MULTIPLE EMULSIONS

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PREPARATION, EVALUATION&APPLICATIONS OFMULTIPLE EMULSIONS : 

PREPARATION, EVALUATION&APPLICATIONS OFMULTIPLE EMULSIONS Prepared by BHAVANI.T M.PHARMACY I-SEM DEPARTMENT OF PHARMACEUTICS TRINITY COLLEGE OF PHARMACEUTICAL SCIENCES 1

CONTENTS : 

CONTENTS INTRODUCTION MULTIPLE EMULSIONS PREPARATION TECHNIQUES EVALUATION APPLICATIONS O/W/O DOUBLE EMULSIONS MARKETED PRODUCTS CONCLUSION BIBILOGRAPHY 2

INTRODUCTION : 

INTRODUCTION Emulsion is a heterogeneous system of one immiscible liquid dispersed in another in the form of droplets. Simple emulsions are classified according to the nature of their continuous or dispersed phase as, water-in-oil (w/o) or oil-in-water (o/w). An emulsifier is present to stabilize the system. 3

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The emulsions can be divided into two groups : Oil in water (O/W) emulsions. 2. Water in Oil (W/O) emulsions. O/W EMULSION: Aqueous phase oil phase 4

W/O EMULSIONS : 

Aqueous phase oil phase W/O EMULSIONS 5

MULTIPLE EMULSIONS : 

MULTIPLE EMULSIONS These are known as Double emulsions. These are more complex systems, as the drops of the dispersed phase contain even smaller dispersed droplets, in most vases identical with the continuous phase, but separated physically from the continuous phase. These are known as “emulsions of emulsions.” 6

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Based on nature of dispersed medium multiple emulsions are two types. O/W/O emulsions. W/O/W emulsions 1. 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 true encloses one or more oil droplets. 7

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2. W/O/W EMULSION SYSTEM: In W/O/W systems, an organic phase (hydrophobic) separates internal and external aqueous phases. 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. 8

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SCHEMATIC DIAGRAM OF W/O/W & O/W/O EMULSIONS 9

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ADVANTAGES: A remarkable degree of biocompatibility. Complete biodegradability. Hydrophilic as well as hydrophobic drugs can be entrapped. Protection from inactivation by the endogenous factors. Increase in drug dosing intervals. Taste masking of bitter drug 10

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DISADVANTAGES: Emulsions have short shelf life. These dosage forms are packed in a plastic or glass containers. So, care should be taken in handling &storage 11

Preparation techniques : 

Preparation techniques Multiple emulsions can be prepared by any of the numerous methods for the preparation of conventional emulsion system, including sonication, agitation and phase inversion. Great care must be exercised in the preparation of the final system. However, because vigorous treatments normally employed for the preparation of primary emulsions will often break the primary emulsion, this results in loss of phase identity. 12

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For preparation of multiple emulsion two different surfactants of opposite nature is used. One surfactant stabilizes the W/O (lipophilic) emulsion while the other stabilizes the O/W (hydrophilic) emulsion. Emulsifiers get adsorbed at the surface of droplets during emulsion formation and prevent them from drawing close enough to aggregate. 13

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Multiple emulsions are prepared by various methods. Two-step emulsification Modified two-step emulsification Phase inversion Membrane emulsification method Micro channel emulsification 14

Two-step emulsification method : 

It is the most common method because it is very easy and gives high yield with reproducibility. Multiple emulsions prepared by re-emulsification of a primary emulsion. In this method two stages involved. Two-step emulsification method 15

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The first stage involves the preparation of the primary emulsion either W/O or O/W type which is then re-emulsified with an excess of aqueous phase or oil phase in presence of second emulsifier to get the multiple emulsions of w/o/w or o/w/o respectively. Generally two emulsifiers are used in the preparation of multiple emulsions. One is lipophilic surfactant and other is hydrophilic surfactant. 16

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Modified two-step emulsification technique : 

This method is different from the conventional two-step technique in two points. Sonication and stirring are used to obtain fine, homogenous and stable w/o emulsion. A continuous phase is poured into a dispersed phase for preparing w/o/w emulsion. This modified method gives high yield and stable emulsion. Modified two-step emulsification technique 18

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Phase inversion (one step method) : 

