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REVIEW ARTICLE e-ISSN: 2454-7867 Available online at www.ijtpls.com International Journal of Trends in Pharmacy and Life Sciences Vol. 1, Issue: 3, 2015: 457-467. A REVIEW ON MICROEMULSION IN NOVEL DRUG DELIVERY SYSTEM N.Srija*, Sharada Srikanth & V. Uma Maheshwar Rao Dept. of Pharmaceutics, CMR College of Pharmacy, Kandlakoya (V), Medchal Road, Hyderabad - 501 401. E.Mail: [email protected] ABSTRACT Microemulsions are one of the best candidates as novel drug delivery system because of their long shelf life, improved drug solubilization with ease of preparation and administration. Microemulsions are thermodynamically stable and optically isotropic liquid solutions of oil, water and amphiphile. They have emerged as novel vehicles for drug delivery which allow controlled or sustained release for ocular, percutaneous, topical, transdermal, and parenteral administration of medicaments. Microemulsions can be easily distinguished from normal emulsions by their low viscosity, transparency and more accurately their thermodynamic stability. Microemulsions have great range of applications and uses such as in pharmaceuticals, agrochemicals, cutting oils, biotechnology, food, cosmetics, analytical applications, environmental detoxification etc. The main objective of this review paper is to discuss Microemulsions as drug carrier system with other possible applications. Key Words: Microemulsions, thermodynamically stable, amphiphile, Solubilization *Corresponding Author: N.Srija Dept. of Pharmaceutics, CMR College of Pharmacy, Kandlakoya (V), Medchal Road, Hyderabad - 501 401. E.Mail: [email protected] Received: 06/08/2015 Revised: 20/09/2015 Accepted: 30/09/2015 INTRODUCTION The formulation and development of novel drug delivery system with the nature of enhancing the effectiveness of existing of drug is an ongoing process in pharmaceutical research. Since there are many types of drug delivery systems that have been developed. The microemulsion concept was introduced in 1940s by Hoar and Schulman who generated 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 an alcohol as a co-surfactant, leading to transparent stable formulation. Microemulsion is defined as microemulsion are clear, transparent, thermodynamically stable dispersions of oil and water, stabilized by an interfacial film of surfactant frequently in combination with a co-surfactant [2].Alternative names for these systems are often used, such as swollen micelle, transparentemulsion, solubilized oil and micellar solution. Microemulsions are discontinuous systems that are essentially 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]. Microemulsions are currently the subject of many investigations because of their wide range of Srija N et al. Int J Trends in Pharm & Life Sci. 2015: 1(3); 457-467. 457 REVIEW ARTICLE e-ISSN: 2454-7867 potential and actual utilizations. The high capacity of Microemulsions for drugs makes them attractive formulations for pharmaceuticals. These systems also offer several benefits for oral administration, including increased absorption, improved clinical potency and decreased toxicity [5]. Advantages of Microemulsion system: 1. Microemulsions are easily prepared and require no energy contribution during preparation this is due to better thermodynamic stability. 2. The formation of microemulsion is reversible. They may become unstable at low or high temperature but when the temperature returns to the stability range, the microemulsionreforms. 3. Microemulsions are thermodynamically stable system and allow self-emulsification of the system. 4. Microemulsions have low viscosity compared to emulsions. 5. Microemulsions act as super solvents for drug can solubilise both hydrophilic and lipophilic drugs including drugs that are insoluble in both aqueous and hydrophobic solvents. 6. Having the ability to carry both lipophilic and hydrophilic drugs. 7. The dispersed phase, lipophilic or hydrophilic (O/W, or W/O Microemulsions) can act as a potential reservoir of lipophilic or hydrophilic drugs, respectively. 8. The use of microemulsion as delivery systems can improve the efficacy of a drug, allowing the total dose to be reduced and thus minimizing side effects [6, 7]. Disadvantages of Micro emulsion Systems: 1. Having limited solubilizing capacity for high melting substances. 2. Require large amount of Surfactants for stabilizing droplets. 