IJN 22667 Transdermal Delivery of Paeonol Using Cubic Gel and Microemu 080311

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2011 Luo t al, publi and lin Dov Mdial P Ltd. Ti i an Opn A atilwi pmit untitd nonommial u, povidd t oiinal wok i poply itd.

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http://dx.doi.org/10.2147/IJN.S22667

Tandmal dlivy of paonol uin ubi land miomulion l

Maofu Luo1,2

Qi sn1

Jinj in cn1

1sool of Pamay, sanai Jiao

Ton Univity, sanai, 2Jianx iUnivity of Taditional cinMdiin, Nanan, Popl rpubliof cina

copondn: Qi snsool of Pamay, sanai JiaoTon Univity, Donuan road 800,sanai 200240, Popl rpubli ofcinaTl +86 21 3420 4049Fax +86 21 3420 4049email [email protected]

Background: The aim o this study was to develop new systems or transdermal delivery o

paeonol, in particular microemulsion gel and cubic gel ormulations.

Methods: Various microemulsion vehicles were prepared using isopropyl myristate as an oil

phase, polyoxyethylated castor oil (Cremophor EL) as a suractant, and polyethylene glycol 400

as a cosuractant. In the optimum microemulsion gel ormulation, carbomer 940 was selectedas the gel matrix, and consisted o 1% paeonol, 4% isopropyl myristate, 28% Cremophor EL/

polyethylene glycol 400 (1:1), and 67% water. The cubic gel was prepared containing 3%

paeonol, 30% water, and 67% glyceryl monooleate.

Results: A skin permeability test using excised rat skins indicated that both the cubic gel and

microemulsion gel ormulations had higher permeability than did the paeonol solution. An in

vivo pharmacokinetic study done in rats showed that the relative bioavailability o the cubic gel

and microemulsion gel was enhanced by about 1.51-old and 1.28-old, respectively, compared

with orally administered paeonol suspension.

Conclusion: Both the cubic gel and microemulsion gel ormulations are promising delivery

systems to enhance the skin permeability o paeonol, in particular the cubic gel.

Keywords: microemulsion gel, cubic gel, transdermal delivery, paeonol

IntroductionPaeonol, the active constituent o Cortex moutan, is widely used in traditional Chinese

medicine as a pain reliever, anticoagulant, antibiotic, and antiatherosclerotic agent.

In recent years, many studies have shown that paeonol has a number o therapeutic

eects, including antianalgesic, antihypertensive, anticoagulant, antibacterial,

anti-inammatory, immunoregulatory, antiatherosclerotic, and central nervous system

inhibitory activities.13

A microemulsion is a nanosized ormulation in which active drug is dispersed in

a mixture o water, oil, and suractant, requently in combination with a cosuractant,

and is an optically clear, stable, isotropic liquid, containing particles with diameters o

100 nm and less.4,5 Incorporation o a gel matrix into an o/w microemulsion provides

the opportunity to obtain properties comparable with those attainable using hydrogels.

Formulations o microemulsion gel were frst reported in 1986,6,7 and since then their

structure and physicochemical properties have been described.810 Microemulsion gels

can increase the permeability o some drugs.

A cubic gel is ormed spontaneously when amphiphilic lipids are placed in an

aqueous environment. A cubic gel consists o a curved bicontinuous lipid bilayer

and has a thermodynamically stable structure. Glyceryl monooleate/water systems

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are an example. They can incorporate small-molecule

drugs and large proteins,11,12 and have the ability to enhance

permeability.13

Currently commercialized preparations o paeonol

include a cyclodextrin injection, oral solution, and ointment.14

Although paeonol preparations o gel and emulsion are being

studied, combinations o paeonol with cubic gel and micro-

emulsion gel have been less widely reported. Paeonol is a

small phenolic compound showing white crystalline needles.

It has the characteristics o a low melting point, volatility,

and poor water solubility. The molecular weight o paeonol

is 166.18, and its chemical structure is 2-hydroxy-4-methoxy

acetophenone (Figure 1). Paeonol is absorbed rapidly ater

oral administration, and its poor oral bioavailability is sug-

gested to be due to rapid and complete frst-pass metabolism

o the drug.15 Paeonol is more suitable or transdermal deliv-

ery. In order to enhance the permeability and stability o

paeonol, the microemulsion gel and cubic gel ormulations

were selected or investigation as drug delivery systems. The

purpose o this work was to prepare a microemulsion gel and

cubic gel or transdermal delivery o paeonol, to study the

skin permeability o paeonol in microemulsion gel and in

cubic gel, and evaluate whether the microemulsion gel and

cubic gel ormulations could improve the bioavailability o

paeonol compared with oral administration.