Preparation of w/o/w double emulsions which included strong mechanical agitation of the water phase containing an hydrophilic emulsion and an oil phase containing large amount of hydrophobic surfactant. An increase in volume concentration of dispersed phase which subsequently leads to the formation of multiple emulsions. A well-defined volume of oil phase is placed in a vessel of pin mixer. Phase inversion (one step method) 20

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An aqueous solution of emulsifier is then introduced successively to the oil phase in the vessel at a rate of 5ml/min, while the pin mixer rotates steadily at 88rpm at room temperature. When volume fraction of the aqueous solution of hydrophilic emulsifier 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. 21

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Membrane emulsification technique : 

In this, a microporous glass membrane with a defined pore size can be used as emulsifying tool. It is based on the principle of dispersing one immiscible phase (dispersing phase) into other phase (continuous phase) by applying pressure. The particle size of the w/o/w emulsion can be controlled with the proper selection of porous glass membrane. Membrane emulsification technique 23

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The relation between membrane pore size and particle size of emulsion exhibits good correlation as described by the formula: Y= 5.03X + 0.19 Where, X= the pore size Y= the mean particle size A microporous glass membrane with narrow pore size range was used successfully for preparing stable simple (o/w) and water-oil-water (w/o/w) type emulsions. 24

Micro channel emulsification : 

It is a novel technique. A two-step emulsification process employing MC emulsification as the second step was used for preparing w/o/w emulsions. The behaviour of internal water droplets penetrating the MC was investigated using ethyl oleate, and MCT as oil phases. They observed successful MC emulsification. The w/o/w emulsion entrapment yield was measured fluorometrically and was found to be 91%. Micro channel emulsification 25

FORMATION OF MULTIPLE EMULSIONS : 

FORMATION OF MULTIPLE EMULSIONS HLB OIL SURFACTANTS PHASE VOLUME NATURE OF ENTRAPPED MATERIAL SHEAR/AGITATION TEMPERATURE RHEOLOGY 26

HLB : 

HLB General procedure for the preparation of w/o/w multiple emulsion may involve the formation of a primary emulsion of water in oil using a lipophilic surfactant with a low HLB (2-8) suitable for the stabilization of such W/O systems. The primary emulsion will then be emulsified in a second aqueous solution containing a second hydrophilic surfactant (HLB 6-16) to promote o/w emulsification. 27

OIL : 

The nature of the oil can affect the behaviour of the system. The oils used to prepare multiple emulsions include liquid paraffin, vegetable oils such ad sesame oil, olive oil, isopropyl myristate etc. Selection of oil phase can affect various emulsion parameters like yield, release profile, particle size and emulsion stability. The release of drug from multiple emulsions is affected by the nature of the oil phase due to the difference in partition coefficient. OIL 28

SURFACTANTS : 

The selection of surfactant depends upon the use of the multiple emulsions. Concentration of surfactant also affects the emulsion yield. An excess of lipophilic surfactant can cause the inversion of w/o/w emulsion to simple o/w emulsion. For the preparation of multiple emulsions two surfactants are necessary, one for the primary emulsion and the other for the dispersion of the primary emulsion. SURFACTANTS 29

PHASE VOLUME : 

PHASE VOLUME It is very important to have proper 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 produce a stable multiple emulsion. 30

Nature of the entrapped material : 

The nature of the entrapped materials may have a bearing on the stability of the system. Due to the nature of the multiple emulsion, the middle phase acts as a membrane, and osmotic effects may become significant. The entrapped solutions may interact with the surfactant or the surface active drugs may be adsorbed at the inter phase, resulting in decreased stability. Nature of the entrapped material 31

Shear/agitation : 

High shear disrupts the large percentage of multiple oil drops and hence results in the instability of system due to tremendous 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. Shear/agitation 32

Temperature : 

Temperature has only an indirect 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 drastic modifications within emulsions. Temperature 33

RHEOLOGY : 

The rheological properties of emulsions are influenced by a number of factors, including the nature of the continuous phase, the phase volume ratio, and to lesser extent 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 generally thicker than w/o/w emulsions, and the consistency of an w/o/w system can be increased by the addition of gums, clays. RHEOLOGY 34

EVALUATION OF MULTIPLE EMULSIONS : 

EVALUATION OF MULTIPLE EMULSIONS Characterization Average globule size & size distribution No. of globules Percent drug entrapment Rheological evaluation Zeta potential In-vitro Stability studies In-vitro drug release 35

