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SEMINAR ON

MICROEMUSION&

SELF EMUSIFICATION SYSTEM

• Guided by: – Mrs. Vaishali thakkar

• Prepared by: – Bhavesh Maktarpara – M.Pharm. 1 st sem

Pharmaceutics

Anand Pharmacy College, ANAND 1



Microemulsion

• Microemulsions are thermodynamically stabledispersions of oil and water stabilized by asurfactant and, in many cases, also acosurfactant.

• Microemulsions can have characteristicproperties such as ultralow interfacial tension,large interfacial area and capacity to solubilizeboth aqueous and oil-soluble compounds.




“Microemulsions are dispersions of nanometer-sized droplets of an immiscibleliquid within another liquid. Droplet formation isfacilitated by the addition of surfactants andoften also co surfactants. ”




Theories of Microemulsion Formation** • Historically, three approaches have been used to explain microemulsion

formation and stability. They are as follows-

1. Interfacial or mixed film theories.2. Solubilization theories.3. Thermodynamic treatments.• The free energy of microemulsion formation can be considered to depend

on the extent to which surfactant lowers the surface tension of the oil waterinterface and change in entropy of the system such that,

Gf = γ a - T S• Where,

– Gf = free energy of formation – A = change in interfacial area of microemulsion – S = change in entropy of the system –

T = temperature – γ = surface tension of oil water interphase• It should be noted that when a microemulsion is formed the change in A is

very large due to the large number of very small droplets formed.• In order for a microemulsion to be formed (transient) negative value of was

required, it is recognized that while value of is positive at all times, it is very

small and it is offset by the entropic component.Anand Pharmacy College, ANAND 4



• The dominant favorable entropic contribution is very largedispersion entropy arising from the mixing of one phase inthe other in the form of large number of small droplets.

• However there are also expected to be favorable entropic

contributions arising from other dynamic processes such assurfactant diffusion in the interfacial layer and monomer-micelle surfactant exchange.

• Thus a negative free energy of formation is achieved whenlarge reductions in surface tension are accompanied by

significant favorable entropic change.• In such cases, microemulsion is spontaneous and the

resulting dispersion is thermodynamically stable.

1. Schulman J.H, Stoeckenius, W., Prince, L.M, J. Phys. Chem., 63, 1677-1680. (1959).Mechanism of formation and structure o f microemulsions by electron Microscopy .2. Prince L.M, J. Colloid Interface Sci., 23,165-173 (1967). A theory of aqueous emulsionsI.Negative interfacial tension at the oil/water interfaceAnand Pharmacy College, ANAND 5



Types of microemulsion systems* • According to Winsor, there are four types of microemulsion phases

exists in equilibria, these phases are referred as Winsor phases• They are,Winsor I: With two phases, the lower (o/w)

microemulsion phases in equilibrium with the upper excess oil.Winsor II: With two phases, the upper (w/o)

microemulsion phase microemulsion phases in equilibrium with lowerexcess water.

Winsor III: With three phases, middlemicroemulsion phase (o/w plus w/o, called bi continous) inequilibrium with upper excess oil and lower excess water.

Winsor IV: In single phase, with oil, water and

surfactant homogenously mixed.

*Aboofazeli R, LawrenceM.J, Int. J. Pharm., 93,161-175 (1993). Investigations into the formation andcharacterization of phospholipid microemulsions. I. Pseudo-ternary phase diagrams of systems containingwater-lecithin-alcohol-isopropyl myristate.* Hasse A, Keipert, S, Eur. J. Pharm. Biopharm., 430, 179-183 (1997). Development and characterization of microemulsions for ocular application.




• Advantages Of Microemulsion Over Other Dosage Forms

– Increase the rate of absorption – Eliminates variability in absorption – Helps solublize lipophilic drug – Provides a aqueous dosage form for water insoluble drugs – Increases bioavailability –

Various routes like tropical, oral and intravenous can be used todeliver the product – Rapid and efficient penetration of the drug moiety – Helpful in taste masking – Provides protection from hydrolysis and oxidation as drug in oil

phase in O/W microemulsion is not exposed to attack by waterand air.

– Liquid dosage form increases patient compliance. – Less amount of energy requirement.




–

Aesthetically appealing products can be formulated as trans-parent o/w or w/o dispersions called microemulsions. – These versatile systems are currently of great technological and

scientific interest to the researchers because of their potential toincorporate a wide range of drug molecules (hydrophilic and

hydrophobic) due to the presence of both lipophilic and hydrophilicdomains.