Materials and methodsMatial

Paeonol (99% purity) was obtained rom Nanjing QingzePharmaceutical Technology Development Co Ltd (Nanjing,

China). Glyceryl monooleate (.99%) was supplied by

Danisco (Copenhagen, Denmark). Carbomer 940 was

purchased rom Shanghai Xietai Chem Co Ltd (Shanghai,

China). Transcutol P and Labraac were kindly donated

by Gatteosse (St Priest, France). Cremophor EL (Crel)

and Cremophor RH 40 (CRH40) were donated by BASF

(Ludwigshaen, Germany). Isopropyl myristate, oleic acid,

ethyl oleate, propylene glycol, castor oil, ethanol, p-octy

polyethylene glycol phenylether, polyethylene glycol 400,

and Tween80 were purchased rom Sinopharm Chemical

Reagent Corporation (Shanghai, China). Soybean oil was

obtained rom Tieling North Asia Medicinal Oil Co Ltd

(Tieling, China).

Pudotnay diaamTo determine the composition o microemulsions, pseudoternary

phase diagrams were constructed by titrating a series o oil,

suractant, and cosuractant with water mixtures at ambient

temperature (25C). Suractants and cosuractants were

blended at dierent mass ratios (1: 2, 1:1, 2:1, 4:1), then each

suractant-cosuractant mixture was mixed with oil, and the

ratio o oil to the suractant and cosuractant mixture was

varied at 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, and 1:9 (w/w).

Water was added drop by drop to the mixture under vigorous

stirring. During titration, the isotropic, liquid crystalline,

and coarse emulsion phases were observed with turbidity-

to-transparency or transparency-to-turbidity transitions

occurring. Clear and transparent ormulations were indicative

o a stable microemulsion, and their compositions were

recorded. The physical states were marked on a pseudoternary

phase diagram representing the suractant and cosuractant

mixture, with the other two axes representing oil and water.

Ppaation of miomulionBased on the phase diagram, dierent ormulae were selected

rom the microemulsion region (Table 1). Exactly 1% w/w o

paeonol was dissolved in the oil, suractant, and cosuractant

mixtures, and water was added drop by drop under magnetic

stirring at room temperature. The control solution was

prepared by dissolving paeonol in phosphate-buered saline

at pH 7.4 to achieve a concentration 400 g/mL and then

stirring the solution at 1000 rpm.

Miomulion doplt iz and mopoloyanalyiMicroemulsion particle size was determined using photo-

correlation spectroscopy (Malvern, Worcestershire, UK) at

OH

O

O

Figure 1 stutu of paonol.
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Tandmal dlivy of paonol

25C. Droplet morphology was observed using transmission

electron microscopy (TEM) (JEM-2010; JEOL, Tokyo,

Japan). One drop o each diluted sample was deposited on

a flm-coated 200-mesh copper specimen grid and allowed

to stand or 10 minutes, ater which any excess uid was

removed with flter paper. The grid was then stained with

one drop o 3% phosphotungstic acid and dried or 5 minutes

beore examination with an electron microscope.

Ppaation of miomulion lCarbomer 940 0.5%2.0% (w/w) swelled ater addition o

water, and pH was adjusted using triethanolamine 0.5%2.0%

(w/w). The oily solution was prepared by mixing Crel, poly-

ethylene glycol 400, isopropyl myristate, and paeonol, and

was then swelled with carbomer 940 and vigorously mixed

until a homogeneous dispersion was obtained.

Ppaation of ubi lPaeonol 3% w/w was mixed with melted glyceryl monooleate

in glass vials at 42C until completely dissolved or dispersed.

Distilled water preheated to 42C was incorporated gradually

into the mixture at 30% w/w. Samples were kept at room

temperature in the dark or 3 days.

In vito pmability tudiThe abdominal skins o male Wistar rats weighing 220 20 g

were used or the permeability experiments, which were

carried out in accordance with the guidelines o the animal

ethics committee at Shanghai Jiao Tong University. The

abdominal skin was careully removed leaving the at tissue

behind. The skin was examined under a magniying lens or

damage or disease, and any skin with a disrupted barrier was

excluded. Freshly prepared abdominal skin was used in the

diusion experiments. Vertical Franz-type diusion cells

(Shanghai Institute o Organic Chemistry) with a diusional

surace area o 0.754 cm2 and a 5 mL cell volume were used

to study the permeability o the microemulsion gel and cubic

gel ormulations. The skin was placed between the donor and

receptor compartments o the cells, with the stratum corneum

side acing the donor compartment. The receiver compartment

was flled with 5 mL o phosphate-buered saline at pH

7.4, with temperature maintained at 32C 0.5C using a

thermostatic water bath (Variomag, Munich, Germany) and

stirring at 600 rpm throughout the experiment. Microemulsion

1 mL and gel 1 g samples containing paeonol were placed into

each donor compartment, and 0.2 mL o the receptor solution

was withdrawn at predetermined time points (hours 1, 2, 3,

4, 5, 6, 7, and 8), then replaced with an equivalent volume o

phosphate-buered saline to maintained a constant volume.

