INTRODUCTION:

Microemulsion may be defined as a system of water, oil and amphiphlilic compounds (surfactant and/or co-surfactant). Jack H. Schulman (1959) first noticed small emulsion-like structure in electron microscope which was termed as microemulsion. It shows effective topical delivery mechanisms for various active pharmaceutical ingredients for the therapeutic as well as the cosmetic applications. The term microemulsion refers to a thermodynamically stable, isotropically clear dispersion of two immiscible liquid, such as oil and water, which is stabilized by an interfacial film of surfactant molecules^[1]

These are modern colloidal drug carrier of the co-surfactant is often required in order to decrease the interfacial tension of this interface, because the fact that a low interfacial tension is essential in microemulsions obtaining. Surfactant molecules contain both a polar as well as an apolar group. So they exhibit a very particular behavior, firstly they get absorbed at the interfaciel where they can fulfill their dual affinity with hydrophilic groups located in aqueous phase and hydrophilic groups in oil or air. Secondly, they mismatching with solvent by micellization process the dispersed phase typically comprises of small particle droplets with a size range of 5nm to 100nm, and has very low oil/water interfacial tension because the droplet size is less than 25% of the wavelength of the visual light, microemulsion are transparent.^.

Their existence of this theoretical structure was later confirmed by use of various technologies, and today we can adopt the definition given by Attwood “a microemulsion is a system of water, oil and amphiphilic compounds (surfactant and co-surfactant) which is a transparent, single optical isotropic and thermodynamic stable liquid”^[2]. Microemulsions represent an interesting and potential quite powerful alternative carrier system for transdermal drug delivery because of their high solubilisation capacity, transparency, thermodynamic stability, facility of preparation, and high diffusion and absorption rates.^[3]In this review article, the various aspects of pharmaceutical microemulsion were compiled together and the target audiences are specifically the M. Pharm and B. Pharm students so that their knowledge towards the subject concern can be enhanced and also at the same time can be motivated towards the publication.

IMPORTANT CHARACTERISTICS OF MICROEMULSIONS^[4]

· Thermodynamically stable (long Shelf –life)

· Optically Clear

· Particle size 10-100 nm

· High Surface area (high Solubilization Capacity)

· Small droplet size

· Enhanced drug Solubilization

· Ease of formation (zero interfacial tension and almost spontaneous formation)

· Ability to be Sterilized by filtration

· Long - term Stability

· High Solubilization capacity for hydrophilic and lipophilic drugs

ADVANTAGES^[5]

· It is easier and painless;

· It avoids direct contact between the drug and the liver;

· It avoids the action of aggressive triggers of intestinal tract against the drug;

· Thermodynamically stable and require minimum energy for formation

· Enhanced drug solubilization and improved bioavailability

· Compatibility in manufacturing

· Microemulsion have wide applications in colloidal drug delivery systems for the purpose of drug targeting and controlled release.

· Long shelf life.

· Helpful in taste masking

DISADVANTAGES^[6]

· The main problem in a microemulsions applications is a high concentration and a narrow range of physiologically acceptable surfactants and co-surfactants.

· It has limited potential topical application due to their toxic and irritant properties of component.

· Large surfactant concentration (10-40%)determines their stability.

· It is poor palatability due to the lipid content leading to the poor patient compliance. Moreover due to their water content, microemulsions cannot be encapsulated in soft gelatin or hard gelatin capsules

LIMITATIONS ^[7]

There are certain factors which limits the use of the microemulsion systems in the pharmaceutical applications:

· There is a common problem of phase separation seen in the case of microemulsions.

· For toxicity reasons, the concentrations of the co-surfactants and the surfactants must be kept low.

· The microemulsion systems are not that much suitable for the intravenous use due to the toxicity of the formulation and till now only a very few studies have been reported on them.

· To reduce the toxicity of the microemulsion systems, the surfactants which are to be used shows to be of “Generally Regarded as Safe” (GRAS) category.

CLASSIFICATION OF MICROEMULSION^[8]

Three types of microemulsions are most likely to be formed depending on the composition:

i. Oil in water microemulsions wherein oil droplets are dispersed in the continues aqueous phase.

ii. Water in oil microemulsions wherein water droplets are dispersed in the continuous oil phase.

iii.Bi-continuous microemulsions where in microdomains of oil and water are inter dispersed within the systems (fig-1).

