curcumin nanoemulsion for transdermal application: formulation and evaluation

http://informahealthcare.com/ddiISSN: 0363-9045 (print), 1520-5762 (electronic)

Drug Dev Ind Pharm, Early Online: 1–7! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.884127

RESEARCH ARTICLE

Curcumin nanoemulsion for transdermal application: formulation andevaluation

Heni Rachmawati, Dewa Ken Budiputra, and Rachmat Mauludin

Department of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia

Abstract

The aim of this work is to develop a curcumin nanoemulsion for transdermal delivery. Theincorporation of curcumin inside a nanoglobul should improve curcumin stability andpermeability. A nanoemulsion was prepared by the self-nanoemulsification method, using anoil phase of glyceryl monooleate, Cremophor RH40 and polyethylene glycol 400. Evaluation ofthe nanoemulsion included analysis of particle size, polydispersity index, zeta potential,physical stability, Raman spectrum and morphology. In addition, the physical performance ofthe nanoemulsion in Viscolam AT 100P gel was studied. A modified vertical diffusion cell andshed snake skin of Python reticulatus were used to study the in vitro permeation of curcumin.A spontaneously formed stable nanoemulsion has a loading capacity of 350 mg curcumin/10 gof oil phase. The mean droplet diameter, polydispersity index and zeta potential of optimizednanoemulsion were 85.0 ± 1.5 nm, 0.18 ± 0.0 and �5.9 ± 0.3 mV, respectively. Curcumin in ananoemulsion was more stable than unencapsulated curcumin. Furthermore, nanoemulsifica-tion significantly improved the permeation flux of curcumin from the hydrophilic matrix gel;the release kinetic of curcumin changed from zero order to a Higuchi release profile. Overall,the developed nanoemulsion system not only improved curcumin permeability but alsoprotected the curcumin from chemical degradation.

Keywords

Curcumin, Higuchi release profile, selfassembly nanoemulsion, shed snake skin,transdermal

History

Received 14 October 2013Revised 15 December 2013Accepted 9 January 2014Published online 7 February 2014

Introduction

Curcumin is a natural polyphenolic compound, usually derivedfrom Curcuma longa Linn. and possess potent anti-inflammatoryproperties following oral or topical administration1–3. Curcuminwas found to inhibit arachidonic acid metabolism, cyclooxygen-ase, lipoxygenase, pro inflammatory cytokines and activation ofnuclear factor-kB. It has very low intrinsic toxicity, even at veryhigh doses. Curcumin has poor solubility in water at acidicor neutral pH and is degraded extensively in an alkalineenvironment, thus limiting its use4. Curcumin also undergoesrapid first-pass metabolism into inactive metabolites, causinglow bioavailability in systemic circulation5. Therefore, severalapproaches have been investigated to increase curcumin bio-logical efficacy, including chemical derivatization, complexformation or interaction with macromolecules and using nano-scale drug delivery systems6.

In the past few years, application of nanotechnology incurcumin formulation has been tried by many researchers becauseof its potential to improve curcumin efficacy7. Encapsulation ofcurcumin in nanoscale carrier systems, such as nanoemulsion, hasshown significant improvement of its bioavailability.Nanoemulsion possess high kinetic stability and can act as acarrier to protect active compounds against extreme conditions8.

Curcumin oil-in-water nanoemulsions, with a mean droplet sizeranging from 79.5 nm to 618.6 nm, have been proven to enhanceanti-inflammatory activity of curcumin. In addition, the stabilityof curcumin can be maintained9. However, none of them aimedfor transdermal application.

Transdermal delivery in the form of a gel or patch is aninteresting alternative for topical route to give local or systemiceffects. It can improve patient compliance and also has somebenefits for curcumin, such as avoiding first-pass metabolism,decreasing side or unwanted effects and enabling constant bloodlevels over longer periods of time. However, curcumin exhibitslow skin penetration resulting in poor efficacy. Recently, a stablecurcumin gel has been produced using 15% alcohol (to dissolvecurcumin in the gel). Dimethylsulfoxide (DMSO) is also neededto improve curcumin release from the gel9. In contrast to commonchemical skin penetration (using enhancers such as organicsolvents, which are generally associated with skin irritation,toxicity and sensitization), a solvent-free topical vehicle based ondrug entrapment in oil/water emulsion droplets of submicronparticle is more efficacious in terms of percutaneous absorptionand is possibly devoid of adverse effects. In addition, theuniqueness of the large internal hydrophobic core of oil/watersubmicronized emulsion droplets allows high solubility for waterinsoluble topically active ingredients and also improves oncarrying water, an excellent softener, to the skin.

