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International Journal of Recent Advances in Pharmaceutical Research

January 2012; 2(1): 9-19 ____________________________________________________________________________________________________________________________________________

Multiple Emulsions: A Review


RAJESH KUMAR, *MURUGESAN SENTHIL KUMAR, NANJAIAN MAHADEVAN
Nanomedicine Research Center, Department of Pharmaceutics, Rajendra Institute of Technology and Sciences, Sirsa, Haryana, India. Abstract
Multiple emulsions are also known as emulsions of emulsions, liquid membrane system or double emulsion. The two major types of multiple emulsions are the w/o/w and o/w/o double emulsions. The most common multiple emulsions are of W/O/W type which are widely used for pharmaceutical purposes. In this review we discuss the preparation, stability, formulation, release mechanism and potential application of multiple emulsions.

Keywords: Multiple emulsion; Stabilization; Release mechanism; Applications.

1.0. INTRODUCTION
Multiple emulsions are novel carrier system which are complex and poly dispersed in nature where both w/o and o/w emulsion exists simultaneously in a single system. Lipophilic and hydrophilic surfactants are used for stabilizing these two emulsions respectively. 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 separated from the aqueous phase by a layer of oil phase compartments [1-3]. In multiple emulsion system solute has to transverse from inner miscible phase to outer miscible phase through the middle immiscible organic phase, so it also called as liquid membrane system [4]. 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 specific applications O/W/O emulsions can also be prepared. ________________________________________________________
*Correspondence Dr. M. Senthil Kumar Professor & Head, Nanomedicine Research Center, Department of Pharmaceutics, Rajendra Institute of Technology and Sciences, Institute of Pharmacy, Hisar Road, Sirsa, Haryana -125 055. India. Email: nanorits@gmail.com

Multiple emulsions may find many potential applications in various fields such as chemistry [5], pharmaceutics [6], cosmetics [7], and food [8]. These emulsions have been investigated as controlled-release drug delivery systems (DDS) [6], as emulsion liquid membranes for simultaneous liquid extraction and stripping of metals [9], organic acids [10] and antibiotics [11], as microcapsules for the protection and controlled release of functional food ingredients [12], for the formulation of reduced-calorie food emulsions [13], etc. Other applications include the use of multiple emulsions as intermediate products to the preparation of inorganic particles [14], lipid nanoparticles [15], polymeric microspheres [16,17], biodegradable microspheres [18], gel microbeads [19], and vesicles such as polymerosomes [20]. For medical applications, a water-soluble therapeutic component can be solubilized within the inner W1 phase of the emulsion globule, which showed prolonged release properties and lessen toxic effects [21]. The stability and release properties of double emulsion can be improved by varying the type and concentrations of surfactants. As suggested by Sausville [22], combining targeted delivery with prolonged release would present a tremendous benefit in cancer therapy. The use of double emulsions to accomplish this combined capability merits consideration. Multiple emulsion system possesses adequate biocompatibility, complete biodegradability and versatility in terms of different oils and emulsifiers being used. Both hydrophilic and hydrophobic drugs can be entrapped and protected, drug targeting especially

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Int J Recent Adv Pharm Res, 2012;2(1):9-19

International Journal of Recent Advances in Pharmaceutical Research


January 2012; 2(1): 9-19 ____________________________________________________________________________________________________________________________________________