Figure 1: Classification of Microemulsions Adopted from K.Senthil Kumar etal, International Journal of Pharmaceutical Sciences Review and Research,(2011),vol.10,38.

Winsor Classification of Microemulsion Systems^[9]

According to Winsor, there are four types of microemulsion phases exists in equilibria, there phase are referred as Winsor phases. They are,

Winsor I: With two phases, the lower (o/w) microemulsion phases in equilibrium with the upper excess oil.

Winsor II: With two phases, the upper microemulsion phase (w/o) microemulsion phases in equilibrium with lower excess water.

Winsor III: With three phases, middle microemulsion phase (o/w plus w/o, called bi-continuous) in equilibrium with upper excess oil and lower excess water.

Winsor IV: In single phase, with oil, water and surfactant homogenously mixed. (As shows fig 2)

THEORIES OF MICROEMULSION FORMATION

Historically, three approaches have been used to explain microemulsion formation and stability. They are as follows-

· Interfacial or mixed film theories.

· Solubilization theories.

· Thermodynamic treatments

Figure 2: O/W, W/O and Bi-continuous Microemulsions, Adopted from Faizi Muzaffar et al International Journal of Pharmacy and Pharmaceutical Sciences, Vol 5, (2013) ,40

When surfactants are added to a mixture containing equal amounts of oil and water either W/O or O/W emulsion will form depending on the molecular interaction of the surfactant with both the oil and water. Different interaction strengths on the both the sides of the surfactant film induce a tension gradient across the surfactant membrane and consequently produce curvature. A geometrical model has been proposed to describe quantitatively the correlation between the structure of surfactant aggregates and geometric packing of surfactants at the interface is called as packing ratio or critical packing parameter (CPP). CPP defines as the ratio of cross sectional area of hydrocarbon chain to that of the polar head of the surfactant molecule at the interface.

Structure of Microemulsion^[10]

Microemulsions or Micellar emulsion are dynamic system in which the interface is continuously and spontaneously fluctuating. Structurally, they are divided in to oil in water (o/w), water in oil (w/o) and bi-continuous microemulsions. In w/o microemulsions, water droplets are dispersed in the continuous oil phase while o/w microemulsions are formed when oil droplets are dispersed in the continuous aqueous phase (Fig 3). In system where the amounts of water and oil are similar, the bi-continuous micro emulsions may result. The mixture oil water and surfactants are able to form a wide variety of structure and phase depending upon the proportions of component

Figure 3: Structure of Microemulsion, Adopted from Faizi Muzaffar et al International Journal of Pharmacy and Pharmaceutical Sciences, Vol 5, ( 2013),40

Difference between emulsion and Microemulsions

Emulsions and Microemulsions (Fig.4) are both stable dispersions of oil-in-water or water-in-oil. Surfactants are the principal agents that enable oil and water to mix. Emulsions are stable dispersions of immiscibleliquids, but they are not thermodynamically stable. The following properties shows the different betweenemulsion and Microemulsions. (Table 1).

Table 1: Difference between emulsion and Microemulsions

Property	Emulsion (Macro emulsion	Microemulsion
Appearance	Cloudy	Transparent
Optical isotropy	Anisotropic	Isotropic
Interfacial tension	High	Ultra low
Microstructure	Static	Dynamic
Droplet size	>500 nm	20-200nm
Stability	Thermodynamically unstable	Thermodynamically stable
Phases	Biphasic	Monophasic
Cost	Higher cost	Lower cost

Figure 4: Difference between emulsion and Microemulsions, Adopted from K. Senthil Kumar etal, International Journal of Pharmaceutical Sciences Review and Research,(2011) ,vol.10 ,38.

METHOD OF PREPARATION

1. Phase Titration Method

Microemulsions are prepared by the spontaneous emulsification method (phase titration method) and can be depicted with the help of phase diagrams. Construction of phase diagram is a useful approach to study the complex series of interactions that can occur when different components are mixed. Microemulsions are formed along with various association structures (including emulsion, micelles, lamellar, hexagonal, cubic, and various gels and oily dispersion of their phase equilibrium and demarcation of the phase boundaries are essential aspects of the study. As quaternary phase diagram (four component system) is time consuming and difficult to interpret, pseudo ternary phase diagram is often constructed to find the different zones including microemulsion zone, in which each corner of the diagram represents 100% of the particular component

