INTRODUCTION:

Now a days it is found that the drugs taken orally are not as effective as desired due to various obstacles coming in the way of oral drug delivery. Today Topical drug delivery system is the most capable mode of drug application as it offers many advantages like increased patience compliance, avoidance of gastrointestinal disturbances, bypass of first pass hepatic metabolism, sustained release formulations and reduced side effects. From all the topical routes (skin, eye, rectum and vagina), skin is the most common site of topical drug administration being the largest organ (large surface area) and its easy accessibility (Gennaro 2000). The major problem associated with topical drug delivery system is that the regular or systemic drug absorption is difficult to be assured (Bachhav and Patravale 2009; Bhaskar et al .,2009; Gaddam and Aukunuru 2010).

Thus recent investigations in the direction of Micro emulsion have shown it to be a versatile vehicle for percutaneous delivery of both hydrophilic and lipophilic drugs. Many papers were published with various suggested formulations. Kreilgaard in his very comprehensive review summarized the main studies published before 2002 in table 1.

In 1959, J.H. Schulman introduced the term “Microemulsion” for transparent solutions of a model four component system. ^(1-3)

He defined Micro emulsions as isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20-200 nm. ^(3-8)

Topical preparations apply to the particular area or part of the body and are formulated in such a manner that the systemic absorption of the medicament is minimal.

In topical formulations, micro emulsions have been proved to increase the cutaneous absorption of both lipophilic and hydrophilic medicaments and therefore a promising vehicle because of its potential for dermal drug delivery when compared to conventional vehicles (emulsions, pure oils, aqueous solutions). ⁽⁹⁾

ADVANTAGES OF MICROEMULSION IN TOPICAL DRUG DELIVERY: ^{(8, 10-13)}

· A large amount of drug can be incorporated in the formulation due to high solubilizing capacity that might increase the thermodynamic activity towards the skin.

· The permeation rate of the drug from micro emulsion may be increased, since the affinity of a drug to the internal phase in micro emulsion can be easily modified to favour portioning into stratum corneum, using different internal phase, changing its portion in micro emulsion.

· The surfactant and cosurfactant in the micro emulsions may reduce the diffusional barrier of the stratum corneum by acting as penetration enhancers.

· The percutaneous absorption of the drug will also increase due to hydration effect of stratum corneum if the water content in micro emulsion is high enough.

· Avoidance of hepatic first pass metabolism of the drug and related toxic effects.

· Direct delivery and targetability of the drug to affected areas of the skin or eyes.

DISADVANTAGES OF TOPICAL DRUG DELIVERY: ⁽⁸⁾

· Skin irritation of contact dermatitis may occur due to the drug and/or excipients.

· Poor permeability of some drugs through the skin.

· Possibility of allergic reactions.

· Can be used only for drugs which require very small plasma concentration for action.

· Enzyme in epidermis may denature the drugs.

· Drugs of larger particle size are not easy to absorb through the skin.

CHALLENGES IN PREPARATION OF TOPICAL MICROEMULSION:

The challenges include controlling the particle size, size distribution, particle crystallinity, morphology and shape, being able to use the nanoparticles for a given purpose, and to produce them from a variety of precursors. It is difficult to control and determine the exact amount of drug that reaches the different skin layer. The drugs and vehicles physicochemical properties are considered to be the main features responsible for the drug differential distribution in the skin. Biocompatible surfactants and cosurfactants used in pharmaceutical Micromeulsions are important technological challenges for the development of adequate delivery systems that can be used in pharmaceutical formulations. Despite the substantial potential of transdermal and dermal drug delivery, only relatively few drugs are available as topical formulations. The main limitation lies in the barrier function of the skin, which is considered one of the most impermeable epithelia of the human body to exogenous substance. Therefore the major challenges for topical formulations today is to provide a sufficient increase in drug penetration into the skin without inducing significant irreversible alterations to the skin barrier function. During the recent decades numerous studies have suggested that a novel vehicle described as micro emulsion have a potential of increasing cutaneous drug delivery of both hydrophilic and lipophilic drugs compared to conventional vehicles.

MECHANISM OF ACTION OF MICROEMULSION: (Figure-1):

Micro emulsion offer advantages over traditional creams and lotions as topical drug delivery. They are used to solubilize drugs and to improve topical drug bioavailability. Micro emulsion may interact with the stratum corneum and disorganize the lipid bilayer due to the presence of surfactants. Thus, these lipids pass as a fluid in a disorderly fashion, increasing the permeability of the skin which leads to loss of barrier properties of skin.

