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Bioavailable curcumin formulations: A review of pharmacokinetic studies in healthy volunteers


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Curcumin is a widely studied natural compound which has shown tremendous in vitro therapeutic potential. Despite that, the clinical efficacy of the native curcumin is weak due to its low bioavailability and high metabolism in the gastrointestinal tract. During the last decade, researchers have come up with different formulations with a focus on improving the bioavailability of curcumin. As a result, a significant number of bioavailable curcumin-based formulations were introduced with the varying range of enhanced bioavailability. The purpose of this review is to collate the published clinical studies of curcumin products with improved bioavailability over conventional (unformulated) curcumin. Based on the literature search, 11 curcumin formulations with available human bioavailability and pharmacokinetics data were included in this review. Further, the data on clinical study design, analytical method, pharmacokinetic parameters and other relevant details of each formulation were extracted. Based on a review of these studies, it is evident that better bioavailability of formulated curcumin products is mostly attributed to improved solubility, stability, and possibly low first-pass metabolism. The review hopes to provide a quick reference guide for anyone looking information on these bioavailable curcumin formulations. Based on the published reports, NovaSol® (185), CurcuWin® (136) and LongVida® (100) exhibited over 100-fold higher bioavailability relative to reference unformulated curcumin. Suggested mechanisms accounting for improved bioavailability of the formulations and details on the bioanalysis methods are also discussed.
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Bioavailable curcumin formulations: A review of pharmacokinetic
studies in healthy volunteers
Rohitash Jamwal
Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA
article info
Article history:
Received 28 March 2018
Accepted 17 May 2018
Available online 4 July 2018
Curcuma longa
Plant extracts
Human pharmacokinetics
Liquid chromatography–mass
spectrometer/mass spectrometer
Curcumin is a widely studied natural compound which has shown tremendous in vitro therapeutic poten-
tial. Despite that, the clinical efficacy of the native curcumin is weak due to its low bioavailability and
high metabolism in the gastrointestinal tract. During the last decade, researchers have come up with dif-
ferent formulations with a focus on improving the bioavailability of curcumin. As a result, a significant
number of bioavailable curcumin-based formulations were introduced with the varying range of
enhanced bioavailability. The purpose of this review is to collate the published clinical studies of cur-
cumin products with improved bioavailability over conventional (unformulated) curcumin. Based on
the literature search, 11 curcumin formulations with available human bioavailability and pharmacokinet-
ics data were included in this review. Further, the data on clinical study design, analytical method, phar-
macokinetic parameters and other relevant details of each formulation were extracted. Based on a review
of these studies, it is evident that better bioavailability of formulated curcumin products is mostly attrib-
uted to improved solubility, stability, and possibly low first-pass metabolism. The review hopes to
provide a quick reference guide for anyone looking information on these bioavailable curcumin
formulations. Based on the published reports, NovaSol
(185), CurcuWin
(136) and LongVida
exhibited over 100-fold higher bioavailability relative to reference unformulated curcumin. Suggested
mechanisms accounting for improved bioavailability of the formulations and details on the bioanalysis
methods are also discussed.
Please cite this article as: Jamwal R. Bioavailable curcumin formulations: A review of pharmacokinetic
studies in healthy volunteers. J Integr Med. 2018; 16(6): 367–374.
Ó2018 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.
1. Introduction . . . ...................................................................................................... 368
2. Methods . . . . . . ...................................................................................................... 368
3. Discussion. . . . . ...................................................................................................... 369
3.1. Overview of bioavailable curcumin formulations . . . . . . . . . . . . . . . . .......................... ............................ 369
3.1.1. Meriva
................................................................................................ 369
3.1.2. LongVida
.............................................................................................. 369
3.1.3. CurQfen
............................................................................................... 369
3.1.4. MicroActive curcumin . . . . . . .............................................................................. 369
3.1.5. Micronized curcumin . . . . . . . .............................................................................. 369
3.1.6. NovaSol
(micellar curcumin) .............................................................................. 370
3.1.7. CurcuWin
............................................................................................. 370
3.1.8. Biocurcumax
........................................................................................... 370
3.1.9. Curcumin C3 Complex
+ Bioperine . . . . . . . . . . . . . . ........................................................... 370
3.1.10. Cavacurmin
........................................................................................... 370
3.1.11. Theracurmin
.......................................................................................... 370
2095-4964/Ó2018 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.
E-mail address:
Journal of Integrative Medicine 16 (2018) 367–374
Contents lists available at ScienceDirect
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3.2. Comparison of different study parameters . . . . . . . . . . . . . . . ............. ............................................... 370
3.2.1. Clinical study design . . . . ................................................................................. 370
3.2.2. Curcumin administration . ................................................................................. 371
3.2.3. Analysis method and quantification of curcumin. . . . . . . . . . . . . . . . . .............................................. 371
3.2.4. Pharmacokinetic parameters . . . . . . . . . . . . . . ................................................................. 372
3.2.5. RB .................................................................................................... 372
3.3. Limitations. . . . . . ................................... ............................................................ 373
4. Conclusion . ......................................................................................................... 373
Conflict of interest . . . . . . . . . . . ......................................................................................... 373
References . ......................................................................................................... 373
1. Introduction
Curcuma longa Linn. (Zingiberaceae), also known as turmeric, is
a perennial plant native to tropical regions of South Asia. Since
ages, the rhizomes of the plant have been used in Indian (Ayur-
veda) and Chinese medicine system as a remedy for a variety of ail-
ments. Traditionally, curcumin is widely used as a spice, food
preservative, and a coloring agent. Many curcumin-based products
which includes capsules, ointments, tablets, cosmetics are
currently marketed worldwide. Curcumin (diferuloylmethane;
1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is
a primary, orange hydrophobic polyphenol pigment obtained from
C. longa rhizome [1]. Other reported constituents of curcumin
include demethoxycurcumin, bisdemethoxycurcumin and volatile
oils [1]. Commercially available curcumin contains a mixture of
75% curcumin, 15% demethoxycurcumin, and 5% bisdemethoxy-
curcumin (about 5%) [2]. However, the focus of this review is
limited to highly abundant curcumin.
Extensive research on curcumin over the past decade has
demonstrated the ability of this compound to modulate multiple
cellular targets, and hence potential as a preventive and therapeu-
tic against a broad range of diseases. The compound possesses a
broad range of biological activities (Fig. 1) that include antioxidant,
anti-inflammatory, antiviral, antibacterial, antifungal, and anti-
cancer activities [3]. A large number of in vitro studies on curcumin
have highlighted its antioxidant [4], anti-inflammatory [5], anti-
cancer [1], antiproliferative [6], nephroprotective [7], neuroprotec-
tive [8], hepatoprotective [9], immunomodulatory [10], and
chemopreventive effects [11]. Also, in vitro studies have reported
that curcumin modulates multiple cell signaling pathways, down-
regulates cell survival gene products, upregulates p53, p21 and p27
and induce apoptosis [12–14]. An in-depth review of the therapeu-
tic roles of curcumin has been previously published elsewhere
[15]. Curcumin is currently marketed as a dietary supplement in
many countries worldwide and also carries a generally recognized
safe status. However, despite the proven preclinical efficacy, poor
solubility, low absorption from the gut, rapid metabolism, and
rapid systemic elimination contribute to an overall low oral
bioavailability [16]. Curcumin is a hydrophobic molecule with a
logP of 3.2, which makes it practically insoluble in water [17].
Further, curcumin has a reported half-life of 10 min in phosphate
buffer at physiological pH (7.4) because of its high instability in
alkaline pH [18]. This further limits the therapeutic potential of
curcumin and continues to be a primary concern in its clinical
use. Even after taking gram doses of curcumin, very low plasma
curcumin levels were detected for conventional curcumin [19].