– These adaptable delivery systems provide protection againstoxidation, enzymatic hydrolysis and improve the solubilization of lipophilic drugs and hence enhance their bioavailability. In addition

to oral and intravenous delivery, they are amenable for sustainedand targeted delivery through ophthalmic, dental, pulmonary,vaginal and topical routes.

– Microemulsions are experiencing a very active development asreflected by the numerous publications and patents being grantedon these systems. Anand Pharmacy College, ANAND 8



Component of Microemulsion System

• A large number of oils and surfactant are available but their use in

the microemulsion formulation is restricted due to their toxicity,

irritation potential and unclear mechanism of action.

• Oils and surfactant which will be used for the formulation of

microemulsion should be biocompatible, non-toxic, clinically

acceptable, and use emulsifiers in an appropriate concentration

range that will result in mild and non-aggressive microemulsion.• The emphasis is, excipients should be generally regarded as safe

(GRAS)[




Main three components1. Oil phase2. Surfactant3. Aqueous Component

•

If a cosurfactant is used, it may sometimes be represented at afixed ratio to surfactant as a single component, and treated as asingle "pseudo-component".

• The relative amounts of these three components can berepresented in a ternary phase diagram.

• Gibbs phase diagrams can be used to show the influence of changesin the volume fractions of the different phases on the phasebehavior of the system.




Oil Component •

The oil component influences curvature by its ability to penetrate andswell 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 and oleic 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.




Surfactants • The role of surfactant in the formulation of microemulsion is to lower the

interfacial tension which will ultimately facilitates dispersion processduring the preparation of microemulsion and provide a flexible around thedroplets.

• The surfactant should have appropriate lipophilic character to provide thecorrect curvature at the interfacial region.

• Generally, low HLB surfactants are suitable for w/o microemulsion,whereas high HLB (>12) are suitable for o/w microemulsion.

• Following are the different surfactants are mainly used for microemulsion- –

Polysorbate (Tween 80 and Tween 20), Lauromacrogol 300, Lecithins, Decylpolyglucoside (Labrafil M 1944 LS), Polyglyceryl-6-dioleate (Plurol Oleique),Dioctyl sodium sulfosuccinate (Aersol OT), PEG-8 caprylic/capril glyceride(Labrasol).




Co surfactants • 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 the interfacialtension and increase the fluidity of the interface.

2. Surfactant having HLB greater than 20 often require the presence of cosurfactant to reduce their effective HLB to a value within the rangerequired 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) andethanol.




Preparation of Microemulsion

• Following are the different methods are usedfor the preparation of microemulsion*:

1. Phase titration method2. Phase inversion method




Phase titration method • Microemulsions are prepared by the spontaneous

emulsification method (phase titration method) and can beportrayed with the help of phase diagram.

• As quaternary phase diagram (four component system) istime consuming and difficult to interpret, pseudo ternaryphase diagram is constructed to find out the different zonesincluding microemulsion zone, in which each corner of thediagram represents 100% of the particular components.

• Pseudo-ternary phase diagrams of oil, water, and co-surfactant/surfactants mixtures are constructed at fixedcosurfactant/surfactant weight ratios.

• Phase diagrams are obtained by mixing of the ingredients,which shall be pre-weighed into glass vials and titrated withwater and stirred well at room temperature . Formation of monophasic/ biphasic system is confirmed by visualinspection. Anand Pharmacy College, ANAND 15






• In case turbidity appears followed by a phaseseparation, the samples shall be considered asbiphasic .

• 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.




Phase inversion method •

Phase inversion of microemulsion is carried out upon addition of excess of the dispersed phase or in response to temperature.

• During phase inversion drastic physical changes occur including

changes in particle size that can ultimately affect drug releaseboth in vitro and in vivo.

• For non-ionic surfactants, this can be achieved by changing the

temperature of the system , – forcing a transition from an o/w microemulsion at low temperature

– to -

– a w/o microemulsion at higher temperatures (transitional phase inversion).Anand Pharmacy College, ANAND 18



• During cooling, the system crosses a point zero spontaneous curvature

and minimal surface tension, promoting the formation of finely

dispersed oil droplets.• Apart from temperature, salt concentration or pH value may also be

considered.

•

A transition in the radius of curvature can be obtained by changing thewater volume fraction.

