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Microemulsions

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<ul><li> 1. Prepared by: Abhijit Dave M.Pharm.2nd sem Pharma TechGuided by: Mr. Milind ThosarBabaria Institute of pharmacy,Vadodara 4/21/2012 1</li></ul><p> 2. Babaria Institute of pharmacy,Vadodara 4/21/2012 2 3. Microemulsionsare thermodynamicallystabledispersions of oil and water stabilized by a surfactantand, in many cases, also a cosurfactant. Diameter -10-140 nm. Microemulsions can have characteristicproperties such as ultralow interfacialtension, large interfacial area and capacity tosolubilize both aqueous and oil-solublecompounds.Babaria Institute of pharmacy, Vadodara4/21/2012 3 4. Microemulsionsaredispersionsofnanometer-sized droplets of an immiscibleliquid within another liquid. Droplet formationis facilitated by the addition of surfactants andoften also co surfactants. And they can be known as Moderncolloidal drug delivery system. Babaria Institute of pharmacy, Vadodara 4/21/2012 4 5. The Microemulsion concept was introducedas early as 1940s by Hoar and Schulman whogenerated a clear single-phase solution bytitrating a milky emulsion with hexanol. Schulman and co-worker (1959)subsequently coined the term microemulsion The microemulsion definition provided byDanielson and Lindman in 1981 will be usedas the point of reference. Babaria Institute of pharmacy, Vadodara 4/21/2012 5 6. Transparent emulsion Swollen micelle Micellar solution Solubilized oil Babaria Institute of pharmacy, Vadodara 4/21/2012 6 7. Macro emulsionMicro emulsion Babaria Institute of pharmacy, Vadodara 4/21/2012 7 8. Babaria Institute of pharmacy, Vadodara 4/21/2012 8 9. FEATURES MACRO EMULSIONMICRO EMULSIONDEFINITION Emulsions consist of roughlyThey constantly evolve spherical droplets of one phase between various structures dispersed into the otherranging from droplet like swollen micelles to bi continuous structure.DROPLET1 20 mm.10 100 nm.SIZEAPPEARANCE Most emulsions are opaque (white) Microemulsions are because bulk of their droplets istransparent or translucent greater than wavelength of light and most oils have higher refractive indices than water. Babaria Institute of pharmacy, Vadodara 4/21/2012 9 10. FEATURESMACRO EMULSION MICRO EMULSIONPHASESTwo OneSTABILITY Stable but coalesce finally More thermodynamicallystable thanmacroemulsionsPREPARATION Require intense agitation Generally obtained byfor their formation.gentle mixing ofingredients.SURFACTANT2-3 % Weight6-8% by weightCONCENTRATION Babaria Institute of pharmacy, Vadodara 4/21/2012 10 11. O/W Microemulsion W/O Microemulsion Bi continuous Microemulsion Babaria Institute of pharmacy, Vadodara 4/21/2012 11 12. Advantages Of Microemulsion Over Other Dosage Forms Increase the rate of absorptionEliminates variability in absorptionHelps solublize lipophilic drugProvides a aqueous dosage form for water insoluble drugsIncreases bioavailabilityVarious routes like tropical, oral and intravenous can be usedto deliver the productRapid and efficient penetration of the drug moietyHelpful in taste maskingProvides protection from hydrolysis and oxidation as drug inoil phase in O/W microemulsion is not exposed to attack bywater and air.Liquid dosage form increases patient compliance.Less amount of energy requirement. Babaria Institute of pharmacy, Vadodara 4/21/2012 12 13. Aesthetically appealing products can be formulated astrans- parent o/w or w/o dispersions calledmicroemulsions. These versatile systems are currently of greattechnological and scientific interest to the researchersbecause of their potential to incorporate a wide range ofdrug molecules (hydrophilic and hydrophobic) due to thepresence of both lipophilic and hydrophilic domains. These adaptable delivery systems provide protectionagainst oxidation, enzymatic hydrolysis and improve thesolubilization of lipophilic drugs and hence enhancetheir bioavailability. In addition to oral and intravenousdelivery, they are amenable for sustained and targeteddelivery through ophthalmic, dental, pulmonary, vaginaland topical routes. Microemulsions are experiencing a very activedevelopment as reflectedofby the numerous publications Babaria Institute pharmacy, Vadodara 4/21/2012 13 14. A large number of oils and surfactant are available buttheir use in the microemulsion formulation is restricteddue to their toxicity, irritation potential and unclearmechanism of action. Oils and surfactant which willbeused for theformulation of microemulsion should be biocompatible,non-toxic, clinically acceptable, and use emulsifiers inan appropriate concentration range that will result inmild and non-aggressive microemulsion.Babaria Institute of pharmacy,Vadodara 4/21/2012 14 15. 