Over the past few years, enormous emphases have been laid on
improving the bioavailability of plant extracts of human benefit
using various pharmaceutical means. Maximizing oral bioavailabil-
ity directly influences plasma concentration as well as the thera-
peutic effects of a compound. Basic thumb rule of all the
approaches is to improve the solubility and hence the bioavailabil-
ity of curcumin. An increase in oral bioavailability is expected to
directly influence plasma concentration as well as therapeutic
effects of curcumin. This will result in lowering of the curcumin
doses and the dose frequency. A large number of approaches have
been utilized to increase the solubility and subsequently the
bioavailability of curcumin [20]. Few of the strategies adopted for
improving the bioavailability of curcumin include curcumin–
piperine complex, curcumin nanoparticles, cyclodextrin inclusions,
curcumin liposomes, and curcumin phospholipids’ complex [3].
The last study reviewing the clinical research on curcumin focused
on the preclinical and clinical pharmacological reports was pub-
lished in 2009 [21]. Since then, a variety of curcumin formulations
have been developed, and subsequent clinical studies with
improved bioavailability have been published. While a large num-
ber of such formulations are developed in academia and as garage
projects, only a few of them are available in the market in one form
or another. Significant differences in study design, volunteer eth-
nicity, methods of sample analysis, sampling time and product
administration were noted.
2. Methods
A literature search was conducted on PubMed/MEDLINE,
Embase, Google Scholar, Cochrane Library and EBSCO between
January 2017 and November 2017. There was no restriction placed
during searches regarding the language, region, or time of publica-
tion. Search terms used to collect the references from electronic
search were ‘‘bioavailable curcumin,” ‘‘curcumin bioavailability,”
and ‘‘curcumin clinical study.” The abstracts of relevant reviews
were inspected, and only pharmacokinetic investigations in
healthy human volunteers were retrieved for the final data extrac-
tion. All the in vitro and animal studies were excluded. Clinical
studies with formulations which are commercially available in
one form or other were selected for this review. Eleven curcumin
formulations were finally selected for the review and data were
extracted from published clinical bioavailability studies in human.
Fig. 1. Some of the reported biological activities associated with curcumin.
368 R. Jamwal / Journal of Integrative Medicine 16 (2018) 367–374
3. Discussion
3.1. Overview of bioavailable curcumin formulations
A detailed table with the curcumin formulations, their major
ingredients, manufacturer and the reported relative bioavailability
(RB) in human is given in Table 1. A significant variation in the
choice of ingredients was observed among the formulations
included in this review. Similarly, it was observed that the strate-
gies used by manufacturers to enhance the bioavailability of cur-
cumin were entirely different too. Increased solubility and
protection from acidic pH (stability) in the gastrointestinal tract
were mainly reported to enhance the bioavailability of curcumin.
3.1.1. Meriva
is a curcumin-phosphatidylcholine phytosome
complex of soy lecithin, microcrystalline cellulose and 18%–20%
curcuminoids [22]. Curcumin has two phenolic hydroxyls and
one enolic hydroxyl group which can form hydrogen bonds with
complementary polar groups of phospholipids. Once curcumin is
complexed with phosphatidylcholine, the hydrophobic core of
the phytosome protects it from degradation while increasing the
cellular uptake through facilitated diffusion across lipophilic cell
membranes [22,32]. A randomized, double-blind, crossover study
in human found that curcumin absorption was about 29-fold
higher for Meriva
compared to unformulated curcuminoid mix-
ture [22]. Interestingly, the plasma demethoxycurcumin was found
as a major plasma curcuminoid despite the curcumin content
being four times higher in the formulation. This suggests that
lecithin favors the higher bioavailability of demethoxycurcumin
from Meriva
3.1.2. LongVida
is a solid lipid curcumin particle (SLCP)-based for-
mulation with improved bioavailability compared to unformulated
curcumin [23]. The curcumin content of LongVida
is between 20%
and 30%. The SLCP complex protects the curcumin from rapid
degradation and excretion thereby improving the systemic cur-
cumin concentration and half-life [23]. Other formulation parame-
ters such as curcumin/lipid/antioxidant ratio and globule-size
distribution are suggested to extend the absorption of curcumin
from the formulation [23]. LongVida
is formulated of turmeric
powder with soy lecithin containing purified phospholipids,
docosahexaenoic acid, vegetable stearic acid, ascorbyl (vitamin C)
esters and other insert ingredients [23]. A single-dose, crossover,
double-blind, comparative pharmacokinetic study in healthy
volunteers found its human RB was approximately 100 [23].
3.1.3. CurQfen
is a novel formulation of turmeric powder and soluble
dietary fibers derived from fenugreek (Trigonella foenum-graecum)
[24]. Soluble fibers, composed of galactose and mannose units form
a nondigestible gel hydrocolloid. The hydrocolloid is suggested
to undergoes fermentation in the colon by the action of
b-mannanase and protect against curcumin degradation in the
gastrointestinal tract [33]. The concentration of curcumin in the
formulation is about 40%, and the amorphous formulation delivers
a slow release of stable colloidal curcumin for improved absorp-
tion. In a study in human, oral absorption of curcumin from
at a dose of 1500 mg (equivalent to 600 mg curcumin)
was 15.8 times more bioavailable compared to unformulated cur-
cumin [24]. Prolonged release from nondigestible soluble fibers,
leading to protection from enzymatic degradation gastrointestinal
tract was proposed as a possible mechanism for increased bioavail-
ability of curcumin [24].
3.1.4. MicroActive curcumin
MicroActive curcumin is a micronized formulation of 25% cur-
cuminoids in a proprietary sustained-release matrix consisted of
polyglycerol esters of fatty acids, medium-chain triglycerides,
hydroxypropyl methylcellulose, sodium alginate, and microcrys-
talline cellulose [25]. The surfactants, oil, and polymers in the for-
mulation were suggested to improve the absorption mainly
through a sustained release and stabilization of curcumin in the
intestine [25]. The bioavailability of MicroActive curcumin was
9.7 times as compared to unformulated 95% pure curcumin in a
single-dose bioavailability study in healthy human volunteers [25].
3.1.5. Micronized curcumin
Micronized curcumin is prepared using ‘‘concentrated powder
form” technology and comprises 25% curcumin power, 58% tri-
acetin and 16.7% panodan and further spray drying on porous sili-
con dioxide [26]. The concentration of curcumin in the finished
micronized curcumin powder is 14.1% [26]. The micronized cur-
cumin was 9-fold better bioavailable than unformulated curcumin
in a comparative single-blind crossover study in healthy adult men
and women [26]. Micronization of curcumin was suggested to
improve the absorption. The process reduces the average diameter
Table 1
Composition, manufacturer and reported relative human bioavailability of different formulations.
Formulation Manufacturer Formulation details References
Indena SpA., Italy Phytosome technology (curcumin, soy lecithin, microcrystalline
cellulose, and 18%–20% curcuminoids)
Verdure Sciences, USA SLCP
technology (solid lipid curcumin particle lipids,
phosphatidylcholine, and 20% curcumin)
Spiceuticals, India (Akay Group) Fenugreek soluble fiber blend, and 40% curcumin [24]
MicroActive curcumin BioActives LLC, USA 25% curcuminoids, a proprietary mixture of polyglycerol esters of fatty
acids, medium-chain triglycerides, hydroxypropyl methylcellulose,
sodium alginate, and microcrystalline cellulose
Micronized curcumin Raps GmbH & Co., KG, Germany Micronized powder (58.3% triacetin, 16.7% panodan, and 25% curcumin
Frutarom, Israel Liquid micelles (93% Tween 80, and 7% curcumin powder) [26]
OmniActive Health Technologies, India 63%–75% polyvinyl pyrrolidine, 10%–40% cellulosic derivatives, 1%–3%
natural antioxidants, and 20%–28% turmeric extract
) Arjuna Natural Extracts Ltd. India
(Dolcas Biotech)
Curcuminoid, essential oil of turmeric (45% ar-turmerone), and
Curcumin C3 Complex
+ Bioperine Sabinsa, USA Bioperine, and curcuminoids [29]
Wacker Chemie AG, Germany
-Cyclodextrin, and 15% (w/w) total curcuminoids [30]
Theravalues Corp., Japan Colloidal-nanoparticles (12% curcuminoids, 46% glycerin, 4% gum
ghatti, 38% water, and 10% curcumin)
R. Jamwal/ Journal of Integrative Medicine 16 (2018) 367–374 369
of drug particles which improves the rate of dissolution by increas-
ing the surface area to drug ratio [34]. Subsequently, slow diffusion
of drug particle protects it from degradation and improves the
3.1.6. NovaSol
(micellar curcumin)
Micellization is a common technique to improve the solubility
of hydrophilic drugs. NovaSol
curcumin micelles were formulated
of 7% curcumin powder (6% curcumin) and 93% Tween-80 [26].Ina
single-blind crossover study in healthy adult men and women, the
bioavailability of curcumin from NovaSol
was 185 folds higher
than that of the same dose of unformulated curcumin [26].
