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A Comparative Pharmacokinetic Assessment of a Novel Highly Bioavailable Curcumin Formulation with 95% Curcumin: A Randomized, Double-Blind, Crossover Study


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Objective: Curcumin exhibits many beneficial health-promoting characteristics. However, its poor oral absorption precludes its general use. This study assessed the bioavailability of a novel curcumin formulation compared to 95% curcumin and published results for various other curcumin formulations. Methods: A randomized, crossover, double-blind, comparator-controlled pharmacokinetic study was performed in 12 healthy adult subjects to determine the appearance of free curcumin and its metabolites curcumin sulfate and curcumin glucuronide in plasma after a single dose of a novel proprietary curcumin liquid droplet micromicellar formulation (CLDM) and unformulated 95% curcumin powder in capsule form. An equivalent 400-mg dose of each product was administered. The 95% curcumin contained 323 mg curcumin, and the CLDM contained 64.6 mg curcumin. Blood samples were drawn and plasma was analyzed for curcumin and its 2 conjugates without enzymatic hydrolysis by liquid chromatography-tandem mass spectroscopy. Results: Plasma levels of curcumin sulfate and curcumin glucuronide after 1.5 hours from CLDM were approximately 20 and 300 ng/mL, respectively, whereas the levels for 95% curcumin were near baseline. Free curcumin reached a maximum level of 2 ng/mL for CLDM and 0.3 ng/mL for 95% curcumin at 1.5 hours. For the CLDM, a small secondary free curcumin peak occurred at 12 hours and a tertiary 1.5-ng/mL peak occurred at 24 hours. The total curcumin absorbed as represented by the area under the curve (AUC)/mg administered curcumin for CLDM was 522 times greater than for the 95% curcumin. Conclusions: The novel CLDM formulation facilitates absorption and produces exceedingly high plasma levels of both conjugated and total curcumin compared to 95% curcumin. A comparison of the Cmax/mg curcumin and AUC/mg of administered curcumin for CLDM with data from pharmacokinetic studies of various enhanced absorption formulations indicate that the greatest absorption and bioavailability are produced with the novel CLDM formulation.
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Journal of the American College of Nutrition
ISSN: 0731-5724 (Print) 1541-1087 (Online) Journal homepage:
A Comparative Pharmacokinetic Assessment of a
Novel Highly Bioavailable Curcumin Formulation
with 95% Curcumin: A Randomized, Double-Blind,
Crossover Study
Sidney J. Stohs, Jin Ji, Luke R. Bucci & Harry G. Preuss
To cite this article: Sidney J. Stohs, Jin Ji, Luke R. Bucci & Harry G. Preuss (2017): A
Comparative Pharmacokinetic Assessment of a Novel Highly Bioavailable Curcumin Formulation
with 95% Curcumin: A Randomized, Double-Blind, Crossover Study, Journal of the American
College of Nutrition, DOI: 10.1080/07315724.2017.1358118
To link to this article:
© 2017 The Author(s)© Sidney J. Stohs, Jin Ji,
Luke R. Bucci, and Harry G. Preuss
Published online: 18 Oct 2017.
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A Comparative Pharmacokinetic Assessment of a Novel Highly Bioavailable Curcumin
Formulation with 95% Curcumin: A Randomized, Double-Blind, Crossover Study
Sidney J. Stohs, PhD, FACN, CNS
, Jin Ji, Ph.D.
, Luke R. Bucci, PhD, CNS
, and Harry G. Preuss, MD, MACN, CNS
School of Pharmacy and Health Professions, Creighton University Medical Center, Omaha, Nebraska, USA;
Brunswick Laboratories,
Southborough, Massachusetts, USA;
Interpath Nutrition, Reno, Nevada, USA;
Department of Biochemistry, Georgetown University
Medical Center, Washington, DC, USA
Received 5 May 2017
Accepted 18 July 2017
Objective: Curcumin exhibits many benecial health-promoting characteristics. However, its poor oral
absorption precludes its general use. This study assessed the bioavailability of a novel curcumin
formulation compared to 95% curcumin and published results for various other curcumin formulations.