to reticuloendothelial system (RES), taste masking and for slow or controlled delivery of drugs. Beside these advantages with multiple emulsions, there are certain associated disadvantages like being difficult to formulate, bulky and susceptible to various routes of physical and chemical degradation. Multiple emulsions have not been commercially exploited 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. Many authors have reviewed the different stabilization methods and different drug release mechanisms [8,23-24]. 1.1. Preparation of multiple emulsions Multiple emulsions are usually formed by a twostep emulsification process using conventional rotor-stator or high pressure valve homogenizers [25]. 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 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 a small encapsulation efficiency (if homogenization is too intensive). Multiple emulsions can alternatively be produced by forcing a primary emulsion through a microporous membrane [2629] or microfabricated channel arrays [19,30,31] into a continuous phase liquid. This results in much less shear than in conventional emulsification processes so that the droplets are intact and both a high entrapment efficiency and monodispersity can be achieved [17,32]. 1.2. Stabilization of multiple emulsions Stability is the major problem of the multiple emulsions. Four possible mechanisms lead to the instability of W/O/W emulsions are 1) coalescence of the internal aqueous droplets; 2) coalescence of the oil droplets; 3) rupture of the oil film resulting in the loss of the internal aqueous droplets, and 4)
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passage of the water and water-soluble substances through the oil layer between both water phases [3]. This can occur in two various ways: via reverse micellar transport created by the lipophilic emulsifier and by simple diffusion across the oil phase connected with osmotic differences between both water phases. The major problem as regards stability is the presence of two thermodynamically unstable interfaces. Two different emulsifiers are necessary for their stabilization: one with a low HLB for the W/O interface and a second one with a high HLB for the O/W interface. There are several approaches to overcome instability- and release-problems in double emulsions. Some of those ideas can be summarized as follows. The inner phase: (i) Stabilizing the inner w/o emulsion by mechanically, or in the presence of better emulsifiers, reducing its droplet size; (ii) Forming L2-microemulsions; (iii) Preparing microspheres; (iv) Increasing the viscosity of the inner water. The oil phase: (i) Modifying the nature of the oil phase by increasing its viscosity or by adding carriers; (ii) Adding complexing agents to the oil. The interfaces: (i) Stabilizing the inner and/or the outer emulsion by using polymeric emulsifiers, macromolecular amphiphiles (proteins, polysaccharides) or colloidal solid particles to form strong and more rigid film at the interface. One can consider both naturally occurring macromolecules (gums, proteins) and synthetic grafted block copolymers with surface activities [33]. The stability of double emulsions can be improved (as explained above) by forming a polymeric film or macromolecular complex across the oil/water interfaces. Omotosho et al. have suggested using macromolecules, and nonionic surfactants to form such stabilizing complexes. The film is formed through interfacial interaction between macromolecules such as albumin and nonionic surfactants [34, 35].

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1.3. Formulation of Multiple Emulsions Florence and Whitehil [3] 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 contained 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 objectives will be to produce a multiple emulsion system that has a high yield of multiple droplets containing the drug entrapped in the innermost phase, and for such a system to have good stability in vitro and the desired release characteristics in vivo. The following factors are identified as being of importance [36] and will be discussed in turn with reference to the w/o/w system: (1) emulsification equipment; (2) nature of the oil phase; (3) volumes of the two dispersed phases; (4) nature and quantity of the emulsifying agents; (5) nature of entrapped materials, including the drug substance; and (6) added stabilizing components (gelling agents, etc.). 1.3.1. Emulsifying equipment The primary emulsion can be prepared using a laboratory mixer or homogenizer to provide a good dispersion of droplets within the appropriate continuous phase [2, 37]. The secondary emulsification stage must disperse the primary emulsion into droplets of suitable size for use in delivery vehicles Excessive mixing, especially at high shear, can cause the primary emulsion droplets to rupture. Low-speed, low-shear mixers should be used, or the system can be shaken by hand. Ultrasonic homogenizers must be used with care for the secondary emulsification step. 1.3.2. Nature of the oil phase The oil phase to be employed in a pharmaceutical emulsion must be nontoxic. The various oils of vegetable origin (soybean, sesame, peanut, safflower, etc.) are acceptable if purified correctly. Refined hydrocarbons such as light liquid paraffin,

