Dissolution and absorption researches of curcumin in solid dispersions with the polymers PVP

Asian Journal of Pharmacodynamics and Pharmacokinetics

Paper ID 1608-2281-2006-06040343-07
Copyright by Hong Kong Medical Publisher

Received July 25, 2006
ISSN 1608-2281 2006 6(4):343-349

Accepted August 30, 2006



Dissolution and absorption researches of curcumin in
solid dispersions with the polymers PVP


Dong-Hui Xu*, Sheng Wang, Jing JIN, Xue-Ting Mei, Shi-Bo Xu
Lab of Traditional Chinese Medicine and Marine Drugs, School of Pharmaceutical Sciences, Sun Yat-Sen
University, Guangzhou 510275, China


Abstract
Aim Curcumin, a natural pigment extracted from the plant Curcuma longa, had wide range of
pharmacological activities. However, low dissolution and oral absorption restricted its application.
Polyvinylpyrrolidione K30 (PVP K30) was applied to improve dissolution and oral absorption of
curcumin. Curcumin-PVP K30 solid dispersions (SDs) in different ratios were prepared by
co-evaporation in ethanol solution. The best ratios of curcumin to PVP K30 was ensured as 1:8 (m:m)
by dissolution rate of cucumin in vitro test. The solubility and the dissolution rate in vitro of curcumin
were significantly raised, compared with curcumin, the solubility of solid dispersion increased at least
880 folds. Methods A sensitive HPLC method was developed to determine pharmacokinetics of
curcumin in rat plasma after oral administration of curcumin-PVP-K30 SDs, Physical mixture (PM) (the
ratio of curcumin in PVP K30 was 1:8) and curcumin-CMC-Na suspension, each sample was
administered three level of dosages which contained curcumin 100, 200 and 400 mg·kg-1, respectively.
The results showed that curcumin concentration of rat plasma administration of curcumin-PVP K30 PM
and curcumin-CMC-Na suspension were under the limited of detection even 4 h after oral
administration. Results On the contrary, the absorption of curcumin-PVP-k30 SD was enhanced and the
concentration-time data was best fit for two-compartment model. The peak levels in blood for three
level dosages were 74.558,110.174 and 193.665ng·mL-1 at about 45min respectively, and the
bioavaibility was 514.646, 609.111 and 1028.627 ng·mL-1·h respectively. Conclusion PVP could
improve dissolution and oral absorption of curcumin in SDs.


Key words
Curcumin; Polyvinylpyrrolidione K30 (PVP K30); solid dispersions ; Dissolution; Absorption


Introduction

extremely low aqueous solubility and degradation at

alkaline pH restricts its pharmaceutical use. In a
Turmeric (C. longa L.) has been used in
recent study, the gastroprotective effect of curcumin
traditional medicine for the treatment of liver
was investigated by ip. Administration. The result
ailments, ulcers, parasitic infections, various skin
showed that curcumin acted as a potent antiulcer
diseases, sprains, inflammation of the joints, cold and
compound to protect indomethacin, stress, and
f l u s y m p t o m s . C u r c u m i n
ethanol induced gastric ulcer?Chattopadhyay?et al.,
( 1 , 7 - b i s - ( 4 - h y d r o x y - 3 - m e t h o x y p h e n y l )
2006?[4]. However, low oral bioavailability restricted
-1,6-heptadiene-3,5-dione), a natural pigment
its application. The bioavailability enhancement
extracted from the plant Curcuma longa, has widely
study was reported in this paper.
pharmacological effects such as antioxidant [1,2,13],

anti-inflammatory [14], anti-microbial, anti-tumor [7,9],
HO
and anti-HIV[5,3]. Unfortunately curcumin has an
OH
______
*Correspondence to Lab of Traditional Chinese Medicine and
MeO
OMe
Marine Drugs, School of Pharmaceutical Sciences, Sun Yat-Sen
OH
O

University, Guangzhou 510275, China. E-mail: Lsdb@zsu.edu.cn,
Tel+Fax: +86-20-84113651
Fig 1. Chemical structure of curcumin