• Initially water droplets are formed in a continuous oil phase by

successively adding water into oil. Increasing the water volumefraction changes the spontaneous curvature of the surfactant from

initially stabilizing a w/o microemulsion to an o/w microemulsion at

the inversion locus.Anand Pharmacy College, ANAND 19



• Many examples of microemulsion basedformulations are now on the market ;

– Among them, the performances of microemulsions are well demonstrated in thereformulation of Cyclosporin A by Novartis into amicroemulsion based formulation marketed underthe trade mark Neoral®

• this has increased the bioavailability nearly bya factor 2.




Characterization Of Microemulsion

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.




The droplet size

• The droplet size distribution of microemulsionvesicles can be determined by either light scatteringtechnique or electron microscopy.

• This technique has been advocated as the bestmethod for predicting microemulsion stability.

– 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-incomputer with the instrument.




Phase analysis and viscosity measurement

• Polydispersity – Studied using Abbe refractometer.

• Phase analysis – To determine the type if microemulsion that has formed the

phase system (o/w or w/o) of the microemulsions is determinedby measuring the electrical conductivity using a conductometer.• · Viscosity measurement

– The viscosity of microemulsions of several compositions can bemeasured at different shear rates at different temperaturesusing Brookfield type rotary viscometer.

– The sample room of the instrument must be maintained at 37 ±0.2°C by a themobath, and the samples for the measurementare to be immersed in it before testing.




In Vitro Drug Permeation Studies• 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 and used.Anand Pharmacy College, ANAND 24



– The passive permeability of lipophilic drug through the skin isinvestigated using Franz diffusioncells with known effectivediffusional area.

– The hydrated skin samples areused. The receiver compartmentmay contain a complexing agentlike cyclodextrin in the receiverphase, which shall increase thesolubility and allows themaintenance of sink conditions inthe experiments.

– Samples are withdrawn at regular

interval and analyzed for amountof drug released.




In Vivo Studies • Bioavailability studies: Skin bioavailability of topical

applied microemulsion on rats – Male Sprague –Dawley rats (400 –500 g), need to be anesthetized

(15 mg/kg pentobarbital sodium i.p.) and placed on their back. – The hair on abdominal skin shall be trimmed off and then

bathed 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 (1.8 cm 2)

and glued to the skin by a silicon rubber. – After 10, 30 and 60 min of in vivo study, the rats shall be killedby aspiration of ethyl ether. – The drug exposed skin areas shall be swabbed three to four

times with three layers of gauze pads, then bathed for 30 s withrunning water, wiped carefully, tape-stripped (X10 strips) andharvested from the animals.




• Determination of residual drug remaining inthe skin on tropical administration.

– The skin in the above permeation studies can be used to

determine the amount of drug in the skin. The skincleaned with gauze soaked in 0.05% solution of sodiumlauryl sulfate and shall bathed with distilled water.

– The permeation area shall be cut and weighed and drug

content can be determined in the clear solution obtainedafter extracting with a suitable solvent and centrifuging.


Ph l i l St di



• Pharmacological Studies – Therapeutic effectiveness can be evaluated for the specific

pharmacological action that the drug purports to show as per statedguidelines.

• Estimation Of Skin Irritancy – As the formulation is intended for dermal application skin irritancy

should be tested. – The dorsal area of the trunk is shaved with clippers 24 hours before

the experiment. – The skin shall be scarred with a lancet. 0.5 ml of product is applied and

then covered with gauze and a polyethylene film and fixed withhypoallergenic adhesive bandage.

– The test be removed after 24 hours and the exposed skin is graded for

formation of edema and erythema. – Scoring is repeated a 72 hours later. – Based on the scoring the formulation shall be graded as

• ‘non -irritant’, • ‘irritant’ and• ‘highly irritant’ . Anand Pharmacy College, ANAND 28



• Stability Studies – The physical stability of the microemulsion must be

determined under different storage conditions (4, 25 and40 °C) during 12 months.

– Depending on different regulatory agency requirement it’ll vary according to them.

– Fresh preparations as well as those that have been keptunder various stress conditions for extended period of time is subjected to droplet size distribution analysis.

– Effect of surfactant and their concentration on size of droplet is also be studied.




Application of microemulsion in delivery of drug

• Oral delivery – Microemulsions have the potential to enhance the solubilization

of poorly soluble drugs (particularly BCS class II or class IV) andovercome the dissolution related bioavailability problems .

