Sarika S. Lokhande*
GES College of Pharmacy, Limb, Satara, Maharashtra
Multiple emulsions are complex polydispersed systems where both oil in water and water in oil emulsion exists concurrently which are stabilized by lipophillic and hydrophilic surfactants respectively. The ratio of these surfactants is important in achieving stable multiple emulsions. Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type multiple emulsions; the previous has wider areas of application. Formulation, preparation techniques and in vitro characterization methods for multiple emulsions are reviewed. It finds extensive range of applications in controlled or sustained drug delivery, targeted delivery, taste masking, bioavailability improvement, enzyme immobilization, etc. Multiple emulsions have also been employed as transitional step in the microencapsulation process and are the systems of increasing interest for the oral delivery of hydrophilic drugs, which are unbalanced in gastrointestinal tract like proteins and peptides Preparation of monodispersed multiple emulsion is important in DDS to improve their stability and to facilitate control of their properties..The study concluded that stable multiple emulsion with high entrapment efficiency can be prepared by two step emulsification method using Spans40, 60, 80 as primary emulsifier and Tween80 as secondary emulsifier.
Multiple emulsions are distinct as emulsions in which both types of emulsions, i.e. water-in oil (w/o) and oil-in water (o/w) exist concurrently. They combine the properties of both w/o and o/w emulsions. These have been described as heterogeneous systems of one immiscible liquid dispersed in another in the form of droplets, which typically have diameters greater than 1μm.
These two liquids forming a system are characterized by their low thermodynamic stability. Multiple emulsions are very multifaceted systems as the drops of dispersed phase themselves contain even smaller droplets, which normally consist of a liquid miscible and in most cases identical with the continuous phase. Both hydrophilic and lipophilic emulsifiers are used for the formation of multiple emulsions. 
Multiple emulsions are promising in many fields, particularly in pharmaceutics and in separation science. Their potential biopharmaceutical applications include their use as adjuvant vaccines, as prolonged drug delivery systems, as sorbent reservoirs in drug overdose treatments and in mobilization of enzymes. Multiple emulsions were also investigated for cosmetics for their probable advantages of prolonged release of active agent, integration of incompatible materials and protection of active ingredients by dispersion in internal phase. The droplets of the dispersed phase contain even smaller dispersed droplets themselves, therefore also called as "emulsions of emulsions". Each dispersed globule in the double emulsion forms a vesicular structure with single or multiple aqueous compartments alienated from the aqueous phase by a layer of oil phase compartments. In multiple emulsion system solute has to transverse from inner miscible phase to external miscible phase through the middle immiscible organic phase, so it is also called as liquid membrane system. The two major types of multiple emulsions are the water-oil-water (w/o/w) and oil-water-oil (o/w/o) double emulsions. The most common multiple emulsions are of W/O/W type, although some precise applications O/W/O emulsions can also be prepared. Multiple emulsions may find many possible applications in various fields such as chemistry, pharmaceutics, cosmetics, and food. These emulsions have been investigated as controlled-release drug delivery systems(DDS) as ‘emulsion liquid membranes’ for simultaneous liquid extraction and stripping of metals, organic acids and antibiotics, as microcapsules for the protection and controlled release of functional food ingredients, for the formulation of reduced-calorie food emulsion etc. Other applications include the use of multiple emulsions as intermediate products to the preparation of inorganic particles, lipid nanoparticles, polymeric microspheres, biodegradable microspheres, gel micro beads, and vesicles such as polymerosomes. For medical applications, a water-soluble beneficial constituent can be solubilised within the inner W1 phase of the emulsion globule, which showed extended release properties and lessen toxic effects. The stability and release properties of double emulsion can be improved by unreliable the type and concentrations of surfactants. Combining targeted delivery with prolonged release would present a great benefit in cancer therapy. The use of double emulsions to accomplish this Multiple emulsions have not been commercially browbeaten because of their inherent thermodynamic instability. A number of attempts have been made in last two decades for improving stability by several investigators. These attempts are; polymerization gelling, additives in different phases, surfactant concentration modulation, interfacial complexation, pro-multiple emulsion approach and steric stabilization. 
