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Review Article CODEN: IJPRNK ISSN: 2277-8713 Jigar Yogi, IJPRBS, 2015; Volume 4(1): 320-340 IJPRBS

Available Online at www.ijprbs.com 320

MICROEMULSION AS ADVANCED TOPICAL DRUG DELIVERY: A REVIEW JIGAR YOGI*,VINESH DABHI,DR. SUNITA CHAUDHARY,MRS. HIRAL SHAH,

MRS. KINJAL SANGHVI Arihant school of pharmacy & Bio research Institute, Gujarat, India

Accepted Date: 01/02/2015; Published Date: 27/02/2015

Abstract: Microemulsions have emerged as novel vehicles for drug delivery which allow sustained or controlled release for percutaneous, peroral, topical, transdermal, ocular and parenteral administration of medicaments. They offer the advantage of spontaneous formation, ease of manufacturing and scale-up, thermodynamic stability, improved drug solubilization of hydrophobic drugs and bioavailability. While microemulsions are used in several fields, this article focuses on the reported investigations for topical applications which exhibit minimal systemic absorption.

Keywords: Microemulsion, Topical delivery, Application

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INTRODUCTION

Definition

Microemulsions (μE) are isotropic, thermodynamically stable, transparent (or translucent)

systems of oil, water and surfactant, frequently in combination with a co-surfactant with a

droplet size usually in the range of 10-100 nm. These homogeneous systems, which can be

prepared over a wide range of surfactant concentration and oil to water ratio, are all fluids of

low viscosity.1

Structure of Microemulsions

FIGURE 1.1(STRUCTURE OF MICROEMULSION)

Microemulsions are dynamic systems in which the interface is continuously and spontaneously

fluctuating. Structurally, they are divided into oil-in-water (o/w), water in oil (w/o) and

bicontinuous microemulsions. In w/o microemulsion, water droplets are dispersed in the

continuous oil phase while o/w microemulsion is formed when oil droplets are dispersed in the

continuous aqueous phase, above figure.1

TOPICAL MICROEMULSION

In principle, microemulsions can be used to deliver drugs to the patients via several routes, but

the topical application of microemulsions has gained increasing interest. The three main factors

determining the transdermal permeation of drugs are the mobility of drug in the vehicle,

release of drug from the vehicle, and permeation of drug into the skin. These factors affect

either the thermodynamic activity that drives the drug into the skin or the permeability of drug

in the skin, particularly stratum corneum. Microemulsions improve the transdermal delivery of

several drugs over the conventional topical preparations. The superior transdermal flux from

microemulsions has been shown to be mainly due to their high solubilization potential for

lipophilic and hydrophilic drugs.



In topical formulations, microemulsions have been proved to increase the cutaneous

absorption of both lipophilic and hydrophilic medicaments when compared to conventional

vehicles (emulsions, pure oils, aqueous solutions). In an extensive review of this type of

applications, Kreilgaard6 et al attribute this performance to a generally higher solubility of the

medicaments in microemulsions, generating an increased concentration gradient towards the

skin. The role of penetration enhancers played by the amphiphilic components of the

microemulsion and the internal mobility of the drug within the vehicle also contribute to the

overall performance of microemulsions in dermal or transdermal drug delivery.2

Table 1: Examples of Topical microemulsion5:

Drug Oil Surfactant/cosurfactant Aqueous

phase

Reference

5- Florouracil IPM AOT Water 11

Aceclofenac Labrafil

M1944CS

Twwen80,span80,1,2-

octanol,cremophor ELP,ethanol

Water 12

Celecoxib IPM Caprylic/capric mono-

/diglycerides,polysorbate80

Water 13

Cyproterone Eucalyptus oil brij30,ethanol Water 14

Diclofenac IPM Lecithin Water 15

Estradiol Epikuron200,

oleic acid, IPM

teen80,span20/ethanol,isopropanol Water 16

Flurbiprofen IPM, ethyl

oleate

aerosol OT,span80 Water 17

Ketoprofen Mygliol 812 Lecithin,n-butanol Water 18

Methotrexate Decanol lecithin,benzyl alcohol Water,PW 19

Nifedipine Benzyl alcohol tween80,taurodeoxycholate Water 20

Sucrose Ethyl oleate labrasol,plurol isostearique Water,154mM

nacl

21

Tetracaine IPM leciyhin,n-propanol Water 22

Valdecoxib Oleic acid labrasol,transcutol Water 23

Valdecoxib Paraffin,jojoba Tween80,brij97,glycerol,sorbitol Water 24

Apomorphine

HCL

IPM Epikuron200 Water 25

Ketoprofen Oleic acid labrasol/cremophor RH40 Water 26

Theory of microemulsion formulation4:

Microemulsion formation and stability can be explained on the basis of a simplified

thermodynamic rationalization. The free energy of microemulsion formation can be considered

to depend on the extent to which surfactant lowers the surface tension of the oil–water

interface and the change in entropy of the system such that 34,

DG f = γDA - T DS



Where, DG f =free energy of formation, γ = Surface tension of the oil–water interface, DA

=Change ininterfacial area on microemulsification, DS = Change in entropy of the system which

is effectively the dispersion entropy, and T = Temperature.

It should be noted that when a microemulsion is formed, the change in DA is very large due to

the large number of nanodroplets are formed. It is seen that while the value of γ is positive at

all times, it is very small and it is offset by the entropic component. The dominant favorable

entropic contribution is very large dispersion entropy arising from the mixing of one phase in

the 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 as surfactant

diffusion in the interfacial layer and monomer-micelle surfactant exchange. Thus a negative

free energy of formation is achieved when large reductions in surface tension are accompanied

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

resulting dispersion is thermodynamically stable.