2. Phase Inversion methods

The most important influence that temperature has on an emulsion is probably inversion that w/o emulsion of benzene in water that was stabilized with sodium state invert to o/w emulsion upon heating the w/o emulsion upon cooling the temperature at which inversion occurs depends on emulsifier concentration and is called phase inversion temperature (PIT). This type of inversion can occur during the formation of emulsion, since they are generally prepared at high temperatures and are then allowed to cool to room temperature. Emulsion formed by a phase inversion technique are generally considered quite stable and are believed to contain a finely dispersed phase. The PIT is generally considered to be the temperature at which the hydrophilic and lipophilic properties of the emulsifier are in balance and is therefore also called the HLB temperature

COMPONENTS OF MICROEMULSION^[11]

Microemulsions are isotropic system, which are difficult to formulate than ordinary emulsion because their formulation is highly specific process involving spontaneous interaction among the constituent molecules. Generally, the Microemulsions formulation involves the following components

a. Oil phase

Toluene, cyclo hexane, mineral or vegetable oil, silicone oil, or esters of fatty acids etc. widely used as oil component.

b. Aqueous phase

The aqueous phase may contain hydrophilic active ingredients and preservatives. Buffer solutions are used

as aqueous phase by some researchers.

c. Surfactant

In order to reduce the interfacial tension, surfactant is necessary one. Hence surfactant with a balanced

hydrophilic and lipophilic property (HLB) is desirable. The selection of surfactant must

1. Reduce the interfacial tension during the preparation of Microemulsions.

2. Provide a flexible film that can readily deform roundsmall droplets.

3. Appropriate hydrophile-lipophile character to provide the correct curvature at the interfacial region for the desired Microemulsions type o/w, w/o or bicontinuous.

1. Primary Surfactant ^[12]

The surfactant are generally ionic, non ionic or amphoteric. The surfactants choosen are generally from the non ionic group because of their good cutaneous tolerance. Only for specific case amphoters are being investigated.

2. Secondary Surfactant

It is otherwise called as co-surfactant. The cosurfactant originally used were short chain fatty alcohol such as pentane, hexanol, benzyl alcohol. These are most often polyols, esters of polyols derivatives of glycerol and organic acids, Poloxamer, Polysorbate 80, Span 20 Cinnamic alcohol, Cinnamicaldehyde. Their main purpose is to make the interfacial film fluid by wedging themselves between the surfactant molecules.

Factors to be considered during the Preparation of Microemulsion^[13]

There are 3 most important factors which are to be kept in mind while preparing a microemulsion system.

· To promote the microemulsion formation the interface should be fluid or flexible enough.

· To provide the no. of surfactant molecules needed to stabilize the microdroplets to be produced by an ultra low interfacial tension the concentration of the surfactant should be high enough.

· The most important requirement for the formation of a microemulsion system is selection of the surfactants which is really a critical process because a very low interfacial tension (<10-3 mN/m) is to be achieved at the oil water interface.

FACTORS AFFECTING THE MICROEMULSION:^[14]

The formation of microemulsion will depend on the following factors

· Packing ratio:

The HLB of surfactant determines the type of microemulsion through its influence on molecular packing and film curvature. (The analysis of film curvature for surfactant association’s leadings to the formation of microemulsion).

· Property of Surfactant, Oil Phase and Temperature

On the nature of surfactants the nature of the microemulsions formed depends. A surfactant consists of the lipophilic tail group and a hydrophilic head group. The points of these groups that are measure of the differential tendency of the water to swell the head group and oil to swell the tail area are important for specific formulations while estimating the H.L.B. of the surfactant in a particular system. When the surfactant is in the presence of a salt or when a high concentration of the surfactant is used then the degree of polar group dissociation becomes lesser and the resulting system may be w/o type. ^[15]

Temperature influences the ionic surfactants strongly which mainly causes increased surfactant counter-ion dissociation. The tail group region of the surfactant monolayer swells up which is influenced curvature by it’s ability to penetrate due to the presence of oil component. For the determination of the effective head group size of the non-ionic surfactants, the temperature plays a very important role. They form normal o/w systems which are hydrophilic when the temperature is very low, but when the temperature is high they form w/o systems and are lipophilic. The microemulsion forms a bi-continuous structure and can co-exist with oil phases and excess water when the temperature is intermediate.

· The chain length, type and nature of co-surfactant:

Alcohols are widely used as a cosurfactant in microemulsions. Addition of shorter chain cosurfactant gives positive curvature effect as alcohol swells the head region more than tail region so, it becomes more hydrophilic.