The samples collected were fltered through a 0.45 m mem-

brane and assayed by high-pressure liquid chromatography.

The cumulative amount o paeonol that permeated through

the rat skins was calculated using the equation:

Cnc

=Cn+ (0.2/5) C

p

Q=Cnc

5/0.754

where Q was the accumulated amount at a given time t, Cn

was the drug concentration o the n sample at the sampling

time, Cp

was the sum o the drug concentration o all

the n-1 samples measured, and Cnc

was the transdermal

concentration ater correction. The cumulative amount (Q)

o paeonol permeated was plotted as a unction o time (t)or each ormulation. The skin permeation rate at steady-

state (Jss, g/cm2/hour) was calculated rom the slope o the

linear portion o the plots oQ versus time. The permeability

coeicient was calculated by dividing Jss

by the initial

concentration o drug in the donor cell (C0):16

permeability coefcient = Jss/C

0

Table 1 compoition of vaiou topial fomulation fo paonol dlivy

Components Formulations

A B C D E F Cubic gel MG

etyl olat 7

Iopopyl myitat 4 4 4 7 10 4

cl:Peg400 = 1:1 28 39 50 28 28 28 28

Wat 67 56 45 64 61 64 30 65

cabom 940 1

Titanolamin 1

gMO 67

Paonol 1 1 1 1 1 1 3 1

Abbreviations: cl, cmopo eL; Peg 400, polytyln lyol; gMO, lyyl monoolat; Mg, miomulion l.


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The penetration-enhancing eect o paeonol was calculated

in terms o the enhancement ratio, and was calculated using

the ollowing equation:17

enhancement ratio = Kp/K

0

where Kp

is the respective ormulation and K0represents the

control solution.

In vivo pmability tudiMale Wistar rats weighing 200230 g were obtained rom the

Animal Center o Shanghai Jiao Tong University, and asted

overnight with ree access to water beore drug administration.

Hairs at the abdominal site were shaved o and the skin area

washed with distilled water the day beore the experiment.

Cubic gel and microemulsion gel (30 mg/kg) were applied

on the skin surace (7.9 cm2), which was then bound with

gauze. Blood samples (0.25 mL) were collected at hours 0,

0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, and 12.0 ater transdermal

administration. For the oral pharmacokinetic studies, paeonol

was suspended in 0.5% sodium carboxymethyl cellulose and

administered (30 mg/kg) as the control. Blood samples were

collected rom the jugular vein at 0, 0.08, 0.25, 0.5, 0.75, 1.0,

1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 12.0 hours ater dosing.

All collected samples were immediately centriuged at

4000 rpm or 10 minutes. Plasma 0.1 mL was added to cin-

namic acid 10 L and vortex-mixed with acetonitrile 2 mL

or 1 minute and centriuged at 10,000 rpm or 10 minutes.

The supernatant was transerred to a clean test tube and

evaporated to dryness at 25C under a stream o nitrogen.

The residue was dissolved in methanol 1 mL, and 20 L o

the sample solution was injected into the high-pressure liquid

chromatography system.

Analyi of paonolPaeonol was analyzed using a reversed phase high-pressure

liquid chromatography system. The chromatographic system

consisted o a Waters 717 Plus autosampler (Waters, Milord,

MA) and a Waters 2487 dual absorbance detector equipped

with a prepacked Hypersil ODS column (150 mm 4.6 mm,

5 m, Dalian Elite Analytical Instruments Co Ltd, Dalian,

China). The mobile phase or analysis o paeonol consisted o

methanol, water, and acetic acid (53:47:0.01, v/v). The eluent

was pumped at a ow rate o 1.0 mL/min. The detector wave-

length was set at 274 nm. The injection volume was 20 L.

statitial analyiAll skin permeability experiments were repeated three times,

and the results expressed as means standard deviation.

Statistical signifcance was assessed using the Students t-test

or multiple comparison. APvalue, 0.05 was considered

to indicate statistical signifcance.