This report describes a more effective and efficient strategy todeliver curcumin via the transdermal route. This work is not onlyfocused on a better release of curcumin from a gel matrix but also

Address for correspondence: Heni Rachmawati, Department of Pharmacy,Bandung Institute of Technology, Ganesha 10, Bandung 40132,Indonesia. E-mail: [email protected]

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on enhancing skin permeation as well as on the stability of thecurcumin to obtain better bioavailability.

Materials and methods

Materials

Curcumin was obtained from PT. Phytochemindo Lestari (Bogor,Indonesia). Glyceryl monooleate (GMO) was purchased from PT.Tritunggal (Jakarta, Indonesia). Polyoxyl 40 hydrogenated castoroil (Cremophor RH40) was purchased from BASF(Ludwigshafen, Germany). Polyethylene glycol 400 (PEG 400),DMSO, triethanolamine (TEA) and potassium dihydrogenphosphate were purchased from Merck (Darmstadt, Germany).Glycerine, propylene glycol, methylparaben and propylparabenwere from Brataco (Jakarta, Indonesia). Viscolam AT 100 P waspurchased from Nardev Chemie (Singapore). Methanol andacetonitrile were of analytical grade and purchased from J.T.Baker (Phillipsburg, NJ). Deionized water was obtained from theSchool of Life Sciences and Technology (Bandung Institute ofTechnology, Bandung, Indonesia). Double distilled water waspurchased from Ippha Laboratories (Bandung, Indonesia). Shedsnake skin of Python reticulatus was obtained from Bandung Zoo(Bandung, Indonesia).

Methods

Preparation of emulsion and nanoemulsion

A conventional emulsion was prepared using GMO (16% w/v) andCremophor RH40 (4% w/v). Curcumin (0.25% w/v) was addedunder stirring to GMO and Cremophor RH40. The mixture wasthen dispersed in water under stirring for 30 min to form anemulsion. This emulsion was used for comparison.

A nanoemulsion of curcumin formed spontaneously in an oilphase of GMO, Cremophor RH40 and PEG 400 (1:8:1). Variousamounts of curcumin (10, 25, 50, 100, 250, 350, 500 and 750 mg)were added to 10 gram of oil phase. Curcumin, oil, surfactant andco-surfactant were stirred at 100 rpm for 2 h. Further sonicationfor 1 h using a bath sonicator (Nagoya S Ultrasonic Cleaner GB-928) was applied to complete the mixing process. To obtainnanoemulsion, deionized water was added to the oil phase at aratio of 5:1 and stirred gently.

Particle size and zeta potential measurement

The particle size, polydispersity index and zeta potential ofnanoemulsion were determined using a particle size and zetapotential analyzer (DelsaTM Nano, Beckman Coulter, Brea, CA).

Determination of incorporation efficiency of curcumin innanoemulsion

The calculation of the incorporation efficiency (IE) of curcumin innanoemulsions was performed by a direct method. The nanoemul-sion was centrifuged at 14 000 rpm for 20 min to break up thenanoemulsion and 5 mL of DMSO was added to 10 mL ofsupernatant to extract the curcumin. The curcumin concentrationin the DMSO phase was determined using a UV-visible spectro-photometer (Beckman DU 7500i, Brea, CA). The %IE of curcuminin the nanoemulsion was calculated using the following equation:

%IE ¼ amount of curcumin encapsulated in nano oil globule

amount of curcumin added into formula�100

Raman spectroscopy of nanoemulsion

To measure the incorporation of curcumin in the nanodroplets,Raman spectra were obtained and recorded on a Bruker Senterra

Raman spectrometer (Ettlingen, Germany) using a diode pumplaser with an excitation wavelength of 785 nm. Spectra were takenwith a laser power of 10 mW for 60 s (curcumin powder), 10 mWfor 180 s (curcumin diluted in GMO) and 50 mW for 180 s (GMO,Cremophor RH40, PEG 400, blank nanoemulsion and curcuminnanoemulsion). Data were acquired between 2200 and 700 cm�1.