EVALUATION OF THE MICROEMULSION SYSTEM :-^[16]

· Visual inspection

By the visual inspection we can check the properties such as fluidity, homogenicity, and optical clarity.

· Examination under Cross Polarising Microscope For the absence of bifringence to eliminate liquid crystalline systems, the microemulsion must be examined under cross polarizing microscope.

· Limpidity test (Percent Transmittance)^[17]

A spectrophotometer is used to measure the limpidity of the microemulsion spectrophotometrically

· Phase behavior studies:

Visual observations, phase contrast microscopy and freeze fracture transmission electron microscopy can be used to differentiate microemulsions from liquid crystals and coarse emulsions. Clear isotropic one-phase systems are identified as microemulsions whereas opaque systems showing bifringence when viewed by cross polarized light microscopy may be taken as liquid crystalline system^.[18]

· Rheology:

Change in the rheological characteristics help in determining the microemulsion region and its separation from other related structures like liquid crystals. Bicontinuous microemulsion are dynamic structures with continuous fluctuations occurring between the Bicontinuous structure, swollen reverse micelle, and swollen micelles^.[19]

· Scattering Techniques:

Scattering techniques such as small angle neutron scattering, small angle X-ray scattering and light scattering have found applications in studies of microemulsion structure, particularly in case of dilute monodisperse spheres,

Accelerated Stability Tests:^[20]

· Centrifugation Stress Testing

Because the stability studies take too much time, so the preference is given to accelerated stress testing. Centrifugation of the microemulsion is done at the speed of 5000-10,000 rpm for 30 mins to check the physical instabilities such as phase inversion, phase separation, creaming, aggregation and the cracking of the formulation. The formulations which are thermally tested previously are taken in the centrifuge sample tubes and are then placed into the centrifugation basket at a correctly balanced equilibrium position at suitable temperature conditions.

· Freeze-thaw cycles (FTC)

The microemulsions are stored at 25°C for 24 hours and followed by being stored at -5°C for 24 hours. This cycle is repeated 3 times and the change in the stability parameters are noticed.

· Term Stability

On the basis of the ICH guidelines the stability can be examined. For 6 months, the microemulsion are stored under ambient conditions and the microemulsion system were examined time to time after 1,3 and 6 months. By visual inspection and the pH, percent transmittance, rheological evaluation and the specific gravity are measured.

· Determination of the Globule Size

The size of the globules can be determined by the light scattering method. By the photomicroscope method the size determination of the globules are much easier.

· Determination of Thermal Stability

20ml of the microemulsion loaded with drugs were stored in a 25 ml transparent borosil volumetric container at three different temperatures i.e. 4°, 25° and 40°C, 1°C in BOD for 1 month. The samples were taken out at definite intervals of time to inspect visually to check any physical changes such as turbidity, coalescence and the loss of clarity. The samples can also be checked to determine the loss of the aqueous phase which is an important aspect of the stability of the microemulsion.

· pH of the Microemulsion

Different samples of the microemulsions are taken in the sample tubes. Then a micro pH meter is used to check the pH of the different samples. Since the pH of the formulation is the factor upon which the microemulsion stability and the bioavailability of the drug through microemulsion at the permeation site depends upon.

IDENTIFICATION TEST FOR TYPE OF MICROEMULSIONS ^[21]

· Dilution test

If the continuous phase is added in microemulsions, it will not crack or separate into phases. If water is added in o/w type of microemulsions it will remain stable.

· Staining test

Water soluble dye such as methylene blue or amaranth is added in water and microemulsion is prepared with oil and surfactant. A drop of Microemulsions is observed under microscope. Background is found to be blue / red and globule will appear colourless respectively.

· Dilutability test

The Microemulsions formed is diluted in 1:10, and 1:100, ratios with double distilled water to check if the system shows any signs of separation.

· Zeta potential measurement^[22]

It must be negative or neutral, which indicate that droplets of micro emulsion having no charge and hence the system is stable. Zeta potential is determined by using Zetasizer. Zeta potential is essentially useful for assessing flocculation since electrical charges on particles influence the rate of flocculation.

· In Vitro Skin Permeation Study

Skin permeation study is conducted to find the permeation of drug through skin. The study must be carried out under the guideline compiled by Committee for the Purpose of Control and Supervision of Experiments on Animal (CPCSEA, Ministry of Culture, Government of India). Those microemulsion formulation which is found to be best in evaluation studies are used. The abdominal skins obtained from male Wistar rats weighing 230±20 g (age, 6–8 weeks) is used for in vitro permeation experiments formulations.