Advantages of Multiple Emulsions:
a. They can mask the bitter taste and odor of drugs, thereby making them more edible. E.g. Castor oil, Cod-liver oil, Chloroquine Phosphate etc.
b. They can be used to extend the release of the drug thereby as long as sustained release action.
c. Vital nutrients like carbohydrates, fats and vitamins can all be emulsified and can be administered to bed ridden patients as sterile intravenous emulsions.
d. Emulsions offer protection to drugs which are vulnerable to oxidation or hydrolysis.
e. Intravenous emulsions of contrast media have been developed to assist in diagnosis.
f. Emulsions are used broadly to formulate externally used products like lotions, creams, liniments.
g. Improvement of enteric or dermal absorption. 
Limitations of multiple emulsions:
The main difficulty associated with multiple emulsions is their thermodynamic instability and their complex structure, which has severely inadequate their usefulness in the many applications of multiple emulsions.
Types of Multiple Emulsions:
The two primary types of multiple emulsions are the water-oil-water (w/o/w) and oil-water-oil
(o/w/o) double emulsions.
Water-in-Oil-in-Water (W/O/W) Emulsion System:
In W/O/W system, an organic phase(hydrophobic) separates internal and external aqueous phase. In other words, W/O/W is a system in which oil droplets may be surrounded by an aqueous phase, which in turn encloses one or several water droplets.
Oil-in-Water-in-Oil (O/W/O) Emulsion System:
In O/W/O systems, an aqueous phase(hydrophilic) separates internal and external oil phase. In other words, O/W/O is a system in which water droplets may be surrounded in oil phase, which in turn encloses one or more oil droplets.
Figure 1: Schematic Representation of AW/O/W Double Emulsion Droplet W/O/W Double Emulsion Droplet.
The objectives will be to create a multiple emulsion system that has a high yield of multiple droplets containing the drug entrappedin the innermost phase, and for such a system to have good stability in vitro and the desired release characteristics in vivo.
Formulation of Multiple Emulsions:
Florence and Whitehil described three different types of multiple emulsions, which they termed A, B, and C. Type A multiple emulsions were those in which only one large internal drop was contained in the secondary emulsion droplet. In type B emulsions, there were several small internal droplets controlled in the secondary emulsion droplet, and type C emulsions were those with a large number of internal droplets present. Only the type C systems have applications in drug delivery and drug targeting.
The oil phase to be employed in a pharmaceutical emulsion must be nontoxic. A variety of oils of vegetable origin (soybean, sesame, peanut, safflower, etc.) are satisfactory if light liquid paraffin, squalane, as well as esters of fatty acids (ethyl oleate and isopropylmyristate) have also been used in double emulsions 1. Oils derived from vegetable sources are biodegradable, whereas those based on mineral oils are only removed from the body very slowly.
As a universal rule, mineral oils produced more stable multiple emulsions (w/o/w) than those produced from vegetable oils 2. The order of decreasing stability and percentage entrapment has been found to be light liquid paraffin >squalane > sesame oil > maize or peanut oil.
Nature and Quantity of Emulsifying Agents:
Two different emulsifiers (lipohilic and hydrophilic) are necessary to form a stable emulsion. In general, for a w/o/w emulsion the optimal HLB value will be in the range 2-7 for the primary surfactant and in the range 6-16 for the secondary surfactant. The concentration of the emulsifiers can also be varied. Too little eemulsifier may result in unbalanced systems, whereas too much emulsifier may lead to toxic effects and can even cause deterioration. An excess of lipophilic surfactant can cause the inversion of w/o/w emulsion to simple o/w emulsion.