Morphology of nanoemulsion

The morphology of nanoemulsion was observed using atransmission electron microscope (TEM; JEM 1400, JEOL,Tokyo, Japan). About 10 mL of sample was dropped in thespecimen place and covered with a 400 mesh grid. After 1 min,10 mL of uranyl acetate was dropped on top of the grid, and thissample was allowed to dry for 30 min before observation underthe electron microscope. This procedure was used to confirm theparticle size in the nanoemulsion as measured using the particlesize analyzer.

Stability study of nanoemulsion

The chemical and physical stabilities of the nanoemulsion werestudied by observation of phase separation, determination ofparticle size, polydispersity index, zeta potential and analysis ofcurcumin content using a UV-visible spectrophotometer. Sampleswere kept at room temperature, and evaluation was performed atday 0 (day of production), day 2, day 5, day 7, day 9, day 12 andday 28. Gravitational tests were also performed to assess thephysical stability of nanoemulsions compared with a conventionalemulsion. Emulsion and nanoemulsion were centrifuged for15 min at 12 000 rpm.

UV-visible spectrophotometric analysis

Quantification of curcumin content in emulsions and nanoemul-sions was carried out using a UV-visible spectrophotometer(Beckman DU 7500i, USA). A calibration curve was preparedusing curcumin diluted in DMSO. The calibration curve waslinear in a range of 1–8 ppm (R2¼ 0.999).

Preparation of curcumin gel

A gel was formulated using Viscolam AT 100P (5% w/v) as thegel matrix. About 0.01% w/v of curcumin powder or curcuminnanoemulsion were dispersed in water first, then mixed with thegel whilst stirring (IKA RW 20 Digital, Wurttemberg, Germany)at 500 rpm for 10 min). A mixture of methylparaben (0.2% w/v),propylparaben (0.05% w/v), glycerine (5% w/v) and propyleneglycol (15% w/v) was added, and the mixture was stirred for 5 minat 500 rpm. TEA was then added dropwise to the formulation withcontinuous stirring (500 rpm, 5 min) to adjust the pH to 6–7 and toproduce proper consistency of the gel.

Characterization of gel

Evaluation of the gel was carried out by visual observation, andmeasuring pH, viscosity and curcumin content. The curcumincontent in the gel was measured using high-performance liquidchromatography (HPLC, Agilent, Santa Clara, CA) with aPhenomenex Luna C-18 column (Phenomenex, Torrance, CA)as previously reported10. The mobile phase consisted ofacetonitrile and phosphate buffer pH 4.5 (55:45 v/v) at a flowrate of 1.0 mL/minute. Fifty microliters of sample was injectedinto the system and curcumin content was determined using anUV detector at �max of 425 nm. A calibration curve was preparedusing curcumin diluted in the mobile phase. The calibration curvewas linear in a range of 0.625–10 ppm (R2¼ 0.999). Prior toHPLC analysis, curcumin contained in gel was extracted with

2 H. Rachmawati et al. Drug Dev Ind Pharm, Early Online: 1–7

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acetonitrile and phosphate buffer pH 4.5 (55:45 v/v) usingforceful stirring on a vortex (IKA Genius 3, Staufen, Germany)and then filtered over a 0.22mm membrane (Sartorius, Gottingen,Germany).

Stability study of gel

Stability of the gel during storage was evaluated over 28 d both atroom temperature and at 40 �C, 75% RH. Samples were takenevery day and evaluated for physical alteration by visualobservation, and measuring pH and viscosity. The changes inthe content of curcumin were also determined.