Methods: A randomized, crossover, double-blind, comparator-controlled pharmacokinetic study was
performed in 12 healthy adult subjects to determine the appearance of free curcumin and its metabolites
curcumin sulfate and curcumin glucuronide in plasma after a single dose of a novel proprietary curcumin
liquid droplet micromicellar formulation (CLDM) and unformulated 95% curcumin powder in capsule form.
An equivalent 400-mg dose of each product was administered. The 95% curcumin contained 323 mg
curcumin, and the CLDM contained 64.6 mg curcumin. Blood samples were drawn and plasma was
analyzed for curcumin and its 2 conjugates without enzymatic hydrolysis by liquid chromatography
tandem mass spectroscopy.
Results: Plasma levels of curcumin sulfate and curcumin glucuronide after 1.5 hours from CLDM were
approximately 20 and 300 ng/mL, respectively, whereas the levels for 95% curcumin were near baseline.
Free curcumin reached a maximum level of 2 ng/mL for CLDM and 0.3 ng/mL for 95% curcumin at
1.5 hours. For the CLDM, a small secondary free curcumin peak occurred at 12 hours and a tertiary 1.5-ng/
mL peak occurred at 24 hours. The total curcumin absorbed as represented by the area under the curve
(AUC)/mg administered curcumin for CLDM was 522 times greater than for the 95% curcumin.
Conclusions: The novel CLDM formulation facilitates absorption and produces exceedingly high plasma
levels of both conjugated and total curcumin compared to 95% curcumin. A comparison of the C
curcumin and AUC/mg of administered curcumin for CLDM with data from pharmacokinetic studies of
various enhanced absorption formulations indicate that the greatest absorption and bioavailability are
produced with the novel CLDM formulation.
Curcumin; curcumin sulfate;
curcumin glucuronide;
Turmeric is a spice and coloring agent derived from the rhi-
zomes of Curcuma longa L., which has also been used for centu-
ries in traditional medicines (1,2). Curcumin is the primary
polyphenol present in turmeric with small amounts of
demethoxycurcumin and bisdemethoxycurcumin (1). These cur-
cuminoids are the major bioactive components responsible for
the nutritional and pharmacological activities of turmeric (210).
Numerous human clinical, animal, and in vitro studies have
examined and demonstrated the health benets of curcumin,
including disease-preventive, antioxidant, anti-inammatory,
tissue protective, immunoprotective, antibacterial, antifungal,
antiviral, antineoplastic, metabolism modulating, and antidepres-
sant properties (310).
The molecular mechanisms associated with the broad spec-
trum of actions are complex. Curcumin exerts a pleiotropic effect,
modulating and regulating multiple targets (2,57,10). Curcumin
inhibits pro-inammatory transcription factors, including
nuclear factor-kappa B, activator of transcription-3, and wnt/
beta-caterin. Curcumin activates peroxisome proliferatoracti-
vated receptor gamma and Nrf2 cell signaling pathways, leading
to the downregulation of tumor necrosis factor, interleukin-6,
resistin, leptin, and monocyte chemostatic protein-1, and upregu-
lates adiponectin. Furthermore, curcumin modulates expression
of a host of enzymes and other gene products (5,710).These
diverse mechanisms account for the wide range of nutritional,
physiological, and pharmacological effects.
Despite the promising nutritional and pharmacological
properties of curcumin, curcumin exhibits low aqueous solubil-
ity, poor gastrointestinal absorption, and poor biodistribution
(48,1114). Furthermore, curcumin has a high rate of metabo-
lism and metabolic inactivation and rapid elimination from the
CONTACT Sidney J. Stohs, PhD, FACN, CNS School of Pharmacy and Health Professions, Creighton University Medical Center, 2500
California Plaza, Omaha, NE 75034.
Color versions of one or more of the gures in the article can be found online at
© 2017 Sidney J. Stohs, Jin Ji, Luke R. Bucci, and Harry G. Preuss
This is an Open Access article. Non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly attributed, cited, and is not altered, transformed, or
built upon in any way, is permitted. The moral rights of the named author(s) have been asserted.