PHASE BEHAVIOUR 5

The relationship between the phase behavior of mixture and its composition can be confined

with the support of phase diagram. The phase behavior of simple microemulsion systems

comprising oil, surfactant and co-surfactant can be studied with the aid of ternary phase

diagrams in which each corner of the diagram represents 100% of the meticulous

component14. However, almost always in case of microemulsions, they contain an additional

component as cosurfactant and/or drug. In the case where four or more components are

involved, pseudoternary diagrams are constructed where a corner represents binary mixture of

two components as surfactant/co-surfactant, water/drug or oil/drug.

FIGURE 2: This represents a pseudoternary phase diagram



Phase rule: The phase rule enables identification of the number of variables depending on

system compositions and conditions. It is depicted as

F = C – P + 2

Where, F is the number of possible independent changes of state or degrees of freedom, C the

number of independent chemical constituents and P the number of phases present in system.

The F value determines the system to be invariant, monovariant, bivariant etc depending on its

value whether zero, 1, 2 or so on. At low surfactant concentration, there is series of equilibria

between phases, referred as winsor phases

Winsor I: The microemulsion phase (o/w) is in equilibrium with the upper excess oil. The

surfactant rich water phase coexists with oil phase where surfactant is only present as

monomers at small concentration.

Winsor II: The upper microemulsion phase (w/o) is in equilibrium with excess of water. The

surfactant rich oil phase coexists with surfactant poor aqueous phase.

Winsor III; The middle microemulsion phase (o/w plus w/o called bicontinuous) is in equilibrium

with excess oil and lower excess water. Surfactant rich middle phase coexists with both excess

water and oil surfactant poor phase

Winsor IV: Here oil, water and surfactant are homogenously are mixed to form isotropic single

phase micellar solution.

Inter-conversion between these phases can be produced by adjusting the proportions of

components. Phase transitions are brought by increasing either electrolyte concentration in

case of ionic surfactants or increasing temperature in case of non ionic surfactants15. Various

investigators have explored on interactions in adsorbed interfacial film to explain the direction

and extent of curvature. Bancroft gave a rule stated as “that phase will be external in which the

emulsifier is most soluble” i.e. oil soluble emulsifiers will form w/o emulsion and water soluble

emulsifiers will form w/o emulsions. The R- ratio was first proposed by winsor to account for

influence of amphiphiles and solvents on interfacial curvature. The R- ratio compares tendency

for amphiphile to disperse in oil, to its tendency to dissolve in water. The R- ratio of cohesive

energies coming from interaction of interfacial layer with oil , divided by energies resulting from

interactions of water determines the preferred interfacial curvature. A balanced interfacial

layer is represented by R=1.



Formulation Considerations1

The challenges in formulating topical microemulsions are:

1. Determining systems that are non-toxic, non-irritating, non-comedogenic and non-

sensitizing.

2. Formulating cosmetically elegant microemulsions.

The microemulsion formulation must have low allergic potential, good physiological

compatibility and high biocompatibility. The components involved in the general formulation of

microemulsions include (a) an oil phase (b) an aqueous phase containing hydrophilic active

ingredients [preservatives and buffers may be included] (c) a primary surfactant [anionic, non-

ionic or amphoteric] (d) secondary surfactant or cosurfactants. Generally non-ionic surfactants

are chosen because of their good cutaneous tolerance, lower irritation potential and toxicity.

Microemulsions can be formulated using singlechain surfactants or double chain surfactants.

Single chain surfactants do not lower the oil water interfacial tension sufficiently and hence

cosurfactants are required. Double chained surfactants like sulfosuccinates can form

microemulsions in the absence of cosurfactants but are too toxic for general pharmaceutical

applications.The cosurfactants even though being indispensable in the formulation of

microemulsions, have exhibited toxicity e.g. Medium chain length alcohols. Hence judicious

choice of surfactants and cosurfactants is of great importance. The use of

polyoxyethylenealcohol ethers has been reported as co-surfacants. Microemulsions prepared

from phospholipids such as lecithins are preferred over synthetic surfactants from the toxicity

point of view. The biocompatibility requirements of the amphiphiles are fulfilled by lecithins

and non-ionic surfactants (Brijs, Arlacel 186, Spans, Tweens and AOT).

The following examples are commonly used formulations components of microemulsions.

Table 2: components of microemulsions

Oil Surfactant Co-surfactant

Ethyl oleate

Mineral oil

IPM

Decanol

Oleic acid

Vegetable oils(coconut

oil,sunflower oil,soyabean

oil,olive oil)

Polysorbate (Tween 80 and

Tween 20)

Lauromacrogol 300,

Lecithins

Decyl polyglucoside(Labrafil

M 1944 LS),Polyglyceryl-6-

dioleate(Plurol

Oleique),Dioctyl sodium

Sorbitan monooleate

Sorbitan monostearate,

Propylene glycol

Propylene glycol monocaprylate

(Capryol 90)

2-(2-

ethoxyethoxy)ethanol(Transcutol

P)



Medium chain length

trigltceride(mugliol 812)

sulfosuccinate(Aerosol

OT),PEG-8 caprylic/capril

glyceride(Labrasol)

Ethanol

Method of preparation1

Phase titration method:

Microemulsions are prepared by spontaneous emulsification method which is illustrated with

help of phase diagrams. Phase diagram construction is practical approach to study complex

series of interaction which occurs when different components are mixed. The aspect of the

phase diagram is phase eqilibria and demarcation of phase boundaries. Most often pseudo-

ternary phase diagrams are constructed to figure out microemulsion zone as quaternary phase

diagram is time consuming and difficult to interpret.