Results and discussionPudotnay diaamPseudoternary phase diagrams o the system containing

isopropyl myristate, Crel, polyethylene glycol 400, and

water are shown in Figure 2. The black areas indicate the

clear o/w microemulsion region. The microemulsion domain

was determined by visual inspection or clarity and uidity

as well as through a cross polarizer or the absence o a

liquid crystalline phase. The rest o the region in the phase

diagram represents turbid and conventional emulsions based

on visual observation. No liquid crystalline structure was

observed using the cross polarizer. Phase studies were used

to estimate the eect o suractant/cosuractant (S/Cos) in

stable o/w microemulsion regions. As shown in Figure 2, the

monophasic zone o o/w microemulsion reaches a maximum

at a S/Cos o 1.

caatiti and pyiomialpopti of t miomulionThe particle size o the microemulsion was one o the most

important properties. All the microemulsions (AF) had

small average droplet diameters o 2760 nm. As a result,

the droplet size o ormulation A was 39.80 4.6 nm. The

morphology o microemulsion ormulation A was character-

ized using transmission electron microscopy (Figure 3), and

showed a spherical shape and uniorm droplet size. Samples

were diluted with distilled water beore testing to avoid

multiscattering phenomena. Ater that, the droplet size o

the diluted microemulsion was not signifcantly changed.

The mean particle size remained consistent or 3 months at

room temperature.

Ppaation of lIn this work, carbomer 940 was added to vehicle A to prepare

the microemulsion gel. We ound that carbomer 940 could

increase the viscosity o the microemulsion, maintain the

microemulsion structure, and provide a good matrix or the

microemulsion gel.

Microemulsion gel containing 0.5% carbomer 940 had

relatively high uidity. The viscosity o the microemulsion

gel increased with increasing concentrations o carbomer

940. However, 2% carbomer 940 resulted in excessive micro-

emulsion gel viscosity. Microemulsion gel containing 1%

carbomer 940 has suitable viscosity or topical application.18


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940 to the microemulsion, possibly because o increased

viscosity and the changing structure o the vehicle.23,24 Inthis work, the addition o 1% carbomer 940 had the same

inuence on the permeability o paeonol.

Figure 4 shows the permeability o paeonol through rat

skin. The cumulative amount o paeonol in the cubic gel was

signifcantly higher (P, 0.05) than that o paeonol in the

microemulsion gel and control solution. With a permeability

coefcient o 8.34 0.49 cm/hour 103, cubic gel was a

better carrier or transdermal delivery o paeonol than the

microemulsion gel and control solution. There may be two

actors accounting or this. Firstly, the content o paeonol in

the cubic gel was higher than in the microemulsion gel, whichmeans that the cubic gel had better drug solubility, which

could contribute to improved absorption o the drug.25,26

Secondly, the structure o the cubic gel might be better than

that o the microemulsion gel or drug delivery. The struc-

ture o the cubic phase is unique and consists o a curved

bicontinuous lipid bilayer, which resembles the structure o

lipid membranes ound in nature,27,28 so might result in good

adhesiveness to the skin and good delivery o the drug.

In vivo pmability tudiThe mean plasma concentration versus time profles or

paeonol ater oral and transdermal administration are shown

in Figure 5, and the mean pharmacokinetic parameters

calculated by DAS2.1.1 are given in Table 3. These show that

paeonol is rapidly absorbed, with a maximum concentration

o 1.64 0.14 g/mL at 0.25 0.06 hours ater a single oral

dose. The time taken to reach maximum concentration o

paeonol in the cubic gel and microemulsion gel was 3 hours

and 2 hours, respectively, ater transdermal administration.

This result is similar to the phenomenon reported by Sun

et al, who detected the maximum concentration at 5 minutes

ater an oral dose.29 This was due to dermal accumulation o

paeonol because o the barrier properties o skin. An increase

in the area under the concentration-time curve (AUC) or

paeonol was observed when the cubic gel and microemulsion

gel were studied. The relative bioavailability o paeonol in

cubic gel and microemulsion gel was 1.51 and 1.28 times

higher, respectively, than ater oral administration o the

drug. Mean residence times ollowing a transdermal dose

o cubic gel and microemulsion gel were 5.63 1.32 hours

and 5.62 1.11 hours, respectively, which were higher than

that or paeonol suspension.

Compared with oral administration, transdermal

administration had a longer time to reach maximum plasma

concentration, a lower maximum plasma concentration,

higher AUC, and higher mean residence time, because o

avoidance o the substantial amount o hepatic frst-pass

metabolism associated with oral administration.