Downloaded by [] at 08:52 18 October 2017
body (4,5,7,1113). Curcumin undergoes rapid conjugation
with some metabolic reduction (13) and, as a consequence, cur-
cumin occurs in the blood primarily as the physiologically and
pharmacologically inactive curcumin sulfate and curcumin glu-
curonide with very little free curcumin (5,1113). Small
amounts of curcumin are also reduced to dihydrocurcumin,
tetrahydrocurcumin, and hexahydrocurcumin, all of which
may have some physiological activity but are primarily conju-
gated as the inactive glucuronide (5,11,12). It has been sug-
gested that in addition to free curcumin, various degradation
and condensation products may have health benets (14).
It is not clear in what form curcumin exists within tissues
and what constitutes the truly active form at the cellular and
molecular levels. The relative importance of the blood levels of
curcumin as well as its glucuronide and sulfate conjugates with
respect to physiological effects is also not well dened. Because
curcumin is known to be more physiologically active than its
conjugated forms, it is assumed that blood levels of free curcu-
min reect greater physiological activity (5,1114) and in order
to exert a physiological response, it must be absorbed. The low
bioavailability of curcumin limits its usefulness in general
health care and as an aid in managing various diseases.
Various approaches have been used (12,1519) to overcome
the poor absorption, rapid metabolism, and poor bioavailability
of curcumin. These strategies have been reviewed and include
formulations with liposomes, micelles, or interaction with mac-
romolecules such as gelatin and polysaccharides such as
g-cyclodextrin (21) and galactomammans (12,32). Further-
more, various nanoparticulate preparations that have been
developed include nanoemulsions, nanomicelles, dendrimers,
conjugates, polymers, nanogels, and solid dispersions (1619).
Although many formulations are effective in increasing absorb-
ability of curcumin, a number of the formulations have limita-
tions because the ingredients are not approved for food use,
due to the large delivery loads required, or because of regula-
tory issues (12).
All of these formulations have shown an increase in blood
levels of total curcumin. However, studies involving these diverse
formulations have not clearly shown an increase in free curcu-
min in the blood. With relatively few exceptions (30,3337),
plasma samples are routinely subjected to enzymatic hydrolysis
due to the fact that the sulfate and glucuronide conjugates are
the predominant forms of curcumin. As a consequence, these
studies result in the subsequent measurement of total curcumin
and not free curcumin (2129,31,32,38) and do not provide a
clear understanding of the potential pharmacokinetic benets of
the formulations with respect to free curcumin.
A novel proprietary curcumin formulation involving liquid
droplet micromicellar (CLDM) technology has been developed
with food-grade materials, and preliminary studies indicate
that it has an exceedingly high (»300 ng/mL) bioavailability.
The present investigation is a randomized, double-blind, cross-
over study comparing the bioavailability of this novel curcumin
formulation with 95% curcumin in healthy subjects. This study
is unique in that this novel formulation results in exceedingly
high plasma levels of free curcumin as well as its conjugates.
Because various formulations contain different amounts of
curcumin, we have calculated and compared the relative phar-
macokinetic efciency on the basis of per milligram of
administered curcumin of this novel curcumin formulation
with published reports involving other formulations as well as
unformulated 95% curcumin.