In vitro diffusion test

A modified vertical diffusion cell and shed snake skin ofP. reticulatus were used to study the permeation of curcumin aspreviously reported10. Prior to the procedure, the shed snake skinwas hydrated and mounted between the donor and receptorcompartments. The system consisted of a donor compartmentwith one gram gel containing curcumin powder or nanoemulsion,and the receptor compartment contained 6 mL of phosphate bufferpH 7.4, at a temperature of 37 �C and slow stirring at 100 rpm.The available diffusion area between the compartments was0.951 cm2. About 1 mL samples were withdrawn through thesampling port of the diffusion cell at predetermined time intervalsover a period of 24 h (5, 10, 15, 30 and 45 min and 1, 1.5, 2, 3, 4,5, 6, 7, 8 and 24 h). The buffer was immediately replenished with1 mL of fresh buffer. The permeated amount of curcumin wasdetermined by HPLC as described previously. These tests weredone in triplicate for each gel containing either unencapsulatedcurcumin or curcumin in a nanoemulsion. The cumulative amountof curcumin, which crossed the shed snake skin was plottedagainst time. The transdermal drug flux was calculated from theslope of the linear portion of the plot. The permeation kineticswere determined (zero order, first order, Higuchi and Kors Meyer-Peppas).

Data analysis

All experiments were done in triplicate, and the data wereexpressed as mean value ± standard deviation. Statistical dataanalyses were performed using Student’s t-test and one-wayANOVA. A value of p50.05 was considered statisticallysignificant.

Results

Formulation and characterization of nanoemulsion

The potential of curcumin encapsulated and delivered as ananoemulsion for transdermal delivery was evaluated with respectto monodispersity, physical stability, in vitro stability andeffectiveness in skin permeability. The visualization of curcuminemulsion versus curcumin nanoemulsion with the same concen-tration is presented in Figure 1. Nanoemulsions have someinteresting physical properties, which distinguish them frommicroscale emulsions. Microscale emulsions typically exhibitstrong scattering of visible light, and, as a result, have a whiteappearance. In contrast, the structures in nanoemulsions are muchsmaller than the wavelengths in visible light, so most nanoemul-sions appear optically transparent.

We determined whether any relationship existed betweentransparency and the amount of the curcumin loaded inside theglobules. As shown in Figure 2, the droplet size of nanoemulsionincreased with the increase of the amount of curcumin added.Increments of the amount of curcumin up to 750 mg resulted

in opaque nanoemulsions, followed by phase separation after afew hours. This indicated that the maximum IE of curcumin hadbeen reached (Table 1) at 750 mg. The droplet size in theemulsion is a crucial factor in self-emulsification because itdetermines the rate and extent of drug release, as well as theabsorption.

The successful incorporation of curcumin in the oil dropletswas supported by Raman spectra (Figure 3). Marked structuraldifferences between pure curcumin, excipients and curcuminnanoemulsion were observed. As indicated, the peaks ofcurcumin powder in the Raman spectra were similar to those ofcurcumin diluted in GMO. Both showed bands at 1626, 1601,1430, 1320, 1250, 1184, 1151 and 962 cm�1. However, theintensity of the peaks decreased, probably due to reduction incrystallinity of curcumin in oil. Peaks in blank nanoemulsion

Figure 1. Physical appearance of nanoemulsion (left) and conventionalemulsion (right) with same curcumin concentration.

Figure 2. Influence of curcumin amount to particle size and poly-dispersity index of nanoemulsion (mean + SD, n¼ 3).

Table 1. Permeation flux of gel containing unencapsulated curcumin andcurcumin nanoemulsion (mean ± SD, n¼ 3).

Sample Flux (mg/(cm2.h))

Gel containing unencapsulated curcumin 0.836 ± 0.004Gel containing curcumin nanoemulsion 1.699 ± 0.050

DOI: 10.3109/03639045.2014.884127 Curcumin nanoemulsion for transdermal application 3

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(1475, 1442, 1287, 1143, 844 and 807 cm�1) corresponded tosome peaks in GMO, Cremophor RH40 and PEG 400, with aminor shift. This might suggest that some interactions occurredbetween nanoemulsion components and water, causing a shift inand broadening of the peaks, as shown in Figure 3(f).

The morphology of curcumin nanoemulsions was analyzedusing TEM and is presented in Figure 4. Visualization ofnanoemulsion using transmission electron microscopy (TEM)imaging is likely the most powerful and accurate technique todetermine a specimens’ morphology, purity and particle sizedistribution. As shown in Figure 4, the droplets were distributedevenly and the particle size was uniform, confirming the particlesize measurements as determined with photon correlationspectrophotometer.