FIGURE 3: Pseudoternary phase diagram of oil, water and surfactant showing microemulsion

region

Phase inversion method:

Phase inversion of microemulsion happens upon addition of excess of dispersed phase. Phase

inversion leads to radical physical changes as change in particle size that alter drug release16.

During cooling, this system crosses the point of zero spontaneous curvature and minimal

surface tension, prompting the formation of finely dispersed oil droplets17. Microemulsions

can be prepared by controlled addition of lower alkanols (butanol, pentanol and hexanol) to

milky emulsions to produce transparent solutions comprising dispersions of either o/w or w/o

or colloidal dispersions. The lower alkanols are called co-surfactants. They lower the interfacial

tension between oil and water sufficiently low for almost spontaneous formation.



Characterization of Microemulsions1,9:

(A) Phase Behavior Studies: Phase behavior studies are essential for the study of surfactant

system determined by using phase diagram that provide information on the boundaries of the

different phases as a function of composition variables and temperatures, and, more

important, structural organization can be also inferred. Phase behaviour studies also allow

comparison of the efficiency of different surfactants for a given application. In the phase

behaviour studies, simple measurement and equipments are required. The boundaries of one-

phase region can be assessed easily by visual observation of samples of known composition.

The main drawback is long equilibrium time required for multiphase region, especially if liquid

crystalline phase is involved. Other useful means and ways of representing the phase behaviour

are to keep the concentration of one component or the ratio of two components constant. As

the number of components increases, the number of experiments needed to define the

complete phase behaviour becomes extraordinary large and the representation of phase

behaviour becomes extremely complex. One approach to characterize these multicomponent

systems is by means of pseudo-ternary diagrams that combine more than one component in

the vertices of the ternary diagram.27

(B) Scattering Techniques for Microemulsions Characterization: Small-angle X-ray scattering

(SAXS), small-angle neutron scattering (SANS), and static as well as dynamic light scattering are

widely applied techniques in the study of microemulsions. These methods are very valuable for

obtaining quantitative informations on the size, shape and dynamics of the components. The

major drawback of this technique is the dilution of the sample required for the reduction of

interparticular interaction. This dilution can modify the structure and the composition of the

pseudophases. Nevertheless, successful determinations have been carried out using a dilution

technique that maintains the identity of droplets. Small-angle X-ray scattering techniques have

been used to obtain information on droplet size and shape.28

Static light scattering techniques have also been widely used to determine microemulsion

droplet size and shape. In these experiments the intensity of scattered light is generally

measured at various angles and for different concentrations of microemulsion droplets.

Dynamic light scattering, which is also referred as photon correlation spectroscopy (PCS), is

used to analyse the fluctuations in the intensity of scattering by the droplets due to Brownian

motion. The self-correlation is measured that gives information on dynamics of the system.29

(C) Nuclear Magnetic Resonance Studies: The structure and dynamics of microemulsions can

be studied by using nuclear magnetic resonance techniques. Self-diffusion measurements using

different tracer techniques, generally radio labeling, supply information on the mobility of the

components. The Fourier transform pulsed-gradient spin-echo (FT-PGSE) technique uses the



magnetic gradient on the samples and it allows simultaneous and rapid determination of the

self-diffusion coefficients (in the range of 10-9 to 10-12 m2s-1), of many components.30

(D) Interfacial Tension: The formation and the properties of microemulsion can be studied by

measuring the interfacial tension. Ultra low values of interfacial tension are correlated with

phase behaviour, particularly the existence of surfactant phase or middle-phase

microemulsions in equilibrium with aqueous and oil phases. Spinning-drop apparatus can be

used to measure the ultra low interfacial tension. Interfacial tensions are derived from the

measurement of the shape of a drop of the low-density phase, rotating it in cylindrical capillary

filled with high-density phase.31

(E) Viscosity Measurements: Viscosity measurements can indicate the presence of rod-like or

worm-like reverse micelle. Viscosity measurements as a function of volume fraction have been

used to determine the hydrodynamic radius of droplets, as well as interaction between droplets

and deviations from spherical shape by fitting the results to appropriate models (e.g. for

microemulsions showing Newtonian behaviour, Einstein’s equation for the relative viscosity can

be used to calculate the hydrodynamic volume of the particles).32

(F) Simple tests Dye Solubilization: A water soluble dye is solubilized within the aqueous phase

of the W/O globule but is dispersible in the O/W globule.A oil soluble dye is solubilized within

the oil phase of the O/W globule but is dispersible in the W/O globule. Dilutability Test O/W

microemulsions are dilutable with water whereas W/O are not and undergo phase inversion

into O/W microemulsion. Conductance Measurement O/W microemulsion where the external

phase is water are highly conducting whereas W/O are not, since water is the internal or

dispersal phase. To determine the nature of the continuous phase and to detect phase

inversion phenomena, the electrical conductivity measurements are highly useful. A sharp

increase in conductivity in certain W/O microemulsion systems was observed at low volume

fractions and such behaviour was interpreted as an indication of a ‘percolative behaviour’ or

exchange of ions between droplets before the formation of bicontinuous structures.