Curcumin incorporated with a nonionic surfactant Tween 80
(polysorbate 80) leads to the formation of liquid micelles which
improves dissolution and absorption.
3.1.7. CurcuWin
is a novel water-soluble curcumin formulation con-
taining 20%–28% turmeric powder, 63%–75% polyvinyl pyrrolidine
(a hydrophilic carrier), 10%–40% cellulosic derivatives and 1%–3%
natural antioxidants [27]. In a randomized, double-blind, crossover
study, the RB of CurcuWin
was 136 times compared to unformu-
lated curcumin [27]. The increase in oral absorption of the cur-
cumin was attributed to increased solubility similar to other
formulations included in the study. Additionally, tocopherol and
ascorbyl palmitate were suggested to prevent degradation of cur-
cumin [27].
3.1.8. Biocurcumax
) is a formulation of turmeric powder
and essential oils of turmeric (45% ar-turmerone) [28]. The relative
human bioavailability of the complex in a crossover study was
about 6.9-fold compared to unformulated curcumin [28]. The
improved absorption of curcumin from the formulation was indi-
cated to noncurcuminoid components of turmeric.
3.1.9. Curcumin C3 Complex
+ Bioperine
Bioperine is one of the first bioavailability enhancers used to
improve the oral absorption of curcumin in humans. Piperine, the
main active constituent of bioperine, is a P-glycoprotein inhibitor
and hence improves the absorption by decreasing the efflux of
absorbed curcumin in the intestine [35]. Bioperine also inhibits
uridine diphosphate-glucuronosyltransferase (UGT) and hence
improves the freely available curcumin in the systemic circulation.
When curcumin was given with piperine (20 mg/kg body weight),
the RB of curcumin was 20-fold compared to curcumin alone [29].
3.1.10. Cavacurmin
is a
-cyclodextrin-based formulation of cur-
cumin developed by Wacker Chemie AG, Germany [30]. Cyclodex-
trins consist of nonreducing chiral glucose-building blocks
arranged in a ring structure with hydrophilic glucose-building
blocks facing outwards which results in a lipophilic cavity on the
inside [36]. Curcumin fits in this lipophilic cavity by weak van
der Waals forces, resulting in an inclusion complex with cyclodex-
trin. The resulting inclusion complexes improve curcumin’s aque-
ous solubility, and hence the absorption. Cavacurmin
showed an
85-fold increase in bioavailability in comparison to unformulated
curcumin administered in a crossover study in human [30].It
was suggested that Cavacurmin
is transported unchanged
through the stomach into the upper intestinal tract where cur-
cumin is absorbed while cyclodextrin molecules are hydrolyzed
by human amylases [30].
3.1.11. Theracurmin
is a colloidal nanoparticle-based formulation of
curcumin. The formulation consists of 10% (w/w) curcumin, 2%
other curcuminoids such as demethoxycurcumin and bis-
demethoxycurcumin, 46% glycerin, 4% gum ghatti, and 38% water
[31]. The colloidal nanoparticle dispersion of curcumin improves
the solubility and its oral bioavailability as found in a human phar-
macokinetic study [31]. The RB of curcumin from Theracurmin
healthy volunteers was almost 16 time as compared to unformu-
lated curcumin. The authors reported that gum ghatti was respon-
sible for improving the solubility and stability of curcumin
formulation. Subsequently, wet-grinding of this mixture yields
nanoparticles which are 100 times smaller than the unformulated
curcumin powder. The combination of improved solubility and
reduced particle size enhances the clinical bioavailability of Ther-
3.2. Comparison of different study parameters
3.2.1. Clinical study design
Most studies were conducted with a blinded, randomized cross-
over design (see Table 2 for complete details). Participants in ran-
domized, double-blind studies are randomly assigned to the
treatment group, and neither researchers nor volunteers are aware
of the treatment. It removes bias in the study and is therefore con-
sidered ‘‘gold standard” of clinical trials [37]. A crossover design is
a within-subject design where each participant serves as his/her
control and receives all treatments, where each is separated by
‘‘washout” period in which no treatment is given [38].
Five formulations included in this review were studied in the
Asians and six in Caucasians. Most of the studies had poor gender
balance except for Theracurmin
, NovaSol
and micronized cur-
cumin. No information on the gender was available for BCM-95
) study. Three studies (LongVida
, CurQfen
Curcumin C3 Complex
+ Bioperine) recruited only males whereas
other studies included volunteers from both sexes. The maximum
number of volunteers in a study was 23 (micronized curcumin and
) and a minimum of six volunteers were recruited for
Table 2
Clinical study design parameters of the different curcumin-based formulations.
Formulation Clinical study design Number of subjects Subject ethnicity References
Randomized, double-blind, crossover 9 (8 males, 1 female) Caucasian [22]
Randomized, crossover, double-blind 6 (all males) Asian (Indian) [23]
Crossover 8 (all males) Asian (Indian) [24]
MicroActive curcumin Crossover 12 (11 males, 1 female) 11 Caucasian, 1 African-American [25]
Micronized curcumin Randomized, double-blind, crossover 23 (10 males, 13 females) Caucasian [26]
Randomized, double-blind, crossover 23 (10 males, 13 females) Caucasian [26]
Randomized, double-blind, crossover 12 (11 males, 1 female) 11 Caucasian, 1 African-American [27]
) Crossover 11 (gender not reported) Asian (Indian) [28]
Curcumin C3 Complex
+ Bioperine Randomized, crossover 10 (all males) Asian (Indian) [29]
Randomized, double-blind, crossover 12 (11 males, 1 female) 11 Caucasian, 1 African-American [30]
Randomized, crossover 14 (8 males, 6 females) Asian (Japan) [31]
370 R. Jamwal / Journal of Integrative Medicine 16 (2018) 367–374
pharmacokinetic study. Schiborr et al. [26] found that
systemic concentration of curcumin was higher in women than
men dosed with Novasol
and micronized curcumin. The details
on the ethnicity, gender, and the number of subjects for these stud-
ies are given in Table 2.
3.2.2. Curcumin administration
Conventional (unformulated) or formulated curcumin was
administered orally in all the studies. The composition and content
of food given to volunteers after administration of curcumin dose
differed significantly. Except for Theracurmin
, volunteers were
fasted overnight before getting the drug, and the curcumin-free
food was provided after drug administration. No information on
fasting status and meals provided to subjects was reported by
authors in the Theracurmin
study [31]. CurcuWin
and Cavacur-
were given to overnight fasted individuals who were fed first
meal 4 h after administration of curcumin [27,30]. In contrast,
Cuomo et al. [22] gave a high-fat meal immediately after curcumin
) administration. MicroActive curcumin and NovaSol
were administered after subjects were given breakfast (30% fat)
[26]. It is worth reiterating here that high-fat meal diet is known
to increase the mean transit time in the intestine and may thereby
enhance the exposure of the drug for absorption [39].
3.2.3. Analysis method and quantification of curcumin
A significant variation in the analysis of curcumin in human
plasma was seen in the trials (Table 3). While some studies used
high-performance liquid chromatography for quantification, others
utilized liquid chromatography–mass spectrometer (LC–MS).