Materials and methods
Curcumin study products
The novel proprietary CLDM formulation (BioCurc) used in
this study was developed and supplied by Boston BioPharm
(Southlake, TX). The 95% curcumin (curcuminoids) used as
such and in the formulation was obtained from Novel Ingre-
dients (East Hanover, NJ; Lot #650036563) and was composed
of approximately 85% curcumin, 13% demethoxycurcumin,
and 2% bisdemethoxycurcumin. The primary constituents of
the study product included 64.6 mg curcumin (76 mg total cur-
cuminoids), lauryl macrogol-32 glycerides, polysorbate-20, DL-
alpha-tocopherol, and hydroxypropyl cellulose and was deliv-
ered in 6 capsules. The comparator product contained 323 mg
95% curcumin (380 mg total curcuminoids) and hydroxypropyl
cellulose in 6 capsules. The study was approved by Institutional
Review Board Services (Pro00011961). The study was con-
ducted by KGK Synergize Inc., Identier
This was a double-blind, randomized, crossover study consist-
ing of healthy adult volunteers (6 male and 6 female) between
the ages of 18 and 45 years with a body mass index (BMI) of
1829.9 kg/m
. Inclusion criteria were as follows: If female, was
not of childbearing potential or was using a medically approved
method of birth control and had a negative urine pregnancy
test result. The subjects agreed to maintain their current levels
of physical activity throughout the study and avoided using
black or white pepper, turmeric, curcumin, or curry; yellow dye
#E100 in the preparation of food; and Indian and Thai cuisines
for the 7-day period prior to the study and for the period of the
study. The subjects agreed to avoid alcohol and caffeine for
12 hours and grapefruit and grapefruit juice for 48 hours prior
to baseline and each subsequent clinic visit. Furthermore, the
subjects agreed to consume only low polyphenols in the diet
(nutritionists counseled on high-polyphenol fruits, vegetables,
supplements, herbal extracts, and whole-grain based foods to
avoid) 3 days prior to baseline and on test days. Finally, the
subjects gave written informed consent to participate in the
Exclusion criteria included a BMI 30 kg/m
; women who
were pregnant, breastfeeding, or planning to become pregnant
during the course of the trial; subjects with unstable medical
conditions as determined by the qualied investigator; subjects
who were smokers; subjects who used St. Johnswort 3 weeks
prior to baseline and during the study; subjects with current or
history of gastrointestinal problems or disease; subjects with
metabolic, endocrine, or chronic diseases; immunocompro-
mised individuals; subjects with clinically signicant abnormal
lab results at screening; subjects who had planned surgery dur-
ing the course of the trial; subjects with a history of or current
diagnosis of any cancer or history of gallbladder issues; subjects
with hyperacidity; and subjects with gastric/duodenal ulcers. In
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addition, subjects were excluded if they had prior use of pre-
scription H2 blockers, proton pump inhibitors, or blood sugar
lowering agents; used blood pressure medication; had donated
blood in the last 2 months; had a history of blood/bleeding
disorders or were taking prescription blood thinners or anti-
platelet therapy; had a history of alcohol abuse (>2 standard
alcoholic drinks per day) or drug abuse within the past
6 months; used medical marijuana; were currently being treated
for hyperlipidemia or had high hypercholesterolemia including
the use of statins and cholestyramine; had participated in a
clinical research trial within 30 days prior to randomization;
had an allergy or sensitivity to study supplement ingredients or
to any food or beverage provided during the study; and were
unable to give informed consent.
Sixteen participants were recruited for the study. Four
female subjects did not complete the study. Two subjects did
not return for the second arm of the study. One subject with-
drew for a health reason unrelated to the study products, and
one subject withdrew during clinic visit 2 due to difculty in
having blood drawn. The demographics of the subjects who
completed the study are presented in Table 1 by gender.
Experimental protocol
The consort chart is provided in Figure 1. At screening and
clinic visit 1, 42 subjects were initially screened, given the
informed consent form, asked to carefully read the information,
and given the opportunity to seek more information if needed.
If agreeable, each subject signed the consent form and received
a duplicate. Once consent was obtained, inclusion and exclu-
sion criteria were reviewed, medical history and concomitant
therapies and current health status were reviewed, seated rest-
ing blood pressure and heart rate were measured, weight and
height were measured and BMI was calculated, and a physical
exam was conducted. Female participants were given urinary
pregnancy tests, and fasting (8 hours) blood samples were col-
lected for complete blood counts, electrolytes (Na, K, Cl), fast-
ing glucose, creatinine, aspartate aminotransferase (AST),
alanine aminotransferase (ALT), gamma glutamyl transpepti-
dase (GGT), and bilirubin. Sixteen subjects (6 males and 10
females) qualied for the study based on the inclusion/exclu-
sion criteria.
At clinic visit 2, subjects were randomized and administered
a single 6-capsule dose of either the CLDM test product (76 mg
curcumin) or the comparator product (380 mg 95% curcumin).
Subjects swallowed the dose in the clinic on an empty stomach
with water after the predose blood sample had been obtained.
