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Pharmacokinetic Study of Nanoparticulate Curcumin: Oral Formulation for Enhanced Bioavailability

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Journal of Biomaterials and Nanobiotechnology, 2013, 4, 291-299
http://dx.doi.org/10.4236/jbnb.2013.43037 Published Online July 2013 (http://www.scirp.org/journal/jbnb)
291
Pharmacokinetic Study of Nanoparticulate Curcumin:
Oral Formulation for Enhanced Bioavailability
R. Ravichandran
Regional Institute of Education, National Council of Educational Research and Training (NCERT), Mysore, India.
Email: ravincert@gmail.com
Received January 22nd, 2013; revised February 23rd, 2013; accepted March 15th, 2013
Copyright © 2013 R. Ravichandran. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Curcumin, a bioactive component of turmeric, which is a commonly used spice and nutritional supplement, is isolated
from the rhizomes of Curcuma longa Linn. (Zingiberaceae). In recent years, the potential pharmacological actions of
Curcumin in inflammatory disorders, cardiovascular disease, cancer, Alzheimer’s disease and neurological disorders
have been shown. However, the clinical application of Curcumin is severely limited by its main drawbacks such as in-
stability, low solubility, poor bioavailability and rapid metabolism. Multifarious nanotechnology-based drug delivery
systems for Curcumin including liposomes, polymeric nanoparticles, solid lipid nanoparticles, micelles, nanogels,
nanoemulsions, complexes and dendrimer/dimer, have been attempted to enhance the oral bioavailability, biological
activity or tissue-targeting ability of Curcumin. We attempted the nanosuspensions based delivery of curcumin. Nano-
nisation renders curcumin completely dispersible in aqueous media. To enhance the curcumin absorption by oral admini-
stration, nanoparticulate solid oral formulation of curcumin was prepared by us and the resulting capsule was then ex-
amined for its efficiency on bioavailability in Male Wistar rats at a dose of 100 mg curcumin/kg body weight and the
pharmacokinetic parameters were compared to those of normal curcumin powder and a commercial curcumin capsule
CUR-500. The bio-distribution of curcumin in organs of rat was also studied. Nanoparticulation significantly raised the
curcumin concentration in selective organs in the body. The results obtained provide promising results for nanoparticu-
late Curcumin to improve its biological activities. Enhanced bioavailability of curcumin in the form of nanoparticle is
likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease. The
available information also strongly suggests that nano-formulation of ingredients such as curcumin may be used as a
novel nutrient delivery system too.
Keywords: Curcumin; Nanoparticles; Pharmacokinetics; Bioavailability
1. Introduction
Turmeric (Curcuma longa Linn), is a crystalline com-
pound which has been traditionally used in medicine and
cuisine in India and other Asian countries. Curcumin, a
hydrophobic polyphenol derived from the rhizome of the
herb Curcuma longa has a wide spectrum of biological
and pharmacological activities. Chemically, curcumin is
a bis-α, β-unsaturated β-diketone (commonly called dife-
ruloylmethane, Figure 1), which exhibits keto-enol tau-
tomerism having a predominant keto form in acidic and
neutral solutions and stable enol form in alkaline medium.
Commercial curcumin contains approximately 77% di-
feruloylmethane, 17% demethoxycurcumin, and 6% bis-
demethoxycurcumin. Traditionally, turmeric has been us-
ed for many ailments, particularly as an anti-inflammato-
ry agent, and curcumin has been identified as the active
Figure 1. Metabolic reduction.
principle of turmeric [1]. Curcumin has been shown to
exhibit antioxidant, anti-inflammatory [2-5] antimicrobial,
and anticarcinogenic [6-10] activities. Additionally, the
hepato- and nephro-protective [11-13] thrombosis sup-
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Pharmacokinetic Study of Nanoparticulate Curcumin: Oral Formulation for Enhanced Bioavailability
292
pressing [14] myocardial infarction protective [15-17] hy-
poglycemic [18-21] and antirheumatic [22] effects of
curcumin are also well established. It is generally recog-
nized that the therapeutic effectiveness of curcumin is
limited due to its poor absorption from the gastrointesti-
nal tract and poor bioavailability due to its rapid metabo-
lism in the liver and intestinal wall. Oral doses result in
only traces appearing in the blood, with most of the dose
being excreted in the feces. The predominant metabolites
in plasma following oral administration of curcumin were
glucuronides and glucuronide/sulfates. The conjugative
enzyme activities for glucuronidation and sulfation of
curcumin were found in liver, kidney and intestinal mu-
cosa. These results indicate that orally administered cur-
cuminoids are absorbed from the alimentary tract and
present in the general blood circulation after largely be-
ing metabolized to the form of glucuronide and glucu-
ronide/sulfate conjugates. Various animal models [23,24]
or human studies [25-28] proved that curcumin is extre-
mely safe even at very high doses. For example, three
different phase I clinical trials indicated that curcumin,
when taken as high as 12 g per day, is well tolerated [26-
28]. Similarly, the efficacy of curcumin in various dis-
eases including cancer has been well established [29].