It is very important to have appropriate order of phase addition while formulation and dispersed phase should be added slowly into the continuous phase for the formulation of a stable multiple emulsion. An optimal (22-50%) internal phase volume can be utilized for the emulsion formulation. Very high phase volume ratio (70-90%) had also been reported to create a stable multiple emulsion.
Factor Affecting Stability of Multiple Emulsion:
Nature of Entrapped Material:
When formulating a w/o/w system the presence of the drug and other mechanism (especially electrolytes) needs to be considered. The nature of drug (hydrophilic or hydrophobic) also is considered. Due to the nature of the multiple emulsions, the middle phase acts as a membrane, and osmotic effects may become important. The entrapped solutions may interconnect with the surfactant or the surface active drugs may be adsorbed at the inter phase, resulting in decreased stability.
High shear disrupts the large percentage of multiple oil drops and hence results in the instability of system due to incredible increase in effective surface area. Therefore, with increased homogenization time, the yield of the system falls rapidly. Generally high agitation speed is used for primary and low speed is used for secondary emulsification for the preparation of multiple emulsions.
Temperature has only an circumlocutory effect on emulsification that is attributed to its effect on viscosity, surfactant adsorption and interfacial tension. Generally, for the primary emulsion formulation temperature is kept at 70˚C, Whereas for multiple emulsion preparation it is kept at 10°C. Large temperature variations during manufacturing, storage, transport and use leads to extreme modifications within emulsions.
The rheological properties of emulsions are influenced by a number of factors, including the nature of the incessant phase, the phase volume ratio, and to lesser amount by particle size distribution. For low internal phase volume emulsions, the consistency of the emulsion similar to the continuous phase; thus, o/w/o emulsions are usually thicker than w/o/w emulsions, and the reliability of a w/o/w system can be increased by the addition of gums, clays.
Effect of Lipophilic Emulsifier
As the concentration of lipophilic surfactant is increases, the swelling capacity of oil globule is increases, and the more the discharge is delayed.
Method of Preparation of Multiple Emulsions
Multiple emulsions are frequently formed by a two step emulsification process using conventional rotor-stator or high pressure valve homogenizers. The primary w/o or o/w emulsion is prepared under high-shear conditions to obtain small inner droplets, while the secondary emulsification step is carried out with less shear to avoid break of the liquid membrane between the deepest and outermost phase. However, the second step often results in highly polydisperse outer drops (if homogenizing conditions are too mild) or in a small encapsulation effectiveness (if homogenization is too intensive). Multiple emulsions can otherwise be produced by forcing a primary emulsion through a microporous membrane or micro fabricated channel arrays into a continuous phase liquid. This results in much less shear than in predictable emulsification processes so that the droplets are intact and both high entrapment efficiency and monodispersity can be achieved.
Two Step Emulsification Method:
Figure.1. Formulation Steps of water: oil: water (w/o/w) multiple emulsion
Preparation of Multiple Emulsion:
Multiple emulsions can be prepared by there-emulsification of a primary emulsion or they can be twisted when an emulsion inverts from one type to another, for example W/O to O/W. The O/W emulsions have small size of internal dispersed phase consequently; it is not used in therapeutics.
a) Phase Inversion Technique or Single Step Technique:
The increase in volume of dispersed phase may cause an increase in the phase volume ratio, which consequently leads to the formation of multiple emulsions. The technique involves the addition of an aqueous phase containing the hydrophilic emulsifier (Tween 80/Sodium Docedyl Sulphate) to an oil phase consisted of liquid paraffin and containing liophillic emulsifier (Span 80). A well distinct volume of oil phase is placed in a vessel of pin mixer. An aqueous solution of emulsifier is then introduced consecutively to the oil phase in the vessel at a rate of 5 ml/min, while the pin mixer rotates steadily at 88 rpm at room temperature.