PHARMACEUTICAL APPLICATIONS^[23]

During the last two decades, microemulsions have been promisingly used as drug delivery system for its advantages include their thermodynamic stability, optical clarity and ease of penetration. The role of microemulsion as drug delivery system shall be discussed herein.

· Oral delivery^[24]

The development of effective oral delivery systems has always been challenging to researchers because drug efficacy can be restricted by instability or poor solubility in the gastrointestinal fluid. Microemulsions have the potential to enhance the solubilization of poorly soluble drugs (particularly BCS class II or class IV) and overcome the dissolution related bioavailability problems. Due to the presence of polar, nonpolar and interfacial domains, hydrophilic drugs including macromolecules can be encapsulated with varying solubility. These systems have been protecting the incorporated drugs against oxidation, enzymatic degradation and enhance membrane permeability. Presently, Sandimmune Neoral (R) (Cyclosporine A), Fortovase (R) (Saquinavir), Norvir (R) (Ritonavir) etc are the commercially available microemulsion formulations. Microemulsion formulation can be potentially useful to improve the oral bioavailability of poorly water soluble drugs by enhancing their solubility in gastrointestinal fluid.

· Parenteral delivery^[25]

The formulation of parenteral dosage form of lipophilic and hydrophilic drugs has proven to be difficult. O/W microemulsions are beneficial in the parenteral delivery of sparingly soluble drugs where the administration of suspension is not required. They provide a means of obtaining relatively high concentration of these drugs which usually requires frequent administration. Other advantages are that they exhibit a higher physical stability in plasma than liposome’s or other vehicles and the internal oil phase is more resistant against drug leaching. Several sparingly soluble drugs have been formulated into O/W microemulsion for parenteral delivery. An alternative approach was taken by Von Corsewant and Thoren in which C3-C4 alcohols were replaced with parenterally acceptable cosurfactants, polyethylene glycol (400) / polyethylene glycol (660) 12-hydroxystearate / ethanol, while maintaining a flexible surfactant film and spontaneous curvature near zero to obtain and almost balanced middle phase microemulsion.

Figure No:5: Pharmaceutical application of microemulsion Adopted from Faizi muzaffar et al International Journal of Pharmacy and Pharmaceutical Sciences, Vol 5, 2013 ,46

· Topical delivery

Topical administration of drugs can have advantages over other methods for several reasons, one of which is the avoidance of hepatic first-pass metabolism, salivary and degradation of the drug in stomach and related toxicity effects. Another is the direct delivery and targetability of the drug to affected areas of the skin or eyes. Nowaday, there have been a number of studies in the area of drug penetration into the skin. They are able to incorporate both hydrophilic (5-flurouracil, apomorphine hydrochloride, diphenhydramine hydrochloride, tetracaine hydrochloride, methotrexate) and lipophilic drugs (estradiol, finasteride, ketoprofen, meloxicam, felodipine, triptolide) and enhance their permeation. Since formation of microemulsion formation requires high surfactant concentration, the skin irritation aspect must be considered especially when they are intended to be applied for a longer period.

· Ophthalmic delivery

In conventional ophthalmic dosage forms, water soluble drugs are delivered in aqueous solution while water insoluble drugs are formulated as suspension or ointments. Low corneal bioavailability and lack of efficiency in the posterior segment of ocular tissue are some of the serious problem of these systems. Recent research has been focused on the development of new and more effective delivery systems.

Microemulsions have emerged as a promising dosage form for ocular use. Chloramphenicol, an antibiotic used in the treatment of trachoma and keratitis, in the common eye drops hydrolyzes easily. Lv et al. investigated the microemulsion composed of Span 20, Tween 20, isopropylmyristate and water as potential drug delivery systems

· Nasal delivery^[26]

Recently, microemulsions are being studied as a delivery system to enhance uptake of drug through nasal mucosa. In addition with mucoadhesive polymer helps in prolonging residence time on the mucosa. Lianly et al. investigated the effect of diazepam on the emergency treatment of status epilepticus. They found that the nasal absorption of diazepam fairly rapid at 2 mg kg^-1 dose with maximum drug plasma concentration reached within 2-3 min.