squalane, as well as esters of fatty acids (ethyl oleate and isopropyl myristate) 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 general 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 [37]. 1.3.3. Volumes of the dispersed phases The quantity of water dispersed in the initial w/o emulsion [expressed as a phase volume ratio, (w/o/w)] can have an influence on both the yield and stability of the final emulsion system. 1.3.4. Nature and quantity of emulsifying agents Two different emulsifiers (lipohilic and hydrophilic) are required 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 emulsifier may result in unstable systems, whereas too much emulsifier may lead to toxic effects and can even cause destabilization [36]. 1.3.4.1. Influence of hydrophilic surfactants on the properties of multiple W/O/W emulsions [38] It is well known that an emulsifier with an optimum HLB value and with chemical properties compatible with emulsion ingredients is necessary to obtain a stable emulsion. HLB values of hydrophilic emulsifiers used for multiple W/OW emulsion preparation are listed in Table 1. Tween 80 is very often used in combination with Span 80 in multiple W/O/W emulsions because of its similar chemical structure to Span 80. It has been found in the majority of cases that the most stable emulsions, in particular, are formed when both emulsifying agents are of the same hydrocarbon chain length. The superior stability of emulsions containing Tween 80 can be linked to two factors:

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(a) the chemical compatibility of Tween 80 and Span 80 and (b) the better HLB value [38]. Table 1: HLB values of hydrophilic emulsifiers used for multiple W/OW emulsion
Chemical structure Ester Polyethoxylated sorbitan and fatty acid esters Tween 80 Tween 20 Polyethoxylated derivatives of stearic acid PEG-20 stearate PEG-40 stearate PEG-40/50 stearate PEG-100 stearate Sucrose ester Sucrose palmitate Ether Polyethoxylated fatty alcohols Laureth-20/23 Steareth-10 Steareth-20 Cetosteareth-12 Cetosteareth-20 Cetosteareth-25 Cetosteareth-30 Oleth-20 Polymer Poloxamer 407 15 16.7 15 17 16.9 18.8 15 HLB value

consisting of 1618 carbon atoms is the ideal chain length. Although the viscosity and droplet size for all emulsifiers vary greatly, NaCl encapsulation immediately after preparation was very high in all cases [38]. 1.3.4.3. Effect of lipophilic emulsifier As the concentration of lipophilic surfactant is increases, the swelling capacity of oil globule is increases, and the more the release is delayed. The influence of the lipophilic surfactant concentration on the swelling of the oil globule can be explained by two different mechanisms. The first one consists in an increase of the rigidity of the second interface by the progressive migration of the lipophilic surfactant. During the second step of multiple emulsion preparation, lipophlic surfactant molecules can diffuse from the first to second interface, were they produce a synergistic effect resulting in membrane strengthening. The second one involves a delay in the in the aqueous droplet coalescence. In course of swelling of the oil globule, the lipophilic surfactant molecules, which are in excess in oily phase, can diffuse to the first interface to fill up free spaces caused by swelling, when required [39]. 1.3.5. Nature of entrapped materials When formulating a w/o/w system the presence of the drug and other components (especially electrolytes) needs to be considered. The nature of drug (hydrophilic or hydrophobic) also be considered. 1.3.6. Added stabilizing components The stabilizers are added for improve the stability of multiple emulsions. These include gelling or viscosity-increasing agents added to internal and/or external aqueous phases (e.g., 20% gelatin, [40] methylcellulose, and similar thickening agents, as well as complexing agents that will lead to liquid crystalline phases at the o/w interface (e.g., 1-3% cetyl alcohol) and gelling agents for the oil phase (e.g., 1-5% aluminum monostearate) [2]. 1.4. Possible mechanism of drug release from multiple emulsions In multiple emulsions, the drug is released from internal to external phase through the oily layer by different mechanism. The release rates are affected

16.9 12.4 15.3 13.4 15.7 16.2 17 15.5 22

1.3.4.2. Comparison emulsifiers

of

all

hydrophilic

It was not possible to obtain stable multiple W/O/W emulsions using sucrose esters. Homogeneous emulsions with small oil droplets could be obtained using Tween emulsifiers and Poloxamer. However, the emulsions were very unstable and phase separation occurred after several days. Multiple emulsions containing polyethoxylated stearate were much more stable, but multiple oil droplets are very large compared with other emulsifiers. Multiple emulsions with optimum properties and long-term stability were able to be obtained using polyethoxylated fatty alcohols. The decisive factor is in this case is the hydrophobic chain length. A chain