Separation of curcumin was achieved by reverse-phase liquid chro-
matography in all the studies. Plasma was used for quantification
of curcumin in all the studies except the one with piperine where
serum was utilized [29]. Despite the fact that curcumin is
extensively conjugated by UGT after absorption [40], studies with
, LongVida
, Curcumin C3 Complex
+ Bioperine and
measured free curcumin in the plasma. It is inter-
esting to note here that quantification of free curcumin in these
studies is mainly at odd with the previous pharmacokinetic studies
in rat and human. It appears that in those formulations where free
curcumin was measured, the formulation per se hindered the
direct access of curcumin (to UGT) and protected from conjugation.
Conversely, in all other studies, plasma was hydrolyzed before
quantification of curcumin. The hydrolysis of conjugated curcumin
in plasma was achieved using b-glucuronidase/sulfatase from Helix
pomatia which has been historically used for quantification of
glucuronide-bound compounds [41]. Glucuronidase liberates the
hydrophilic aglycone moiety attached to curcumin by UGT and
allows for quantification of curcumin. None of the studies which
hydrolyzed the plasma samples quantified the free curcumin in
plasma without hydrolysis. Initial aglycone curcumin should have
been subtracted from deconjugated curcumin as that would have
allowed more meaningful data to the researchers.
Liquid–liquid extraction of curcumin from plasma was adopted
by all the studies in the review. Methanol, chloroform, ethyl acet-
ate and a mixture of ethyl acetate with methanol were among the
solvents used for extraction of curcumin. The choice of solvent for
extraction of curcumin and its conjugates is debatable. As cur-
cumin is a lipophilic compound, use of ethyl acetate is an ideal sol-
vent for the extraction of free curcumin from plasma. However, the
conjugation of glucuronic acid to curcumin by UGT makes it hydro-
philic and would lead to suboptimal extraction with ethyl acetate.
Alternatively, a 1:1 (v/v) mixture of ethyl acetate/diethyl ether can
be used for extraction of free and conjugated curcumin from
plasma [41]. Acetonitrile and methanol also extract a significant
number of phospholipids from plasma. Methyl tert-butyl ether
and n-butyl chloride remove the negligible amount of plasma
Table 3
Analytical methods and related parameters of the different curcumin-based formulations.
Formulation Analysis technique Internal standard Sample hydrolysis Extraction solvent Analyte measured References
HPLC–MS/MS Not used Hydrolysis, b-glucuronidase/sulfatase Ethyl acetate Free curcumin after hydrolysis [22]
HPLC-PDA Not used No hydrolysis Methanol Free curcumin [23]
HPLC-UV Not used No hydrolysis Ethyl acetate Free curcumin [24]
MicroActive curcumin HPLC-UV Not used Hydrolysis, b-glucuronidase/sulfatase 95% Ethyl acetate + 5% methanol Free curcumin after hydrolysis [25]
Micronized curcumin HPLC-fluorescence Not used Hydrolysis, b-glucuronidase/sulfatase 95% Ethyl acetate + 5% methanol Free curcumin after hydrolysis [26]
HPLC-fluorescence Not used Hydrolysis, b-glucuronidase/sulfatase 95% Ethyl acetate + 5% methanol Free curcumin after hydrolysis [26]
HPLC–MS/MS Salbutamol Hydrolysis, b-glucuronidase/sulfatase Ethyl acetate Free curcumin after hydrolysis [27]
) HPLC-UV Not used No hydrolysis Ethyl acetate Free curcumin [28]
Curcumin C3 Complex
+ Bioperine HPLC-UV Not used No hydrolysis Methanol
Free curcumin [29]
HPLC–MS/MS Salbutamol Hydrolysis, b-glucuronidase/sulfatase Ethyl acetate Free curcumin after hydrolysis [30]
HPLC–MS/MS Mepronil Hydrolysis, b-glucuronidase/sulfatase Chloroform Free curcumin after hydrolysis [31]
Used the serum for quantification of curcumin. HPLC: high-performance liquid chromatography; MS: mass spectrometer; PDA: photodiode array; UV: ultraviolet.
R. Jamwal/ Journal of Integrative Medicine 16 (2018) 367–374 371
phospholipids and should be considered by researchers in future
studies [42]. We and others have previously described in detail
the methodology to study matrix effects including common phos-
pholipid transitions to be monitored [42,43]. Elution of curcumin
at the same retention time of phospholipids should be avoided,
and chromatographic conditions should be modified accordingly
to separate the compound of interest and co-eluting phospholipids.
Nowadays, hydrolysis can be avoided altogether, and free cur-
cumin and conjugated curcumin can be simultaneously quantified
on selective and sensitive LC–MS/MS instruments. Pure standards
of curcumin’s conjugates are commercially available. This offers a
quick and simple sample preparation without the need of hydrol-
ysis step which can introduce variability due to incomplete hydrol-
ysis of the curcumin conjugates among samples. Also, curcumin
conjugates are bound significantly to plasma proteins and can
add to the variability in hydrolysis efficiency.
It is worth mentioning that most studies did not use an internal
standard during the analysis of the plasma or serum samples from
the bioavailability studies. This is a significant shortcoming in
these studies as an internal standard improves the accuracy, preci-
sion, and robustness of the quantitative assay [44]. Interestingly,
salbutamol was used as internal standard in CurcuWin
clinical studies, and mepronil was used in Theracur-
study [27,31].
3.2.4. Pharmacokinetic parameters
Absorption, distribution, metabolism, and excretion determine
the fate of a drug after administration. The oral bioavailability of
a drug is the fraction of administered drug that reaches systemic
circulation escaping the first-pass metabolism in the intestine
and liver. Besides hepatic and intestinal metabolism, oral bioavail-
ability is also dependent on several other factors. Such important
factors include physicochemical properties of the drug, degrada-
tion in the lumen, lipophilicity of the drug, gastric emptying time
and dose. The information on pharmacokinetic parameters of dif-
ferent formulations is tabulated in Table 4.
The maximum observed systemic concentration of a drug is ter-
med as C
(maximum drug concentration) whereas the time to
reach this level is called T
, time to reach maximum drug con-
centration; C
represents the rate at which a compound is
absorbed; the area under the drug concentration–time curve
(AUC) denotes the extent of absorption of the drug. AUC is often
used to compare the RB of a new formulation with a reference
product. A direct comparison of AUC, T
, and C
among the for-
mulations is not possible due to variability in the dose of curcumin
administered. However, it is evident from the Table 4 that all the
curcumin formulations significantly increased the AUC and C
when compared to unformulated curcumin. As AUC is dependent
on the rate of elimination and administered dose of a drug, it is evi-
dent that formulating curcumin prolongs the systemic exposure. It
is important to note that while some formulations increased the
, others had an opposite effect. The T
for unformulated
curcumin (control) among the different studies ranged from 0.5
to 12 h showing almost a 15-fold difference. In contrast, for
bioavailable formulations, T
ranged from 0.69 to 8.8 h among
formulations with an approximately 12-fold range.
3.2.5. RB
AUC presents a more reliable measure of bioavailability com-
pared to C
as it takes into account the systemic exposure of drug
Table 4
Pharmacokinetic parameters of curcumin from the different curcumin-based formulations and reference (unformulated curcumin).