Several clinical studies dealing with the efficacy of cur-
cumin in humans can also be cited [1,30]. The pharma-
cological safety and efficacy of curcumin make it a po-
tential compound for treatment and prevention of a wide
variety of human diseases. In spite of its promising the-
rapeutic index, the biological activity of curcumin is se-
verely limited due to its poor bioavailability and hence
has not yet been approved as a therapeutic agent. Effec-
tive methods to deliver such substances to increase their
bioavailability have been a major challenge in current
biomedical and food research. Earlier we have reported
the preparation and characterisation of curcumin nano-
suspension for enhanced solubility and dissolution veloc-
ity followed by the development of an oral curcumin na-
nocrystal capsule formulation [31]. The present study
was designed to evaluate this capsule formulation for im-
proved pharmacokinetic parameters and hence the bio-
availability and food functionality following oral admini-
stration in rats.
2. Materials and Methods
2.1. Materials
Curcumin was a gift sample from Indsaff Inc., Bhuba-
neswar, India. Curcumin nanosuspensions were stabiliz-
ed by Polyvinyl alcohol (PVA, molecular weight 90,000,
Sigma-Aldrich, USA) and sodium dodecyl sulfate (Fluka
Switzerland). Milli-Q Plus water, double-distilled water
(Millipore, USA) was used as dispersion medium. The
other chemicals were of analytical reagent grade (SRL,
Mumbai, India).
2.2. Preparation of Curcumin Nanosuspensions
The curcumin nanosuspension on a lab scale is typically
produced by pre-milling (with SDS 0.2%) followed by
high pressure homogenization in pure water using a con-
tinuous Micron LAB 40 at room temperature, applying
20 homogenization cycles at 1500 bar. The formulation
of curcumin nanosuspension was prepared using Curcu-
min 10%, Polyvinyl alcohol 2% and Water 88%.
2.3. Formulations of the Curcumin Capsule
Curcumin was admixed to the capsule excipients by a
tumbler (Turbula, Willy A. Bachofen, Basel, Switzer-
land). The mixed powder was filled into hard gelatin cap-
sule no. 2 using a simple filling capsule equipment for
lab scale. The final product of the capsules were collect-
ed and immediately transferred into dry plastic containers
and tightly sealed. Formulation: Curcumin nanocrystal
500 mg; Excipient (mg): Lactose 15; Avicel PH 102 190;
Magnesium stearate 1.
2.4. Experimental Animals
Male Wistar rats weighing 250 g were used in this study
in accordance with institutional guidelines and approval
of local ethics authorities. The animals were fed with
commercial pellet diet (Kamadenu Agencies, Bangalore,
India) and water ad libitum. The animals were acclima-
tized to laboratory hygienic conditions for 10 days before
starting the experiment. The animals were maintained in
groups of six and were fasted for 8 h prior to the com-
mencement of the study.
2.5. Animal Treatment
Male Wistar albino rats were kept under a twelve-hour
light/dark cycle on standard lab chow. Animals were
fasted overnight and received Curcumin nanocrystal-load-
ed capsules, marketed CUR-500 capsules and common
curcumin powder at 100 mg/Kg body weight by oral ga-
vage. At 30, 60, 90 and 120 min, animals were exsangui-
nated under terminal anaesthesia. Group size was 6 rats
per time point. Whole blood was collected by cardiac
puncture into heparinized tubes, centrifuged immediately
at 7000 × g for 15 min, plasma was then decanted and
stored at 80˚C until analysis. The organs (liver, heart,
spleen, lung, kidney and brain) were removed and trans-
ferred into 50 ml tubes.