(G) Electron Microscope Characterization Transmission Electron Microscopy (TEM) is the most

important technique for the study of microstructures of microemulsions because it directly

produces images at high resolution and it can capture any co-existent structure and micro-

structural transitions.34 There are two variations of the TEM technique for fluid samples.

1. The cryo-TEM analyses in which samples are directly visualized after fast freeze and freeze

fructose in the cold microscope. 2. The Freeze Fracture TEM technique in which a replica of the

specimen is images under RT conditions.



Stability Studies: The stability of the microemulsion has been assessed by conducting long term

stability study and accelerated stability studies. In long term stability study, the system is kept

at room temperature, refrigeration temperature (4-8 ˚C) and elevated temperature (50±2 ˚C).

Over the time period, microemulsion systems are evaluated for their size, zeta potential, assay,

pH, viscosity and conductivity. On long term study, the activation energy for the system and

shelf life of the system may be calculated as like other conventional delivery system.

Accelerated stability studies are the essential tools to study the thermodynamic stability of

microemulsions. It can be done by centrifugation, heating/cooling cycle and freeze/thaw cycles.

(H) Determination of permeability coefficient and flux: Excised human cadaver skin from the

abdomen is used for permeation study. The skin is stored at 4oC and the epidermis separated.

The skin is first immersed in purified water at 60oC for 2 min and the epidermis then peeled off.

Dried skin samples can be kept at 200C for later use. Alternatively the full thickness dorsal skin

of male hairless mice may be used.

FIGURE 3: Franz diffusion cell

The skin shall be excised, washed with normal saline and then used. The passive permeability

of lipophilic drug through the skin is investigated using Franz diffusion cells with known

effective diffusional area. The hydrated skin samples are used for the study. The receiver

compartment contains a complexing agent like cyclodextrin in the receiver phase, which

increases the solubility and allows the maintenance of sink conditions in the experiments.

Samples are withdrawn at regular interval and analyzed for amount of drug released.35



In- vivo Studies:

(I) Bioavailability studies: Skin bioavailability of topical applied microemulsion on rats: Male

Sprague–Dawley rats (400–500 g) are needed to be anesthetized (15 mg/kg pentobarbital

sodium i.p.) and placed on their back. The hair on abdominal skin is 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 is applied on the skin surface (1.8 cm2) and

glued to the skin by a silicon rubber. After 10, 30 and 60 min of invivo study, the rats are killed

by aspiration of ethyl ether. The drug exposed skin areas is swabbed three to four times with

three layers of gauze pads, then bathed for 30 s with running water, wiped carefully, tape-

stripped (X10 strips) and harvested from the animals. 35

(J) Determination of residual drug remaining in the skin on tropical administration: The skin in

the above permeation studies can be used to determine the amount of drug in the skin. The

skin cleaned with gauze soaked in 0.05% solution of sodium lauryl sulfate and is bathed with

distilled water. The permeation area is cut and weighed and drug content is determined in the

clear solution obtained after extracting with a suitable solvent and centrifuging.35

Pharmacological Studies: Therapeutic effectiveness is evaluated for the specific

pharmacological action that the drug purports to show as per stated guidelines. 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 with hypoallergenic adhesive bandage. The test be removed after

24 hours and the exposed skin is graded for formation of edema and erythema. Scoring is

repeated 72 hours later. Based on the scoring the formulation shall be graded as ‘non-irritant’,

‘irritant’ and ‘highly irritant’.35

(K) Evaporation at constant humidity

A thin layer of microemulsion was placed in a Petri vessel in a closed chamber at 37% Relative

humidity (MgCl2.6 H20). At scheduled times, the weight loss and the rheological flux of the

microemulsions wsere determined. The system were then analyzed by microscopy.8

(L) Water resistance

Water resistance was tested on amounts of microemulsion spread on a collagen felt sheer and

placed in water. Microemulsions with a poor water resistance gave an aqueous dispersion. The

sheets used consisted of pure collagen (sequence alpha 1, first type).8



APPLICATION

Topical microemulsion9

(1)Low-surfactant microemulsion gels were formulated and characterized to enhance topical

delivery of poorly soluble drugs. It was found that the choice of viscosity imparting agent

(Xanthan gum or Carbopol 934) played an important role in governing drug release from

microemulsion gels.36

(2)Ketoconazole loaded microemulsion for percutaneous absorption showed a good stability

for a period of three months. It was found that the percutaneous absorption of ketoconazole

depends on microemulsion composition. Histopathological investigation of rat skin revealed

the safety of microemulsion formulations for topical use.37

(3) A novel dithranol-containing phospholipid microemulsion system was developed and

characterized for enhanced skin permeation and retention.