The interaction between the cell membrane and the micro emulsion formula lead to changes in membrane permeability, the first sign of the cytoplasmic membrane damage is the release of potassium ions (K+) followed by inorganic phosphate and then 260 nm absorbing materials such as RNA, DNA, some amino acids and proteins (Lambert and Hammond, 1973). The results show two phases of leakage. Phase 1 indicates an initial leakage related to micro emulsion penetration and its effect upon the fungal cell wall and is possibly periplasmic leakage. The second phase is due to leakage caused by micro emulsion effects upon the cytoplasmic membrane resulting in major cytoplasmic leakage. The initial periplasmic leakage may be related to the effects of the micro emulsion upon the cell wall structure. Structurally, the fungal cell wall is composed of complex network of proteins and polycarbohydrates that varies in composition depending upon the fungal species. Disruption of this protein/carbohydrate matrix results in a structurally defective cell wall, rendering the fungal cell sensitive to osmotic lysis (Russell, 2007). The second phase may be due to leakage caused by the action of the micro emulsion on the cytoplasmic membrane. The cytoplasmic membrane is a fluid phospholipid bilayer containing proteins and sterols. Ergosterol is the predominant sterol in many pathogenic fungi (Russell, 2007).

Fu et al. (2006) showed that the antifungal activities of micro emulsions prepared with glycerol monolaurate (GML) as the oil and Tween as surfactant had higher antimicrobial activity than GML alone. Later work by the same group on a monolaurin micro emulsion system exhibited antimicrobial activity against Bacillus subtilis, E. coli, Aspergillus Niger and Penicillium digitatum (Fu et al., 2009). Food-grade micro emulsions have been of increasing interest to researchers and exhibit great potential in industrial applications (Flanagan and Singh, 2006) where glycerol monolaurate (GML) micro emulsions show enhanced antimicrobial activities against S. aureus (Zhang et al., 2007). Food-grade dilution-stable

Micro emulsions are effective antibacterial systems against B. subtilis (Zhang et al., 2008a), E. coli and S. aureus (Zhang et al., 2009). The antifungal activity of a food-grade dilution-stable micro emulsion indicates that micro emulsions effectively inhibit the growth of moulds A. Niger and Penicillium italicum (Zhang et al., 2008b,c) and the yeast Candida albicans and Saccharomyces cerevisiae (Zhang et al., 2010). These studies have led to our greater understanding and interest in the antimicrobial nature of micro emulsions.

These findings suggest that the micro emulsion formula might increase cell permeability and membrane fluidity, whereby the micro emulsion may be inserted between the fatty acyl chains that make up the membrane lipid bilayer. This supposition is supported by the work of Changez et al. (2006), who found that micro emulsions caused the disruption of intercellular junctions leading to an increase in intercellular gaps. The surfactant and phospholipids, used in the tested formation was found to increase the fluidity of the intercellular lipids. Additionally, Deli (2009) observed that surfactants, including the non-ionic surfactants (e.g. polysorbate 20), at the cellular tight junctions can rapidly and reversibly open Para cellular tight junctions. Subsequently, such increases in permeability and membrane fluidity might disrupt lipid packing and cause changes to cytoplasmic membrane properties and functions. These results clearly indicate that the micro emulsion is capable of significant anti-membrane and anti-cell wall activity resulting in the gross disturbance and dysfunction of cell envelope structure and function. This level of dysfunction could potentially result in the death of the cell and may explain the rapid loss of cell viability observed in the kinetics of killing experiment.

The results of the kinetics of killing of micro emulsions formula clearly indicate that micro emulsions are effective antimicrobial agents, with a rapid killing rate against budding yeasts (C. albicans and Rhodotorula spp.), spore-forming fungi (A. Niger) and fission yeasts (S. pombe). Such rapid biocidal activity is indicative of a direct attack on the structural integrity of the cell rather than a secondary effect through metabolic inhibition (Gilbert, 1984). The LT90% value of 58 s for S. pombe is less than that for C. albicans and Rhodotorula spp. (110 and 107 s respectively), which indicates that S. pombe is more sensitive than the other yeasts to the micro emulsion formula. S. pombe does not contain chitin in its cell wall, and this may confer a slightly higher level of sensitivity upon this yeast when compared to the other tested fungi (Tajadura et al., 2004).

It is clear from this study that the antifungal mode of action of micro emulsions is largely due to an initial periplasmic leakage, followed by gross membrane dysfunction, internalization of the micro emulsion and subsequent coagulation of cytoplasmic components and organelles.

TOPICAL DRUG DELIVERY POTENTIAL OF ME:

Topical administration offers several attractions compared to traditional routes. Three main mechanisms had been proposed to explain the advantages of micro emulsion for the transdermal delivery of drugs.

· First, the high solubility potential for both lipophilic and hydrophilic drugs of micro emulsion systems might increase thermodynamic activity towards the skin.

· Second, ingredients of micro emulsion, acting as permeation enhancers, might destroy the structure of stratum corneum and increase the flux of drug via skin.