When volume fraction of the aqueous solution exceeds 0.7, the continuous oil phase is substituted by the aqueous phase containing a number of the vesicular globules among the simple oil droplets, leading to phase inversion and formation of W/O/W multiple emulsion.
b) Two-Step Emulsification:
Multiple emulsions are usually formed by a two-step emulsification process using conservative rotor-stator or high pressure valve homogenizers. The primary W/O orO/W emulsion is prepared under high-shear circumstances to obtain small inner droplets, while the secondary emulsification step is carried out with less shear to avoid rupture of the liquid membrane between the innermost and outermost phase. However, the second step often results in highly polydisperse outer drops (if homogenizing conditions are too mild) or in small encapsulation efficiency (if homogenization is too intensive) 
Behaviour of Multiple Emulsions in Biological System:
ME’s have been administered by oral, parentral (i.v., i.m., s.c.) and topical routes (nasal, ocular, transdermal) routes. After oral administration ME is almost absorbed entirely from lymphatic pathway in involvement with intestinal lipoproteins specifically chylomicrons, produced by enterocytes. They may directly be absorbed through intestinal macrophage system & Payers Patches to increase access into mesenteric lymph from where they are drained into circulation through thoracic lymph duct. Thus, they are able to carry bioactives within them avoiding degradation in intestine as well as liver. After parenteral (i.v. or i.m.) administration the emulsions are readily taken up by circulatory macrophage system to lymphatics as well as liver into fat metabolism pathway. Through other parenteral routes, the emulsion droplets gain access to nearby lymphatic node through interstitial spaces of lymphatic vessels which are comparatively porous as compared to blood capillaries which have tight intracellular junctions.
Possible mechanism of drug release from multiple emulsion:
In multiple emulsions, the drug is free from internal to external phase through the oily layer by different mechanism. The release rates are affected by a variety of factors such as droplet size, pH, phase volume and viscosity etc. The various Mechanisms are:
a) Diffusion mechanism:
This is most common transport mechanism where unionized hydrophobic drug diffuses throughout the oil layer in the stable multiple emulsions. Drug transport has been found to follow first order kinetics and obeyed Fick’s law of diffusion.
b) Micellar transport:
Converse micelles consisting of nonpolar part of surfactant lying exterior and polar part inside encapsulate hydrophilic drug in core and permeate through the oil membrane because of the external lipophillic nature. Inverse micelle can encapsulate both ionized and unionized drugs.
Recently, the release of tetradecane from atetradecane/water/hexadecane multiple emulsions was investigated using the differential scanning calorimetry technique. Micellar diffusion rather than molecular dispersion was considered to be the preponderant mechanism for mass transfer..
c) Thinning of the oil membrane:
Due to osmotic pressure difference, the oil membrane became thin, so the water and drug easily diffused. This pressure difference also provides force for the transverse of molecule.
d) Rupture of oil phase:
According to this mechanism rupturing of oil membrane can come together both aqueous phases and thus drug could be released easily.
In-Vitro Drug Release:
The drug released from the aqueous inner phase of a W/O/W emulsion can be estimated using the predictable dialysis technique. The W/O/W emulsion was placed in the dialysis bag & dialyzed against 200 ml of phosphate saline buffer pH 7.4 at 37±1˚c & a sink condition was maintained while sink contents were stirred continuously using a magnetic stirrer. Aliquots were withdrawn at unusual time intervals and estimated using standard procedure and the data were used to estimate increasing drug release profile
Application of Multiple Emulsions:
Multiple emulsions in cancer therapy:
The majority anticancer drugs are used as emulsions because they are water-soluble. In the form of an emulsion it is possible to control release rates of medicine and restrain strong side effects of the drug. A single emulsion cannot be used since W/O emulsions usually have such a high viscosity that infusion of emulsions to arteries/capillaries via catheters is complicated. Also O/W emulsions are not an alternative because they do not encapsulate the drug. But W/O/W emulsion systems are appropriate drug carriers because of the encapsulation of the drug in the internal water phase and the low viscosity due to the external water phase.