The results propose that the developed microemulsion systems have a promising potential to

improve topical delivery of dithranol.38

(4)Oxymatrne (OMT), a water-soluble drug, has a very low oral bioavailability.Formulated

oxymatrine–phospholipid complex (OMT–PLC) can improve the lipid solubility and effectiveness

of OMT. A combination of a microemulsion and an OMT–PLC represents an effective vehicle for

topical delivery of OMT.39

(5)Due to its poor oral bioavailability, a topical drug delivery system of griseofulvin (GF) is

needed. A griseofulvin loaded into solid lipid nanoparticles was prepared using a simple

microemulsion technique. The GF release was to be a prolong release of 63.53% within 12 h.40

(6)Microemulsions incorporated into l% carbopol 974P gel base containing terbinafine

hydrochloride were formulated and evaluated for topical delivery. The release controlling

ability of microemulsion containing gel formulations was significantly improved in comparison

to commercial cream.41

(7)A topical preparation containing aceclofenac was developed using an oil-in-water

microemulsion system. In vitro permeability of aceclofenac from the microemulsions was

evaluated. The results indicate that the microemulsion system studied is a promising tool for

percutaneous delivery of aceclofenac.42

(8)Lecithinsed microemulsions were prepared and evaluated as topical deliveryvehicles of

tretinoin.43



(9)The addition of colloidal silica in microemulsions simultaneously loaded with vitamins C and

E enhanced skin bioavailability of vitamins by its dual influence on delivery characteristics of

microemulsions as well as on skin properties.44

(10)A three-compartment (donor, skin, and receiver) mass balance model was introduced to

describe the effect of surfactant content on lecithin-linker microemulsion-mediated topical

transport. The model was used to fit the permeation profile of lidocaine formulated in different

microemulsion types. It was demonstrated that surfactant concentration has a fairly small

effect on the mass transfer coefficients, suggesting that permeation enhancement via

disruption of the structure of the skin is not a relevant mechanism in these microemulsions.45

(11)Microemulsions containing 5-aminolevulinic acid (5-ALA) were formulated and

characterized for topical photodynamic therapy. The microemulsion developed carried 5-ALA to

the deeper skin layers.46

(12)Microemulsion formulation was designed for hesperetin topical dosage form. In vivo study

revealed that the hesperetin-loaded microemulsion showed considerable topical whitening

effect and reduced skin irritation when compared with the non-treatment group.47

(13)Microemulsions containing mono-diglycerides were found to be an efficient and safe

system to increase lycopene delivery to the skin and the antioxidant activity in the tissue.48

(14)The in vitro release of valdecoxib incorporated in microemulsion based emulgel

formulations was increased as the proportion of the surfactant (tween-80) increased. Maximum

amount of valdecoxib gets partitioned in stratum corneum with the highest amount of tween-

80.49

(15) Dexamethasone microemulsion systems were investigated as potential drug delivery

vehicles. The permeation data demonstrated that microemulsion formulations enhanced

dexamethasone flux 200–400 fold over the control, but permeability coefficients were reduced

by 4 times. The superior transdermal flux of dexamethasonewas due to 1000-fold improvement

in the solubilization of dexamethasone by microemulsions using lecithin.50

(16)Water-in-oil microemulsion as a carrier significantly increased the intradermal delivery of

quercetin where it exerts antioxidative effects.51

(17)Microemulsions were formulated using 1-decanol, oleic acid or oleyl alcohol as oils to verify

the effect of the oils on pig-skin permeation and accumulation of acyclovir (ACV). The presence

of oleyl alcohol or oleic acid increased the flux but not the drug skin accumulation compared to

a control suspension. A two-fold increase in ACV accumulation was found using the



microemulsions containing 1-decanol, maintaining intact the structure of the stratum

contemn.52,53

(18)Microemulsions incorporating both lipophilic (vitamin E) and hydrophilic (vitamin C)

antioxidants were formulated for skin protection against free radical damage. The absorption of

vitamins C and E in reconstructed human epidermis (RHE) layers was in general enhanced by

microemulsions compared to solutions. By varying the composition of microemulsions, RHE

absorption of the two vitamins can be considerably adjusted.54

(19)Microemulsion systems were examined as possible carriers for enhanced skin bioavailability

of cyclosporin A (CysA). In rat dermal applied with the bicontinuous microemulsion containing

CysA, the deposition of the drug into the skin and subcutaneous fat was respectively almost 30

and 15-fold higher than the concentrations comparedwith oral administration. Systemic

distribution in the blood, liver and kidneywasmuch lower following topical administration than

that following oral administration Topical delivery of CysA is of immense concern for the cure of

autoimmune skin disorders. With elevated local concentrations and least distribution to other

organs via the distribution, topical microemulsion vehicle loaded with CysA might deliver

maximal therapeutic effect to the local tissue while avoiding side effects seen with systemic

therapy.55

(20)Topical microemulsion of capsaicin without surfactant was developed. In the system

composed of water, benzyl alcohol and propylene glycol, the permeation rate increased with

the enhancement of benzyl alcohol and water. But water content had little effect on the

permeation rate in the microemulsions with ethanol as cosurfactant.56

Cosmetic microemulsions10

Applications of microemulsions in cosmetics can be found in numerous patents and research

articles about formulations of skin-care, hair-care, and personal-care products. Besides general

advantages, i.e., good appearance, thermodynamic stability, high solubilization power, and

ease of preparation, microemulsions can provide the cosmetic product to be more efficient and

stable. In this review, some applications of microemulsions in cosmetics, especially in skin-care

products, are shown.