3. Micro emulsion stability is influenced by environmental parameters such as temperature and pH [8]. Difference between Emulsion and Microemulsions [9]: Table 1: Comparison between Emulsion and Microemulsion S.No Emulsion Microemulsion 1 Emulsions are thermodynamically unstable, they may remain stable for long periods of time, will ultimately undergo phase separation on standing to attain a minimum in free energy. Microemulsions are thermodynamically stable, it can have essentially infinite lifetime assuming no change in composition, temperature and pressure, and do not tend to separate. Srija N et al. Int J Trends in Pharm & Life Sci. 2015: 1(3); 457-467. 458 REVIEW ARTICLE e-ISSN: 2454-7867 2 They are lyophobic. They are on the borderline between lyophobic and lipophilic colloids 3 Most emulsions are opaque (white) because bulk of their droplets is greater than wavelength of light and most oils have higher refractive indices than water Microemulsions are transparent or translucent as their droplet diameter are less than ¼ of the wavelength of light, they scatter little light 4 Emulsions consist of roughly spherical They constantly evolve between droplets of one phase dispersed into the various structures ranging from droplet other. like swollen micelles to bi-continuous structure 5 Droplet diameter 1–20mm. Droplet diameter 10–100nm. 6 Inefficient molecular packing Efficient molecular packing 7 Direct oil/water contact at the interface. No direct oil/water contact at the interface. STRUCTURE OF MICROEMULSION 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 bicontinuous 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. In system where the amounts of water and oil are similar, the bi-continuous Microemulsions may result [32]. The mixture oil water and surfactants are able to form a wide variety of structure and phase depending upon the proportions of component [10]. Fig. 1: Microemulsion Structure TYPES OF MICROEMULSION SYSTEMS: According to Winsor, there are four types of microemulsion phases exists in equilibria, these phases 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. Srija N et al. Int J Trends in Pharm & Life Sci. 2015: 1(3); 457-467. 459 REVIEW ARTICLE e-ISSN: 2454-7867 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 [11]. Fig. 2: O/W, W/O and Bi-continuous Microemulsions THEORIES OF MICROEMULSION FORMULATION The formulation of microemulsion is based on various theories that effect and control their stability and phase behavior. These theories are: 1. Thermodynamic theory 2. Solubilization theory 3. Interfacial theory Thermodynamic theory: Formulation and stability of microemulsion can be expressed on the basis of a simplified thermodynamic mechanism. The free energy of microemulsion formation can be dependent on the extent to which surfactant lowers the surface tension of the oil–water interface and the change in entropy of the system, thus [12]: DG f = γDA - T DS Where, DG f = Free Energy of formation, γ =Surface Tension of the oil–water interface, DA = Change in interfacial area on micro emulsification, DS = Change in entropy of the system which is effectively the dispersion entropy, and T = Temperature. Srija N et al. Int J Trends in Pharm & Life Sci. 2015: 1(3); 457-467. 460 REVIEW ARTICLE e-ISSN: 2454-7867 It is found that when a micro emulsion is formed, DA is changed to a large extent due to the large number of very small droplets formed. It is must to know that while the value of γ is positive at all times, it is very small, and is offset by the entropic component. The dominant favorable entropic contribution is the very large dispersion entropy arising from the mixing of one phase in the other in the form of large numbers of small droplets. However, favorable entropic contributions also come from other dynamic processes such as monomer-micelle surfactant exchange and surfactant diffusion in the interfacial layer. When large reductions in surface tension are found by significant favorable entropic change, a negative free energy of formation is achieved. In that case, micro emulsification is spontaneous and the resulting dispersion is thermodynamically stable [13]. Solubilization theory: The formation of microemulsion is oil soluble phase and water phase by micelles or reverses micelles in micellar gradually become larger and swelling to a certain size range results [14]. Interfacial theory: The interface mixed-film theory i.e. a negative interfacial tension theory, according to this theory the micro-emulsion has been capable to form instantaneous and spontaneously generate a negative interfacial tension in the surfactant and co-surfactant in working together. The film, which may consist of surfactant and cosurfactant molecules, is considered as a liquid ‘‘two dimensional’’ third phase in equilibrium with both oil and water. Such a monolayer could be a duplex film, i.e. giving different properties on the water side and oil side. According to the duplex film theory, the interfacial tension γT is given by the following expression [14]: γT = γ(O/W) --- π Where, γ (O/W) a = Interfacial Tension (reduced by the presence of the alcohol). γ (O/W) a is significantly lower than γ(O/W) in the absence of the alcohol. COMPONENTS OF MICROEMULSIONS 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, cyclohexane, 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. Srija N et al. Int J Trends in Pharm & Life Sci. 2015: 1(3); 457-467. 