Nanoemulsions have many interesting physical properties, whichare different from, or are more extreme, than those of microscaleemulsions. We examined the (enhanced) shelf stability ofnanoemulsions and monitored physical alterations as well as thechemical degradation of curcumin. We found that particle size,polydispersity index, zeta potential and %IE of nanoemulsionwere relatively stable over 14 d of storage. No agglomeration wasobserved as confirmed by the constant particle size and particledistribution.

Figure 3. Raman spectra of (a) curcuminpowder, (b) GMO, (c) Cremophor RH40, (d)PEG 400, (e) curcumin diluted in GMO, (f)blank nanoemulsion and (g) curcuminnanoemulsion.

Figure 4. Transmission electron microscopy (TEM) image of curcuminnanoemulsion. (magnification: 10 000�).


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Formulation and stability study of curcumin gel

Stability study of gel were established over 28 d at roomtemperature and 45 �C, 75% RH. We followed the appearanceby eye and measured pH, viscosity and curcumin concentration inthe gel. The formation of curcumin crystals was only observed ingels containing curcumin powder and not in gels containingcurcumin nanoemulsions (figure not shown). Crystallizationoccurred due to the limited solubility of curcumin in thehydrophilic matrix gel. Curcumin nanoemulsions could beeasily dispersed preventing physical and chemical problemswith the curcumin. Curcumin nanoemulsions enhanced thesolubility of curcumin in aqueous gels, and at the same time,protected curcumin from degradation, as can be seen in thestability profile as depicted in Figure 6.


In vitro diffusion test for all gels were performed using a modifiedvertical diffusion cell and shed snake skin of P. reticulatusas a membrane. Shed snake skin is easily available withoutcausing harm to the snake, as a relatively large amount of skinis periodically shed by each snake. Shed snake skin closely

resembles the stratum corneum of the human skin. The vascularstructures and collageneous connective tissues found in snake andhuman skin are also similar11. There is also similarity of thicknessbetween shed skin of P. reticulatus and the stratum corneum ofhuman skin, which approximately lie in the range of 11–16 mmand 15 mm, respectively12,13. Permeation of curcumin through theskin of P. reticulatus is shown in Figure 7.

Discussion

Formulation and characterization of nanoemulsion

Nanoemulsion using our established composition formed sponta-neously after water addition. Self nanoemulsification is onlyachieved with some oils, surfactants and co-surfactants at acertain ratio. Selection of an appropriate oily phase is veryimportant as it influences the selection of other ingredients inoil/water nanoemulsions. Usually, the oil with the maximumsolubility for the selected drug is chosen as the oily phase for theformulation of nanoemulsions. This helps to achieve maximumdrug loading14. Generally, surfactant alone cannot lower the oil–water interfacial tension sufficiently to yield a nanoemulsion; thisnecessitates the addition of an amphiphilic short chain molecule

Figure 6. (A) Degradation profile of curcumin from gel containing curcumin nanoemulsion and gel containing unencapsulated curcumin, stored for28 d at room temperature (A) and in climatic chamber (B) (mean + SD, n¼ 3).

Figure 7. Permeation profiles of curcumin through shed snake skin fromgel containing curcumin nanoemulsion and gel containing unencapsulatedcurcumin (mean + SD, n¼ 3).

Figure 5. Influence of curcumin concentration on the incorporationefficiency of curcumin nanoemulsion (mean + SD, n¼ 3).


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or cosurfactant to lower the surface tension close to zero.Cosurfactants penetrate into the surfactant monolayer, providingadditional fluidity to the interfacial film and thus disrupting theliquid crystalline phases, which are formed when the surfactantfilm is too rigid14.

Figure 3 shows a transmission electron micrograph of acurcumin nanoemulsion (formula F6). The droplets are sphericand nearly monodisperse in accordance with the data presented inTable 1.