(21)Alpha-tocopherol (alpha-T) is an active ingredient extensively used in skin-care products. As

an antioxidant, it scavenges and destroys aggressive oxidizing agents and free radicals, the

important factors in the processes of skin aging. Its permeation from various delivery systems,

i.e., simple solution, gels, emulsions, and microemulsions was investigated using an in vitro

micro-Yucatan pig skin model. The result indicated that a microemulsion formulation was the

best topical delivery system for alpha-T compared with the other studied systems.58



(22)The high solubilization power of microemulsions can be used to prepare the transparent

liquid products of lowsoluble substances. The o/w microemulsions were prepared as

transparent vehicles for sunscreens, 4- methylbenzilidene camphor, or octyl

methoxycinnamate. Soya lecithin, decylpolyglucose, cyclomethicone, menthol, allantoin, and

stearyl methicone were used as microemulsion compositions. There was a report that the

sunscreen microemulsions provided good skin feel, waterproof effect, nonstickiness, and easy

spread.59

(23)Lycopene, an antioxidant with low solubility in both water and oil, reportedly could be

prepared in transparent liquid form by microemulsification. Its solubilization efficiency In

microemulsions containing jojoba oil, water, polyoxyethylene-10EO-oleyl alcohol (Brij 96V), and

hexanol was higher than that in each pure component. Although incorporation of lycopene into

microemulsionsaltered microemulsion droplet shape from spherical to threadlike, the products

were still transparent and attractive for cosmetic uses.60

(24)Decamethyl cyclopentasiloxane is a good solvent for silicone soils; however, its suitable

formulations are required. The association structures formed in the system containing a 1 : 1

mixture of decamethyl cyclopentasiloxane and cetyl isooctanoate as an oil component,

polyoxyethylene (8 mol) glyceryl monoisostearate as a surfactant, and ethanol aqueous

solution as an aqueous component was characterized and investigated for detergency of

silicone soils. From the results of characterization, bicontinuous microemulsions were observed

at oil/water ratio of 3 : 7. The results of detergency suggested that the microemulsions

comprising oil/water ratios of 1 : 1 to 7 : 3 exhibited maximum detergency. Hence, bicontinuous

microemulsions of this system provided a good solution for cleansing silicone soils.61

(25)Microemulsion formulations not only improve product efficiency as described above but

also enhance stability of the active ingredients. For instance, the photostability to ultraviolet B

irradiation of arbutin and kojic acid, whitening agents, was higher in o/w microemulsions

comprising lecithin and an alkyl glucoside as amphiphiles than in aqueous solutions.62

(26)To formulate an optimal microemulsion system for an active ingredient, the factors that

influence the stability of the product have to be considered. Type of microemulsions

contributes to the stability of the active ingredients. For example, ascorbyl palmitate was more

stable in w/o than in o/w microemulsions because the cyclic ring of the active ingredient that

was sensitive to oxidation and located to water phase was shield in microemulsion droplets.

Nevertheless, other factors such as an initial concentration of the active ingredient, oxygen, and

light also influenced the stability of ascorbyl palmitate in microemulsion system. In contrast to

ascorbyl palmitate, sodium ascorbyl phosphate was stable in both types of microemulsions.63



(27)Microemulsions of sodium ascorbyl phosphate were studied for topical delivery

characteristics. The release profiles showed that the microemulsion types influenced on

released amount of sodium ascorbyl phosphate, i.e., less sodium ascorbyl phosphate from w/o

systems was released than from o/w systems. The researchers explained that the location of

sodium ascorbyl phosphate in the microemulsions significantly influenced its release profiles.4

(28)Moreover, the nature of microemulsions was found to be a crucial parameter for

permeation of an active ingredient through heat-separated human epidermis.57,65

REFERENCE

1. Sarkhejiya naimish et al., “Emerging trend of microemulsion in formulation and research;

International Bulletin of Drug Research”, 1(1): 54-83.

2. Padmini et al., “Microemulsions For Topical Use– A Review”, Indian Journal of

Pharmaceutical Education & Research, 2011, Vol 45(1).

3. Srinivasa Rao et al., “Microemulsions: A novel drug carrier system”, International Journal of

Drug Delivery Technology 2009; 1(2): 39-41.

4. Sajal Kumar et al., “Microemulsions- Potential Carrier for Improved Drug Delivery”, Asian

Journal of Biomedical and Pharmaceutical Sciences, 1 (1) 2011, 1-5.

5. Ritika et at., “Microemulsion system in role of expedient vehicle for dermal application”,

Journal of Drug Delivery & Therapeutics,2012, 2(4), 23-28

6. Kreilgaard M., “Influence of microemulsions on cutaneous drug delivery”, Bulletin Technique

Gattefossé; 2002;95 :79 – 100.

7. Madhav and Gupta, “A review on microemulsion based system”, International Journal of

Pharmaceutics & Research; 2011; Vol. 2(8): 1888-1899

8. Eugenia carlotti et al., “O/W microemulsion as a vehicle for sunscreens”, Journal of

Cosmetics science,54, 451-462.

9. M. Fanun, “Microemulsions as delivery systems”, Current Opinion in Colloid & Interface

Science, 17 (2012) 306–313

10. P Boonme, “Applications of microemulsions in cosmetics”, Journal of Cosmetic

Dermatology,6, 223–228



11. Gupta RR et al. “AOT water in oil microemulsion as a penetration enhancer in transdermal

drug delivery of 5-florouracil”, Colloids Surface B Biointerfaces, 2005, 41, 25-32.

12. Lee J et al, “Formulation of microemulsion systems for transdermal delivery of aceclofenac”,

Archives of Pharmcal Research, 2005, 28(9), 1097-1102.

13. Subramaniyam et al. “Enhanced in vitro percutaneous absorption and in vivo

antiinflammatory effect of selective cyclooxygenase inhibitor using microemulsion”,Drug

Development and Industrial Pharmacy, 2005, 31, 405-416.

14. Biruss B et al, “Evaluation of an eucalyptus oil containing topical drug delivery system for

selected steroid hormones”, International Journal of Pharmaceutics,2007, 328, 142–151

15. Dreher F et al. “Interaction of lecithin microemulsion gel with human stratum corneum and

its effect on dermal transport”, Journal of Controlled Release, 1997, 45, 131-140.