· Third, the drug from micro emulsion might be increased because the affinity of a drug to the internal phase could be modified easily (Delgado-Charro et al., 1997; Baroli et al., 2000; Kreilgaard, 2002).

There are several advantages of micro emulsion for topical drug delivery.

· First, the concentration of drugs in skin increases because large amount of drug can be incorporated in the formulation.

· Second, the increased thermodynamic activity of the drug may favour its partitioning into the skin.

· In addition, the ingredients of micro emulsion may reduce the diffusional barrier of the stratum corneum (SC) and increase the permeation rate of drug via skin by acting as permeation enhancers (Peltola et al., 2003).

So it is promising for both transdermal and dermal delivery of drugs as an efficient route of drug administration (Kreilgaard, 2002; Rhee et al., 2001; Kreilgaard et al., 2000; Baboota et al., 2007; Kamal et al., 2007; Chen et al., 2007). In principle, micro emulsions can be used to deliver drugs to the patients via several routes, but the topical application of micro emulsions has gained increasing interest. The three main factors determining the transdermal permeation of drugs are the mobility of drug in the vehicle, release of drug from the vehicle, and permeation of drug into the skin. These factors affect either the thermodynamic activity that drives the drug into the skin or the permeability of drug in the skin, particularly stratum corneum.

Micro emulsions improve the transdermal delivery of several drugs over the conventional topical preparations such as emulsions (Ktistis and Niopas, 1998; Kreilgaard et al., 2000) and gels (Gasco et al., 1991; Kriwet and Müller-Goymann, 1995). Mobility of drugs in micro emulsions is more facile (Kriwet and Müller-Goymann, 1995; Trotta, 1999; Kreilgaard et al., 2000), but the gel former in micro emulsion will increase its viscosity and further decrease the permeation in the skin (Gasco et al., 1991). The superior transdermal flux from micro emulsions has been shown to be mainly due to their high solubilisation potential for lipophilic and hydrophilic drugs. This generates an increased thermodynamic activity towards the skin (Trotta et al., 1997; Kreilgaard et al., 2000; Alvarez-Figueroa and Blanco-Méndez, 2001). The drug may also be retained in the droplets of micro emulsion formulation that will decrease its permeation in the skin. For example, the increased concentration of surfactant in dispersed systems may decrease drug release and its permeation in the skin (Ktistis and Niopas, 1998).On the other hand, micro emulsions may affect the permeability of drug in the skin. In this case, the components of micro emulsions serve as permeation enhancers. Several neat compounds used in micro emulsions have been reported to improve the transdermal permeation by altering the structure of the stratum corneum. In spite of numerous advantages in comparison with other colloidal vehicles, micro emulsions often require a high content of surfactant that can lead to skin irritation (Kumar and Mital, 1999; Lawrence and Rees, 2000). The concentration of surfactant can sometimes be reduced by the addition of cosurfactants (Sagitani and Friberg, 1980). The majority of the work reported in the scientific literature concerns micro emulsion systems based on pharmaceutically unacceptable cosurfactants such as short- or medium-chain alcohols (Kumar and Mital, 1999; Lawrence and Rees, 2000). The good biological acceptance of non-ionic surfactants (Kibbe, 2000) as well as ability to form micro emulsions that are insensitive to pH and electrolyte concentration are the main motives for their extensive use (Kumar and Mital, 1999; Lawrence and Rees, 2000). It has been recently reported that certain mixtures of non-ionic surfactants can provide enhancement of solubilisation of water in water-in-oil micro emulsions (Hiuberts and Shah, 1997; Sagitani and Friberg, 1980). There have been several studies involving low-irritant caprylocaproyl macrogolglycerides based micro emulsions as drug delivery vehicles for topical application (Gašperlin and Špiclin, 2001; Delgado-Charro et al., 1995; Kreilgaard, 2001). In order to facilitate caprylocaproyl macrogolglycerides based micro emulsions formation, the surfactants based on polyglycerol fatty acid esters have been used as cosurfactants (Gašperlin and Špiclin, 2001; Delgado-Charro et al., 1995; Kreilgaard, 2001). All the same, it has been recently reported that caprylocaproyl macrogolglycerides based micro emulsion systems incorporating isopropyl myristate as oil phase, have a large micro emulsion region in their phase diagrams (Choi et al., 1997).Due to the variety of structures occurring in them (water-in-oil (W/O), oil-in-water (O/W), or continuous structures in which water continuous and oil continuous domains are separated by surfactant monolayers), micro emulsions display a rich behaviour regarding the release of solubilized material. Also, one can reach sustained release if the interactions between drug and surfactant and/or partitioning of the drug between oil and water phases strongly affect the drug release (Kumar and Mital, 1999).