2.6. Sample Preparation
Curcumin and curcumin metabolites were extracted from
plasma by solid phase extraction. Plasma (1 ml) was load-
ed onto a 1cc Oasis HLB cartridge, washed with 25:25:1
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Pharmacokinetic Study of Nanoparticulate Curcumin: Oral Formulation for Enhanced Bioavailability 293
methanol:water:glacial acetic acid (1 ml), and eluted with
1 ml of methanol containing 2% glacial acetic acid. Elu-
ant was evaporated to dryness at 45˚C under a stream of
nitrogen, and the residue was re-suspended in 75 μl of
50% aqueous acetonitrile. Standard solutions of curcu-
min (5 - 1000 ng/ml) were prepared in 1 ml human plas-
ma (obtained from local blood bank) and extracted as de-
scribed above. Extraction efficiency was 59% with 2.5
and 4.5% intra and inter day variability, 99% accuracy
and response was linear over the range 5 - 1000 ng/ml
with an R2 value consistently of 0.999. The organs were
weighed and homogenized in isotonic KCl. An aliquot
(0.5 ml) of it was mixed with 2 ml of acetone: formic
acid (9:1), and the mixture was immediately vortexed.
The samples were then centrifuged at 6000 rpm for 10
min at 4˚C and the supernatant was collected and pre-
served at 20˚C before further sample assay. After cen-
trifuging at 12,000 rpm for 15 min, 20 μl of supernatants
were collected and analyzed by the HPLC system.
2.7. HPLC Analysis of Curcumin
A validated sensitive and selective high-performance li-
quid chromatography (HPLC) method using UV-vis de-
tection was used for the determination and quantifica-
tion of curcumin and its metabolites. The HPLC system
consisted of a Shimadzu LC 6A HPLC instrument equip-
ped with a solvent delivery pump, a Rheodyne injector
valve and a variable wavelength UV detector. The col-
umn used was reversed phase C 18 analytical column
(4.6 × 250 mm, particle size 5 µm), with mobile phase
consisting of two components: A, 10 mM ammonium
acetate pH 4.5; B, acetonitrile. Initial conditions were
95% A progressing to 55% A at 20 min and 5% A at 33
min. The flow rate was maintained at 1 mL/min at 45 ±
2˚C. The eluate was monitored at 420 nm. Retention time
for curcumin, curcumin sulfate and curcumin glucuron-
ide were 8, 7.4 and 7.1 min respectively. Free curcumin
is completely insoluble in water therefore the concentra-
tion of curcumin was calculated using standard curve of
curcumin in ethanol. The data was recorded and calcu-
lated using Winchrome software.
2.8. Pharmacokinetic Analysis
Pharmacokinetic calculations were performed on each
individual set of data using the WinNonlin Standard Edi-
tion Version 2.1 by non-compartmental method. Pharma-
cokinetic results are represented as mean ± SEM. Sta-
tistical analysis was performed by t test (SPSS version
10.0) to compare different groups. The level of signifi-
cance was set at p < 0.05.
3. Results and Discussion
Earlier we have developed a capsule containing oral solid
formulation of nanoparticulate curcumin and investigated
its dissolution behavior in different medium. The study
was very successful and the data is being published. This
Cur-NS-B had LD particle size distribution of 0.1 μm (<
d 10%), 0.2 μm (< d 50%), 1.8 μm (< d 90%) and 2.8 μm
(< d 99%). PCS size 306 nm, Zeta potential (mV) of 6.4
in water and 2.7 in original medium. Visual examina-
tion of crystals in nanosuspensions from images of the
nanosuspensions from light microscopy and scanning
electron microscopy showed fine stable homogeneous
distribution. It showed very good physical and chemical
stability over 3 and 6 months period respectively. A
spray drying process was employed to obtain dried cur-
cumin nanocrystals having good re-dispersability, satura-
tion solubility and dissolution velocity. LD values were
0.13 μm (< d 10%), 0.4 μm (< d 50%), 3.1 μm (< d 90%)
and 3.9 μm (< d 99%). PCS size was 321 nm and PI of
0.38. In general, the saturation solubility of the nano-
crystals was distinctly 5 fold higher than for microparti-
cles. Free curcumin is poorly soluble in aqueous media,
with macroscopic undissolved flakes of the compound
visible in the solution (Figure 2(a)); in contrast, nano-
particulate curcumin is a clear, dispersed formulation, with
its hue derived from the natural colour of curcumin (Fig-
ure 2(b)). The results also showed the superiority of cur-
cumin nanocrystals in dissolution behavior and was in
agreement with the Noyes-Whitney equation. According
to these results, curcumin nanocrystals are suitable for
incorporation into solid dosage form, such as tablets, cap-
sules, pellets etc. Accordingly a capsule containing these
nanoparticulate curcumin was formulated as given in ex-
perimental section and tested for its bio-efficacy.