Multiple emulsions in herbal drugs:
Apart from its targeted sustained release, producing the herbal drug into emulsion will also make stronger the stability of the hydrolyzed materials, improve the penetrability of drugs to the skin and mucous, and reduce the drugs' stimulus to tissues. So far, some kinds of herbal drugs, such as camptothecin, Bruceajavanica oil, coixenolide oil and zedoary oil have been made into emulsion.
The use of w/o/w multiple emulsion as a new form of adjuvant for antigen was first reported by Herbert. These emulsions elicited enhanced immune response than antigenalone. Rishendra and Jaiswal developed a multiple emulsion vaccine alongside Pasteurella multocida infection in cattle. This vaccine contributed both humoral as well as cell-mediated immune responses in defense against the infection.
A multiple emulsion of aqueous oxygen transportation material in oil in outer aqueous segment is suitable for provision of oxygen for oxygen transfer processes. Haemoglobin multiple emulsions in physiologically well-matched oil in an outer aqueous saline solution is provided in adequately small droplet size to provide oxygen flow through blood vessels to preferred body tissues or organs thereby providing a blood substitute.
Concerning this approach Talegaonkar and Vyas were prepared poloxamer 403 containing sphere in- oil-in water(s/o/w) multiple emulsion of Diclofenac sodium by gelatinization of inner aqueous phase and they examined the effect of poloxamer 403 on surface alteration for opposite targeting to reticuloendothelial system-rich organs. The consequences concluded that this multiple emulsion system containing poloxamer has ability to retards the RES uptake of drugs mainly to liver, brain and targeting to non-RES tissues such as lungs, inflammatory tissue.
Multiple emulsions in diabetes:
Toorisaka et al. Developed a S/O/W emulsion for oral administration of insulin. Surfactant-coated insulin was dispersed in the oil by ultrasonication, this dispersionwas mixed with the outer water phase with ahomogenizer and finally, the S/O/W emulsion thus obtained was adjusted to a constant particle size by passage through SPG membrane. The S/O/W emulsion showed hypoglycemic activity for a long period after oral administration to rats.
Multiple emulsions in food:
Another probable application of double emulsions is in the food industry. Preliminary studies have been performed in the field of entrapment of a flavor constituent in a release system. Susceptible food materials and flavours can be encapsulated in W/O/W emulsions.
Sensory tests have indicated that there is a important taste difference between W/O/W emulsions and O/W emulsions containing the same ingredients, and that there is a delayed release of flavour in double emulsions.
Drug over dosage treatment:
This system could be utilized for the over dosage treatment by utilizing the difference in the pH. For example: barbiturates. In these emulsions, the inner aqueous phase of emulsion has the necessary buffer and when emulsion is taken orally, acidic pH of the stomach acts as an external aqueous phase. In the acidic phase barbiturate remains mainly in unionized form which transfers through oil membrane into inner aqueous phase and getsionized. Ionized drug has less attraction to cross the oil membrane thereby getting entrapped. Thus, entrapping overload drug in multiple emulsions cures over dosage.
Multiple emulsions of chloroquine, an antimalarial agent has been effectively prepared and had been establish to mask the bitter taste efficiently. Taste masking of chlorpromazine, an antipsychotic drug has also been reported by multiple emulsions.
