar stroma, Descemet's membrane, and the endothelium—is the main pathway for intraocular absorption.

Due to the rise in patients with acquired immunosuppression brought on by prolonged use of immunosuppressive drugs, long-term broad-spectrum antibiotics, and AIDS, the frequency of ocular fungal infections has significantly grown over the past few decades (17–22). The epidemiology of the disease endogenous endophthalmitis, which typically develops in immunocompromised patients with chronic systemic disease, associated septicemia receiving broad-spectrum systemic antibiotic therapy, intravenous hyperalimentation with chronic indwelling catheters, and other risk factors, is linked to the pathogenesis of eye infections. (22).

Fungal Eye Infections:

Eye infections caused by fungi are rare and can affect different parts of the eye. Fungal keratitis (FK) refers to those that affect the outer layer of the eye, while fungal endophthalmitis refers to those that affect the inside layer of the eye (23). fungus FK is one of the more sluggish and persistent ocular fungus diseases that occur in hot, humid tropical regions. In developing nations, it is responsible for 30 to 50 percent of all instances of microbial keratitis. Risk factors include using corticosteroids, having diabetes, and having been injured (by implantation) with plant material. (24-25).

Fig 1: Types of Fungal Infections in eyes

Noval Approaches for Ocular Fungal Infections: 

Recent decades have seen a rise in interest in the application of nanotechnology to ocular medication delivery systems (26). In terms of increased drug penetration, prolonged ocular surface retention time, and targeted distribution, nano-based formulations are superior to conventional ones. Drugs can stay on the ocular surface for a longer period of time by using nano-based delivery systems that increase adherence to the ocular surface and decrease washout caused by tear and blinking behavior. Also, they increase the drug's bioavailability and effectiveness by enabling it to pass through the ocular barrier and reach its intended target. Additionally, fewer side effects could be avoided along with improved pharmacokinetics and drug distribution profiles. The advantage of the nanoscale characteristic allows the nano-based eye drops to treat ocular illnesses with less medication, less frequently, and with better patient compliance. (27)

Fig 2: Noval Approaches For Ocular Fungal Infections

Physiochemical Principles of MEs:

MEs belong to the most promising submicron carriers of drug delivery, especially for poorly water-soluble drugs. (28) MEs are composed of basically 4 different phases, which are the oil phase, aqueous phase, surfactants, and co-surfactants (29-30). MEs are thermodynamically stable, inexpensive, and relatively easy to produce.25 Isopropyl myristate & natural oils, (30-31) such as olive oil, (32) castor oil, and coconut oil, oleic acid, and triacetin have been widely applied for the development of ocular MEs. (33-34) The most commonly used co-surfactants in ocular MEs are ethanol and glycerol. (36) Pentanol and hexanol are not frequently used due to their irritation. (37)

According to the type and the number of surfactants in formulations, ME can be water-in-oil (W/O) or oil-in-water (O/W), or bi-continuous or liquid crystalline. Furthermore, the selection of water and oil phases, as well as surfactant/co-surfactant systems, should be done carefully, since these components could affect the stability and the toxicity of the system. (38) They present droplet size ranges between 10 and 100 nm and do not have a tendency to coalesce. (39) While preparing the MEs, the usage of high concentration and few physiologically optimal surfactants and co-

surfactants generate the main problem in terms of the application of these drug delivery systems.  (40-41)

Phase diagrams study: Phase diagrams are developed in order to gather the best elements and their concentration, which may result in a larger ME existence area. To create the pseudo-ternary phase diagrams, a significant amount of oil, water, and co-surfactant/surfactant mixes are used. The creation of the monophasic or biphasic system is then determined via eye inspection. To sum up, phase separation occurs after turbidity when the formulations are bi-phasic.

Fig 3: A General Schematic Illustration Of Phase Diagram Construction

To obtain the best ingredients and their concentration, phase diagrams are made, which may result in a larger ME existence area. To create the pseudo-ternary phase diagrams, a significant amount of oil, water, and co-surfactant/surfactant mixes are used. After that, a visual inspection is used to establish whether a monophasic or bi-phasic system has been created. To sum up, phase separation occurs after turbidity when the formulations are bi-phasic.

Stability—MEs' stabilization According to reports, one of the most crucial qualities that should be assessed is the stability of MEs because the nature of drugs may have an impact on this attribute. MEs are typically thermodynamically stable, but in the bi-continuous area, their microstructure is constantly changing (42). According to the International Council for Ha

rmonisation of Technical Inspection (42) The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines48, which recommend storing MEs at various temperatures (4C, 25C, and 37C and 75% - 5% Relative Humidity [RH]) and time frame settings, are used to test for stability. The following physicochemical differentiations are checked for in MEs: phase separation, drug entrapment, precipitation, and changes in particle size. A sample example of potential instabilities in ocular MEs is shown in Figure.

according to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines,48 which propose to store MEs in different temperature conditions (4C, 25C, and 37C and 75% – 5% Relative humidity [RH]) and time frame. As follows, MEs are inspected for any physicochemical differentiation, including phase separation, drug entrapment, precipitation, and particle size changes. Figure 3 shows a representative illustration of possible instabilities in ocular MEs.