461 REVIEW ARTICLE e-ISSN: 2454-7867 The selection of surfactant must be: 1. Reduce the interfacial tension during the preparation of Microemulsions. 2. Provide a flexible film that can readily deform round small 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 discontinuous [15]. METHOD OF FORMULATION Microemulsions are prepared when interfacial tension at the oil/water is kept at very low level. Interfacial layer is kept very much flexible and fluid concentration of surfactants should be high enough to give surfactant molecules to be stabilized the microemulsion at an extremely low interfacial tension. Two main method are reported for the formulation of microemulsion, these are 1. Phase Inversion Method 2. Phase Titration Method 1. Phase titration method: Microemulsions are prepared by spontaneous emulsification method which is illustrated with help of phase diagrams. Phase diagram construction is practical approach to study complex series of interaction which occurs when different components are mixed. The aspect of the phase diagram is phase equilibrium and demarcation of phase boundaries. Most often pseudo-ternary phase diagrams are constructed to figure out microemulsion zone as quaternary phase diagram is time consuming and difficult to interpret [16]. 2. Phase inversion method: Phase inversion of microemulsion happens upon addition of excess of dispersed phase. Phase inversion leads to radical physical changes as change in particle size that alters drug release. During cooling, this system crosses the point of zero spontaneous curvature and minimal surface tension, prompting the formation of finely dispersed oil droplets. Microemulsions can be prepared by controlled addition of lower alkanols (butanol, pentanol and hexanol) to milky emulsions to produce transparent solutions comprising dispersions of either o/w or w/o or colloidal dispersions. The lower alkanols are called co-surfactants. They lower the interfacial tension between oil and water [16]. MARKETED MICROEMULSIONS There are certain Microemulsions which are commercially available in the market. (Table 2) [17]. Srija N et al. Int J Trends in Pharm & Life Sci. 2015: 1(3); 457-467. 462 REVIEW ARTICLE e-ISSN: 2454-7867 Table 2: Microemulsions based marketed product Brand name Composition Manufactured by Sandimmune Cyclosporin A Novartis Neoral® Fortovase ® Saquinavir Roche laboratories Norvir ® Ritonavir Abbott Laboratories EVALUATION PARAMETERS OF MICROEMULSION SYSTEM Physical appearance: For Physical appearance microemulsion can be inspect visually for homogeneity, fluidity and optical clarity [18]. 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 monodisperese spheres, when polydisperse or concentrated systems such as those frequently seen in Microemulsions [19]. Limpidity Test (Percent Transmittance): The limpidity of the microemulsion can be measured spectrophotometrically using spectrophotometer [19]. Drug stability: The optimized microemulsion was kept under cold condition (4-8°C), room temperature and at elevated temperature (50 ± 2 °C). After every 2 months the microemulsion can be analyzed for phase separation, % transmittance, globule size and % assay [19]. Globule size and zeta potential measurements: The globule size and zeta potential of the microemulsion can be determined by dynamic light scattering, using a Zetasizer HSA 3000 [20]. Assessment of the Rheological Properties (viscosity measurement): The rheological properties play an important role in stability. It can be determined by Brookfield digital viscometer. Change in the rheological characteristics help in determining the microemulsion region and its separation from other region. Discontinuous microemulsion are dynamic structures with continuous fluctuations occurring between the discontinuous structure, swollen reverse micelle, and swollen micelles [20]. Electrical conductivity: The water phase was added drop wise to a mixture of oil, surfactant and cosurfactant and the electrical conductivity of formulated samples can be measured using a conduct meter at ambient temperature and at a constant frequency of 1 Hz [20]. Drug solubility: Drug was added in excess to the optimized microemulsion formulation as well as each individual ingredient of the formulation. After continuous stirring for 24 h at room temperature, samples were withdrawn and centrifuged at 6000 rpm for 10 min. The amount of soluble drug in the optimized formulation as well as each individual ingredient of the formulation was calculated by subtracting the drug Srija N et al. Int J Trends in Pharm & Life Sci. 2015: 1(3); 457-467. 