1.Oil phase2.Surfactant3.Aqueous Component If a cosurfactant is used, it may sometimes be represented at a fixed ratio to surfactant as a single component, and treated as a single "pseudo-component". The relative amounts of these three components can be represented in a ternary phase diagram. Gibbs phase diagrams can be used to show the influence of changes in the volume fractions of the different phases on the phase behavior of the system.Babaria Institute of pharmacy,Vadodara 4/21/2012 15 16. The oil component influences curvature by its ability to penetrate and swell the tail group region of the surfactant monolayer. As compare to long chain alkanes, short chain oil penetrate the tail group region to a greater extent and resulting in increased negative curvature (and reduced effective HLB). Following are the different oil are mainly used for the formulation of microemulsion:1.Saturated fatty acid-lauric acid, myristic acid,capric acid2.Unsaturated fatty acid-oleic acid, linoleic acid,linolenic acid3.Fatty acid ester-ethyl or methyl esters of lauric, myristic andoleic acid. The main criterion for the selection of oil is that the drug should have high solubility in it. This will minimize the volume of the formulation to deliver the therapeutic dose of the drug in an encapsulated form.Babaria Institute of pharmacy,Vadodara 4/21/2012 16 17. The role of surfactant in the formulation of microemulsion is tolower the interfacial tension which will ultimately facilitatesdispersion process during the preparation of microemulsion andprovide a flexible around the droplets. The surfactant should have appropriate lipophilic character toprovide the correct curvature at the interfacial region. Generally, low HLB surfactants are suitable for w/omicroemulsion, whereas high HLB (&gt;12) are suitable for o/wmicroemulsion. Following are the different surfactants are mainly used formicroemulsion- Polysorbate (Tween 80 and Tween 20), Lauromacrogol 300, Lecithins,Decyl polyglucoside (Labrafil M 1944 LS), Polyglyceryl-6-dioleate (PlurolOleique), Dioctyl sodium sulfosuccinate (Aersol OT), PEG-8 caprylic/caprilglyceride (Labrasol). Babaria Institute of pharmacy, Vadodara 4/21/2012 17 18. Cosurfactants are mainly used in microemulsion formulation for following reasons: They allow the interfacial film sufficient flexible to take up different curvatures required to form microemulsion over a wide range of composition.1.Short to medium chain length alcohols (C3-C8) reduce theinterfacial tension and increase the fluidity of the interface.2.Surfactant having HLB greater than 20 often require the presenceof cosurfactant to reduce their effective HLB to a value within therange required for microemulsion formulation. Following are the different cosurfactant mainly used for microemulsion: sorbitan monoleate, sorbitan monosterate, propylene glycol, propylene glycol monocaprylate (Capryol 90), 2-(2-ethoxyethoxy)ethanol (Transcutol) and ethanol.Babaria Institute of pharmacy,Vadodara 4/21/2012 18 19. Babaria Institute of pharmacy,Vadodara 4/21/2012 19 20. Packing ratio Property of surfactant Property of oil phase Temperature Chain length Type and nature of cosurfactantBabaria Institute of pharmacy, Vadodara4/21/2012 20 21. Following are the different methods are used for the preparation of microemulsion*:1.Phase titration method2.Phase inversion method Babaria Institute of pharmacy, Vadodara 4/21/2012 21 22. Microemulsions are prepared by the spontaneousemulsification method (phase titration method) andcan be portrayed with the help of phase diagram. As quaternary phase diagram (four component system)is time consuming and difficult to interpret, pseudoternary phase diagram is constructed to find out thedifferent zones including microemulsion zone, in whicheach corner of the diagram represents 100% of theparticular components. Pseudo-ternary phase diagrams of oil, water, and co-surfactant/surfactants mixtures are constructed atfixed cosurfactant/surfactant weight ratios. Phase diagrams are obtained by mixing of theingredients, which shall be pre-weighed into glass vialsand titrated with water and stirred well at roomtemperature. Formation of monophasic/ biphasicsystem is confirmed by visual inspection.Babaria Institute of pharmacy,Vadodara 4/21/2012 22 23. Babaria Institute of pharmacy,Vadodara 4/21/2012 23 24. In case turbidity appears followed by a phaseseparation, the samples shall be consideredas biphasic. In case monophasic, clear and transparentmixtures are visualized after stirring; thesamples shall be marked as points in thephase diagram. The area covered by these points is considered asthe microemulsion region of existence. Babaria Institute of pharmacy, Vadodara 4/21/2012 24 25. Phase inversion of microemulsion is carried out uponaddition of excess of the dispersed phase or inresponse to temperature. During phase inversion drastic physical changes occurincluding changes in particle size that can ultimatelyaffect drug release both in vitro and in vivo. For non-ionic surfactants, this can be achieved bychanging the temperature of the system, forcing a transition from an o/w microemulsion at low temperature to a w/o microemulsion ofat higher temperaturesBabaria Institute pharmacy,Vadodara 4/21/2012 25 26. During