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Characterization: Emulsions are mostly characterized by the size distribution of the droplet and other physical properties such as dielectric properties, thermal behaviour, rheological properties, and other microscopic and macroscopic observation. Macroscopic examination: Primary observations like color, consistency and homogeneity are frequently used to ensure formation of an emulsion. Type of multiple emulsions formed (w/o/w or o/w/o) can be validated by dilution with the external phase. 36

Microscopic examination : 

The optical microscopy method, stage micrometer can be used for globule size determinations of both multiple emulsion droplets as well as droplets. However, this method has two main drawbacks; Simple small drops passes to form large simple drop which gives a false impression of multiple nature. If the internal droplets are very small in size these can not be viewed due to reflection light from the oil droplets surface. Microscopic examination 37

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Various other techniques used to characterize emulsions like coulter-counter, freeze-fracture electron microscopy and scanning electron microscopy are also used to determine average globule size and size distribution of multiple emulsion droplets. 38

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Number of Globules: Number of globules per cubic millimeter can be measured using a haemocytometer cell after appropriate dilution of the multiple emulsions. The globules in five groups of 16 small squares (total 80 small squares) can be counted and the total number of globules in per cubic mm is calculated using the formula: 39

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Percent Drug Entrapment: Percent entrapment of drug or active moiety in the multiple emulsion is generally determined using dialysis, centrifugation, filtration and conductivity measurements. However, recently an internal tracer/marker was used to evaluate the entrapment of an impermeable marker molecule contained in the inner aqueous phase of w/o/w emulsion. 40

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The % Entrapment can be calculated using the following equation : 41

RHEOLOGICAL EVALUATION : 

The rheology of multiple emulsions is an important parameter as it relates to emulsion stability and clinical performance. The viscosity and interfacial elasticity are two major parameters, which relate to product rheology. The viscosity of the multiple emulsions can be measured by Brookfield rotational Viscometer. RHEOLOGICAL EVALUATION 42

Zeta-potential : 

The zeta potential and surface charge can be calculated using Smoluchowski’s equation from the mobility and electrophoretic velocity of dispersed globules using the Zeta-Potentiometer. The apparatus consists of cylindrically bored micro-electrophoresis cell equipped with platinum-iridium electrodes to measure the electrophoretic mobility of the diluted w/o/w emulsion. Zeta-potential 43

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Zeta potential was calculated using following formula: 44

In Vitro Stability Studies : 

Phase separation is a phenomenon by which one phase of emulsion gets separated due to coalescence. Percentage phase separation is the volume of phase in percentage separated from the total volume of emulsion after storage. 20ml of freshly prepared w/o/w emulsion is kept in 25ml of graduated cylinder and allowed to stand for defined period at 40˚c. The volume of separated aqueous phase (vsep) is observed periodically at regular intervals. In Vitro Stability Studies 45

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percent phase separation is calculated using following formula: 46

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In Vitro Drug Release: The drug released from the aqueous inner phase of a W/O/W emulsion can be estimated using the conventional dialysis method using a cellophane tubing. Typically, 5ml of (w/o/w) multiple emulsion is placed in the dialysis tube which is then tied at both ends by thread and placed in basket (usually 100rpm) and dialyzed against specified dissolution media (usually 200ml) at 37±1˚C. 47

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Aliquots were withdrawn at different time intervals and replaced with fresh dissolution media and estimated using standard procedure and the data were used to calculate cumulative drug release profile. 48

APPLICATIONS : 

Water-in-oil-in-water (w/o/w) multiple emulsions have several potential applications in pharmaceuticals, food technology, separation sciences and in cosmetics. The various pharmaceutical applications include immobilization of enzymes, red blood cell substitute, transdermal delivery, bioavailability enhancement, taste masking, drug targeting, prolonged delivery of drugs etc. APPLICATIONS 49

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Some important applications of multiple emulsions: Controlled and sustained drug delivery Drug targeting Vaccine adjuvant Enzyme immobilization As a preparative tool for microencapsulation technology Drug over dosage treatment/ detoxification Protection action Taste masking Cosmetics and health care Miscellaneous 50

Controlled and sustained drug delivery : 

The basic potential of multiple emulsions (both w/o/w and o/w/o) in clinical therapeutics is in the prolonged and controlled release of drugs. In both systems drug present in innermost phase has to cross several phases before it is available for absorption for the system. W/o/w emulsions for parentaral delivery are more convenient to handle, use, and inject due to lower viscosity of these systems. Controlled and sustained drug delivery 51