3.1. Pharmacokinetic Parameters of Curcumin
and Its Metabolites in Rat Plasma
In the present investigation, Curcumin nanocrystal-load-
ed capsules, marketed CUR-500 capsules and common
curcumin powder were chosen for the pharmacokinetics
studies. Figure 3 shows the mean plasma curcumin con-
centration versus time profiles before and after oral ad-
ministration of Curcumin nanocrystal-loaded capsules,
(
a
)
(
b
)
Figure 2. (a) Free curcumin is poorly soluble in aqueous
media, and macroscopic flakes can be seen floating in the
bottle. (b) In contrast, curcumin nanoparticles are fully dis-
persible in aqueous media.
Copyright © 2013 SciRes. JBNB
Pharmacokinetic Study of Nanoparticulate Curcumin: Oral Formulation for Enhanced Bioavailability
Copyright © 2013 SciRes. JBNB
294
Figure 3. Concentration of curcumin in rat plasma after a single oral administration of: Curcumin nanocrystal-loaded cap-
sules, marketed CUR-500 capsules and common curcumin powder (100 mg curcumin/kg body weight). All nano data showed
a significant difference at P < 0.01 (vs common curcumin powder group). Values are represented as means ± SEMs (n = 6).
capsules group (410.2 ± 70.4 μg/L) was much higher
than that obtained with marketed CUR-500 capsules
(92.3 ± 17.9 μg/L) (Table 1). The AUC0-120 value of
curcumin after oral administration of Curcumin nano-
crystal-loaded capsules was 31502.8 μg min/L, which
was 4 fold greater than that after marketed CUR-500 cap-
sules administration. The values obtained for common
curcumin powder was little less than that of CUR-500.
Further we compared plasma levels of curcumin metabo-
lites mainly curcumin glucuronide and curcumin sulfate
in animals that had received either unformulated or nan-
oformulated curcumin (Table 1). A similar trend was ob-
served here also. The metabolites were very many folds
in much shorter time with nanoformulation as compared
to nonformulated curcumin. Several lines of studies have
demonstrated that administration of nanoparticles would
enhance drug absorption and systemic bioavailability
[33]. It could thus be possible that nanoparticulate cur-
cumin also similarly exerts an activation effect on cur-
cumin absorption in the gastrointestinal (GI) tract. Our
experiment revealed that smaller the particle size greater
the effect on enhanced curcumin absorption by oral ad-
ministration (Figure 3). Accordingly, it seems that the
nanonisation of curcumin leads to a substantial improve-
ment in curcumin absorption. We considered three possi-
ble explanations of the above results: 1) Enhanced bioa-
vailability of nanoformulation might be attributed to the
direct uptake of nanoparticles through the GI tract, 2)
increased permeability by surfactants, and 3) decreased
degradation and clearance. First, the uptake of curcumin
in a nano form could be accomplished through the GI
tract, where particle size plays a dominant role in absorp-
tion rate [34]. The mechanisms involved in such uptake
include the diffusion of particles through mucus and ac-
cessibility to an enterocyte surface, epithelial interaction
and cellular trafficking, and exocytosis and systemic dis-
marketed CUR-500 capsules and common curcumin
powder, at a dose of 100 mg of curcumin/Kg body weight
for each treatment group. The peak concentration (Cmax)
and time of peak concentration (Tmax) were obtained di-
rectly from the individual plasma curcumin concentration
versus time profiles. The area under the concentration-
time curve from 0 to 120 min (AUC0-120) was calculated
using the trapezoidal method [32]. The AUC determines
the bioavailability of the drug for a given dose of the
formulation. These oral pharmacokinetic parameters are
listed in Table 1. As shown in Figure 3, plasma curcu-
min concentrations were significantly higher in rats ad-
ministrated Curcumin nanocrystal-loaded capsules than
in those administrated marketed CUR-500 capsules or
common curcumin powder, at all time points. The Cmax
value of curcumin in the Curcumin nanocrystal-loaded
Table 1. Pharmacokinetic parameters derived from rat pla-
sma.*
Sample AUC0-120 min
(μg min/L)
Cmax
(μg/L plasma) Tmax (min)
Curcumin powder 5642.6 84.6 ± 10.7 120
Curcumin glucuronide 212418.4 2571 ± 34.8 90
Curcumin sulfate 15824.6 81.6 ± 6.2 120
CUR-500 Curcumin 7832.6 92.3 ± 17.9 120
Curcumin glucuronide 294314.1 3663 ± 21.9 90
Curcumin sulfate 18248.7 89.9 ± 2.4 120
Nanoparticulate
curcumin 31502.8 410.2 ± 70.4 30
Curcumin glucuronide 4762662.4 42044.8 ± 66.2 60
Curcumin sulfate 25824.6 338 ± 14.4 90
*AUC: area under the blood concentration vs time curve; Cmax: maximum
concentration; and Tmax: time to reach Cmax.