Different amounts of curcumin loaded in the oil droplets didnot significantly impact the zeta potential of nanoemulsions, aslisted in Table 2. Distinct from other colloidal systems, thephysical stability of nanoemulsions does not depend on zetapotential. High amounts of surfactant formed rigid films coveringthe surface of oil droplets, maintaining sufficient distancebetween droplets. The use of the non-ionic surfactant,Cremophor RH40, in high amounts might be responsible for thelow value of zeta potential found in this study. Cremophorcontains a fatty acid ester15, which was dissociated, forming anegatively charged free fatty acid that contributed to the negativevalue of the zeta potential. Different zeta potential values atdifferent amounts of curcumin in nanoemulsion might beattributed to the interaction of the functional groups in curcuminwith functional groups of other component in the formula. Zhanget al.16 also found that blank nanoemulsion and nanoemulsioncontaining curcumin have different zeta potentials. This might bedue to an alteration on the surface electrostatic double layer ofdroplets, because of the formation of intermolecular hydrogenbonds among the hydroxyl groups in curcumin and some relatedgroups containing oxygen or nitrogen atoms in the surfactant,cosurfactant and oil16.

Raman spectrophotometer showed some interesting spectra incurcumin nanoemulsions. The peak at 1626 cm�1, which isattributed to carbonyl groups, shifted to 1635 cm�1. Moreover, theintensity of the symmetric aromatic ring stretching vibrations ofcurcumin in 1601 cm�1 was reduced. The ratio of intensity at1626 and 1601 cm�1 in curcumin powder was 0.67. The ratio ofintensity of curcumin nanoemulsion at 1635 and 1601 cm�1 wasfound to be 1.03. This showed the presence of a surroundingobstacle opposing the Raman active vibrational mode17. Theexcipient molecules surrounding the curcumin used in the formulareduced the intensity of the curcumin peak and shifted the spectra.Some peaks of the excipients were seen as weak bands at 1130and 849 cm�1.

Figure 5 gives information about %IE of nanoemulsion. It isassumed that the amount of oil influences the IE of a compound ina nanoemulsion system. At low amounts of oil curcumin cannotbe dissolved and incorporated completely. As a result, unencap-sulated curcumin was still present outside the nanoemulsiondroplets, and the IE of nanoemulsion decreased. Based on thesepreliminary results, we chose a formulation composed of 350 mgcurcumin in 10 gram of oil. This formula was then tested forstability and incorporated into gel.


The physical stability of nanoemulsion can easily deducted fromthe value of the zeta potential. A zeta potential of nearly 30 mVensures a high energy barrier toward coalescence of disperseddroplets. However, this value is based on experiments and not theonly indicator to predict nanoemulsion stability18. Conventionalemulsions show low stability as indicated by sedimentation ofcurcumin at storage at room temperature. Nanoemulsion oftenresults in better physical stability7. Curcumin, which is incorpo-rated in an oily phase in a nanoemulsion, does not come in contactwith the water in the external phase. It is likely that ananoemulsion thus provides an inert environment for curcumin.Curcumin in nanoemulsions was effectively protected fromdegradation19.

Formulation and stability study of curcumin gel

The viscosity and pH of all gels tested in this study were relativelystable after storage for 28 d at room temperature or at 40 �C.Viscosity of gels ranged between 2000 and 2700 cps, whichmeans that the gels are relatively easy to pour, but viscous enoughto stick to the skin and to remain physically stable over time. ThepH for all gels tested was in an acceptable range of 6.2–6.9.Although the surface of the human skin has a pH between 5.5 and5.9, application of gels with a pH up to neutral did not causeirritation20.

Compared to gels containing unencapsulated curcumin, gelswith curcumin nanoemulsions were more stable at both roomtemperature and 40 �C, in terms of curcumin content in gel(Figure 6). There was a 3-fold (room temperature) and 4.6-fold(climatic chamber) improvement in stability of nanoemulsion gelsover unencapsulated curcumin gels. These improvements werestatistically significant (p50.05). This suggests that surfactantand co-surfactant in nanoemulsions play an important role inimproving curcumin stability in gels.