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Haemoglobin multiple emulsions as an oxygen delivery system (or) As oxygen substitute: Multiple emulsions has been extended as a stable oxygen carrier system. A concentrated solution of haemoglobin (Hb) was encapsulated in the form of a Hb-in-oil-in-water (Hb/o/w) multiple emulsion. Hb/o/w multiple emulsions was prepared to stimulate red blood cell (RBC) properties. 53

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Bioavailability enhancer: 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 protecting drugs in physiological, ionic/enzymatic environment in the GIT where otherwise these gets degraded like proteins, peptides or bypassing the hepatic first pass metabolism. 54

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Targeted drug delivery systems: Site specify is very important prerequisite for any pharmacotherapy. Ideal approach for a drug delivery system is to deliver drug only at the diseases tissue/organ and not affecting other undiseased tissue (Drug targeting). Drug targeting minimizes the adverse effects of drugs by specifically concentrating drug in diseased tissue. Several micro particular interest for the cytotoxic drugs (Anti-cancer agent) because of high toxicity for non-diseased tissue. 55

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Multiple emulsions system had also been prepared for several cytotoxic agents, targeting different tumors. These can be used as lymphotropic carriers for drug targeting. 56

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Taste masking: Multiple emulsions has been employed for the taste masking of drugs like chloroquine. It is an anti-malarial agent and has bitter taste. Several biocompatible/edible oils had been used for masking taste and improving the masking potential. 57

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Treatment of drug overdose: Multiple emulsions of w/o/w types are used for the treatment of drug over dosing. A w/o/w system was designed to remove acidic drugs like barbiturartes and salicylates from the gastrointestinal tract by entrapping unionized drug, permeating through the oil membrane into the inner basic phase, where it is converted to an oil insoluble anion. 58

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Cosmetics and health care: Multiple emulsions are used for moisturizing, nutritive and protective action, when applied in the form of sun screams, hand creams, makeup cleansers, perfume preparations. In o/w/o emulsion consisted of a primary oil-in-water-phase consisting of a viscoplastic gel containing at least one organic UV-absorbent in the oil droplets, while the secondary oil phase (silicone oil) containing one or more inorganic UV-absorbents. 59

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The use of silicones within o/w/o multiple emulsions has been suggested to offer two principal advantages: The silicones with the lowest molecular weight decrease the oily touch. Due to the large range of viscosity, this excipient influences the skin distribution of actives after topical application. 60

O/W/O DOUBLE EMULSIONS : 

O/W/O DOUBLE EMULSIONS o/w/o double emulsions were considered to have less potential applications. Stability of retinol (vitamin A alcohol) was compared in three different emulsions: o/w, w/o and o/w/o. The stability in the o/w/o emulsion was the highest among the three types of emulsions. The remaining percentages, at 50˚c after 4weeks, were of 56.9, 45.7, and 32.3, in the o/w/o, w/o, and o/w emulsions, respectively. 61

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The stability of retinol in the o/w/o emulsion increased with increasing inner oil phase ratio, whereas in o/w it was unaffected by the oil fraction. Addition of anti-oxidants(sodium ascorbate, and EDTA) to the o/w/o emulsion improve the stability of retinol up to 77.1% at 50˚c after 4 weeks. So, it is concluded that the o/w/o emulsion is a useful formula to stabilize vitamin A. 62

MARKETED PRODUCTS : 

MARKETED PRODUCTS 63

CONCLUSION : 

CONCLUSION Multiple emulsions known to be promising delivery systems for both pharmaceuticals and cosmetic materials. The possibility of encapsulating active substances within liquid membranes may lead to interesting opportunities in both fields. Thus the formulation, manufacturing, stabilization, analysis and potential application of multiple emulsions are discussed. 64

BIBILOGRAPHY : 

BIBILOGRAPHY S.P Vyas & Khar in Targeted and controlled drug delivery Novel carrier systems;pg no. 305-328 Y. Madhusudan Rao, A V Jithan, Advances in Drug Delivery, volume-I, pp 213-250 A.T. Florence and D.Whitehill: “The formulation and Stability of Multiple Emulsions” Int. J. Pharm. 11, 277 (1982). www.google.co.in 65

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THANK YOU 66