· Drug targeting

Drug targeting to the different tissues has evolved as the most desirable goal of drug delivery. By altering pharmacokinetics and biodistribution of drugs and restricting their action to the targeted tissue increased drug efficacy with concomitant reduction of their toxic effects can be achieved. A novel microemulsion formulation for tumor targeting of lipophilic antitumor antibiotic aclainomycin A (ACM). They reported that a folate-linked microemulsion is feasible for tumour targeted ACM delivery. They also reported that folate modification with a sufficiently long PEG chain on emulsions is an effective way of targeting emulsion to tumour cells.

· Periodontal Delivery ^[27]

Periodontal disease is a collective term for a number of progressive oral pathological afflictions like inflammation and degeneration of the gums, periodontal ligaments, cementum and its supporting bone. It is a major cause of tooth loss. The invention of Brodin et al. included a novel pharmaceutical composition comprising local anaesthetic in oil form, surfactant, water and optionally a taste masking agent. The composition was in the form of an emulsion or microemulsion and had thermoreversible gelling properties i.e. it was less viscous at room temperature than after introduction onto a mucous membrane of a patient. The surfactant in the formulation imparted the thermoreversible gelling properties. Preferred surfactants were Poloxamer 188®, Poloxamer 407® and Arlatone 289®. The composition could be used as a local anaesthetic for pain relief within the oral cavity in conjunction with periodontal scaling and root planning and overcame the problem with the existing topical products (jelly, ointment or spray) such as lack of efficacy due to inadequate depth of penetration, too short duration and difficulties in administration due to spread, taste etc.

· Cellular Targeting

Nucleic acids delivered to cells are promising therapeutics. The invention of Monahan et al. Included insertion of nucleic acid into a reverse micelle for cell delivery. They referred w/o microemulsions to as reverse micelles. The reverse micelle had the property to compact the nucleic acid for easier delivery. To further enhance the delivery, other molecules such as a surfactant having a disulfide bond or a polyion might be added to the nucleic acid-micelle complex. Another advantage of the invention was the use of reverse micelles for gene delivery to the cells. The micelle containing the compacted polynucleotide could be utilized as a reaction vesicle in which additional compounds such as polycation could be added to the DNA. Additionally, the polynucleotide/reverse micelle system was used as a vesicle for template polymerization of the DNA or caging of the DNA in which the polycation was crosslinked. Another advantage was that the micelle might be cleaved under physiological conditions involved along the transfection (process of delivering a polynucleotide to a cell) pathway for better recovery and purification.

CONCLUSION:

Today microemulsions have shown to be able to liable drug, controlled release, increased drug solubility, increased bioavailability reduced patient variability, increased rate of absorption, helps solubilize lipophilic drug, various routes like topical, oral and intravenous can be used to deliver the product, helpful in taste masking and increased patient compliance. So, use of microemulsion drug delivery system is most attractive and suitable area of research, offering not only many challenges to overcome but also potential extra ordinary benefits. Furthermore, it has proven possible to formulate preparations suitable for most routes of administration. With this compilation we assure that the content of the article would be a useful tool to understand the in-depth knowledge of the subject concern.

ACKNOWLEDGMENT:

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors are also grateful to the e-library of Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India, 490001 for providing UGC-INFLIBNET facility. The authors acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.

REFERENCES:

1. Heuschkel S., Goebel A., Neubert R.H. Microemulsion – Modern colloidal carrier for dermal and transdermal drug delivery. Journal of Pharmaceutical Science. 97(2); 2008:603-631.

2. Faizi Muzaffar, U.K. Singh, Lalit Chauhan, Review on Microemulsion as Futuristic Drug Delivery, International Journal of Pharmaceutical Sciences, Vol-5 Issue 5( 3), 2005.

3. Baße A and Keipert S. Development and characterization of microemulsions for Ocularapplication. Europ. J. Pharm. Biopharm 1997; 43: 179-183.

4. Rohit Ramesh Shah, Chandrakant Shripal Magdum, Shitalkumar Shivagonda Patil, Nilofar Shanawaj Niakwade, Preparation and evaluation of aceclofenac topical Microemulsions, Iranian Journal of Pharmaceutical Research 10. (9), 2010, 5-11.

5. Baroli B, Lopez Quintele MA, Delgadocharr MB, Fadda AM, Blanco-Mendz J, Microemulsions for topical delivery of 8-methoxsalen,J.contol Rel.,69,2000,209-218.