Formulation Intervention Dose C
(ng/mL) T
(h) AUC
(ng h/mL) t
(h) RB
297 mg curcumin 50.3 ± 12.7 3.8 ± 0.6 538.0 ± 130.7
NR 48 [22]
1295 mg curcumin 9.0 ± 2.8 6.9 ± 2.2 122.5 ± 29.3
650 mg curcuminoids 22.4 ± 1.9 2.4 ± 0.4 95.3 ± 4.6
7.5 ± 2.4 100 [23]
650 mg curcuminoids < 1 ND ND ND
600 mg curcumin 0.4 ± 0.2 (mg/g) 1 8100 ± 287
(mgh/g) NR 15.8 [24]
1000 mg curcumin 0.02 ± 0.01 (mg/g) 0.5 510 ± 123
(mgh/g) NR
500 mg curcumin NR 4
887.5 ± 549.9
NR 9.7 [25]
500 mg curcumin NR NR 91.8 ± 50.0
410 mg curcumin 15.3 ± 8.9 8.8 ± 6.4 214.6 ± 106.4
NR 9 [26]
410 mg curcumin 2.6 ± 4.9 7.5 ± 8.2 24.1 ± 42.6
410 mg curcumin 1189.1 ± 518.7 1.1 ± 0.4 4474.7 ± 1675.2
NR 185 [26]
410 mg curcumin 2.6 ± 4.9 7.5 ± 8.2 24.1 ± 42.6
376 mg curcuminoids 27.3 ± 6.4 1.4 ± 0.5 307.6 ± 44.6
NR 136.3 [27]
1800 mg total curcuminoids 2.3 ± 0.3 7.4 ± 1.0 10.8 ± 1.7
2000 mg curcuminoids 456.9
(mg/g) 3.44
(mgh/g) 4.96
27 [28]
2000 mg curcuminoids 149.8
(mg/g) 2
(mgh/g) 2.63
Curcumin C3
2000 mg curcumin with
180 ± 30 0.69 ± 0.07 80 ± 10
0.11 ± 0.02 20 [29]
2000 mg curcumin 6 ± 5 1
376 mg curcuminoids 73.2 ± 17.5 1
327.7 ± 58.1
NR 85 [30]
1800 mg total curcuminoids ND 12
3.9 ± 0.5
30 mg curcumin 29.5 ± 12.9 1
113 ± 61
NR 15.9 [31]
30 mg curcumin 1.8 ± 2.0 6
4.1 ± 7.0
Control: unformulated curcumin.
NR: not reported; ND: not detected; AUC: area under the drug concentration–time curve; C
: maximum drug concentration; RB: relative bioavailability; T
: time at
maximum drug concentration.
Mean ± standard error of mean.
Mean ± standard deviation.
No reported standard deviation or error.
372 R. Jamwal / Journal of Integrative Medicine 16 (2018) 367–374
over time. In contrast, C
measures only one-time point and is
less robust to gauge the extent of total absorption. Therefore, RB
of formulated curcumin compared to unformulated curcumin
was used to determine the improvement in the absorption. The
RB was calculated using the equation given below:
where Dose UC is the dose of unformulated curcumin, Dose FC rep-
resents dose of formulated curcumin and AUC
represents the area
under the curve over time (0–t) for formulated curcumin (FC) and
unformulated curcumin (UC), respectively.
RB ranged from 9 to 185 among the eleven bioavailable cur-
cumin formulations (Fig. 2). NovaSol
(185-fold) was reported
with highest RB compared to unformulated curcumin, and Micro-
nized curcumin (9-fold) with the least (Table 4). Micelle-based cur-
cumin formulation NovaSol
was reported to escape phase
separation in gastrointestinal tract, delivering most of the cur-
cumin to the intestinal wall for absorption. CurcuWin
and Long-
were also reported to have 100-fold bioavailability
relative to conventional unformulated curcumin, suggesting that
approaches which increase the total surface area significantly,
improve the bioavailability.
3.3. Limitations
Interestingly, a substantial difference in the pharmacokinetic
parameters of curcumin from different formulations could be
attributed to dissimilarities in dose, formulation, clinical design,
analysis methods and populations in which the formulations were
studied. Significant differences in the sampling time after oral
administration in these studies may impact the AUC, C
. The different gastric emptying time contributes significantly
to the interindividual and interpopulation variability in drug
absorption from the intestine. Therefore, the choice of food and
time after which the meal was provided to volunteer may also
impact the bioavailability and is another constraint when compar-
ing these studies. An accurate comparison of different formulations
can only be achieved by a large crossover study, comparing differ-
ent formulations, using the same analytical method (free or conju-
gated curcumin) and a same method of administration (fasted or
nonfasted, ethnicity). Such studies have been attempted in the past
but only a handful of formulations were studied, and results were
often different than the one reported by original articles due to the
reasons listed above [27,30].
4. Conclusion
Curcumin’s health benefits are limited due to poor solubility
and pharmacokinetics. Efforts are currently made by different
research groups to improve the bioavailability of curcumin to har-
ness the proven in vitro efficacy and therapeutic promise. The
recent decade has seen a rise in curcumin-based formulations
addressing its solubility and stability. However, extensive variabil-
ity in the studies makes it difficult to directly compare and con-
clude which formulation is better than the other. The absolute
values of these studies are difficult to compare due to variances
in study design, population, analytical methods, and administra-
tion of the product. Harmonized large clinical studies in human
are needed to investigate how these curcumin formulations com-
pare to each other but remain a constraint due to monetary and
commercial reasons.
Conflict of interest
The review provides author’s perspective of these curcumin for-
mulations and has no conflict of interest to declare.
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... Cur, a class IV drug of the biopharmaceutical classification system (BCS), is poorly water-soluble, exhibiting a logP value of 3.2, and is incompletely absorbed. 11 According to absorption and distribution studies, Cur is absorbed approximately 60% in the gastrointestinal tract and undergoes extensive hepatic first-pass metabolism, which leads to poor bioavailability. 3,12,13 Furthermore, the storage of Cur should be carefully monitored for its photodegradable property. ...
... 35,36 Thus, drugs embedded in SLNs effectively avoid hepatic first-pass metabolism, enhancing the pharmacological effects of the drug. 9,11,35,36 Moreover, this formulation can be used as a brain-targeted drug delivery system when absorbed into the systemic circulation, overcoming one of the most important challenges in pharmaceutical sciences. 37,38 Although the blood−brain barrier, a highly selective semipermeable border, protects the brain parenchyma against circulating toxins or pathogens, it allows the diffusion of hydrophobic molecules. ...
Full-text available
Curcumin (Cur) has anticancer properties but exhibits poor aqueous solubility, permeability, and photostability. In this study, we aimed to develop a solid lipid nanoparticle (SLN) system to enhance Cur bioavailability. The characteristics of Cur-loaded SLNs prepared by sonication were evaluated using UV-vis and Fourier transform infrared spectroscopy. The mean particle size of the stearic acid-based, lauric acid-based, and palmitic acid-based SLNs was 14.70-149.30, 502.83, and 469.53 nm, respectively. The chemical interactions between Cur and lipids involved hydrogen bonding and van der Waals forces. The formulations with high van der Waals forces might produce a neat arrangement between Cur and lipids, leading to a decrease in particle size. The Cur formulations showed enhanced cytotoxicity in HeLa, A549, and CT-26 cells compared with pure Cur. Additionally, the anticancer effect is dependent on particle size and the type of cell line. Therefore, Cur-loaded SLNs have the potential for use in anticancer therapy.
... It was marketed as a product with 285× increased oral bioavailability of curcumin and is sold as capsules and tablets [30]. The curcumin content in Longvida ® is reported to be 20-30% w/w [31]. The health benefits of taking Longvida ® have been well-documented by published research studies. ...
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Several therapeutically active molecules are poorly water-soluble, thereby creating a challenge for pharmaceutical scientists to develop an active solution for their oral drug delivery. This study aimed to investigate the potential for novel polymer-surfactant-based formulations (designated A and B) to improve the solubility and permeability of curcumin. A solubility study and characterization studies (FTIR, DSC and XRD) were conducted for the various formulations. The cytotoxicity of formulations and commercial comparators was tested via MTT and LDH assays, and their permeability by in vitro drug transport and cellular drug uptake was established using the Caco-2 cell model. The apparent permeability coefficients (Papp) are considered a good indicator of drug permeation. However, it can be argued that the magnitude of Papp, when used to reflect the permeability of the cells to the drug, can be influenced by the initial drug concentration (C0) in the donor chamber. Therefore, Papp (suspension) and Papp (solution) were calculated based on the different values of C0. It was clear that Papp (solution) can more accurately reflect drug permeation than Papp (suspension). Formulation A, containing Soluplus® and vitamin E TPGs, significantly increased the permeation and cellular uptake of curcumin compared to other samples, which is believed to be related to the increased aqueous solubility of the drug in this formulation.
