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Modern colloidal drug delivery system Micro emulsions are clear, transparent, thermodynamically stable dispersions of oil and water, stabilized by an interfacial film of surfactant frequently in combination with a co-surfactant. Diameter - 10-140 nm. INTRODUCTION

Cont……. : 

Cont……. In this type of system, the two liquids tend to separate out in two layers. And to avoid this, a third substance called as an emulsifier is added, act by: they tend to adsorb at interface, where they can fulfill their dual affinity with hydrophilic groups located in aqueous phase and hydrophobic groups in oil or air. they reduce the mismatch with solvent through a specific kind of aggregation process known as micellization

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The Microemulsion concept was introduced as early as 1940s by Hoar and Schulman who generated a clear single-phase solution by titrating a milky emulsion with hexanol. Schulman and co-worker (1959) subsequently coined the term microemulsion The microemulsion definition provided by Danielson and Lindman in 1981 will be used as the point of reference. HISTORICAL BACKGROUND

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Transparent emulsion Swollen micelle Micellar solution Solubilized oil ALTERNATIVE NAMES

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To delivery of hydrophilic as well as lipophilic drug as drug carriers because of its improved drug solubilization capacity, long shelf life, easy of preparation and improvement of bioavailability. MAJOR GOALS


EMULSION Vs MICRO EMULSION: Shape Macro emulsion Micro emulsion



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ADVANTAGES These are thermodynamically stable and require minimum energy for formation. Ease of manufacturing and scale-up Improved drug solubilization and bioavailability. This system is reckoned advantageous because of its wide applications in colloidal drug delivery systems for the purpose of drug targeting and controlled release The formation of micro emulsion is reversible.  They may become unstable at low or high temperature but when the temperature returns to the stability range, the micro emulsion reforms. The use of microemulsion as delivery systems can improve the efficacy of a drug, allowing the total dose to be reduced and thus minimizing side effects.


DISADVANTAGES Use of a large concentration of surfactant and co-surfactant necessary for stabilizing the nanodroplets. Limited solubilizing capacity for high-melting substances The surfactant must be nontoxic for using pharmaceutical applications Micro emulsion stability is influenced by environmental parameters such as temperature and pH.  These parameters change upon micro emulsion delivery to patients.

Types of micro emulsion : 

Types of micro emulsion O/W Microemulsion                W/O Microemulsion Bi continuous Microemulsion

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Oil in water microemulsions wherein oil droplets are dispersed in the continuous  aqueous phase Water in oil microemulsions wherein water droplets are dispersed in the continuous oil phase; Bi-continuous microemulsions wherein micro domains of oil and water are inter dispersed within the system. In all three types of micro emulsions, the interface is stabilized by an appropriate combination of surfactants and/or co-surfactants.


THEORIES OF MICRO EMULSION Interfacial or mixed film theory Solubilization Theory Thermodynamic theory

Thermodynamic theory : 

Thermodynamic theory The process of formation of oil droplets from a bulk oil phase is accompanied by an increase in the interfacial area ∆A, and hence an interfacial energy ∆G . The entropy of dispersion of the droplets is equal to T ∆ S and hence the free energy of formation of the system is given by the expression. ∆G       =    ٧∆A     -  T ∆ S

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When the interfacial tension is made sufficiently low that the interfacial energy becomes comparable to or even lower than the entropy of dispersion. The free energy of formation of the system becomes zero or negative.  This explains the thermodynamic stability of micro emulsions. The co-surfactant along with surfactant lower the interfacial tension to a very small even transient negative value                                     At this value, interface would expand to form fine dispersed droplets.                              Adsorb more surfactant and co-surfactant until their bulk condition is depleted enough to make interfacial tension positive again This process is known as “Spontaneous Emulsification” which forms the micro emulsion.