6. Adnan Azeem, Mohammad Rizwan, Farhan Ahmad J, Zeenat Khan I, Roop Khar K, Mohammed Aqil and Sushama Talegaonkar, Emerging Role of Microemulsions in Cosmetics, Recent Patents on Drug Delivery & Formulation., 2, 2008, 275-289.

7. Hoar, T.P. and Schulman, J.H. Transparent water in oil dispersions: the oleopathic hydromicelle. Nature. 152:1943: 102-107.

8. Solans, C. and Kunieda, H. Industrial Applications of Microemulsions, New York, NY: Marcel Dekker. 1997.

9. Kumar, P. and Mittal, K.L. Hand Book of Microemulsions: Science and Technology, New York, NY: Marcel Dekker. 1998.

10. Moulik, S.P. and Mukherjee, K. On the versatile surfactant aerosol-OT: Its physicochemical and surface chemical behaviors and uses. Proc. Indian Natl. Sci. acad. A62:1996: 215-222.

11. Paul, B.K. and Moulik, S.P. Microemulsions: Over view. J. Disp. Sci. Technol. 18: 1997: 301-367.

12. J. H. Schulman, W. Stoeckenius, L. M. Prince, Mechanism of formation and structure of micro emulsions by electron microscopy, J. Phys. Chem., ( 63) 1959: 1677–1680 .

13. Vyas. S. P, Khar. R. K; Submicron emulsions in targeted and controlled drug delivery; Novel Carrier Systems; CBS Publishers and Distributors, New Delhi, 2002: 282–302.

14. Malcolmson C, Lawrence M; Three-component non-ionic oil-in-water microemulsions using polyoxyethylene ether surfactants; Colloids Surf., B Biointerfaces., (4) 1995: 97–109.

15. Constantinides PP, Scalars JP, Lancaster C, Marcello J, Marks G,Ellens H; Formulation and intestinal absorption enhancement evaluation of water-in-oil microemulsions incorporating medium-chain glycerides; Pharm Res;( 11) 1994: 1385–90 .

16. Brime B, Moreno M.A, Frutos G, Ballesteros MA, Frutos P; Amphotericin B in oil-water lecithin-based microemulsions: formulation and toxicity evaluation; Journal Pharm Sci., 91(4) 2002: 1178–85.

17. Ashok Patel R, Pradeep vavia R; Preparation and In vivo Evaluation of Self-Microemulsifying Drug Delivery System Containing fenofibrate; The AAPS Journal., (9) 2007: 344-352.

18. Sahwini Rasal, Mahajan H S, Shaikh H T, Suran S J; Development and characterization of nasal mucoadhesive microemulsions of sumatriptan succinate .

19. Monahan. S .D, Wolff. J. A., Slattum. P. M, Hagstrom. J. E., Budker. V.G.: US20026429200 (2002).

20. Wheeler. J. J; Bally. M. B; US5478860 (1995).

21. Maranhao. R. C.; US5578583 (1996).

22. Shiokawa T, Hattori Y, Kawano K; Effect of polyethylene glycol linker chain length of folate-linked microemulsions loading aclacinomycin A on targeting ability and antitumour effect in vitro and in vivo; Clin Cancer Res.,( 11) 2005: 2018-2025.

23. Wermling D. P, Miller J. P, Archer S. M, Manaligod J. M, Rudy. A. C; Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous and intramuscular administration; J Clin Pharmacol. (41)2001: 1225-1231.

24. Dorman DC, Brenneman KA, McElveen AM, Lynch SE, Roberts KC, Wong BA; Olfactory transport: A direct route of delivery of inhaled managanese phosphate to the rat brain; J Toxicol Environ Health.,( 65) 2002, 1493-1511.

25. 28. Jain N K, Progress in controlled and novel drug delivery system, , 1,CBS Publisher, New delhi, 2004:309-340.

26. Boonme P. Applications of microemulsions in cosmetics. J Cosmet Dermatol, 6(4)2007: 223-228.

27. Azeem A, Khan ZI, Aqil M, Ahmad FJ, Khar RK, Talegaonkar S. Microemulsions as a surrogate carrier for dermal drug delivery. Drug Dev Ind Pharm, 35(5)2009: 525-547.

Received on 24.12.2016 Modified on 23.03.2017

Research J. Pharm. and Tech. 2017; 10(5): 1509-1516.

DOI: 10.5958/0974-360X.2017.00266.9