463 REVIEW ARTICLE e-ISSN: 2454-7867 present in the sediment from the total amount of drug added. The solubility of drug in microemulsion was compared with respect to its individual ingredients [21]. In-vitro drug release: The diffusion study can be carried out on a modified Franz diffusion cell, within volume of 20mL. The receptor compartment was filled with of buffer .The donor compartment was fixed with cellophane membrane, containing the microemulsion formulation and the plain drug solution, separately. At predetermined time intervals samples were withdrawn from the receptor compartment and analyzed for drug content, using a UV spectrophotometer at specific wavelength [21]. APPLICATIONS OF MICROEMULSION Microemulsion in pharmaceuticals: Parenteral administration: Parenteral administration (especially via the intravenous route) of drugs with limited solubility is a major problem in the pharmaceutical industry because of the extremely low amount of drug actually delivered to a targeted site. Microemulsion formulations have distinct advantages over Microemulsion systems when delivered parenterally because of the fine particle, microemulsion is cleared more slowly than the coarse particle emulsion and, therefore, have a longer residence time in the body. Both O/W and W/O microemulsion can be used for Parenteral delivery [22]. Oral administration: Oral administration of microemulsion formulations offer several benefits over conventional oral formulation including increased absorption, improved clinical potency, and decreased drug toxicity. Therefore, microemulsion has been reported to be an ideal delivery of drugs such as steroids, hormones, diuretic and antibiotics [23]. Topical administration: Topical administration of drugs can have advantages over other methods for several reasons, one of which is the avoidance of hepatic first pass metabolism of the drug and related toxicity effects. Another is the direct delivery and targetability of the drug to the affected area of the skin or eyes [24]. Ocular and pulmonary delivery: Ocular and pulmonary delivery for the treatment of eye diseases, drugs are essentially delivered topically. O/W Microemulsion have been investigated for ocular administration, to dissolve poorly soluble drugs, to increase absorption and to attain prolong release profile [24]. Microemulsions in biotechnology: Many enzymatic and biocatalytic reactions are conducted in pure organic or aqua-organic media. Biphasic media are also used for these types of reactions. The use of a pure polar media causes the denaturation of biocatalysts. The use of water-proof media is relatively advantageous. Enzymes in low water content display and have: Srija N et al. Int J Trends in Pharm & Life Sci. 2015: 1(3); 457-467. 464 REVIEW ARTICLE e-ISSN: 2454-7867 1. Increased solubility in non-polar reactants. 2. Possibility of shifting thermodynamic equilibria in favour of condensations. 3. Improvement of thermal stability of the enzymes, enabling reactions to be carried out at higher temperatures [25]. Solubilization of drug in microemulsion: Microemulsion possesses interesting physicochemical properties, i.e. transparency, low viscosity, thermodynamic stability, high solubilization power. Because of these specific properties of microemulsion can be useful as a drug delivery system. Different categories of drugs can be solubilized in microemulsion systems for their better therapeutic efficacy [26]. CONCLUSION Microemulsions have a very crucial importance in the drug delivery system as well as in the industrial process. They can be used to optimize drug targeting without a concomitant increase in systemic absorption. The role of microemulsion in providing novel solutions to overcome the problems of poor aqueous solubility of highly lipophilic drug compounds and provide high, more consistent and reproducible bioavailability. Microemulsions can also be used to achieve drug targeting however challenges remain, primarily because of the layers of barriers that these systems need to overcome to reach to the target. Microemulsion has been shown to be able to protect labile drug, control drug release, and reduce patient variability. 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