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Xu DH et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(4):343-349

Cyclodextrins (CD) are a family of cyclic
de-ionized water were all HPLC grade from Fisher
oligosaccharides which can form inclusion Scientific (Pittsburgh, PA, USA). A stock solution of
complexes with large organic molecules (Stella and
curcumin (100 µg.mL-1) was prepared by dissolving
Rajewski, 1997)[15], thus improving their dissolution
the appropriate amount of the authentic sample in
rate. The most common are the ?-, ?-, and
methanol. Work solutions of curcumin were prepared
?-cyclodextrins formed by, respectively, six, seven
by diluting the stock solution with methanol to yield
and eight glucose units. The studies of the inclusion
certain concentrations and estradiol solution was
complexes of curcumin with the common host
prepared by dissolving in methanol.
compounds cyclodextrins (CDs) have been reported

[1]. Curcumin forms strong 2:1 host:guest inclusion
Apparatus and chromatography
complexes with cyclodextrins. When no cyclodextrin
Chromatographic analyses were performed on a
was present the pseudo first-order rate constant (k0)
HPLC system consisting of a 7225i Rheodyne
was 22.4 h-1. Even at the lowest cyclodextrin
injector with a 20-µl loop (USA), a Dionex P680
concentration (0.1%) a more than 50- fold increase in
pump and a Dionex 340U DAD detector (Germany).
stability was observed, which indicated that more
Chromatograms were processed by Chromeleon
than 98% of the curcumin molecules were included in
chromatography management system (Dionex,
the cyclodextrin cavity. More than a 500-fold
Germany). Separation was achieved on a
increase in stability could be obtained by further
reversed-phase Kromasil 100-5C18 column (Eka,
addition of some of the cyclodextrins [10].
Sweden). The mobile phase was prepared by mixing
Historically, water-soluble carriers such as high
41% acetonitrile, 23%methanol, 35% de-ionized
molecular weight polyvinylpyrrolidones (PVP) have
water and 1% acetic acid (v/v/v/v) and the flow rate
been the most common carriers used for solid
was 1.0ml/min. a visible wavelength of 428nm was
dispersions (SDs). For solid dispersions PVP K12 to
used to detect curcumin and an ultraviolet
K30 (MW 2500-50,000) has been widely used. PVP
wavelength of 280nm was used to detect internal
K30 has been used in improve solubility of silybin,
standard ?-17-estradiol.
carbamazepine[18,15]. PVP K30 was applied to

improve dissolution of curcumin in 0.1N HCl [12].
Animals
In this present study we employed solid
Male specific pathogen-free Wistar rats were
dispersion technique to improve dissolution and
obtained from The Laboratory Animal Center of
bioavailability of curcumin. The dissolution rate of
Guangdong Province, China, and housed in The
curcumin in SDs with PVP K30 in different ratios
Laboratory of Traditional Chinese Medicine and
(1:2, 1:4, 1:6, 1:8, 1:10) was compared, meanwhile
Marine Drugs, School of Pharmaceutical Sciences,
the physical mixture was administered as comparison.
Sun Yat-Sen University, Guangdong Province, China.
The best ratio of curcumin to PVP were used by oral
Rats were kept in plastic cages in a room with a 12h
administration to rats. The bioavailability of light/dark cycle and with central air conditioning
curcumin in plasma concentration was measured by
(25 ,
? 70% humidity). Rats were allowed free access
HPLC methods.
to tap water and pellets rodent diet. The animals used

in this study were handled in accordance with the
Materials and methods
Guidelines for Animal Experimentation of Sun