Direct versus premix membrane emulsification:
Membrane emulsification (ME)methods are depicted schematically in Fig.2.Inconventional direct ME (Fig.2a), fine droplets are twisted in situ at the membrane /continuous phase interface by pressing a pure dispersed phase through the membrane. In order to make sure a regular droplet detachment from the pore outlets, shear stress is generated at the membrane/continuous phase interface by recirculating the continuous phase using a low shear pump (Fig.3a) or by agitation in a stirring vessel (Fig.3b).The rate of mixing should be high adequate to provide the required tangential shear on the membrane surface, but not too extreme to induce further droplet break up. Another approach uses systems equipped with a moving membrane, in which the droplet lack of involvement from the pore outlets is stimulated by rotation or vibration of the membrane within a stationary continuous phase (Fig.3c). Even in the absence of any tangential shear, droplets can be spontaneously detached from the pore outlets at small dispersed phase fluxes (Fig.3d), predominantly in the presence of fast adsorbing emulsifiers in the continuous phase and for a pronounced noncircular cross section of the pores. However, there are several disadvantages of direct ME and this lead to implementation of ‘premix’ ME in which a preliminarily emulsified coarse emulsion (rather than a single pure dispersed phase) is required through the membrane (Fig.2b).This is achieved by mixing the two immiscible liquids together first using a predictable stirrer mixer, and then passing this preliminarily emulsified emulsion through the membrane. If the dispersed phase of provide for emulsion wets the membrane wall and suitable surfactants are dissolved in both liquids phases, the process may result in phase inversion, i.e., a coarse oil in-water (O/W) emulsion may be inverted intoa fine W/O emulsion (Fig.2c) and vice versa (Williams and Goran T, 2005).
Fig.2. Schematic diagram of membrane emulsification methods (Williams and Goran T, 2005)
Fig.3. Membrane emulsification systems for controlling hydrodynamic conditions near the membrane surface (Williams and Goran T, 2005) 
Multiple Emulsion for Local Immunosuppression:
A possible approach to avoid the difficulty of systemic Immunosuppression and concurrently enhance immunosuppressive agents locally to the site of the target organs. W/O/W multiple emulsion has been developed for the delivery of immunosuppressant.
Multiple emulsions have also been used to improve bioavailability of lipophilic drugs, which have high first pass metabolism. Multiple emulsion increases bioavailability of drugs either by defensive drugs in physiological, ionic/enzymatic environment in the GIT where otherwise these gets degraded like proteins, peptides or by passing the hepatic first pass metabolism.
Enzymatic exchange of water insoluble, highly lipophilic substrates, such as steroids, can be carried out in a multiple emulsion. The enzyme is contained in a microdroplet ‘water pool’, whereas the organic phase contains the substrate solution. For example hydrocarbon based liquid surfactant membranes have been used to immobilize Urease.
Drug over Dosage Treatment:
This system could be utilized for the overdosage treatment by utilizing the difference in the pH. For example: barbiturates. In these emulsions, the inner aqueous phase of emulsion has the essential buffer and when emulsion is taken orally, acidic pH of the stomach acts as an outside aqueous phase. In the acidic phase barbiturate remains mainly in unionized form, which transfers through oil membrane into inner aqueous, phase and gets ionized. Ionized drug has less similarity to cross the oil membrane thereby getting entrapped. Thus, entrapping excess drug in multiple emulsions cures overdosage.
Multiple emulsions of chloroquine, an antimalarial agent has been effectively prepared and had been found to mask the bitter taste efficiently Taste masking of chlorpromazine, an antipsychotic drug has also been reported by multiple emulsions.
The Multiple Emulsion is one of the advanced drug delivery systems for the enhancement of the various characteristics of the drugs like bioavailability, taste, release rate etc. The advances include various novel formulations for the betterment of the drug administration and improvement in the deliciousness of the drug by incorporating them into a variety of formulations. The Multiple Emulsion is the complex polydispersed system containing an emulsion included in another emulsion, which can be used in many applications like taste masking, sustained release, delivering the unbalanced drug and avoidance of the drug from the environment etc Three routes to fabricate emulsions had been described. All the investigations carried out so distant show that membrane emulsification offers great potential in manufacturing ‘made to measure’ emulsions and other solid particulates.
Author are thankful to Gourishankar college of D pharma, Limb Satara for providing valuable help and authors are also Thankful Mr. Raje V.N, Principal, Gourishankar college of D pharma, Limb, Satara for providing necessary guidance for this work.
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