Pharmacokinetic Study of Nanoparticulate Curcumin: Oral Formulation for Enhanced Bioavailability 295
semination. A drug particle size of approximately 200
nm allows for efficient uptake in the intestine, particu-
larly in the lymphoid sections of this tissue [35], and
therefore bypass of the first-pass metabolism in the liver
[36]. Second, GI absorption of drugs with low water so-
lubility is enhanced when they are nanosuspension to in-
crease surface area [37]. Thus, the surfactants involved in
the formulations could affect the permeability and solu-
bility of drugs across the membrane of the GI tract. Third,
by incorporation into nano form, curcumin can be em-
bedded into the phospholipid bilayer. This reduces its ex-
posure to bacteria as well as enzymatic degradation dur-
ing the absorption process. This also allows for prolong-
ed contact with the intestinal wall due to the adhesive
property that nano form exhibit toward the epithelial mu-
cosal surface of the small intestine [38]. Accordingly, it
seems that nanonisation of curcumin is highly advanta-
geous for optimizing food functionality. Several studies
have found that curcumin also has an antioxidant activity
in vitro [39].
3.2. Pharmacokinetic Parameters of Curcumin
in Rat Organs
The pharmacokinetic parameters of curcumin in rat or-
gans are given in Table 2. In the curcumin powder and
commercial product, the AUCs of curcumin in kidney
(168.4; 194.6) and liver (76.2; 79.8) were larger than in
other organs, indicating that more curcumin was in these
two organs. The least was found in heart and brain (32 to
36). One possible reason for these results is that the sys-
temic circulation of curcumin in the body is limited since
a substantial amount of curcumin is distributed to the li-
ver and kidney, where it is metabolized and eliminated
[40]. However, when nanoparticulate curcumin was ad-
ministrated, a significant amount of curcumin was found
in spleen and lung, and the AUC of curcumin in these
organs were 1624.2 and 458.8, respectively. The levels
of nanoparticulate curcumin amassed in spleen tissue is
closely related to phagocytic cell uptake in the reticulo-
endothelial system [41]. The lung accumulation contrib-
utes to the filtration of pulmonary capillary beds follow-
ing nanoparticulate curcumin administration [42]. In the
case of brain and heart the increase was only marginal
compared to other organs but still being significant. Bas-
ed on the finding that the main organs of distribution in
the nanoparticulate curcumin treated group, are the spleen
and lungs instead of the liver and kidney in conventional
curcumin treated group, the advantage of nanoparticle in
our study is credited with the fact that formulation has
prohibited curcumin distributing to major organs meta-
bolized drugs. The same observation could be made from
the data obtained for Cmax and Tmax. However the Tmax
data gives some more interesting features. While there is
a general decrease in this value across the organs studied,
Table 2. Pharmacokinetic parameters derived from rat
organs for curcumin content.
Organs AUC
(μg min/g)
Cmax
(μg/g)
Tmax
(min)
Kidney
Curcumin powder 168.4 21.1 90
CUR-500 Curcumin 194.6 24.4 90
Nanoparticulate curcumin 286.4 24.8 60
Liver
Curcumin powder 76.2 8.6 90
CUR-500 Curcumin 79.8 8.4 90
Nanoparticulate curcumin 182.6 19.8 90
Lung
Curcumin powder 72.6 9.3 120
CUR-500 Curcumin 74.2 9.8 120
Nanoparticulate curcumin 458.8 37.2 60
Spleen
Curcumin powder 62.6 7.9 120
CUR-500 Curcumin 64.6 7.6 120
Nanoparticulate curcumin 1624.2 172.2
30
Brain
Curcumin powder 36.2 4.6 120
CUR-500 Curcumin 36.6 4.8 120
Nanoparticulate curcumin 82.8 8.2 90
Heart
Curcumin powder 32.6 3.8 120
CUR-500 Curcumin 33.0 4.0 120
Nanoparticulate curcumin 52.8 6.8 90
*AUC: area under concentration curve; Cmax: maximum concentration; and
Tmax: time to reach Cmax.
the decrease is remarkable in spleen and lungs. Thus na-
noparticle proves to be much different in its reach, distri-
bution and action.