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by the various factors such as droplet size, pH, phase volume and viscosity etc [2]. 1.4.1. Diffusion mechanism This is most common transport mechanism where unionized hydrophobic drug diffuses through the oil layer in the stable multiple emulsions. Drug transport has been found to follow first order kinetics and obeyed Ficks law of diffusion [41]. 1.4.2. Micellar transport Inverse micelles consisting of nonpolar part of surfactant lying outside and polar part inside encapsulate hydrophilic drug in core and permeate through the oil membrane because of the outer lipophillic nature. Inverse micelle can encapsulate both ionized and unionized drugs [42]. Recently, the release of tetradecane from a tetradecane/water/hexadecane multiple emulsion was investigated using the differential scanning calorimetry technique. Micellar diffusion rather than molecular diffusion was considered to be the preponderant mechanism for mass transfer [4]. 1.4.3. Thinning of the oil membrane Due to osmatic 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 [43]. 1.4.4. Rupture of oil phase According to this mechanism rupturing of oil membrane can unite both aqueous phases and thus drug could be released easily [4]. 1.4.5. Facilitated diffusion (Carrier-mediated transport) This mechanism involves a special molecule (carrier) which combines with the drug and makes it compatible to permeate through the oil membrane. These carriers can be incorporated in internal aqueous phase or oil membrane [4]. 1.4.6. Photo-osmotic transport The mechanism of this transport process is not very clear. Transport of the drug through the oil membrane takes place with the help of the light [44,45].

1.4.7. Solubilization of internal phase in the oil membrane It is a conspicuous transport mechanism. In this solubilization of minute amounts of the internal phase in the membrane phase results in the transport of very small quantities of materials [4]. 1.5. Application of multiple emulsions 1.5.1. Multiple emulsions in cancer therapy Most 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 suppress strong side effects of the drug. However, a single emulsion cannot be used since W/O emulsions generally have such a high viscosity that infusion of emulsions to arteries/capillaries via catheters is difficult. Also O/W emulsions are not an option because they do not encapsulate the drug [24]. But W/O/W emulsion systems are suitable drug carriers because of the encapsulation of the drug in the internal water phase and the low viscosity due to the external water phase. For the application of W/O/W emulsions as drug delivery systems it is important to prepare a very stable W/O/W emulsion in which countless submicron water droplets are encapsulated. Higashi and coworkers prepared such a new drug delivery system for treating hepatocellular carcinoma (HCC) using W/O/W emulsions prepared with iodinated poppy-seed oil (IPSO) and water soluble epirubicin. The emulsion accumulates in the small vessels in the tumor when injected to the liver via the hepatic artery [4548]. Clinical studies showed that the size of IPSO microdroplets influenced the anti-tumor effect of the therapy: very small droplets passed through the tumor, while very large droplets did not reach the tumor. This confirms the importance of a controlled droplet size, which was not feasible before the membrane emulsification technique was developed [48]. Nakajima et al. prepared ethanol-in-oil-inwater (E/O/W) emulsions which are capable to encapsulate functional components that have a low solubility with respect to water and oil but are soluble in ethanol [49]. An example is taxol which is