Yat-Sen University.
Reagents and chemicals

Curcumin
Preparation of solid dispersions
(1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadien
Curcumin in SDs with PVP K30 in different
e-3,5-dione) (purity>99%) was purchased from
ratios (1:2, 1:4, 1:6, 1:8, 1:10) were separately
Tianjin Guangfu Fine Chemical Research Institute,
obtained by conventional solvent evaporation method.
China; Ranitidine hydrochloride was purchased from
Curcumin and PVP K30 were dissolved in minimum
Alpharma Co.; PVP K30 was purchased from BASF
volume of ethanol and the solvent was removed
Pharmacy Co. Ltd;?-17-estradiol acetate was under vacuum in a rotavapor at 65°C and 80rpm for
obtained from Xianju Pharmacy of Zhejiang Province,
8h. The resultant solid dispersion was pulverized in
China; Acetonitrile, methanol, acetic acid and
mortar and pestle, passed through a 250-µm sieve

344

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Xu DH et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(4):343-349

(mesh size 60), kept in vacuum-desiccator at 40°C for
divided into nine groups. The rats in each group were
24h, then stored in a desiccator at room temperature.
administered a dosage of low, medium and high
During dissolution study, pure curcumin and its SDs
levels (equivalent to curcumin 100, 200, 400 mg.kg-1)
was dissolved in 10% ethanol (V:V) and passed
of pure curcumin, curcumin-PVP K30 SDs and
through 80-µm sieve, and measured at a visible
curcumin mixtures, respectively. Blood samples
wavelength of 428 nm at 25°C .
(0.5mL) were drawn via canthus vein at time 15, 30,

60, 90, 120, 180, 240, 360, 480, and 600 min after
Preparation of standard and quality control
oral administration. The blood samples were
samples and blood samples
centrifugated at 3500 rpm for 10min and were
The powdered curcumin 4.0mg was dissolved
immediately treated for analysis.
in 5.0mL methanol, to achieve the desired

concentration 800µg·mL-1 (stock standard).
The concentration of curcumin in rat plasma
Two-hundred microlitre of standard and unknown
after oral administration was determined from the
were diluted 1:1 in de-ionzed water and vortexed
peak area by using the equation for linear regression
for 30 seconds. 10 µL internal standard working
from the calibration curve. All data were
solution (20µL·mL-1) ?-17-estradiol acetate and 2
subsequently processed by 3P97 Pharmacokinetics
mL extracting reagent ethyl acetate were then added,
Program (The section of Mathematical Pharmacology
and sample was re-vortexed. After centrifugation at
of Chinese Mathematical Pharmacological Society
12,000 rpm for 2min, the upper organic layer was
group). The data were presented as mean±SD of
removed into a clean micro-centrifuge tube and
means(mean±SD).
dried under a stream of nitrogen gas using a low

heat setting at 40 . T
?
he sample was re-suspended
Results
in 100 µL of mobile phase and vortexed for 30s and

then transferred to an injection sample vial (about
Dissolution research of curcumin by PVP K30
20µL) for HPLC quantification.
SDs

In dissolution study, pure curcumin and its SDs
HPLC analytical run
Curcumin in plasma was separated and
was dissolved in 10% ethanol (V:V) and passed
quantified by HPLC using ultraviolet (UV)
through 80-µm sieve, and measured at a visible
detection at a wavelength of 428nm which internal
wavelength of 428nm at 25°C. PVP K30 could
standard ?-17-eatradiol acetate was detected at a
improve dissolution rate of curcumin. The best ratios
wavelength of 280nm. The quantitation of curcumin
of curcumin to PVP K30 was ensured as 1:8 (m:m)
was accomplished by peak area ratio (curcumin to
by dissolution rate of cucumin in vitro test. The
internal standard) and was based on a standard
typical HPLC chromatograms of rat plasma samples
curve in a plasma[7].
were shown in Fig 2. Retention times for estridiol and
curcumin were approximately 3.7 and 4.7 min,

respectively. No endogenous substances were found
Bioavailability research of curcumin by PVP
to interfere with the analysis.
K30 SDs
Twenty-seven rats (weighing 280±20g) were