... Curcumin has low bioavailability; this can be caused by low absorption of curcumin, high metabolism, and fast elimination from the body [30]. The low bioavailability of curcumin has been seen in several animal and human studies [31]. Other studies have shown that the presence of a mucus barrier consisting of glycoproteins, water, and lipids can hinder its diffusion from the lumen to the surface of enterocytes. ...
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Background and aim: Developing curcumin into nanosized particles is one of the approaches to overcome the limited use of curcumin. This study aimed to prepare curcumin into nanosized particles to increase the curcumin level in the rat's liver and hepatoprotective effect in rats. Materials and methods: Curcumin into nanosized particles formulated using ionic gelation method. Rats were divided into four groups (n = 6): Normal, negative, curcumin, and curcumin modified into nanosized particles were treated with 100 mg/kg body weight orally for 14 days. Hepatic curcumin level was investigated using liquid chromatography with tandem mass spectrometry, antioxidant activity by malondialdehyde (MDA), and hepatoprotective effect by aspartate transaminase (AST), alanine transaminase (ALT), and histopathology. Results: The curcumin level in the rat's liver in the curcumin group was 12.19 ng/mL, and that in those receiving modified into nanosized curcumin was 209.36 ng/mL. The MDA levels in the normal, negative, curcumin, and curcumin modified into nanosized particles groups were 1.88, 4.87, 3.38, and 1.04 nmol/L, respectively. The AST levels in these groups were 57.12, 130.00, 102.13, and 74.28 IU/L, and the ALT levels were 21.63, 61.97, 39.38, and 28.55 IU/L. The liver histopathology scoring showed that curcumin in nanosized particles was better than curcumin in degeneration of fat, lymphocyte infiltration, and necrosis. Conclusion: There was a 17 times increase in curcumin level in the liver of rats treated with curcumin modified into nanosized particles. Curcumin modified into nanosized particles showed more significant improvement as antioxidant and hepatoprotector than curcumin.
... Curcumin is a bioactive polyphenolic molecule that has been widely applied for wound treatment in pre-clinical and clinical practices due to its anti-inflammatory, antioxidant, and antimicrobial effects [8][9][10]. Nevertheless, the therapeutic performance of curcumin is restricted by its poor pharmacodynamic action, which mainly arose from its hydrophobic skeleton, rapid metabolism, and instability in the physiological fluid [11]. ...
The underprivileged pharmacodynamic action of curcumin, which arose from its low water solubility and rapid metabolism, restricts its therapeutic performance. In this study, (2-Hydroxy isopropyl)-β-cyclodextrin (HPβCD) as a macrocycle host molecule was employed to enhance the availability and control release of curcumin by forming a host-guest inclusion complex within an in-situ forming alginate hydrogel. The formation of the inclusion complexes of curcumin with a single host molecule was characterized by FTIR, XRD, TGA, SEM, and DLS analyses. The inclusion complex of curcumin and HPβCD (HPβCD-Cur) showed a high encapsulation efficiency of 88.2 %. According to DLS results, aqueous dispersion of HPβCD-Cur exhibited a unimodal histogram after 2 and 7 days with average particles size of 207.5 and 230.6 nm, respectively. This observation could be because of the formation of an inclusion complex that effectively distributed in solution and prevented curcumin agglomeration. The prepared alginate hydrogel containing HPβCD-Cur demonstrated >87 % reduction in colonies of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, which significantly is higher than that for Alg/Cur (<69 %). The Alg/HPβCD-Cur hydrogel exhibited a high water uptake of 470 % after 2 h, and a curcumin cumulative release of 80 % over 72 h, with proper cytocompatibility. Consequently, it was shown that the HPβCD carrier could act as an apt host molecule that can properly encapsulate curcumin and enhance its release from the Alg/HPβCD-Cur hydrogel.
... I. Hydrophobicity. With a log octanol/water partition coefficient (logP) value of 3.2, curcumin is practically insoluble in water and highly soluble in lipids (Jamwal, 2018). Its water solubility will be affected by the pH value of the environment in which it is located. ...
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Abstract Turmeric is a natural active substance extracted from the Zingiberaceae plant, containing a variety of derivatives, the main component being curcumin. Curcumin has a wide range of sources, low cost, and has strong antioxidant, anti-inflammatory, anti-cancer, antibacterial and other physiological functions, but it has problems such as poor water solubility, poor stability, and low bioavailability. There are certain interactions (hydrophobic interactions, electrostatic interactions, hydrogen bonds, etc.) between curcumin and bio-based proteins or polysaccharides, which can be combined to form different encapsulation systems, which can effectively improve the poor water solubility, poor stability and intestinal problems such as low bioavailability. This article focuses on the types of natural bio-based encapsulation systems (emulsion, liposome, micelle, nanoparticles, gels, and microcapsules), mechanisms and their applications in the food field of curcumin.
... First, interspecies differences notwithstanding, the administered dose, type of solvent/vehicle, experimental design, and analytical method may differentially affect PK parameters. 74 This is illustrated by the rather wide relative concentration range per time point as presented in Figure 2. Some of the solvents/solubilizers that were used are micelleforming surfactants (such as Kolliphore and Tween) that may prolong the systemic presence of curcumin. The consequences of curcumin solubilization by these excipients before or after intravenous administration on PK are further elaborated in section S3.1. ...
Full-text available
Curcumin nanoformulations for intravenous injection have been developed to offset poor absorption, biotransformation, degradation, and excessive clearance associated with parenteral delivery. This review investigates (1) whether intravenous nanoformulations improve curcumin pharmacokinetics (PK) and (2) whether improved PK yields greater therapeutic efficacy. Standard PK parameters (measured maximum concentration [Cmax], area under the curve [AUC], distribution volume [Vd], and clearance [CL]) of intravenously administered free curcumin in mice and rats were sourced from literature and compared to curcumin formulated in nanoparticles, micelles, and liposomes. The studies that also featured analysis of pharmacodynamics (PD) in murine cancer models were used to determine whether improved PK of nanoencapsulated curcumin resulted in improved PD. The distribution and clearance of free and nanoformulated curcumin were very fast, typically accounting for >80% curcumin elimination from plasma within 60 min. Case-matched analysis demonstrated that curcumin nanoencapsulation generally improved curcumin PK in terms of measured Cmax (n = 27) and AUC (n = 33), and to a lesser extent Vd and CL. However, when the data were unpaired and clustered for comparative analysis, only 5 out of the 12 analyzed nanoformulations maintained a higher relative curcumin concentration in plasma over time compared to free curcumin. Quantitative analysis of the mean plasma concentration of free curcumin versus nanoformulated curcumin did not reveal an overall marked improvement in curcumin PK. No correlation was found between PK and PD, suggesting that augmentation of the systemic presence of curcumin does not necessarily lead to greater therapeutic efficacy.