Preparation Methods:

Phase Titration Method: The water titration technique involves determining the ratios of oil/surfactant and, at times, cosurfactant and subsequently titrating them with a predetermined gradient of water. The determination of added water volume is recorded upon the detection of changes in phase number or physical characteristics, such as the presence of turbidity or gelation. After the calculation of the relative quantities of the three constituents, a pseudo-ternary graph is constructed, wherein the boundaries demarcating each Winsor category are identified. The use of graphical representation facilitates the selection of the optimal water/oil/surfactant system for specific applications. (43, 44)

Ramalho et al. formulated a microemulsion through the process of water titration. The microemulsion was composed of isopropyl myristate as the oil phase, caprylocaproyl polyoxyl-8 glycerides as the surfactant, and water. The microemulsion was optically homogeneous and transparent Fernandez-Pena et al. developed stable microemulsion systems consisting of oleic acid as the oil phase, a mixture of alkyl polyglucoside and soybean lecithin as surfactants, and water using the water dilution method.

Phase Inversion Method: The phase inversion technique entails changing the phase from O/W to W/O either by maintaining the composition constant while changing the temperature (phase inversion temperature, PIT0) or by introducing an excess amount of the dispersed phase (46) under constant temperature conditions. (45) PIC undergoes particle change as a result of the addition of a dispersed phase, which triggers a phase transition. On the other hand, phase inversion in PIT is brought on by a reduction in interfacial tension (after cooling).

Ee et al. created a nanoemulsion using the temperature-phase inversion method. When kept at the ideal temperature, the resulting ultra-small droplet sizes varied from 35 nm to 54 nm and had a low PDI of about 0.2. Calligaris et al. produced microemulsions with various lipid phases and Tween 80 as a surfactant using the same technique. The chemical stability of a microemulsion was discovered to be improved after curcumin was added to the lipid phase.

Rotary Stator Emulsification: The rotor-stator mixers consist of a rotating rotor and an external stator that are both stationary (47, 48). The emulsion is discharged through the stationary rotor at a high velocity after being attracted toward the rotor head as the rotor rotates [206]. The reduction in particle size is caused by the robust shear, tension, and grinding forces that emerge from the interaction between the rotor and stator (49).

A stable oil-in-water nanoemulsion with a phenolic compound-rich aqueous phase was made by Niknam et al. The mixing process took 10 minutes, and 20,000 rpm was the rotor's reported rotating speed. Using this technique, the nanoemulsion's droplet size was measured to be 105.8 10.3 nm and its PDI value to be 0.255 0.045. The authors of the study claim that the kind of surfactant has an impact on how stable nanoemulsions are physically, with soy lecithin, Tween 20, and WPI having the highest degrees of stability (50). Scholz et al. created a stable nanoemulsion that lasted for at least three months using a rotor-stator system. The production process took 5 minutes, and the stirring speed employed was 36,000 rpm. The researchers claim that employing a rotor with an ultrafine slit size could accelerate processing.

Ultra Sonication Method: In this method, the use of high-intensity acoustic waves causes the formation of tiny droplets. (51) The crucial information regarding the function of ultrasounds and associated phenomena was already covered in Section 3.3. Due to its low surfactant usage (52, 53), non-toxicity, safety, and eco-friendliness (54, 55) the aforementioned method has advantages. In terms of the polydispersity index, the resulting particles also have a modest size and long-term stability. (54, 56) In one study, Guzman et al. used this technique to create nanoemulsions, using P. edilus var. edilus seed oil (PEO) as the oil phase and a mixture of sorbitan trioleate and polysorbate 80 as the surfactant. It was found that an ultrasonic power of 85.28 W and an irradiation time of 5.96 min were the ideal emulsification conditions.

Microfluidizer: The emulsions are microfluidized using an IA microfluidizer (57). The operation of the above system is controlled by the complex dynamics of microchannels designed expressly for this purpose (58). The homogenizing fluid is forced through the microchannel network of the interaction chamber by a positive-dispersion pump. The fluid moves via small channels and strikes a substrate, severely disrupting the structures and resulting in reduced-size particles (57). The final particle size is influenced by a variety of factors, including the number of passes, treatment pressure, and material properties. (59)

Tocotrienol-enriched nano-emulsions were made by Goh et al. utilizing a variety of surfactants. The outcomes of the experiment reveal that following ten homogenization cycles with increasing pressure.

Fig 4: Types And Methods Of Synthesis For Microemulsions

High-pressure homogenizer: Homogenization at high pressure is accomplished in a homogenizer, which is best suited for fluids with low to moderate viscosities. Prior to homogenization, an initial mixture composed of oil, water, surfactant, and/or cosurfactant is created. The original unprocessed mixture is added to the homogenizer, where a piston forces it through a succession of nozzles of varying sizes. Larger droplets fragment into smaller ones due to cavitation, turbulence, and shear forces. A few of the factors influencing the outcome are the nozzle's diameter, the emulsion's viscosity, the number of passes, and the homogenising pressure. Low surfactant use, rapid emulsification, and emulsion stability of the method. The method's low surfactant requirement, short emulsification time, and emulsion stability are seen to be benefits.Shi et al. used Sichuan pepper essential oil to generate a nanoemulsion. According to the statistics, the system exhibited good stability during the investigation. The average particle size and zeta potential of the nanoemulsion specifically changed over time, going from 125.07 nm and 33.12 mV to 134.53 nm and 29.27 mV, respectively.

Conclusion:

In the fields of pharmaceutical technology and ophthalmology, ocular medication transporters are crucial. Due to the complicated tissue structure and anatomical and physiological barriers of the eye, ocular drug administration has been a long-standing concern. Nanotechnology has thus been particularly successful in this area of research. We have listed the benefits and drawbacks of the various ocular nano-delivery systems. Different nanocarriers have different advantages. Ocular bioavailability is hampered by the special features of the eye and the ocular barriers because tear fluids wash the topically injected medication solution away. Therefore, it is essential to design and create new, effective drug delivery systems for the treatment of ocular diseases.

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