Table 1. Dissolution rate of curcumin in solid dispersion?mean±SD?n?5?
Time
Dissolution rate (?)
?min?
Cur
SD (1:2)
SD (1:4)
SD (1:6)
SD (1:8)
SD (1:10)
5 0.55±0.15 0.32±0.17 1.04±0.20 17.35±2.67 75.70±3.57 81.32±2.46
10 0.58±0.12 1.43±0.19 4.59±0.33 20.39±2.36 80.52±3.11 81.50±2.95
15 0.73±0.17 3.49±0.24 5.23±0.30 22.62±2.10 85.43±2.45 84.00±3.18
30 0.97±0.27 3.74±0.29 6.36±0.28 39.21±3.30 85.96±3.02 86.05±2.97
45 1.62±0.26 3.85±0.23 6.62±0.25 41.00±3.04 86.94±2.23 87.03±2.16
60 2.16±0.27 3.90±0.22 7.55±0.27 42.25±1.97 87.30±2.70 87.57±2.16
90 2.36±0.34 3.99±0.16 7.55±0.21 41.98±2.25 87.84±2.23 88.19±2.36

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Xu DH et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(4):343-349
















Fig 2. High-performance liquid chromatogram of plasma. Curcumin was extracted from blood collected 1h after oral
administered curcumin PVP K30 SDs 1:?-17-estradiol; 2: curcumin


f
250
100mg/Kg curcumin

200mg/Kg curcumin

200
400mg/Kg curcumin


150

100


curcumin (ng/ml)
50

Plasma concentration o
0

0
5
10
15

Time (h)
Fig3. Plasma concentration-time profile following oral administration of three doses of curcumin-PVP K30 solid dispersions
to rats. (equivalent to curcumin 100, 200, 400 mg.kg-1).


The calibration curve obtained from the peak-area
between 7.86 and 14.50%. The intra- and inter-day
ratio (Y) and plasma concentration presented good
precisions of the curcumin assay in plasma were
linearity over the range (30~800ng.ml-1), the
acceptable as indicated by the coefficients of
regression equation (C=221.26Y+25.12, n=6, variation, which were always smaller than 10%. The
r=0.999). The limits of the lowest concentration on
intra-assay RSDs for curcumin at concentrations of
the calibration curve can be measured with
150, 300 and 600 ng.mL-1 were 4.62%, 4.80% and
acceptable precision (RSD<15%). The recovery of
3.20%, respectively. And the inter-assay RSDs at the
added curcumin from rat plasma was 102.59, 101.63
concentrations for curcumin were 6.63%, 5.99% and
and 97.17% for concentration 150, 300 and
4.51%, respectively. The detection limit for curcumin,
600ng.mL-1, respectively. The results of the extraction
at signal-to-noise ratio of 3, was 20 ng.ml in rat
efficiency of plasma at low, medium and high
plasma.
concentration levels were 85%, 80% and 81%,

respectively. And the coefficient of variation was
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Xu DH et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(4):343-349

Table 2. Pharmacokinetic parameters of curcumin-PVP K30 solid dispersions
in rats after oral administration (n=3, mean±SD )
Parameter 100mg.kg-1
200 mg.kg-1
400 mg.kg-1
A/ ng.ml-1
33.704±44.240 220.224±48.725 985.771±124.109
B/ ng.ml-1
56.782±46.571 76.072±16.885 84.890±28.815
?/1/h
1.362±1.481
1.093±0.162 1.554±0.746
?/1/h
0.152±0.045 0.140±0.026 0.104±0.041
V/F(c)/ (mg.kg-1)/(ng.ml-1) 1.165±0.044 1.098±0.102
1.023±0.038
T1/2?/h
0.862±2.390 0.643±0.088 0.498±0.187
T1/2?/h
4.837±1.396 5.067±0.986 7.658±3.767
K21/h-1
1.315±1.513 0.509±0.105 0.428±0.280
K10/ h-1
0.173±0.045 0.300±0.017 0.386±0.061
K12/ h-1
0.026±0.045 0.424±0.104 0.861±0.449
AUC/(ng.ml-1)·h
514.646±101.163 609.111±26.713 1028.627±161.403
CLs/ mg.kg-1h-1/(ng.ml-1) 0.200±0.044 0.329±0.014
0.395±0.057