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an anticancerous terpenoid can be used in cancer treatment by incorporating it in E/O/W emulsion. Khopade et al. were prepared multiple emulsion of 6-mercaptopurine by incorporation of sphingomyelins (SM) and monosialogangliosides (GM1) in the oily phase and by coating with lipidgrafted polyethylene glycol (PEG-PC) and concluded that PEG-PC-coated multiple emulsions are superior as prolonged release and extended blood circulating carriers compared to multiple emulsions having GM1 or SM [50]. The same co-workers were prepared PEG-PC coated multiple emulsion bearing 6-mercaptopurine and studied antitumor activity on the murine leukemia cell line L-1210 in vitro and showed that decreased uptake and cytotoxicity were observed and Mean survival time (MST) was increased due to sustained release and effective delivery of drug from the formulation [51]. Methotrexate is effective antineoplastic drug but for effective cancer chemotherapy, it is necessary to deliver a sufficiently high concentration of anticancer agents into the tumor site for a required period and to minimize their concentration in other tissue compartments of the body because of their adverse reactions. Parenteral administration of methotrexate as a water-oil-water emulsion enhances its therapeutic activity against the mouse R 1 lymphoma and rat Walker tumour. Methotrexate incorporated into a water-oil-water emulsion based on Squalane as the oil exhibited the greatest therapeutic activity. A single dose of 3 mg/kg in the emulsion form gave a greater prolongation of survival time of mice bearing the R1 lymphoma than five daily doses (total dose, 15 mg/kg) of methotrexate in aqueous solution [52]. Similarly cytarabine (cytosine arabinoside) is an important antimetabolite, and its effectiveness in the treatment of acute lymphocytic and granulocytic leukemias is well established. A chemotherapeutic effect similar to that of five daily doses of cytosine arabinoside in aqueous solution could also be obtained against the R1 lymphoma by a single dose of this drug in a water-oil-water emulsion formulation [52]. Takahashi et al. prepared multiple emulsion of bleomycin and studied on rat. Found the concentration of bleomycin in tumour tissues of rats was 2 to 7 times higher after intratumoral
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injection of w/o or w/o/w emulsions than those produced by local administration of an aqueous solution of the drug. The same group of workers utilized the lipid absorbing ability of the lymphatic system to facilitate delivery of the drug especially to the regional lymph nodes. A comparison of the radioactivity in the regional lymph nodes after intratesticular injection of various types of preparation containing the labeled anticancer agent 5-FU showed that the highest value was observed in w/ o/ w emulsion followed by w/o, o/ w emulsions, and aqueous solution [53]. Vinblastine sulphate as a single aqueous injection caused a gradual increase in the number of bone marrow cells arrested in metaphase for up to four hours after administration. When the drug was administered in a multiple emulsion, the increase in the number of arrested metaphases was still continuing after 48 hours [54-55]. Perilla ketone is an investigational lipophilic cytotoxic agent which is typically administered i.v. in 5% dextrose [56]. The multiple emulsion formulation appears stable over several days suggests that an emulsion could be prepared de novo from raw materials which would be both stable and active over a sufficiently long period of time. Penclomedine is a novel cytotoxic agent. The emulsion formulation of Penclomedine was tested for antitumor activity in mice by both intraperitoneal and i.v. administration. Preliminary results suggest that this emulsion preparation shows improved cytotoxic activity compared to a suspension of the solid drug in a comparable dosage range [57]. Lin et al. prepared multiple emulsion containing doxorubicin hydrochloride studies in Sprague Dawley rats. They concluded that HCO-60 play an important role in sustained behavior of double emulsion [58]. Jing-Long et al. formulated multiple emulsions for sustained release of etoposide from formulation, so that maintained therapeutic conc. for longer time and reduce side effect [59].