According to these distribution results, curcumin can
arrive in organs, where it can perform its pharmacodyna-
mic activities, as demonstrated by previous studies. After
nano-formulation, the concentration of curcumin in these
organs was significantly increased. These pharmacokine-
tic data suggest that nanoparticulate curcumin might of-
fer greater therapeutic effect than conventional curcumin
from a pharmacodynamic perspective. Therefore, the dis-
tribution results of curcumin and nanoparticulate curcu-
min to the site of action are vital for dose determination,
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Pharmacokinetic Study of Nanoparticulate Curcumin: Oral Formulation for Enhanced Bioavailability
296
time to administration and toxicity in pre-clinical and cli-
nical therapeutic research.
3.3. Problems of Curcumin Bioavailability
The reasons for reduced bioavailability of any agent with-
in the body are low intrinsic activity, poor absorption,
high rate of metabolism, inactivity of metabolic products
and/or rapid elimination and clearance from the body.
Studies to date have suggested a strong intrinsic activity
and, hence, efficacy of curcumin as a therapeutic agent
for various ailments. However, studies over the past three
decades related to absorption, distribution, metabolism
and excretion of curcumin have revealed poor absorption
and rapid metabolism of curcumin that severely curtails
its bioavailability [29]. The main problems of curcumin
bioavailability are low serum levels, limited tissue dis-
tribution, apparent rapid metabolism and short half-life.
3.4. Promises
The absorption, bio distribution, metabolism, and elimi-
nation studies of curcumin have, unfortunately, shown
only poor absorption, rapid metabolism, and elimination
of curcumin as major reasons for poor bioavailability of
this interesting polyphenolic compound. Some of the
possible ways to overcome these problems are: Adju-
vants, which can block metabolic pathways of curcumin,
are one of the major means that are being used to im-
prove its bioavailability; Liposomes, Micelles, and Phos-
pholipid complexes are other promising novel formula-
tions, which appear to provide longer circulation, better
permeability, and resistance to metabolic processes. Re-
cently a novel formulation to deliver curcumin embed-
ding phospholipid vesicles or lipid-nanospheres (Cm)
into tissue macrophages through intravenous injection
has been developed [43]. More recently, curcumin or a
curcumin analogue encapsulated in a colloidal drug a
liposome is considered as excellent drug delivery sys-
tems since they can carry both hydrophilic and hydro-
phobic molecules [44]. Experimental evidences shows
47% to 56% enhanced intestinal absorption of curcumin
when embedded with micelles then free curcumin in vi-
tro [45] in rats. The molecular and chemical structure of
curcumin plays a crucial role in its biological activity.
Reports suggest change in antioxidant activity of curcu-
min due to isomerization. With a view to achieve im-
proved biological activity of curcumin through structural
modifications or curcumin derivatives and/or its analo-
gues research was made by various research groups [46].
For example, a curcumin analogue EF-24 had shown in-
creased antitumor activity in comparison to curcumin in
vitro and in vivo, and increased bioavailability of EF-24
was also demonstrated by 60% and 35%, respectively in
male and female mice [47]. Another strategy to improve
the biological activity of curcumin is by chelation with
various metals as compared to free curcumin. The pres-
ence of two phenolic groups and one active methelene
group in a curcumin molecule makes it an excellent lig-
and for any chelation [48].
3.5. Nanoparticles
Recently, targeted and triggered drug delivery systems
accompanied by nanoparticle technology have emerged
as prominent solutions to the bioavailability of therapeu-
tic agents. Nanoparticle-based delivery systems will pro-
bably be suitable for highly hydrophobic agents like cur-
cumin circumventing the pitfalls of poor aqueous solu-
bility. However, very few studies have been published ci-
ting curcumin nanoparticles. A recent study by Bisht et
al. reported the synthesis, physicochemical characteriza-
tion and cancer related application of a polymer-based
nanoparticle of curcumin namely “nanoparticulate curcu-
min” with less than 100 nm size. Nanoparticulate curcu-
min, is made up of the micellar aggregates of cross-link-
ed and random copolymers of Nisopropylacrylamide
(NIPAAM), with N-vinyl-2-pyrrolidone (VP) and poly
(ethyleneglycol) monoacrylate (PEG-A). Nanoparticulate
curcumin, unlike free curcumin, is readily dispersed in
aqueous media. Nanoparticulate curcumin was found to
have similar in vitro activity as that of free curcumin in
pancreatic cell lines. Like free curcumin, nanoparticulate
curcumin also inhibits activation of the transcription fac-
tor NFκB, and reduces steady state levels of pro-inflam-
matory cytokines like interleukins and TNF-R. However,
the authors neither determined the in vivo effect of na-
noparticulate curcumin in mice nor its biodistribution to
show any potential increase in efficacy of nanaocurcumin
over free curcumin in vivo [49]. Solid lipid nanoparticles
(SLNs) loaded with curcuminoids for topical application
were developed and characterized by Tiyaboonchai et al.