The time of dose was recorded and the timing of blood draws
was based on the dose time. Blood samples were drawn at
15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours,
4 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, and
14 hours postdose for analysis of plasma curcumin levels. All
subjects were provided the same meals on the 2 test days, and
the amounts consumed were recorded. Participants remained
in the clinic for the 14-hour time period.
Subjects returned to the clinic (visit 3) for the 24-hour blood
sample collection and for the 48-hour blood sample collection
(visit 4). There was a minimum of 14 dayswashout prior to
the second test period (clinic visit 5) at which time the cross-
over product was given and the above procedure was repeated,
including clinic visits 6 and 7 for the 24- and 48-hour blood
sample collections, respectively. Twelve subjects (6 males and 6
females) completed the study and there were no adverse effects
observed or reported by any of the participants. One subject
Table 1. Demographic data for participants who completed the study.
Parameter Males Females
Age 28.7 §7.7 years 29.8 §6.7 years
Height 204.2 §27.4 cm 162.0 §28.4 cm
Weight 80.4 §10.8.3 kg 63.8 §11.2 kg
BMI 24.8 §3.1 kg/m
23.6 §3.4 kg/m
BMI Dbody mass index.
Six males and 6 females. Results are presented as mean §SD.
Figure 1. Consort chart.
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withdrew consent and elected not to participate prior to visit 2.
Two female subjects were lost after completion of arm 1, visit 4.
One was lost to follow-up and the other withdrew for personal
reasons. One subject was a no-show for the nal visit (visit 7;
see Figure 1).
Analytical methods
Blood samples (minimum of 6 mL of whole blood each) were
collected in vacutainer tubes with EDTA as the anticoagulant.
The samples were immediately centrifuged at 2500 gat 4C for
15 minutes, and 3 aliquots of 1-mL plasma supernatant, with-
out disturbing the white buffy layer, were collected and depos-
ited into cryotubes, which were then frozen and stored at
¡80C until analysis. The samples were extracted according to
the method of Cao et al. (20).
The samples were analyzed for free curcumin, curcumin sul-
fate, and curcumin glucuronide by high-performance liquid
chromatographytandem mass spectrometry using a Waters
Atlantis C-18 column (2.1 mm £50 mm, 3.0 mm) for the liq-
uid chromatography separation on a Shimadzu LC-20AT sys-
tem and a negative ion mode, multiple reaction monitoring
tandem mass spectrometry method for compound quantica-
tion with an AB Sciex 4000 Q trap system and a triple quadru-
pole mass spectrometer (Shimadzu Corp., Kyoto, Japan). The
daughter ions of compounds were determined by fragmenta-
tion experiments and the most abundant daughter ions were
selected for compound quantications (20). The developed
method was applied to quantify curcumin and its targeted
Curcumin standards
Calibration curves were prepared using human blood plasma
spiked with standard solutions extracted side by side with the
test plasma samples. Calibration curves were prepared for
curcumin, curcumin glucuronide, and curcumin sulfate. Curcu-
min was purchased from Sigma Aldrich (St. Louis, MO,
USA), curcumin sulfate was obtained from TLC Pharmaceu-
tical Standards (Aurora, ON, Canada), and curcumin glucu-
ronide was procured from Toronto Research Chemicals Inc.
(Toronto, ON, Canada). Correlation coefcients for all meth-
ods achieved R
values >0.990.
Statistical analysis
Statistical analyses were performed with GraphPad Prism 7.0 (La
Jolla, CA, USA). A paired 2-tailed ttest was used to compare
values between 95% curcumin and CLDM periods. Area
under the curve (AUC), k
were determined by
GraphPad Prism. The built-in XY nonlinear regression curve
analysis for AUC in GraphPad Prism was employed which uses
the standard trapezoidal rule to calculate peak areas. Because
some subjects showed no apparent uptake of curucmin, post hoc
responder rates of C
for total curcumin were determined by
comparison to 2 published studies that used a similar dose of
results of these studies, an average C
of 20 ng/mL was used as
a threshold of response for chi-square analysis with Yates
Numerous human pharmacokinetic studies have been con-
ducted with 95% curcumin (curcuminoids). This study com-
pared the pharmacokinetic properties of unformulated 95%
curcumin with the novel CLDM, BioCurc, under the same
experimental conditions and in the same subjects. Plasma
blood levels of curcumin glucuronide, curcumin sulfate, free
curcumin, and total curcumin are presented in Figure 2, after
orally ingesting capsules of either the CLDM, which delivered
Figure 2. Plasma levels of curcumin glucuronide, curcumin sulfate, free curcumin, and total curcumin after a single dose of the study products.