–

These systems have been protecting the incorporated drugsagainst oxidation, enzymatic degradation and enhancemembrane permeability.

– Presently , Sandimmune Neoral(R) (Cyclosporine A),Fortovase(R) (Saquinavir), Norvir(R) (Ritonavir) etc. are thecommercially available microemulsion formulations.

– Microemulsion formulation can be potentially useful to improvethe oral bioavailability of poorly water soluble drugs byenhancing their solubility in gastrointestinal fluid.




• Parenteral delivery – The formulation of parenteral dosage form of lipophilic and

hydrophilic drugs has proven to be difficult. – O/w microemulsions are beneficial in the parenteral delivery of

sparingly soluble drugs where the administration of suspensionis not required.

– They provide a means of obtaining relatively high concentrationof these drugs which usually requires frequent administration.

–

Other advantages are that they exhibit a higher physical stabilityin plasma than liposome’s or other vehicles and the internal oilphase is more resistant against drug leaching.

– Several sparingly soluble drugs have been formulated into o/wmicroemulsion for parenteral delivery.




• Topical delivery – Topical administration of drugs can have advantages over

other methods for several reasons, one of which is theavoidance of hepatic first-pass metabolism of the drug andrelated toxicity effects.

– Another is the direct delivery and targetability of the drugto affected areas of the skin or eyes.

– Now a day, there have been a number of studies in thearea of drug penetration into the skin.

–

They are able to incorporate both hydrophilic (5-flurouracil, apomorphine hydrochloride, diphenhydraminehydrochloride, tetracaine hydrochloride, methotrexate)and lipophilic drugs (estradiol, finasteride, ketoprofen,meloxicam, felodipine, triptolide) and enhance theirpermeation.




• Ophthalmic delivery – Low corneal bioavailability and lack of efficiency in the posterior

segment of ocular tissue are some of the serious problem of conventional systems.

– Recent research has been focused on the development of newand more effective delivery systems.

– Microemulsions have emerged as a promising dosage form forocular use.

– Chloramphenicol, an antibiotic used in the treatment of trachoma and keratitis, in the common eye drops hydrolyzes

easily. – Fialho et al. studied microemulsion based dexamethasone eyedrops which showed better tolerability and higherbioavailability. The formulation showed greater penetration inthe eye which allowed the possibility of decreasing dosingfrequency and thereby improve patient compliance.




• Nasal delivery – Recently, microemulsions are being studied as a delivery system

to enhance uptake of drug through nasal mucosa. – In addition with mucoadhesive polymer helps in prolonging

residence time on the mucosa. – Lianly et al. investigated the effect of diazepam on the

emergency treatment of status epilepticus. – They found that the nasal absorption of diazepam fairly rapid at

2 mg kg-1 dose with maximum drug plasma concentrationreached within 2-3 min




• Drug targeting – Drug targeting to the different tissues has evolved asthe most

desirable goal of drug delivery. – By altering pharmacokinetics and biodistribution of drugs and

restricting their action to the targeted tissue increased drugefficacy with concomitant reduction of their toxic effects can beachieved.

– Shiokawa et al. reported a novel microemulsion formulation fortumor targeting of lipophilic antitumor antibiotic aclainomycin A(ACM).

–

They reported that a folate-linked microemulsion is feasible fortumour targeted ACM delivery. – They also reported that folate modification with a sufficiently

long PEG chain on emulsions is an effective way of targetingemulsion to tumour cells.




Self Emulsification Drug DeliverySystem






• Self-emulsifying formulations spread readily in thegastrointestinal (GI) tract, and the digestive motility of the stomach and the intestine provide the agitationnecessary for selfemulsification.

• These systems advantageously present the drug indissolved form and the small droplet size provides alarge interfacial area for the drug absorption.

• SEDDSs typically produce emulsions with a droplet sizebetween 100 –300 nm while self-microemulsifying drugdelivery systems (SMEDDSs) form transparentmicroemulsions with a droplet size of less than 50 nm.




• Composition of SEDDSs – The self-emulsifying process is depends on:

• The nature of the oil –surfactant pair• The surfactant concentration• The temperature at which self-emulsification occurs.




• Oils – Oils can solubilize the lipophilic drug in a specific

amount. It is the most important excipient because itcan facilitate self-emulsification and increase the

fraction of lipophilic drug transported via theintestinal lymphatic system, thereby increasingabsorption from the GI tract.