Curcuminoid loaded SLNs having 450 nm size were
found to be stable for 6 months at room temperature and
gave prolonged in vitro release of curcuminoids up to 12
h. Furthermore, the light and oxygen sensitivity of cur-
cuminoids was strongly reduced by incorporating curcu-
minoids into this unique type of formulation. An in vivo
study with healthy volunteers reveled the improved effi-
ciency of a topical application cream containing curcu-
minoid loaded SLNs over that containing free curcuma-
noids [50]. Overall, nanoparticle based systems for cur-
cumin delivery is still in its infancy and much progress is
warranted in this area.
3.6. Nanoparticle Mediated Delivery Systems
Nanoparticles-based materials have attracted much atten-
tion in recent years because of their characteristic size
and geometry dependent chemical and physical proper-
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Pharmacokinetic Study of Nanoparticulate Curcumin: Oral Formulation for Enhanced Bioavailability 297
ties [27]. Nanoparticles are of great scientific interest as
they are effectively a bridge between bulk materials and
atomic or molecular structures. Literature survey suggests
nanoparticle research is an area of intense scientific re-
search, due to wide potential applications in human ther-
apy. Nano particles are sized between 1 and 100 nm. Na-
noparticles have a very high surface area to volume ratio.
This makes the particles very reactive or catalytic [51].
Nanoparticles are easier to pass through cell membranes
in organisms and get interacted rapidly with biological
systems [51]. Recently, nanoparticle technology emerged
as a potential area of targeted drug delivery systems and
make biologically availability of therapeutic agent. Na-
noparticle-mediated delivery systems will probably be
the most suitable for highly hydrophobic agents like cur-
cumin, circumventing its poor aqueous solubility [52,53].
However, very limited studies were made and the com-
plete mechanism regarding nanoparticle mediated curcu-
min delivery system is still unknown [54].
4. Conclusion
The present work clearly demonstrated the superiority of
nanoparticulate curcumin obtained through nanosuspen-
sion over normal/commercial curcumin in being more bi-
oefficient, suggesting novel delivery strategies for curcu-
min in therapeutic applications. This pharmacokinetic
study offers significant promises and is worthy of further
exploration in attempts to enhance the bioavailability,
medicinal value, and application of this interesting mole-
cule from Mother Nature.
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... Nanocrystals have already been shown to increase dissolution rates for curcumin [75] and resveratrol [76,110] compared to crude compounds. They have also provided improved the oral bioavailability of these compounds in animal models, as seen by the severalfold increases in AUC and c max compared to administration of larger free drug particles [110,111]. A negative aspect of nanocrystals presents itself in their high surface free energy, which increases the potential for agglomeration, and thus necessitates the use of stabilisers. ...
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... It reduces the tumor growth by inductions of apoptosis, suppression of proliferation as well as prevention of metastasis [3]. But the poor solubility, instability and low bioavailability are the major obstacles for biological application of CUR inside the body [4,5]. To circumvent these barriers, various delivery strategies and systems are developed for curcumin delivery [2,6,7]. ...
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Combination of natural polymer and nanoparticle has always been fascinating for biomedical applications. Here, we have demonstrated a simplified dessolvation-coprecipitation technique for the development of gelatin grafted Fe3O4 magnetic nanoparticles (Gel-MNPs), and investigated their potential applications in drug delivery and hyperthermia therapy. XRD, TEM, FTIR, TGA and light scattering techniques were used to confirm the phase formation of core Fe3O4 MNPs and their successful surface modification with gelatin moieties. The Gel-MNPs showed good aqueous colloidal stability and pH dependent surface charge characteristics. The hydrophobic anticancer agent, curcumin was employed as a model drug to investigate the loading and release properties of Gel-MNPs. A loading efficiency of about 95% was achieved at drug to particle ratio of 1:10 and curcumin loaded Gel-MNPs (Cur-Gel-MNPs) exhibited pH dependent release behaviour of loaded drug with higher release at mild acidic environment. These Cur-Gel-MNPs have shown dose dependent cytotoxicity towards lung (A549) and breast (MCF-7) cancer cell lines. Further, CUR-Gel-MNPs exhibited enhanced heat activated killing of cancer cells under AC magnetic field, suggesting their usefulness for magnetic hyperthermia therapy.
