INTRODUCTION:

The enhancement of the effectiveness of existing drug is a continuous process in pharmaceutical research. Hence, various drug delivery system has been developed. One such system is microemulsion which was introduced by Hoar and Schulman in 1940s. They prepared a clear single-phase solution by triturating a milky emulsion with hexanol^[1]. They prepared the first microemulsion by dispersing oil in an aqueous surfactants solution and adding alcohol as a co-surfactant, resulting inthe clear, stable formulation. Thus, microemulsionsare clear, transparent, thermodynamically stable dispersions of oil and water, stabilized by an interfacial film of surfactant frequently in combination with a co-surfactant ^[2^].They are also called as a swollen micelle, transparentemulsion, solubilized oil and micellar solution. Microemulsions are biphasic systems that are mainly composed of bulk phases of water and oil separated by a surfactant/cosurfactant rich interfacial region ^[3]. These systems have advantages over conventional emulsions in that they are thermodynamically stable liquid systems and are spontaneously formed ^[4^]. They are currently the critical subject of research due to their wide range of potential and utilization. Their high potential makes them attractive for the development of pharmaceutical formulations. These systems also offer several benefits for oral administration, including increased absorption, improved clinical potency and decreased toxicity ^[5].

In 1956 Jack H. Schulman, first noticed small emulsion structure and termed it as a microemulsion. This small emulsion structure showed effectiveness for delivery of topical preparation as well as osmotic application. Thus, a thermodynamically stable, isotropic friendly clear dispersion of two immiscible liquid (oil and water) which stabilizes by an interfacial film of surfactant molecules is termed as a microemulsion. Microemulsions can predominantly use to deliver drugs to the patients through various route. In the present study, graduates have gathered the information from the available resources and compiled the article so that it can be available to them in published form. Although the subject is explored one, the intention for the publication of the present work is to seed the interest towards the publication so that they can learn the process thoroughly.

Advantages of Microemulsion Based Systems^[6-8]

Microemulsionshave following advantages:

1. They are thermodynamically stable system and additionally, allows self-emulsification.

2. They can solubilize both hydrophilic and lipophilic drugs and thus, are also called as a super solvent.

3. They are compatible with manufacturing.

4. They provide enhance solubilization resulting in improved bioavailability.

5. They can be used in preparing sustained as well as controlled release formulation.

6. They can prevent or reduce first pass metabolism.

7. They have a low viscosity as compared to other ordinary emulsions.

8. They help in minimizing the total dose by improving the efficacy of the drug which also results in eliminating the side effects if any caused.

9. They have reversible nature, i.e., at the low or high temperature they become unstable,but once the temperature returns to the stability range, they again resume their property.

Disadvantages of Microemulsion Based Systems

The microemulsions have few disadvantages:

1. They require a significantamount of surfactants and cosolvents for stabilizing droplets.

2. They have the limited solubilizing capacity for high melting substances.

3. Their stability is influenced by environmental conditions like temperature, pH, etc.

Limitations

Factors that obstruct the use of microemulsion as drug delivery system:

1. Low concentration of surfactants and co-surfactants are expected to prevent toxicity.

2. Phase separation is more prone to happen.

3. The lack of toxicity studies.

TYPES OF MICROEMULSIONS ^[9-12]

Winsor has classified microemulsion in four types depending upon the phases exists in equilibria. These phases are called as Winsor phases. They include:

1. Oil- in- water microemulsion or Winsor I

2. Water – in oil microemulsion or Winsor II

3. Bicontinuousmicroemulsion or Winsor III

4. Single phase homogeneous mixture or Winsor IV

1. Oil- in- water microemulsion or Winsor I: In this type of microemulsion the continuous phase is water and oil is surrounded by a surfactant film. They have larger interaction volumethan the w/o microemulsions.

2. Water-in-oil microemulsion or Winsor II:In this type oil is continuous phase surrounding droplets of water. They are also called as “reverse micelles” because the polar headgroups of the surfactant are frontinginto the droplets of water, with the fatty acid tails facing into the oil phase. They are used orally or parenterallyand may be destabilized by the aqueous biological system.

3. Bicontinuousmicroemulsion or Winsor III: In this type of microemulsion both water and oil are present as the continuous phase. Hence, they are mainly used for topical drug delivery.

4. A single phase homogeneous mixture or Winsor IV: In this type oil, water and surfactants are mixed forming a uniquehomogenous mixture.

Figure 1: Components of Microemulsion

COMPONENTS OF MICROEMULSION

The main constituents of microemulsion include:

1. Oil phase

2. Surfactant (Primary surfactant)

3. Co-surfactant (Secondary surfactant)

4. Co-Solvent

1. Oil phase: Oil phase is one of the important excipients in the microemulsion. It has the property to solubilize lipophilic drug molecules which results in improvising the absorption of drugs (lipophilic or hydrophilic) through lipid layer present in the body^[13]. The unique property of oil to penetrate the cell wall makes it useful for delivery of lipophilic drugs. Oil phase influences the swelling of tail group region of the surfactant. Examples: Saturated fatty acids: lauric, myristic and capricacid Unsaturated fatty acids: oleic acid, linoleic acid and linolenicacid, Fatty acid esters: ethyl or methyl esters of lauric, myristic and oleic acid, etc.

2. Surfactants: The dispersion of all the components in the microemulsion is regulated by surfactant by reducing the interfacial tension. The surfactants used in this system include Non-ionic, Anionic, Cationic, Zwitterionic^[14]. The stability of microemulsions is decided by the nature of surfactants used. Examples: Polyoxyl 35 castor oil (Cremophor EL), Polyoxyl 40 hydrogenated, castor oil (Cremophor RH 40), Polysorbate 20 (Tween20), Polysorbate 80 (Tween80), d-α-tocopherol polyethyleneglycol 1000 succinate (TPGS), Solutol HS-15, etc.