16. Peltola S et al. “Microemulsions for topical delivery of estradiol”, International Journal of

Pharmaceutics, 2003, 254, 99-107.

17. Ambade et al. “Formulation and evaluation of flurbiprofen microemulsion”, Current Drug

Delivery, 2007, 5, 32–41.

18. Paolino et al. “Lecithin microemulsion for topical administration of ketoprofen:

percutaneous absorption through human skin and human skin tolerability” International

Journal of pharmaceutics, 2002, 244, 21-31.

19. Trotta M & Pattarino F. “Influence of counterions on the skin permeation of methotrexate

from w/o microemulsions”, Pharmaceutica Acta Helvetica, 1996, 71, 135-140.

20. Boltri L & Morel S. “In vitro transdermal permeation of nifedipine from thickened

microemulsions”, Journal of Pharmaceutical Belg, 1994, 49, 315–320.

21. Delgaddo-Charro et al. “Delivery of hydrophilic solute from novel microemulsion system”

European Journal of Pharmaceutics and Biopharmaceutics, 1997, 43, 37-42.

22. Changez M & Chander J. “Transdermal permeation of tetracaine hydrochloride by lecithin

microemulsion: In vivo”, Colloids Surface B Biointerfaces, 2006, 48, 58–66.

23. Derle DV et al. “A comparative in vitro evaluation of transdermal permeation of valdecoxib

and its complex with HP- -cyclodextrin from microemulsion based gel” Indian Drugs, 2006, 43,

625–629.



24. Hadidi GNE & Ibrahim HK. “Microemulsions as vehicles for topical administration of

voriconazole: formulation and in vitro evaluation”, Drug Development and Industrial Pharmacy,

2012, 38(1), 64-72.

1. 25.Peira et al. “Transdermal permeation of apomorphine through hairless mouse skin from

microemulsion” International Journal of Pharmaceutics, 226: 47-51.

25. Rhee et al. “Transdermal delivery of ketoprofen using microemulsions” International

Journal of Pharmaceutics; 228: 161-170.

26. Sinko PJ and Singh Y. In Martin’s Physical Pharmacy and Pharmaceutical Sciences; Lippincott

Williams & Wilkins, Philadelphia, 2005, 410.

27. Acosta E et al. “Induced Electric Birefringence and Viscosity Studies in Microemulsions”,

Colloids Surfaces A: Physicochem. Eng. Aspects, 1996; 106, 11–21.

28. Schurtenberger P & Peng Q. “Structure and Phase Behaviour of Lecithin-based

Microemulsions: A Study of Chain Length Dependence”, Journal of Colloid Interface Science,

1993; 156, 43–51.

29. Shinoda K, Araki M, Sadaghiani A, Khan A and Lindman B. “Lecithin-based Microemulsions:

Phase Behaviour and Microstructure.” Journal of Physiology & Chemestry, 1991; 95, 989–993.

30. Vyas SP., and Khar RK. “In Submicron Emulsions in Targeted and Controlled Drug Delivery,

Novel Carrier Systems”, CBS Publishers and Distributors, 2002, 282.

31. Mehta SK, Kavaljit XX and Bala K, “Phase Behaviour, Structural Effects, Volumetric and

Transport Properties in Nonaqueous Microemulsions”, Phys. Rev, 1999; 59, 4317–4325.

32. Hasse A and Keipert S, “Development and Characterisation of Microemulsions for Ocular

Application”, European Journal of Pharmaceutics and Biopharmaceutics, 1997; 43, 179–183

33. Kumar P., and Mittal KL. In Handbook of Microemulsion Science and Technology; 1st Edn;

CRC Press, New York, 1999, pp 411

34. Madhav and Gupta, “A review on microemulsion based system”, International Journal of

Pharmaceutical Science & Research, 2011; Vol. 2(8): 1888-1899

35. Shalviri A, Sharma A, Patel D, Sayani A. “Low-surfactant microemulsions for enhanced

topical delivery of poorly soluble drugs”, Journal of Pharmaceutical Science, 2011;14:315–24.



36. Patel MR, Patel RB, Parikh JR, Solanki AB, Patel BG. “Investigating effect of microemulsion

components: in vitro permeation of ketoconazole”, Pharmaceutical Development &

Technology, 2011;16:250–8.

37. Raza K, Negi P, Takyar S, Shukla A, Amarji B, Katare OP. “Novel dithranol phospholipid

microemulsion for topical application: development, characterization and percutaneous

absorption studies”, Journal of Microencapsulation, 2011;28:190–9.

38. Cao FH, OuYangWQ,Wang YP, Yue PF, Li SP. “A combination of amicroemulsion and a

phospholipid complex for topical delivery of oxymatrine” Arch Pharmaceutical Research,

2011;34: 551–62.

39. Anurak L, Chansiri G, Peankit D, Somlak K. “Griseofulvin solid lipid nanoparticles based on

microemulsion technique”, Adv Mater Res 2011;197–198:47–50.

40. Dabhi MR, Nagori SA, Sheth NR, Patel NK, Dudhrejiya AV. “Formulation optimization of

topical gel formulation containing micro-emulsion of terbinafine hydrochloride with simplex

lattice design”, Micro Nanosyst 2011;3:1–7.

41. Shah RR, Magdum CS, Patil SS, Niakwade NS. “Preparation and evaluation of aceclofenac

topical microemulsion” Iran Journal of Pharmaceutical Research, 2010;9:5–11.