... This increase in bioavailability is explained for several reasons. Firstly, nanoparticles are easier to pass through cell membranes in organs and get interacted rapidly with biological systems, so nanosized delivery systems will probably be the most appropriate for highly hydrophobic agents such as CUR [46]. Secondly, due to P-gp inhibitory function by TA, CUR particles prolonged intestinal retention and improved trans-epithelial transport properties [47]. ...
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Curcumin (CUR) has been used in the treatment of various diseases such as cough, fever, skin disease, and infection because of various biological benefits such as anti-inflammatory, antiviral, antibacterial, and antitumor activity. However, CUR is a BCS class 4 group and has a limitation of low bioavailability due to low solubility and permeability. Therefore, the purpose of this study is to prepare a nanosuspension (NSP) loaded with CUR (CUR-NSP) using a statistical design approach to improve the oral bioavailability of CUR, and then to develop CUR-NSP coated with tannic acid to increase the mucoadhesion in the GI tract. Firstly, the optimized CUR-NSP, composed of sodium dodecyl sulfate (SDS) and polyvinylpyrrolidone/vinyl acetate (PVP/VA), was modified with tannic acid (TA). The particle size and polydispersity index of the formulation measured by laser scattering analyzer were 127.7 ± 1.3 nm and 0.227 ± 0.010, respectively. In addition, the precipitation in distilled water (DW) was 1.52 ± 0.58%. Using a differential scanning calorimeter and X-ray diffraction analysis, the stable amorphous form of CUR was confirmed in the formulation, and it was confirmed that CUR-NSP formulation was coated with TA through a Fourier transform-infrared spectroscopy. In the mucoadhesion assay using the turbidity, it was confirmed that TA-CUR-NSP had higher affinity for mucus than CUR-NSP under all pH conditions. This means that the absorption of CUR can be improved by increasing the retention time in the GI tract of the formulation. In addition, the drug release profile showed more than 80% release, and in the cellular uptake study, the absorption of the formulation (TA-CUR-NSP) containing TA acting as an inhibitor of P-gp was increased by 1.6-fold. In the evaluation of antioxidant activity, the SOD activity of TA-CUR-NSP was remarkably high due to TA, which improves cellular uptake and has antioxidant activity. In the pharmacokinetic evaluation, the maximum drug plasma concentration of the TA-coated NSP formulation was 7.2-fold higher than that of the pure drug. In all experiments, it was confirmed that the TA-CUR-NSP is a promising approach to overcome the low oral bioavailability of CUR.
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Curcumin is used as nutraceutical. It is a yellow pigment derived from turmeric (Curcuma longa). It can be used as anti-diabetic, antibacterial, anti-tumor, anti-rheumatic, anti-viral and anti-cancer agent. But poor solubility, rapid degradation and low bioavailability have limited its use in clinical practice. The best way to overcome these problems is to load curcumin in poly lactic co-glycolic acid (PLGA) nanoparticles. Curcumin loaded PLGA nanoparticle increase the bioavailability and absorption of drug. The focus of study was to introduce a method for preparation of nanoparticle with a view to increase the aqueous solubility of curcumin, and to characterize the prepared nanoparticles and access their antibacterial activity and to modify the pharmacokinetic behavior of drug. The nanoparticles were prepared by nanoprecipitation method and it was found that the prepared nanoparticles lies within nanometer range. The evaluation of in-vitro release of curcumin loaded nanoparticle showed that formulation possess high drug loading capacity and entrapment efficiency (89.4%). A minimum inhibitory concentration of curcumin was determined for a variety of bacterial strains and was compared to that of commercially available antibiotic ampicillin. It was found that value of MIC of curcumin was much more pronounced than ampicillin against Staphylococcus aureus and Escherichia coli. The pharmacokinetics parameters were calculated by the pharmacokinetic APO software. The results of comparative pharmacokinetics of these nanoparticles in comparison to the pure standard showed that AUC of Cur NP was 95.38 h.mg/L much greater than pure curcumin (13.6 h.mg/L). The value of Cmax for Cur NP was also increased to 12.50µg/ml as compared to 1.50µg/ml of curcumin alone. Similarly, the value of Tmax was also increased. The increase in Cmax and Tmax values after administering curcumin loaded PLGA nanoparticles can be explained by controlled and sustained release of curcumin from PLGA nanosystem.
... Parenteral administration of Curcumin improved its efficacy by alleviating oxidative stress parameters on experimental induced oxidative stress by nitro-glycerine administration in rats [46]. Kidney concentration of curcumin nanoformulation was increased compared with conventional Curcumin proving a better bioavailability for kidney tissue [55]. Therefore, the pharmacodynamics perspective and renal tissue dispersion of Curcumin can be improved by nanoformulation. ...
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