Plasma concentrations of curcumin were below
choose ethyl acetate as the extraction solvent.
the limit of detection (20 ng.mL-1) after oral
Furthermore, the ethyl acetate extraction possessed
administration of the pure drug and physical mixtures
an easier transfer step than chloroform extraction
to rats even the dosage was as high as 400mg.kg-1. At
because the ethyl acetate resides above the plasma
all time intervals, the plasma levels of the solid
sample after centrifugation while chloroform resides
beneath the aqueous phase. The mean extraction
dispersions could be detected. The profiles of the
efficiency of ethyl acetate achieved 80.8%.
plasma concentration of curcumin versus time after




The chromatographic conditions used to
oral administration of curcumin-PVP K30 solid
quantify curcumin in rat plasma were base on
dispersions were depicted in Fig 3. The data of
modification of the method developed by Heath et al.
plasma curcumin concentration of the to quantifying curcumin in human plasma and urine[7].
curcumin-PVP-K30 PM and curcumin-CMC-Na
The influence of the chromatographic parameters on
suspension were under the limited of detection even 4
the retention time was investigated by varying the
h after oral administration. On the contrary, the
proportion of water in the mobile phase. The
bioavailability of curcumin-PVP-K30 SD fit best a
detection wavelength was modified and selected with
two-compartment open model by 3P97 428nm for curcumin and 280 nm for estridiol,
Pharmacokinetics Program. The peak levels in blood
resulting in a good sensibility for detection of
for three level dosages were 74.558, 110.174,
curcumin and estridiol. The chromatographic
193.665ng.mL-1 at about 45min respectively, and the
conditions selected estridiol as internal standard
bioavaibility was 514.646, 609.111, 1028.627 resulted in a good separation between curcumin and a
ng.mL-1 · h-1 respectively. Estimates for the run time of less than 6 min. The HPLC conditions we
pharmacokinetic parameters of curcumin solid
developed for analysis of curcumin in plasma were
dispersions were shown in Table 1.
convenient, sensitive, accurate and capable of

handling large batches with short analysis time.
Discussion

The developed method was used to evaluate the
In the extraction of curcumin, we had tried to
curcumin-PVP K30 SDs in vivo, and the physical
treat blood sample with chloroform, acetonitrile, and
mixtures and pure drug were administered as control.
ethyl acetate in the preliminary experiment. The
Plasma concentrations of curcumin were below the
extraction efficiency of acetonitrile was comparably
limit of detection (20 ng . mL -1 ) after oral
low. Chloroform and ethyl acetate provided high
administration of the pure drug and physical mixtures
extraction efficiency, but considering toxicity and
to rats but could be detected after oral administration
chloroform was easy emulsification, finally, we
of the solid dispersions at all time intervals which
347

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Xu DH et al. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006; 6(4):343-349

indicated that the solid dispersions improved oral
K30 solid dispersions was much higher than pure
absorption and bioavailability. One determinant
curcumin and physical mixtures, it was obviously that
factor for absorption is drug dissolution which is
the plasma concentration of curcumin was
influenced by the solubility of the drug in the
comparatively low and the plasma concentration of
gastrointestinal fluids. The curcumin-PVP K30 SDs
curcumin decreased rapidly 1h after oral
we developed significantly enhanced dissolution rate
administration of the solid dispersions to rats, which
and solubility of curcumin thus could improved oral
may be associated with the biotransformation in vivo.
absorption. Time to reach Cmax (Tmax) was about 44
By adding curcumin in the suspensions of hepatocyte
min which was in corresponden with the dissolution
or liver microsomal, Wahlstrom et al. found 90% of
rate in vitro study.
urcumin disappeared and metabolited within 30min
Although the bioavailability of curcumin-PVP
(Vajragupta et al.,2005) [17] and Pan et al.