Nanoparticle drug delivery systems have drawn considerable attention worldwide due to their unique characteristics and advantages in anticancer drug delivery. Herein, the curcumin (Cur) loaded nanomicelles with two-stage drug release behavior were developed. β-Cyclodextrin (β-CD) and cholesterol were conjugated onto both ends of the poly(ethylene glycol) (PEG) chain to obtain an amphiphilic β-CD-PEG-Chol. The Cur was loaded into the cavities of β-CD and nanomicelle when the β-CD-PEG-Chol self-assembled to the Cur@β-CD-PEG-Chol nanomicelles (Cur@CPC NMs). These Cur@CPC NMs are spherical particles with a particle size of 120.9 nm. The Cur drug loading capacity of Cur@CPC NMs are 61.6 ± 6.9 mg/g. The release behavior of Cur from Cur@CPC NMs conformed to a two-stage mode of "burst-release followed by sustained-release". The prepared Cur@CPC NMs possess high storage stability and excellent hemocompatibility. Moreover, these Cur@CPC NMs exhibit satisfactory antioxidant activity and anticancer activity, resulting in significant reduction in intracellular H2O2-induced ROS and a nearly 50% lethality rate of HepG-2 cells. Meanwhile, the Cur@CPC NMs show good anti-inflammatory activity, by which the secretion of inflammatory factors of IL-6 and TNF-α are inhibited. Overall, the developed Cur@CPC NMs show application prospects in anticancer drug delivery systems.
We report for the first time that curcumin is successfully encapsulated into a new natural pre-formed carrier, which was derived from arthrospore cell wall particles (APs) of probiotic Geotrichum candidum LG-8 and mainly composed of beta-1,4-glucan. Vacuum infusion process was used for efficient encapsulation of curcumin. The results showed that the encapsulation efficiency and yield of APs were 36.5 ± 0.9% and 730.6 ± 26.5 μg/g (wet basis), respectively. Compared to the other probiotic carriers such as Saccharomyces cerevisiae, it could more effectively maintain the antioxidant property and storage capacity of curcumin under high temperature conditions. Simulated digestion was conducted to study in vitro release of curcumin encapsulated in APs, and showed a maximum bioaccessibility of 65.6 ± 3.8%. In view of low-cost culture method, simple encapsulation process and high encapsulation capacity, G. candidum arthrospores as new natural encapsulation carriers have potential superiority in the practical application in food industry.
Scope: Preclinical models have demonstrated the anti-inflammatory and lipid-lowering effects of curcumin. Innovative formulations have been developed to overcome the poor bioavailability of native curcumin. The study hypothesizes that the bioavailability of micellar curcumin is superior to native curcumin and investigates the potential anti-inflammatory and proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration lowering effects. Methods and results: In this double-blind, randomized, crossover trial, 15 healthy volunteers receive micellar or native curcumin (105 mg day-1 ) for 7 days with a ≥7 days washout period. Curcumin and metabolite concentrations are quantified by high-performance liquid chromatography with fluorescence detection (HPLC-FD), and pharmacokinetics are calculated. To analyze anti-inflammatory effects, blood samples (baseline, 2 h, 7 days) are stimulated with 50 ng mL-1 lipopolysaccharides (LPS). Interleukin (IL)-6, tumor-necrosis factor (TNF-α), and PCSK9 concentrations are quantified. Micellar curcumin demonstrates improved bioavailability (≈39-fold higher maximum concentrations, ≈14-fold higher area-under-the-time-concentration curve, p < 0.001) but does not reduce pro-inflammatory cytokines in the chosen model. Subjects receiving micellar curcumin have significantly lower PCSK9 concentrations (≈10% reduction) after 7 days compared to baseline (p = 0.038). Conclusion: Micellar curcumin demonstrates an improved oral bioavailability but does not show anti-inflammatory effects in this model. Potential effects on PCSK9 concentrations warrant further investigation.
3,5‐Di[(E)‐arylidene]‐1‐[3‐(4‐methylpiperazin‐1‐yl)alkyl]piperidin‐4‐ones 7 a−k were synthesized through dehydrohalogenation of 1‐(2‐chloroacyl)piperidin‐4‐ones 5 a−k with N‐methylpiperazine (6). High antiproliferation potencies were observed by most of the synthesized agents against both HCT116 (colon) and MCF7 (breast) cancer cell lines relative to the standard references (sunitinib and 5‐fluorouracil). The synthesized agents are of dual activity against topoisomerases I and IIα however, with higher efficacy against topoisomerase IIα rather than topoisomerase I. Flow‐cytometry cell cycle studies support the observed antiproliferation properties and exhibit the capability of 1‐(2‐chloroacetyl)‐3,5‐bis[(E)‐4‐chlorobenzylidene]piperidin‐4‐one (5 e) and 3,5‐bis[(E)‐4‐bromobenzylidene]‐1‐[2‐(4‐methylpiperazin‐1‐yl)acetyl]piperidin‐4‐one (7 g) to arrest the HCT116 cell cycle progression at G1/S and G1 phases, respectively. Noticeable anti‐SARS‐CoV‐2 properties were observed by many synthesized agents. 3,5‐Bis[(E)‐4‐chlorobenzylidene]‐1‐[3‐(4‐methylpiperazin‐1‐yl)propanoyl]piperidin‐4‐one (7 f) is the most effective anti‐SARS‐CoV‐2 synthesized with high SI. Applicability of the highly effective candidates synthesized as antitumor and anti‐SARS‐CoV‐2 is due to the safety observations against normal (RPE1 and VERO‐E6) cells. QSAR models validated internally and externally, support their possibility for optimizing more hits/leads. A series of piperidone‐piperazine conjugates were synthesized through dehydrohalogenation of 1‐(2‐chloroacyl)piperidin‐4‐ones with N‐methylpiperazine. Some of the prepared conjugates reveal potential antiproliferative (HCT116, MCF7) properties with dual activity against topoisomerases I and IIα. Anti‐SARS‐CoV‐2 properties with safe profile against normal (RPE1 and VERO‐E6) cells were also noticed by the synthesized agents. QSAR supported the bio‐properties observed.
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PurposeThe optimal health benefits of curcumin are limited by its low solubility in water and corresponding poor intestinal absorption. Cyclodextrins (CD) can form inclusion complexes on a molecular basis with lipophilic compounds, thereby improving aqueous solubility, dispersibility, and absorption. In this study, we investigated the bioavailability of a new γ-cyclodextrin curcumin formulation (CW8). This formulation was compared to a standardized unformulated curcumin extract (StdC) and two commercially available formulations with purported increased bioavailability: a curcumin phytosome formulation (CSL) and a formulation of curcumin with essential oils of turmeric extracted from the rhizome (CEO). Methods Twelve healthy human volunteers participated in a double-blinded, cross-over study. The plasma concentrations of the individual curcuminoids that are present in turmeric (namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were determined at baseline and at various intervals after oral administration over a 12-h period. ResultsCW8 showed the highest plasma concentrations of curcumin, demethoxycurcumin, and total curcuminoids, whereas CSL administration resulted in the highest levels of bisdemethoxycurcumin. CW8 (39-fold) showed significantly increased relative bioavailability of total curcuminoids (AUC0−12) in comparison with the unformulated StdC. Conclusion The data presented suggest that γ-cyclodextrin curcumin formulation (CW8) significantly improves the absorption of curcuminoids in healthy humans.
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Cannabis is used widely in the United States, both recreationally and for medical purposes. Current methods for analysis of cannabinoids in human biological specimens rely on complex extraction process and lengthy analysis time. We established a rapid and simple assay for quantification of Δ(9)-tetrahydrocannabinol (THC), cannabidiol (CBD), 11-hydroxy Δ(9)-tetrahydrocannabinol (11-OH THC) and 11-nor-9-carboxy-Δ(9)-tetrahydrocannbinol (THCCOOH) in human plasma by U-HPLC-MS/MS usingΔ9-tetrahydrocannabinol-D3 (THC-D3) as the internal standard. Chromatographic separation was achieved on an Acquity BEH C18 column using a gradient comprising of water (0.1% formic acid) and methanol (0.1% formic acid) over a 6 min run-time. Analytes from 200μL plasma were extracted using acetonitrile (containing 1% formic acid and THC-D3). Mass spectrometry was performed in positive ionization mode, and total ion chromatogram was used for quantification of analytes. The assay was validated according to guidelines set forth by Food and Drug Administration of the United States. An eight-point calibration curve was fitted with quadratic regression (r(2)>0.99) from 1.56 to 100ngmL(-1) and a lower limit of quantification (LLOQ) of 1.56ngmL(-1) was achieved. Accuracy and precision calculated from six calibration curves was between 85-115% while the mean extraction recovery was >90% for all the analytes. Several plasma phospholipids eluted after the analytes thus did not interfere with the assay. Bench-top, freeze-thaw, auto-sampler and short-term stability ranged from 92.7 to 106.8% of nominal values. Application of the method was evaluated by quantification of analytes in human plasma from six subjects.