– Long-chain triglyceride and medium-chain triglycerideoils

– Modified or hydrolyzed vegetable oils havecontributed widely to the success of SEDDSs owing totheir formulation and physiological advantages




• Surfactant – Nonionic surfactants with high hydrophilic –

lipophilic balance (HLB) values are used in

formulation of SEDDSs (e.g., Tween, Labrasol,Labrafac CM 10, Cremophore, etc.).

– The usual surfactant strength ranges between 30 –60% w/w of the formulation in order to form astable SEDDS.




• Cosolvents – Cosolvents like diehylene glycol monoethyle ether

(transcutol), propylene glycol, polyethylene glycol,polyoxyethylene, propylene carbonate,tetrahydrofurfuryl alcohol polyethylene glycolether (Glycofurol), etc., may help to dissolve largeamounts of hydrophilic surfactants or thehydrophobic drug in the lipid base.

– These solvents sometimes play the role of thecosurfactant in the microemulsion systems.




Formulation of SEDDSs

• The following should be considered in theformulation of a SEDDS:

– The solubility of the drug in different oil,

surfactants and cosolvents. – The selection of oil, surfactant and cosolvent

based on the solubility of the drug and thepreparation of the phase diagram.

– The preparation of SEDDS formulation bydissolving the drug in a mix of oil, surfactant andcosolvent.




• The addition of a drug to a SEDDS is criticalbecause the drug interferes with the self-emulsification process to a certain extent, whichleads to a change in the optimal oil –surfactantratio.

• So, the design of an optimal SEDDS requirespreformulation-solubility and phase-diagram

studies. In the case of prolonged SEDDS,formulation is made by adding the polymer orgelling agent




Mechanism of self-emulsification

• According to Reiss, self-emulsification occurswhen the entropy change that favorsdispersion is greater than the energy requiredto increase the surface area of the dispersion.

Where,DG is the free energy associated with the processN is the number of dropletsR is radius of dropletS is interfacial tension




Characterization of SEDDSs • The primary means of self-emulsification assessment is visual

evaluation. The efficiency of self-emulsification could beestimated by determining the rate of emulsification, droplet-size distribution and turbidity measurements.

• Visual assessment. This may provide important informationabout the self-emulsifying and microemulsifying property of themixture and about the resulting dispersion.

• Turbidity Measurement. This is to identify efficient self-

emulsification by establishing whether the dispersion reachesequilibrium rapidly and in a reproducible time.




• Droplet Size. – This is a crucial factor in self-emulsification performance because it

determines the rate and extent of drug release as well as the stability of the emulsion.

– Photon correlation spectroscopy, microscopic techniques or a Coulter

Nano sizer are mainly used for the determination of the emulsion dropletsize. – The reduction of the droplet size to values below 50 μm leads to the

formation of SMEDDSs, which are stable, isotropic and clear o/wdispersions.

• Zeta potential measurement. – This is used to identify the charge of the droplets. In conventional SEDDSs,

the charge on an oil droplet is negative due to presence of free fatty acids.• Determination of emulsification time.

– Self-emulsification time, dispersibility, appearance and flowability wasobserved and scored according to techniques described in H. Shen et al.

used for the grading of formulations.Anand Pharmacy College, ANAND 47



References• Microemulsions- Potential Carrier for Improved Drug Delivery

INTERNATIONALE PHARMACEUTICA SCIENCIA April-June 2011 Vol. 1 Issue 2http://www.ipharmsciencia.com ISSN 2231-5896 ©2011 IPS, Sajal KumarJha1*, Sanjay Dey1, Roopa Karki2

• N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS) withpolyglycolyzed glycerides for improving in vitro dissolution and oral absorptionof lipophilic drugs," Int. J. Pharm. 106, 15 –23 (1994).

• J.R. Crison and G.L. Amidon, "Method and formulation for increasing thebioavailability of poorly water-soluble drugs," US Patent No. 5,993,858, issuedNovember 30, 1999.

• P.P. Constantinides, "Lipid microemulsions for improving drug dissolution and

oral absorption: physical and biopharmaceutical aspects," Pharm. Res. 12,1561 –72 (1995).• N. Gursoy et al., "Excipient effects on in vitro cytotoxicity of a novel paclitaxel

selfemulsifying drug delivery system," J. Pharm. Sci. 92, 2420 –2427 (2003).

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