In order to investigate a drug delivery potential of micro emulsion vehicles, it is necessary to characterize their microstructure as well as a microstructure of drug loaded micro emulsions. The formation process and gradual changes in micro emulsion microstructure can be monitored quantitatively by measuring the electrical conductivity and rheological properties of system (Kumar and Mital, 1999; Lawrence and Rees, 2000).Apart from the micro emulsion structure and composition, the incorporated drug molecules participate in the microstructure of the system and may influence it due to molecular interactions, especially if the drug possesses amphiphilic and/or mesogenic properties (Müeller-Goymann et al., 1995).

PATENTS ON TOPICAL MICROEMULSION DRUG DELIVERY SYSTEM

Table 1: Patents on Topical ME and Related Research Work

US patent/ App. No.	Patent Title	Patent Owner	Issue/ Publication Date
8647647	Silver Oxide Formulation having Improved Whiteness Characteristics⁽⁷⁸⁾	Antelman Perry	Jan 27 2011
8647671	Composition and methods for treatment of skin disease⁽⁷⁹⁾	Pearlman Dale L.	Sept 19 2013
8642655	Systems and methods for preventing cancer and treating skin lesions⁽⁸⁰⁾	Johnson Benjamin	Sept 13 2013
8410313	Topical liquid agent for the treatment of dermatophytosis⁽⁸¹⁾	Parsy Christophe Claude et al	Jan 31 2013
8445543	Combination of adapalene and benzoyl peroxide for treating acne lesion⁽⁸²⁾	Vernet Abou Chacra et al	May 31 2012
8636989	Topical Skincare Formulations Comprising Plant Extract⁽⁸³⁾	Florence Tiffani et al	Sept 12 2013
8632811	Silica Based Antibacterial and Antifungal Formulation⁽⁸⁴⁾	Santra Swadeshmukul	Dec 10 2008
8633191	Antimicrobial and Antifungal Shampoo for Mammals specially for Humans and Dogs⁽⁸⁵⁾	Perry Stephen C.	Mar 23 2006
8556181	Antifungal Plant Proteins and Method of Their Use⁽⁸⁶⁾	Twiste Josef	Jan 26 2012

MARKETED FORMULATION OF TOPICAL MICROEMULSION SYSTEM

Table 2: Currently Available Medication for Topical Microemulsion

Drug	Trade Name	Manufacturer	Indication
Ketamine	Allermyl	Virbac	Anaesthetic, Hallucinogen
Ibuprofen	Solvium	Chefaro (Akzo)	NSAID
Cyclosporine A	Neoral	Novartis	Immunosuppressant
Clotrimazole	Candid V	Canesten	Antifungal

REASON FOR LESS COMMERCIAL AVAILABILITY OF MARKETED PRODUCTS OF MICROEMULSION:

Despite their favourable properties, MEs have not enjoyed wide commercial success, with only a few commercial products on the market. One reason for their limited use likely stems from the narrow range of pharmaceutically acceptable surfactants and co-surfactants available for designing ME formulations. In addition, high concentrations of surfactants, often required for their formation, can result in skin irritation. Use of ME for topical application is also limited by their low viscosity; therefore, viscosity imparting agents are required to increase the viscosity of formulations ⁽⁸⁾. Determining a proper viscosity imparting agent can be difficult since modification of the rheological behaviour of the formulations can negatively impact ME stability, drug release rates and the large water/oil interface. An ideal polymer must be soluble in the continuous phase to display non-covalent intermolecular interactions, which act cooperatively and lead to the formation of a polymer network ⁽⁸⁾. Further, the polymers must be biocompatible and exhibit few interactions with surfactants and other formulation excipients in order to be pharmaceutically acceptable ^{(9, 10)}.

RECENT TRENDS AND FUTURE DEVELOPMENTS:

During the last two decades lot of research work has been carried out on micro emulsion system for providing novel solutions to overcome the problems of poor aqueous solubility of highly lipophilic drug compounds and provide reproducible bioavailability. Industrial point of view, it can be easily scaled up with considering relative cost of commercial production. Microemulsion can also be used for cosmetic purpose and drug targeting. Now a day, research work is focused on the production of safe, efficient and more compatible micro emulsion constituents which will further enhance the utility of this novel delivery system.

CONCLUSION:

Topical ME based drug delivery systems suggest that significant amount of drug can be administered into deep skin layers and more over efficiency is also increased. Superiority of ME over other system can be explained by the fact that it has both lipophilic and hydrophilic domains as well as Nano size particles which are responsible for better penetration and increased activity . The hydrophilic domain hydrates the skin’s stratum corneum to a great extent and thereby plays an important role in percutaneous absorption of drug. And also the hydrophilic layer disturbs the lipid bilayer which increases the penetration of oil domains.

Thus it can be concluded that ME system has more advantage than other topical system.

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