IJN 22667 Transdermal Delivery of Paeonol Using Cubic Gel and Microemu 080311
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7/31/2019 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.
Intnational Jounal of Nanomdiin 2011:6 16031610
International Journal of Nanomedicine Dovepress
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O r I g I N A L r e s e A r c h
open access to scientifc and medical research
Opn A Full Txt Atil
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
Number of times this article has been viewed
This article was published in the following Dove Pressjournal:
International Journal of Nanomedicine
3 August 2011
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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.
References1. Riley CM, Ren TC. Simple method or the determination o paeonol in
human and rabbit plasma by high-perormance liquid chromatography
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