cooling, the system crosses a point zerospontaneous curvature and minimal surface tension,promoting the formation of finely dispersed oil droplets. Apart from temperature, salt concentration or pH valuemay also be considered. A transition in the radius of curvature can be obtained bychanging the water volume fraction. Initially water droplets are formed in a continuous oilphase by successively adding water into oil. Increasing thewater volume fraction changes the spontaneous curvatureof the surfactant from initiallystabilizinga w/omicroemulsion to an o/w microemulsion at the inversionBabaria Institute of pharmacy,locus.Vadodara 4/21/201226 27. Many examples of microemulsionbasedformulations are now on the market ; Among them, the performances of microemulsionsare well demonstrated in the reformulation ofCyclosporin A by Novartis into a microemulsionbased formulation marketed under the trade markNeoral this has increased the bioavailability nearly bya factor 2.Babaria Institute of pharmacy, Vadodara4/21/2012 27 28. 1. The droplet size,2. viscosity,3. density,4. turbidity,5. refractive index,6. phase separation and7. pH measurements shall be performed to characterize the microemulsion. Babaria Institute of pharmacy, Vadodara 4/21/2012 28 29. Thedropletsize distribution ofmicroemulsion vesicles can be determinedby either light scattering technique orelectron microscopy. This technique has been advocated as thebest method for predicting microemulsionstability. Dynamic light-scattering measurements. The DLS measurements are taken at 90 in a dynamic light-scattering spectrophotometer which uses a neon laser of wavelength 632 nm. The data processing is done in the built-in computer with the instrument.Babaria Institute of pharmacy,Vadodara 4/21/2012 29 30. Polydispersity Studied using Abbe refractometer. Phase analysis To determine the type if microemulsion that has formedthe phase system (o/w or w/o) of the microemulsions isdetermined by measuring the electrical conductivityusing a conductometer. Viscosity measurement The viscosity of microemulsions of several compositionscan be measured at different shear rates at differenttemperatures using Brookfield type rotary viscometer. The sample room of the instrument must be maintainedat 37 0.2C by a themobath, and the samples for themeasurement are to be immersed in it before testing.Babaria Institute of pharmacy,Vadodara 4/21/2012 30 31. Determination of permeability coefficient and flux Excised human cadaver skin from the abdomen can be obtained from dead who have undergone postmortem not more than 5 days ago in the hospital. The skin is stored at 4C and the epidermis separated. The skin is first immersed in purified water at 60C for 2 min and the epidermis then peeled off. Dried skin samples can be kept at -20C for later use. Alternatively the full thickness dorsal skin of male hairless mice may be used. The skin shall be excised, washed with normal saline andBabaria Institute of pharmacy,Vadodara 4/21/201231 32. The passive permeability oflipophilic drug through theskin is investigated usingFranz diffusion cells withknown effective diffusionalarea. The hydrated skin samplesare used.The receivercompartment may contain acomplexing agentlikecyclodextrin in the receiverphase, which shall increasethe solubility and allows themaintenanceofsinkconditionsin theexperiments. Samples are withdrawn atregular interval and analyzedfor amount of drug released. Babaria Institute of pharmacy, Vadodara 4/21/2012 32 33. Bioavailability studies: Skin bioavailability of topicalapplied microemulsion on rats Male SpragueDawley rats (400500 g), need to beanesthetized (15 mg/kg pentobarbital sodium i.p.) andplaced on their back. The hair on abdominal skin shall be trimmed off and thenbathed gently with distilled water. Anesthesia should be maintained with 0.1-ml pentobarbital(15 mg/ml) along the experiment. Microemulsions must be applied on the skin surface (1.8cm2) and glued to the skin by a silicon rubber. After 10, 30 and 60 min of in vivo study, the rats shall bekilled by aspiration of ethyl ether. The drug exposed skin areas shall be swabbed three to fourtimes with three layers of gauze pads, then bathed for 30 swith running water, wiped carefully, tape-stripped (X10strips) and harvested from the animals.Babaria Institute of pharmacy, Vadodara4/21/2012 33 34. Determination of residual drug remaining inthe skin on tropical administration. The skin in the above permeation studies can beused to determine the amount of drug in theskin. The skin cleaned with gauze soaked in0.05% solution of sodium lauryl sulfate and shallbathed with distilled water. The permeation area shall be cut and weighedand drug content can be determined in the clearsolution obtained after extracting with a suitablesolvent and centrifuging.Babaria Institute of pharmacy,Vadodara 4/21/2012 34 35. Pharmacological Studies Therapeutic effectiveness can be evaluated for the specificpharmacological action that the drug purports to sho...</p>