PHASE DIAGRAM Phase diagram is a plot showing the condition of pressure and temperature under which two or more physical states can exist together in a state of dynamic equilibrium. Micro emulsion consist of three component namely: Oil Water Surfactant and co surfactant The concentration of co surfactant is varied. So a ternary diagram can be formed

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The surfactant concentration in the electrolyte solution can be kept constant and the co-surfactant concentration can be the third variable. This enables us to utilize the conventional triangular phase diagram plot. Temperature variations are then represented by slices across a parallel-sided triangular prism.

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With high oil concentration surfactant forms reverse micelles capable of solubilizing water molecules in their hydrophilic interior. Continued addition of water in this system may result in the formation of W/O micro emulsion in which water exists as droplets surrounded and stabilized by interfacial layer of the surfactant / co-surfactant mixture. At a limiting water content, the isotropic clear region changes to a turbid, birefringent one. Upon further dilution with water, a liquid crystalline region may be formed in which the water is sandwiched between surfactant double layers. Finally, as amount of water increases, this lamellar structure will break down and water will form a continuous phase containing droplets of oil stabilized by a surfactant / co-surfactant (O/W microemulsions)

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The composition of the three-component systems are shown as the intersections of the broken lines. The ends of the ‘tie-lines’ give the compositions of the two phases, while the ‘lever rule’ gives the amounts of each. Any change to the system which changes the hydrophobic balance of the surfactant may enable us to move from one type of system to another.

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Constant temperature the change of a surfactant to one with a longer chain length would take us from left to right in the figure. A similar result can be achieved by changing the polarity of the water phase (by the addition of short-chain alcohols, for example), increasing the temperature for a non-ionic surfactant or increasing the electrolyte

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At low surfactant concentration, there exist an equilibria, three phases are referred to as Winsor phases. They are: Winsor I: Winsor II: Winsor III: Winsor IV:

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Phase diagram can be constructed by water titration method Rohit Ramesh Shah et.al carried work on Preparation and Evaluation of Aceclofenac Topical Microemulsion. The ratios of surfactant to co-surfactants were chosen to be 1:2, 1:1, 2:1, and 4:1, and such mixtures were prepared. These mixtures (S/CoS) were mixed with the oil phase to give the weight ratios of 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90. Water was added drop by drop and stirred using a magnetic stirrer until a homogeneous dispersion or solution was obtained. After each addition, the system was examined for the appearance and flow properties. The end point of the titration was the point where the solution becomes cloudy or turbid. The quantity of the aqueous phase required to make the mixture turbid was noted.

Formation of Microemulsion : 

Formation of Microemulsion Micro emulsion is formed when the interfacial tension at the O/W interphase are brought very low level. The interfacial tension is kept highly flexible and fluid.

Role of surfactant : 

Role of surfactant The surfactant used to stabilize the micro emulsion system are: Non ionic Zwitter ion Cationic Anionic The use of hydrophilic surfactant oil swollen type or oil-in –water micro emulsions. The use of lipophilic surfactant produces water swollen type or water-in oil micro emulsion The combination of ionic and nonionic surfactant , can be very effective at the extent of microemulsion region

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The change of temperature at the maximum solubilization is very sensitive to as the solubilization increases. If temperature insensitive three phase system are produced micro emulsion are stable against temperature change.

Factors affecting micro emulsion formation : 

Factors affecting micro emulsion formation Packing ratio Property of surfactant Property of oil phase Temperature Chain length Type and nature of cosurfactant

Packing ratio : 

Packing ratio HLB of surfactant determines the type of micro emulsion through its influence on packing and film curvature. The analysis of film curvature for surfactant association’s leadings to the formation of micro emulsion. Critical packing ratio is given by: c.p.p= V/(a×l) where, V-volume of surfactant molecule a- head group surface area l- length If c.p.p is between 0-1,interface curves towards water(positive) If c.p.p is greater than 1, interface curves towards oil(negative) If c.p.p is equal to1, then either bicontinuous or lamellar structure.