Water, the main component in gels, hydrates the skin and causesthe cells in the stratum corneum to swell, thus making drugchannels wide, resulting in improved cumulative permeation21.This study shows a significant improvement (1.6-fold, p50.05) ofcumulative curcumin permeated from nanoemulsion gels com-pared to gel containing unencapsulated curcumin (Figure 7). Thepermeation flux was calculated from the curve of cumulativeamounts of curcumin permeated versus time. Statistical compar-ison of the flux in a 24-h experiment shows that nanoemulsiongels provide a flux (p50.05), which is higher than fromconventional curcumin gel, as seen in Table 1. This is inagreement with previous data, which showed a significantimprovement of cumulative curcumin permeated from nanoemul-sion gel. Nanoemulsion interact with the stratum corneum,altering both the lipophilic and polar pathways, resulting in

Table 2. In vitro permeation kinetics of gel containing unencapsulated curcumin and curcumin nanoemulsion.

Sample Model r2 Equation

Gel containing unencapsulated curcumin Zero order 0.995 y¼ 0.835x + 1.440First order 0.989 y¼ 0.067x + 0.392Higuchi 0.976 y¼ 3.537x� 2.117Kors Meyer-Peppas 0.985 y¼ 0.678x + 0.282

Gel containing curcumin nanoemulsion Zero order 0.954 y¼ 1.162x + 5.220First order 0.893 y¼ 0.057x + 0.741Higuchi 0.991 y¼ 4.097x + 2.252Kors Meyer-Peppas 0.971 y¼ 0.340x + 0.816


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increased permeation rates. Alterations in the tight junctionproperties of the stratum corneum also provide improvedpermeation by increased solubilization or extraction of lipidspresent in the stratum corneum, as well as increased membranefluidity. Another possible mechanism is direct permeation ofloaded drug from the nanoemulsion droplets to the stratumcorneum. We suggest that nanosized droplets in nanoemulsions inthe continuous phase can carry the drug through the skin barrierand can move easily into the stratum corneum, resulting inenhancement transfer of the drug from nanoemulsion as alsoreported by other groups21–23. Figure 7 also shows a burst in theinitial release of curcumin from the gel. Due to the hydrophilicnature of the polymer used, the polymeric matrix of the gelforms loose channels within the network, causing fast initialrelease of drug.

Based on the cumulative amount of curcumin permeatedthrough the shed snake skin membrane, the permeation kineticswere determined. Four kinetic equations are appropriatefor transdermal delivery kinetics: zero order, first order, Higuchiand Kors Meyer-Peppas24. Curves were plotted fromcumulative curcumin permeated versus time (zero order),log cumulative curcumin permeated versus time (first order),cumulative curcumin permeated versus the square root of time(Higuchi) and log cumulative curcumin permeated versus log time(Kors Meyer-Peppas), respectively. The correlation coefficient ofeach of these permeation kinetics was calculated and compared(Table 2). The permeation kinetic best fitted was indicated by valueof correlation coefficient. As shown in Table 2, the permeationprofiles of free and nanoemulsion of curcumin followed zero-orderand Higuchi release kinetic, respectively. The difference inpermeation kinetics of active compound was influenced by theconcentration of both the polymer used and the active compound25.However, as the gel composition containing unencapsulatedcurcumin and curcumin nanoemulsion were similar, the observeddifference in kinetics in this study can only due to the form ofcurcumin, i.e. in dissolved or in crystalline states.

Conclusions

Curcumin is widely used as a potent anti-inflammatory herbaldrug. Its activity is similar to the NSAIDs in inflammatory painmanagement. An early study pointed out that the hydroxyphenylunit in curcumin confers anti-inflammatory activity. Someproblems are related to the oral administration of curcumin, andtopical application is difficult due to its low permeability throughthe skin. Our gel-containing nanoemulsion of curcumin seems tobe promising as a transdermal delivery system for curcumin.Mixing of GMO:Chremophor RH40:PEG 400 (1:8:1) resulted inthe spontaneous formation of nanoemulsion, and successfullyencapsulated curcumin with better physicochemical stability,prolonged shelf life and enhanced skin permeability. Astransdermal delivery requires this permeability to provide therequired therapeutic dose, encapsulation of curcumin intonanoemulsion seems to be promising for transdermal deliveryof curcumin.

Aknowledgements

We thank to JICA (Japan International Cooperation Agency) forfinancially supporting this work. An appreciation was also conveyed toDr. H. J. Doddema and Dr. Wangsa Tirta Ismaya for careful grammaticalcorrection.

Declaration of interest

The authors report no declarations of interest.

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curcumin nanoemulsion for transdermal application: formulation and evaluation

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