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Curcumin is a natural anti-inflammatory agent that has been used for treating medical conditions for many years. Several experimental and pharmacologic trials have demonstrated its efficacy in the role as an anti-inflammatory agent. Curcumin has been shown to be effective in treating chronic conditions like rheumatoid arthritis, inflammatory bowel disease, Alzheimer's and common malignancies like colon, stomach, lung, breast, and skin cancers. As treatments in medicine become more and more complex, the answer may be something simpler. This is a review article written with the objective to systematically analyze the wealth of information regarding the medical use of curcumin, the “curry spice”, and to understand the existent gaps which have prevented its widespread application in the medical community.
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Curcumin, a pigment from turmeric, is one of the very few promising natural products that has been extensively investigated by researchers from both the biological and chemical point of view. While there are several reviews on the biological and pharmacological effects of curcumin, chemistry reviews are comparatively scarcer. In this article, an overview of different aspects of the unique chemistry research on curcumin will be discussed. These include methods for the extraction from turmeric, laboratory synthesis methods, chemical and photochemical degradation and the chemistry behind its metabolism. Additionally other chemical reactions that have biological relevance like nucleophilic addition reactions, and metal chelation will be discussed. Recent advances in the preparation of new curcumin nanoconjugates with metal and metal oxide nanoparticles will also be mentioned. Directions for future investigations to be undertaken in the chemistry of curcumin have also been suggested.
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The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard. The relative absorption of a curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) in comparison to a standardized curcumin mixture (CS) was investigated in a randomized, double-blind, crossover human study in healthy volunteers. Samples were analyzed by HPLC-MS/MS. Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001). A formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants significantly increases curcuminoid appearance in the blood in comparison to unformulated standard curcumin CS, CTR and CP.
Context: Curcumin has a number of beneficial effects, such as functioning as a potent antioxidant,1 anti-inflammatory, 2 and anticancer agent. Because of its poor oral bioavailability, very high oral doses and repeated dosing have been used to obtain effective plasma levels, with mixed results. High doses of curcumin may cause gastric disturbance, often resulting in poor patient compliance. Objective: The objective of this study was to compare the relative bioavailability of MicroActive Curcumin-an advanced, micronized formulation of curcumin that is 25% curcuminoids in a sustained release matrix-with that of an unformulated, 95% pure curcumin powder. Design: A dissolution study compared the solubility of the formulated and the unformulated curcumin. The research team also performed a single-dose, 12-h, crossover uptake study with 10 participants and a high-dose tolerability and accumulation study with 3 participants, comparing the 2 forms of curcumin. Setting: The study was done in MAZE Laboratories (Purchase, NY, USA). Participants: Ten healthy male and female volunteers, aged 21-66 y, took part in the single-dose study. Three participants, 2 female and 1 male aged 40-55 y, took part in the tolerability and accumulation study. The participants were people from the community. Intervention: For the dissolution study, the research team filled hard gelatin capsules with unformulated 95% curcumin powder and the MicroActive Curcumin powder to the equivalent of 25 mg curcuminoids. For the single-dose study, participants received 500 mg of curcumin in 2 forms. MicroActive Curcumin capsules were administered after breakfast, and blood samples were drawn at 1, 2, 4, 8, and 12 h postdose. After a 7-d washout period, the protocol was repeated for unformulated, 95% curcumin powder capsules. For the tolerability study, the unformulated, 95% curcumin powder was given at a dose that provided 2 g of curcumin for 7 d followed by 5 g of curcumin for an additional 7 d. After a washout period of 14 d, the protocol was repeated with MicroActive Curcumin. Participants then continued to take the MicroActive Curcumin for >3 mo. Outcome measures: For the dissolution study, the curcumin was quantified at room temperature using reverse-phase, high-performance liquid chromatography (HPLC) with a Phenomenex Luna column (150 × 4.6 mm, 5 μm) (Phenomenex Inc, Torrance, CA, USA). For the single-dose and the tolerability studies, hydrolysis of conjugates and extraction of curcuminoids from the plasma were performed. The curcuminoids were quantified using reverse-phase HPLC with an ultraviolet-visible detector as described above. Results: The dissolution study indicated that the sustained-release curcumin had greater dissolution for 12 h at all points tested, compared with the unformulated curcumin. Very little of the unformulated curcumin powder had been released at the end of the 12 h. The results of the single-dose uptake study indicated that the sustained-release formula was 9.7 × more bioavailable than the unformulated powder (P < .001, paired t test). Additionally, all participants showed uptake from the sustained-release formulation. That formulation also resulted in significant increases in the plasma demethoxylated curcuminoids, but the research team did not observe the same increases for the unformulated curcumin powder. The sustained-release formulation was well tolerated, without adverse effects in the high-dose tolerability study. Conclusions: Formulation of micronized curcumin in a combination of surfactants, oils, and polymers improves the absorption of curcumin. In addition, the unique plasma demethylated curcuminoid profile may enhance the therapeutic effects of MicroActive Curcumin not observed with unformulated curcumin at moderate and well-tolerated doses. MicroActive Curcumin was well tolerated, without any adverse effects in a high-dose tolerability study. These properties have the potential to make high-dose curcumin supplementation more accessible through simplified incorporation into food and beverage preparations.
Internal standards (ISs) are commonly used in liquid chromatography-mass spectrometry (LC-MS) bioanalysis. The main purpose of utilizing ISs is to improve the accuracy and precision of quantitation as well as the robustness of bioanalytical methods. The accuracy and precision of reported concentrations and the reliability of bioanalytical methods can be significantly improved through the proper use of a good IS. Then, what is a good IS? How should its concentration be determined? When and how should it be added? Why are stable isotope labeled ISs preferred yet one should still be cautious in their usage? Should IS responses be monitored during incurred sample analysis? What are the root causes of IS response variations? What are their potential impacts on the integrity of reported concentrations? These questions are addressed in this chapter with a focus on small molecules (molecular weights typically less than 1000 Da).
The essential oil composition and total phenolic content (TPC) of curcuminoids were studied in rhizomes of nine Curcuma longa L. accessions. Curcuminoids, present in commercially available turmeric rhizomes, play vital roles in various pharmacological activities. A simple, rapid, and sensitive high performance liquid chromatography photodiode array (HPLC-PDA) method was optimized for simultaneous determination of curcuminoids, namely, a mixture of curcumin, demethoxy curcumin (DMC), and bisdemethoxy curcumin (BDMC) in rhizomes of C. longa. Chromatographic separation was performed on an RP C18 column within 13 minutes (11.4 to 12.95 minutes). Elution was accomplished by the application of acetonitrile and 1.5% acetic acid in water in a gradient system with flow rate of 2.0 mL min−1. PDA was employed for qualitative and quantitative analysis. The calibration curves were found linear (0.99) for all cucuminoids; the limit of detection and quantification ranged between 1.01 µ g mL−1 to 1.16 µ g mL−1 and 2.30 µ g mL−1 to 3.05 µ g mL−1, respectively, while recovery values ranged between 97.97% to 98.32%. The amount of curcumin varied from 0.46% to 2.17%, DMC from 0.13% to 0.92% and BDMC from 0.06% to 0.52%. The validated method was successively used to determine the above compounds in C. longa rhizomes. The TPC in rhizomes ranged from 14.12 mg g−1 to 27.72 mg g−1. The chemical composition of rhizome essential oil, analyzed by gas chromatography mass spectrometry (GCMS,) showed large variations in major compounds like ar-tumerone (7.31–38.66%), β-curcumene (1.58–24.53%), and curlone (1.55–15.97%).