3. Co-surfactants: The spontaneous formation of the microemulsion is caused by co-surfactants. They enhance the fluidity of the interface and break the liquid crystalline or gel structure which triggers the formation of microemulsion^[15]. Examples: ethanol, butanol, propylene glycol, amines or acids, etc. However, they are added in minimal amount along with surfactants.

4. Co-solvents:They are organic solvents that aids to dissolve high concentration of surfactants and lipid soluble drugs. Examples: ethanol, butanol, propylene glycol, etc.

Figure no. 2 Formation of Microemulsion

METHOD OF PREPARATION

Two methods are used to prepare microemulsion. However, the principle used primarilyin the formation of microemulsion predominantly used lowering of the interfacial tension of oil/water. The methods which are used are as follows:

1. Phase titration Method

2. Phase inversion Method

1. Phase Titration Method^[16]

This method is also called as spontaneous emulsification method.This method can be described by the help of phase diagrams. Phase diagram construction is easy and very useful approach to study the complex series of interactions that can occur when different components are mixed.However, the understanding of the phase equilibrium and separation of the phase boundaries are essential elements to be known for this method.

2. Phase Inversion Method^[17]

This method involves the addition of an excess of dispersed phase for preparation of microemulsion. Phaseinversion results to fundamental physical changes like change in particle size which modifies the drug release. In this method, the formation of finely dispersed oil droplet occurs during cooling which causes the system to cross the point of minimal surface tension.

FACTORS AFFECTING THE FORMULATION OF MICROEMULSION^[18-20]

1. Surfactant Property: The number of surfactants and presence of any other salt with surfactants can affect the degree of dissociation of polar groups. As surfactants have both lipophilic and hydrophilic group,they can easily influence the type of microemulsion to be prepared.

2. Oil phase Property: Swelling of the tail group region of the surfactant get affected by the oil phase. Oil phase stimulates the curvature of surfactant to penetrate. Thus, they also influence the type of microemulsion to be prepared.

3. Packing Ratio: The packing and film curvature of surfactants is determined by HLB scale. This study helps in the formation of the microemulsion.

4. Temperature: Temperature is a critical parameter which affects microemulsion. The surfactants when added at low-temperature act as hydrophilic and form o/w type system. Whereas, at high temperature, they are lipophilic and can form bicontinuous structure.

EVALUATION OF MICROEMULSION^[21]

The evaluation parameters for microemulsion are as follows

1. Viscosity: The viscosity is determined by using Brookfield viscometer.

2. pH: Measured by digital pH meter.

3. Drug Content: API based micro-emulsion is subjected to extract API from microemulsion in an appropriate solvent. Suitable dilution is made with solvent and concentration is measured by the UV-visible spectroscopic method at its maximum wavelength by keeping solvent as the reagent blank.

4. Centrifugation: This parameter is measured to evaluate physical stability. The microemulsionis centrifuged at ambient temperature and 5000 RPM for 10 min to evaluate the system for creaming or phase separation. The system will be observed visually for appearance.

5. Conductivity: Electric conductivity of micro-emulsion is measured at ambienttemperature with digital conductometer.

6. Dilution Test: If continuous phase is added into microemulsion, it will not be separated into phases. 50-100 times continuous phase dilution of microemulsion will be carried out and visually checked for phase separation and clarity.

7. Percentage Transmittance Measurement: Micro-emulsion will be diluted to 50–100 times with continuous phase. The %transmittance of the formulation is measured using UV-Visible spectrophotometer at a specific wavelength.

8. Zeta potential and Micelle Size analysis: Micelle size, Size distribution and zeta potential of microemulsion are determined using particle size analyzer.

9. In-vitro-Release Study: It is carried out using Franz diffusion cell.

APPLICATION OF MICROEMULSION SYSTEM

1. Oral Delivery:Microemulsion formulation posse various advantages over conventional drug delivery system like; increased absorption, improved clinical potency, enhanced clinical potency, decreased drug toxicity, etc. Hence, microemulsionsare reported as a goodvehicle for delivery of drugs like steroids, hormones, diuretic,and antibiotics.

2. Parenteral Delivery:Microemulsions show longer residence time in the body.The fine particles in microemulsion get cleared slowly. Hence, it is used in the parenteral delivery of drugs.^[22]

3. Topical Delivery: Microemulsion causes prevention of drug from first pass metabolism and degradation of the drug in the stomach and also prevent toxicity effect. Thus, theyare also used in topical delivery.

4. Other pharmaceutical applications are Nasal delivery, Drug targeting, Cellular targeting, Brain targeting, Periodontal targeting, Tumor targeting, etc.^[23]

CONCLUSION:

Microemulsions are easy, suitable and commercially viable vehicle for delivery of medicaments by enhancing drug absorption and by reducing the toxic effect. They can be used in drug targeting. Suitable excipient selection like surfactants, cosurfactants, etc. are responsible for the formation of microemulsions. Microemulsions proved as a potential candidate to protect drugs,control drug release, increase drug solubility, increase bioavailability and reduce patient variability. Thus, microemulsion based delivery systems are an attractive and suitable area of research.In all, it was good to see that the students were propelled towards the said target and they have now know the basics of the publication process. Henceforth, this article will definitely prove to be a milestone in their future research carrier.

ACKNOWLEDGMENT:

The author wants to show a sincere gratitude to the Rungta College of Pharmaceutical Sciences and Research for providing necessary facilities for the completion of work.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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