thought curcumin glucuronide, dihydro-curcumin
modified cyclodextrins. Journal of Photochemistry and
glucuronide, tetrahydro-curcumin glucuronide and
Photobiology A: Chemistry 2005;173( 3):230-237.
tetrahydro-curcumin were the major metabolites in
2.
Barik A, Mishra B, Liang S, Mohan H. Evaluation of a new
vivo(Pan et al., 1999)[11]. It was yet not clear that the
copper (II)–curcumin complex as superoxide dismutase
metabolism of curcumin proceed in small intestine or
mimic and its free radical reactions. Free Radical Biology
in liver. The rapid rates of metabolism and
and Medicine 2005; 39(6):811-822.
3.
Chai H, Yan SY, Lin P, Lumsden AB. 2005.Curcumin
biotransformation of curcumin might be the reason of
Blocks HIV Protease Inhibitor Ritonavir-Induced Vascular
low plasma concentration, hence further experiment
Dysfunction in Porcine Coronary Arteries. Journal of the
needed to be conducted to fully investigate the
American College of Surgeons, 2005; 200( 6):820-830.
relationship between the pharmacokinetics and
4.
Chattopadhyay I, Bandyopadhyay U, Biswas K, Maity P,
biotransformation.
Banerjee R. K Indomethacin inactivates gastric peroxidase
The method we developed to determine the
to induce reactive-oxygen-mediated gastric mucosal injury
plasma concentration of curcumin was rapid, precise
and curcumin protects it by preventing peroxidase
and convenient. This study demonstrated that the oral
inactivation and scavenging rective oxygen, Free Radical
bioavailability of curcumin was significantly
Biology and Medicine 2006;in Press.
improved by preparation of PVP K30 SDs, and
5.
Dorai T, Aggarwal BB. Role of chemopreventive agents in
curcumin-PVP K30 SDs could be applied in
cancer therapy. Cancer Letters 2004; 215(2):129-140.
6. Cabral Marques HM. Structure and properties of
pharmacological activities of curcumin.
cyclodextrins. Inclusion complex formation, Rev Port Farm
In Ayurveda, turmeric has been used internally
1994; XLIV (2): 77–83.
as a stomachic, tonic and blood purifier and
7.
Hahm ER, Gho YS, Park S, Park C. Synthetic curcumin
externally in the prevention and treatment of skin
analogs inhibit activator protein-1 transcription and
diseases (The Wealth of India, 2001). The present
tumor-induced angiogenesis. Biochemical and Biophysical
gastroprotective researches showed that the
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curcumin-PVP K30 SDs possess gastroprotective
8.
Ireson C, Orr S, Jones D.J . Characterization of metabolites
activity as evidenced by its significant inhibition in
of the chemopreventive agent curcumin in human and rat
the formation of ulcers induced by various physical
hepatocytes and in the rat in vivo, and evaluation of their
and chemical agents. The oral bioavailability and
ability to inhibit phorbol ester-induced prostaglandin E2
protective effects of curcumin were enhanced in solid
production. Cancer Research, 2001; 61(3):1058-1064.
9.
Stella JV, Rajewski RA. Cyclodextrins: their future in drug
dispersions with the polymers PVP-K30, which
formulation and delivery. Pharm. Res 1997; 14 (5), 556–567
indicated that curcumin could be developed into a
10. .Lumsden AB, Yao QZ, Chen CY, Literat A. Regulation of
new anti-ulcerogenic drug.
pro-inflammatory cytokine expression by curcumin in

hyaline membrane disease (HMD). Life Sciences 2001;
Acknowledgements
70(3): 253–267.
Project supported by the National Natural
11. Pan MH, Huang TM, Lin JK. Biotransformation of
Science Foundation of China, No. 30170105;
curcumin through reduction and glucuronidation in mice.
Supported Program of New Century Excellent Talent
Drug Metabolism & Disposition 1999; 27(4):486-494.
?No.NCET-04-0808?; Supported Program of Fok
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obtained by spray drying. Int. J Pharm 2004; 271:281-286.
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