The mechanism or the enhanced transdermal penetration

o microemulsion gel and cubic gel or paeonol might be

attributable to several actors. Firstly, the high concentration

(1%) o paeonol in the microemulsions resulted in high

concentration gradients, which might be the main mechanism

Table 2 Permeability coefcient and enhancement ratio of paeonoltou xid at kin fom diffnt vil

Vehicle Kp(cm/hour) 103 Enhancement ratio

contol 3.06 0.10

A 6.53 1.09* 2.13

Mg 5.88 0.28* 1.92

cubi l 8.34 0.49** 2.73

Notes:*P, 0.05, **P, 0.01, ompad wit ontol; a valu pnt man

tandad dviation of at lat t xpimnt.

Abbreviation: Mg, miomulion l.

0 2 4 6 8 10

Time (h)

0

200

400

600

800

1000

Cumulativeamount(g/cm

2)

Cubic gel

Microemulsion gel

Control solution

Figure 4 T umulativ amount of paonol fom ubi l (--) and miomulion

l (--) and ontol olution (--).

Note: rult a xpd a man tandad dviation of at lat t

xpimnt.

Figure 3 Tanmiion lton miopotoapy of paonol miomulion.


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Tandmal dlivy of paonol

by which paeonol in a microemulsion gel penetrates

the skin.26

Microemulsions could act as drug reservoirs whereby

drug is released rom an inner phase to an outer phase and

then into the skin.24 Secondly, due to the small droplet size,

droplets settling in close contact with the skin might penetrate

the skin surace.24

In the case o cubic phase gel, glyceryl monooleate could

intercalate with the extracellular lipid matrix o the skin, and

disrupt its well organized compact structure.30 Some studies

have reported that enhanced transdermal delivery o drugs

may depend on a disordered state, or depend on a dierent

order o lipids, given that intercellular lipids can rearrange

into a cubic phase under specifc circumstances.31

In both the in vitro permeability and in vivo bioavailability

experiments, a correlation was obtained between the

outcomes o the in vitro permeability model and the in vivo

bioavailability data. The in vitro permeability experiments

indicate that the cubic gel ormulation yielded the highest

permeability coefcient o the three tested ormulations, and

this was also the case in the in vivo assessment model, with

the AUC o the cubic gel ormulation being higher than that

o the other two ormulations.

ConclusionIn this study, novel microemulsion gel and cubic gel ormu-

lations or transdermal delivery o paeonol were developed.

Our results indicate that both the cubic gel and microemulsion

gel ormulations had a higher permeability coefcient than

the control group. An in vivo pharmacokinetic study in rats

showed that the relative bioavailability o the cubic gel and

the microemulsion gel was enhanced by about 1.51-old and

1.28-old, respectively, compared with oral administration

o paeonol suspension. These data collectively support the

hypothesis that cubic gel and microemulsion gel ormulations

are promising delivery systems to enhance the skin perme-

ability o paeonol, especially the cubic gel.

05 10

Time (h)

C(ng/mL)

150

500

1000

1500

2000Oral administration

Microemulsion gel transdermal administration

Cubic gel transdermal administration

2500

Figure 5 Plama onntation of paonol followin oal and tandmal adminitation to at.

Notes: Man tandad dviation; n = 6; --, oal adminitation; --, miomulion l tandmal adminitation; --, ubi l tandmal adminitation.

Table 3 Pamaokinti paamt obtaind aft oal and

tandmal adminitation of paonol in at

Parameter Transdermal administration Oral

administrationCubic gel MG

cmax

(/mL) 0.68 0.10* 0.72 0.15* 1.64 0.14

Tmax

(ou) 3.00 0.16** 2.00 0.32** 0.25 0.06

T1/2

(ou) 2.58 0.13 3.45 0.49** 1.54 0.29

AUc (/mL/ou) 4.60 0.54* 3.89 1.01 (n) 3.04 0.42

MrT (ou) 5.63 1.32* 5.62 1.11* 1.64 0.33

Notes: Data a xpd a t man tandad dviation fo ix at; *P, 0.05,

ompad wit oal adminitation; **P, 0.01, ompad wit oal adminitation.

Abbreviations:AUc, aa und t onntationtim uv; Mg, miomulion

l; cmax

, maximum concentration; ns, not signicant; Tmax

, tim to a maximum

onntation; T1/2

, limination alf-lif; MrT, man idn tim.


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AcknowledgmentsThe work was supported by the Shanghai Municipal Committee

o Science and Technology (grant No. 08DZ1971304),

the National Basic Research Program o China (No.

2007CB936004), and the National Pharmaceutics Technology

Platorms or Innovative Drugs (No. 2009ZX09310-007).

DisclosureThe authors report no conicts o interest in this work.

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IJN 22667 Transdermal Delivery of Paeonol Using Cubic Gel and Microemu 080311

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