Role of surfactants : 

Role of surfactants Surfactant contains two group hydrophilic and lipophilic group. Hydrophilic single chain of surfactant such as ceto methyl ammonium bromide dissociates completely in dilute solution and forms o/w micro emulsion. When high concentration of surfactant is used or when the surfactant is in presence of salt , degree of dissociation of hydrophilic group is lesser and then resulting solution leads to the formation of w/o emulsion.


PROPERTY OF OIL PHASE Oil phase also influence curvature by its ability to penetrate Swell the tail group region of the surfactant monolayer. Short chain oil such as alkanes, penetrate the lipophilic region than long chain oils Swelling of tail results into an increased negative curvature to W/O microemulsion.


TEMPERATURE Temperature plays important role in determining the effective head group size of nonionic surfactants. At low temperature, they are hydrophilic and form normal o/w emulsion. At high temperature, they are lipophilic and form w/o system. At an intermediate temperature, ME coexist with excess water and oil phase and form bicontinous structure.


THE CHAIN LENGTH, TYPE AND NATURE OF COSURFACTANT Alcohols are widely used as a cosurfactant in microemulsions. Addition of shorter chain co-surfactant gives positive curvature effect as alcohol swells the head region more than tail region so, it becomes more hydrophilic and o/w type is favoured Longer chain co-surfactant favours w/o type by alcohol swelling more in chain region than head region.

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PHASE BEHAVIOUR Phase contrast microscopy and freeze fracture transmission electron microscopy can be used to differentiate micro emulsions from liquid crystals and coarse emulsions. Clear isotropic one-phase systems are identified as micro emulsions whereas opaque systems showing bifringence when viewed by cross polarized light microscopy may be taken as liquid crystalline system.


SIZE AND SHAPE Small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), and static as well as dynamic light scattering Transmission Electron Microscopy (TEM) is the most important technique for the study of microstructures of micro emulsions because it directly produces images at high resolution and it can capture any co-existent structure and micro-structural transitions.


RHEOLOGY Brookfield viscometer Change in the rheological characteristics help in determining the micro emulsion region and its separation from other related structures like liquid crystals. Bicontinuous micro emulsion are dynamic structures with continuous fluctuations occurring between the bicontinuous structure, swollen reverse micelle, and swollen micelles


PREDICTION OF TYPE OF EMULSION Type – I  The surfactant is preferentially soluble in water and oil-in-water (O/W) micro emulsions form (Winsor I).  The surfactant-rich water phase coexists with the oil phase where surfactant is only present as monomers at small concentration. Type – II   The surfactant is mainly in the oil phase and water-in-oil (W/O) micro emulsions form.  The surfactant-rich oil phase coexists with the surfactant-poor aqueous phase   (Winsor II) Type – III  A three-phase system where a surfactant-rich middle-phase coexists with both excess water and oil surfactant-poor phases (Winsor III or middle-phase micro emulsion). Type – IV A single-phase (isotropic) micellar solution, that forms upon addition of a sufficient quantity of amphiphile (surfactant plus alcohol)

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Oral drug delivery Ocular drug delivery Pulmonary drug delivery Transdermal drug delivery Parenteral drug delivery For solubilization of drug In biotechnlogy others

Oral drug delivery : 

Oral drug delivery Advantages of microemulsions: increased absorption improved clinical potency decreased drug toxicity Ritchel et.al(1990) studied the absorption of cyclosporine (potent, cyclic endekapeptide). Poor bioavailability 2 w/o microemulsion-sorbitol ester polyoxyethylene glycolmonoether. LMW alcohol, fatty ester and water.

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Ritchel et.al(1991) studied the absorption of three peptides-insulin, vasopressin and cyclosporine in o/w microemulsion. Surjyanarayan Mandal(2010) studied absorption of atorvastatin by oral route. Atorvastatin is a poor water-soluble drug and has a very low absolute bioavailability (about 5%) due to rapid metabolism in the gut and liver Prepared ME by using various oils (Sunflower oil, Isopropyl Myristate, soya bean oil, Labrafil M 1944CS, Capmul CMC), surfactant (Labrafac CC, Tween 60, Cremophor EL, Cremophor RH 40), and cosurfactants (PEG 400, PEG 600, glycerol, ethanol) was determined. Pradip (2005) et.al. studied on the bioavailability of acyclovir.