42. Khanna S, Katare OP, Drabu S. “Lecithinised microemulsions for topical delivery of tretinoin”

International Journal of Drug Development & Research, 2010;2:711–9.

43. Rozman B, Gosenca M, Gasperlin M, Padois K, Falson F. “Dual influence of colloidal silica on

skin deposition of vitamins C and e simultaneously incorporated in topical Microemulsions”,

Drug Development & Pharmacy, 2010;36:852–60.

44. Yuan JS, Yip A, Nguyen N, Chu J, Wen XY, Acosta EJ. “Effect of surfactant concentration on

transdermal lidocaine delivery with linker microemulsions”, International Journal of

Pharmaceutics, 2010;392:274–84.

45. Campos Araújo LMP, Thomazine JA, Lopez RFV. “Development of microemulsions to

topically deliver 5-aminolevulinic acid in photodynamic therapy”, Europian Journal of

Pharmaceutics & Biopharmaceutics, 2010;75,48–55.

46. Tsai YH, Lee KF, Huang YB, Huang CT, Wu PC. “In vitro permeation and in vivo whitening

effect of topical hesperetin microemulsion delivery system”, International Journal of

Pharmaceutics, 2010;388:257–62.



47. Lopes LB, Van DeWall H, Li HT, Venugopal V, Li HK, Naydin S, “Topical delivery of lycopene

using microemulsions: enhanced skin penetration and tissue antioxidant Activity”, Journal of

Pharmaceutical Science, 2010;99:1346–57.

48. Saleem MA, Bansal A, Khalid S, Sadath A, Najmuddin M. “Development of microemulsion

based emulgel formulations of valdecoxib”, Indian Drugs, 2010;47:31–8.

49. Bajpai M, Sharma PK, Mittal A. “A study of oleic acid oily base for the tropical delivery of

dexamethasone microemulsion formulations”, Asian Journal of Pharmaceutics, 2009;3: 208–

14.

50. Kitagawa S, Tanaka Y, Tanaka M, Endo K, Yoshii A, “Enhanced skin delivery of quercetin by

microemulsion”, Journal of Pharmaceutics & Pharmacology, 2009;61:855–60.

51. Shishu G, Rajan S, Kamalpreet A. “Development of novel microemulsion-based topical

formulations of acyclovir for the treatment of cutaneous herpetic infections”, AAPS

PharmSciTech 2009;10:559–65.

52. Peira E, Chirio D, Carlotti ME, Spagnolo R, Trotta M. “Formulation studies of microemulsions

for topical applications of acyclovir”, Journal of Drug Delivery & Science Technology,

2009;19:191–6.

53. Rozman B, Gasperlin M, Tinois-Tessoneaud E, Pirot F, Falson F. “Simultaneous absorption of

vitamins C and E from topical microemulsions using reconstructed human epidermis as a skin

model”, Europian Journal of Pharmaceutics & Biopharmaceutics, 2009;72:69–75.

54. Liu H, Wang Y, Lang Y, Yao H, Dong Y, Li S. “Bicontinuous cyclosporin A loaded water-

AOT/tween 85-isopropylmyristate microemulsion: structural characterization and dermal

pharmacokinetics in vivo”, Journal of Pharmaceutical Science, 2009;98:1167–76.

55. Zhang P, Gao W, Zhang L, Chen L, Shen Q, Wang X, “In vitro evaluation of topical

microemulsion of capsaicin free of surfactant”, Biological Pharmaceutical Bullatin, 2008;31:

2316–20.

56. Junyaprasert VB, Boonme P, Songkro S, Krauel K, Rades T. “Transdermal delivery of

hydrophobic and hydrophilic local anesthetics from o/w and w/o Brij 97-based

microemulsions”, Journal of Pharmaceutics & Pharmaceutical Science, 2007;10: 288–98

57. Rangarajan M, Zatz JL. “Effect of formulation on the topical delivery of alpha-tocopherol”,

Journal of Cosmetical Science, 2003;54:161–74.



58. Carlotti ME, Gallarate M, Rossatto V. “O/W microemulsion asa vehicle for sunscreens”,

Cosmetic Science, 2003;54: 451–62.

59. Garti N, Shevachman M, Shani A. “Solubilization oflycopene in jojoba oil microemulsion”

JAOCS, 2004;81:873–7.

60. Watanabe K, Noda A, Masuda M, Kimura T, Komatsu K,Nakamura K. “Bicontinuous

microemulsion type cleansing containing silicone oil II: characterization of the solution and its

application to cleansing agent”, J Oleo Sci 2004;53:547–55.

61. Gallarate M, Carlotti ME, Trotta M, Grande AE, Talarico C. “Photostability of naturally

occurring whitening agents in cosmetic microemulsions”, Journal of Cosmetic Science,

2004;55:139–48.

62. Spiclin P, Gasperlin M, Kmetec V. “Stability of ascorbyl palmitate in topical microemulsions”,

International Journal of Pharmaceutics, 2001;222: 271–9.

63. Spiclin P, Homar M, Zupancic-Valant A, Gasperlin M. “Sodium ascorbyl phosphate in topical

microemulsions”, International Journal of Pharmaceutics, 2003;256:65–73.

64. Boonme P, Songkro S, Junyaprasert V. “Skin permeation of dibucaine-loaded in Brij 97

microemulsions”, Ho Chi Minh City,Vietnam; 2005: 478–82.

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