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Yanagie et al. [60] treated the hepatocellular Carcinoma by Neutron Capture therapy using Intra-arterial administration of Boron-Entrapped water-in-oil-in-water emulsion. In this therapy tumour cell destruction takes place when there is a nuclear reaction between 10 Boron atoms and thermal neutrons, so it is necessary to accumulate efficient 10 boron atoms to tumour cells for effective results. They were prepared 10 BSH entrapped W/O/W emulsion and delivered to HCC by intra-artergial infusion and showed that 10 boron concentrations in VX-2 tumour by W/O/W emulsion was superior to those by conventional emulsion, thus concluded that double emulsion would be applied for boron delivery carrier in HCC treatment. 1.5.2. Multiple emulsions in herbal drugs Apart from its targeted sustained release, producing the herbal drug into emulsion will also strengthen 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. For example, Zhou et al. studied the influence of the elemenum emulsion on the human lung adenocarcinoma cell line A549 and protein expression. Results showed that the elemenum emulsion has a significant inhibition on the growth and proliferation of the A549 in vitro and it showed a time and dosedependent relationship. Elemenum emulsion is a type of new anti-cancer drug with great application prospects. Furthermore, it has no marrow inhibition and no harm to the heart and liver [61]. 1.5.3. Vaccine/vaccine adjuvant The use of w/o/w multiple emulsion as a new form of adjuvant for antigen was first reported by Herbert [55]. These emulsions elicited better immune response than antigen alone. Rishendra and Jaiswal [62] developed a multiple emulsion vaccine against Pasteurella multocida infection in cattle. This vaccine contributed both humoral as well as cell-mediated immune responses in protection against the infection. It was concluded that this multiple emulsion based vaccine can be successfully used in the effective control of haemorrhagic septicaemia. Recently, multiple water-in-oilRajesh et al.
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in-water (w/o/w) emulsion formulations, containing influenza virus surface antigen hemagglutinin were prepared and were characterized in-vitro and in-vivo in wistar albino rats. SDS-PAGE technique was used for evaluating hemagglutinin and in vitro release of antigen respectively. Results suggested that multiple emulsion formulations carrying influenza antigen have advantage over conventional preparation and can be effectively used as one of the vaccine delivery system with adjuvant properties. In an another report by the same researchers they concluded that multiple emulsion and nanoparticle formulations containing influenza virus surface antigen Hemagglutinin were more effective in eliciting an immune response in rats than the conventional vaccine [63-64]. 1.5.4. Oxygen substitute A multiple emulsion of aqueous oxygen carrying material in oil in outer aqueous phase is suitable for provision of oxygen for oxygen transfer processes. A hemoglobin multiple emulsion in physiologically compatible oil in an outer aqueous saline solution is provided in sufficiently small droplet size to provide oxygen flow through blood vessels to desired body tissues or organs thereby providing a blood substitute. A process is provided wherein hemoglobin, a fragile material, is formulated into high hemoglobin content water-in-oil-in-water multiple emulsions while maintaining high yields and high oxygen exchange activity [65]. 1.5.5. Inverse targeting Regarding this approach Talegaonkar and Vyas were prepared poloxamer 403 containing spherein-oil-in-water (s/o/w) multiple emulsion of diclofenac sodium by gelatinization of inner aqueous phase and they examined the effect of poloxmer 403 on surface modification for inverse targeting to reticuloendothelial system-rich organs. The results concluded that this multiple emulsion system containing poloxamer has capability to retards the RES uptake of drugs mainly to liver, brain and targeting to non-RES tissues such as lungs, inflammatory tissue [66]. 1.5.6. Multiple emulsions in diabetes Toorisaka et al. [67] developed a S/O/W emulsion for oral administration of insulin. Surfactant-coated

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insulin was dispersed in the oil by ultrasonication, this dispersion was mixed with the outer water phase with a homogenizer and finally, the S/O/W emulsion thus obtained was adjusted to a constant particle size by passage through a SPG membrane. The S/O/W emulsion showed hypoglycemic activity for a long period after oral administration to rats. 1.5.7. Multiple emulsions in food Another possible application of double emulsions is in the food industry. Preliminary studies have been performed in the field of entrapment of a flavor component in a release system [68]. Sensitive food materials and flavours can be encapsulated in W/O/W emulsions. Sensory tests have indicated that there is a significant 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. 1.5.8. 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 basic 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 gets ionized. Ionized drug has less affinity to cross the oil membrane thereby getting entrapped. Thus, entrapping excess drug in multiple emulsions cures over dosage [69]. 1.5.9. Taste masking Multiple emulsions of chloroquine, an antimalarial agent has been successfully prepared and had been found to mask the bitter taste efficiently [70-71]. Taste masking of chlorpromazine, an antipsychotic drug has also been reported by multiple emulsions [4]. Acknowledgments The authors wish to acknowledge Dr. Rajendar Singh Sra, Chairman and Shri. Om Parkash, Director, Rajendra Institute of Technology and Sciences, Sirsa for their encouragement and support.

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