Topical drug delivery : 

Topical drug delivery Microemulsions may enhance transdermal drug delivery primarily by the following effects: Micro emulsions can exhibit a high solubilization capacity for both lipophilic and hydrophilic drugs, thus more drug can be loaded into the microemulsion, which increases the concentration gradient across the skin without depletion. The reservoir effect of the internal phase maintains a constant driving force of drug from the external phase to the skin and prolongs absorption. Since the diffusion of the drug into the skin only occurs from the external phase of the micro emulsion, the internal phase continually supplies drug to the external phase so that it remains saturated with the drug.

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The formulation components may affect skin permeability, i.e. surfactants, cosurfactants, and oils may act as permeation enhancers by disrupting the SC lipid organization, thus increasing drug diffusion, or by increasing the partition of the drug in the skin. Chemical enhancers may be incorporated in the microemulsion, which will also improve dermal and transdermal delivery of drugs. The very low interfacial tension required for microemulsion formation is also responsible for the excellent wetting properties, which ensures excellent surface contact between the membrane and the vehicle. There is no clear consensus in the literature regarding the influence of droplet size of the microemulsion on drug permeation. A recent study by Izquierdo et al. showed no apparent relationship between droplet size and dermal or transdermal delivery of tetracaine after 24 h.

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Rohit R Shah(2009) et.al. topical delivery of fluconazole, this has poor solubility and absorption.

Ocular and intranasal drug delivery : 

Ocular and intranasal drug delivery For the treatment of eye diseases, drugs are essentially delivered topically. O/W microemulsions have been investigated for ocular administration, to dissolve poorly soluble drugs, to increase absorption and to attain prolong release profile. Hasse and keipett(1997) preparaed microemulsion containing pilocarpine were formulated using lecithin,PG and PEG 200 as cosurfactant and IPM as oil phase.the formulation had low viscosity with refractive index leading to ophthalmic application

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Amrish Kumar(2009) et.al. formulated sertraline HCl for intranasal administration Nasal cavity has used as alternative route for the drugs with poor water solubility, susceptible to acidic or enzymatic degradation and hepatic metabolism. The objective of the present study was to improve solubility of sertraline hydrochloride (STH), formulate microemulsions containing STH to accomplish rapid onset of action and to bypass the first-pass metabolism

Parenteral Drug Delivery : 

Parenteral Drug Delivery Parenteral administration (especially via the intravenous route) of drugs with limited solubility is a major problem extremely low amount of drug actually delivered to a targeted site.  Microemulsion formulations have distinct advantages over macroemulsion systems when delivered parenterally because of the fine particle microemulsion is cleared more slowly than the coarse particle emulsion and, therefore, have a longer residence time in the body.  Both O/W and W/O microemulsion can be used for parenteral delivery.

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O/w as the carrier for lipophilic drug -IV ,IM and SC Keipert et.al.(1989) o/w emulsion as a vector for FC, Ca antagnoist, steroids. Kakutani (1991) et.al reported the targeting potential of o/w ME containing lipophilic drug to RE system. Higher PC better will targeting of drug. w/o ME –hydrophilic drug prolong the release of drug by SC and IM.

Solubilization of drug in ME : 

Solubilization of drug in ME Due to its physiochemical property i.e. transparency, low viscosity,thermodynamic stability, high solubility. Can be used for the delivery of drugs like anti neoplastics, peptides, steroids, vitamins, LA .

Conclusion : 

Conclusion Microemulsions are optically isotropic and thermodynamically stable liquid solutions of oil, water and amphiphile. Microemulsions are readily distinguished from normal emulsions by their transparency, low viscosity and more fundamentally their thermodynamic stability. Drug delivery through microemulsions is a promising area for continued research with the aim of achieving controlled release with enhanced bioavailability and for drug targeting to various sites in the body.

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