Downloaded by [] at 08:52 18 October 2017
76 mg curcumin, or the unformulated 95% curcumin, which
delivered 380 mg curcumin.
Although blood samples were drawn for a total of 48 hours,
the data are presented only for 8 hours for the glucuronide, sul-
fate, and total curcumin, which were close to baseline at this
time point. After administration of the novel CLDM, highest
plasma levels were achieved with curcumin glucuronide, which
reached almost 300 ng/mL at 1.5 hours postdosing (Figure 2A).
Under the same conditions, plasma curcumin glucuronide fol-
lowing administration of 5-fold more curcumin associated with
the unformulated 95% curcumin achieved peak levels that were
near baseline (approximately 1 ng/mL).
The novel CLDM study product resulted in plasma levels of
curcumin sulfate at the 1.5-hour time point that reached
approximately 20 ng/mL, as compared to plasma levels for this
metabolite associated with 95% curcumin that were approxi-
mately 1 ng/mL (Figure 2B). The data for free curcumin are
presented over 48 hours following administration of the 2
products (Figure 2C). Free curcumin reached a maximum
plasma level of approximately 2 ng/mL for the CLDM and
0.3 ng/mL for the 95% curcumin (Figure 2C) at the 1.5-hour
time point. However, a small secondary free curcumin peak
was observed for the CLDM at 12 hours, and a much larger
peak of approximately 1.5 ng/mL occurred at the 24-hour time
point. Free curcumin from administration of the 95% curcumin
remained near baseline over this period of time.
The total plasma curcumin over 8 hours is presented in
Figure 2D. Because total curcumin is usually measured and
reported after hydrolysis, and because the plasma samples
were not hydrolyzed in this study, total curcumin was
determined by correcting for actual curcumin content asso-
ciated with curcumin sulfate and curcumin glucuronide,
which was not done for the graphs of curcumin glucuronide
(Figure 2A) and curcumin sulfate (Figure 2B). As a conse-
quence, the amount of total curcumin (Figure 2D)appears
to be less than the amount of curcumin glucuronide
(Figure 2A). What is evident is the large peak of total cur-
cumin present in the plasma over the rst 4 hours with a
of approximately 220 ng/mL for the novel CLDM
study product. The total curcumin in the plasma from the
unformulated 95% curcumin comparator remained near
baseline. The amount of total curcumin consisting of free
curcumin, curcumin glucuronide, and curcumin sulfate that
was absorbed as represented by the area under the curve
(AUC)/mg administered curcumin for the study product
was 94 times greater than for the 95% unformulated curcu-
min (Table 2).
Mean C
values (§standard error of the mean, SEM) for
total curcumin for CLDM and the unformulated 95% curcumin
were 277.24 §58.75 and 1.22 §0.31, respectively (p<0.0007,
paired 2-tailed ttest). The C
value for the study product was
116 times greater than for the 95% curcumin based on the
same amount of material (400 mg). However, when the data
were normalized for the relative amount of curcumin con-
sumed, the C
for the study product was over 1180 times
greater than for the unformulated 95% curcumin.
The T
, and k
values for free curcumin, curcumin
sulfate, curcumin glucuronide, and total curcumin for both
unformulated 95% curcumin and the CLDM study product are
presented in Table 2. In most other pharmacokinetic studies
involving curcumin formulations, these values are usually only
provided for total curcumin after enzymatic hydrolysis. The
for the total unformulated 95% curcumin and CLDM
were 8.6 §4.8 hours and 1.5 §0.07 hours.
Mean total curcumin AUC(0- to 8-hour) values (§SEM) for
the CLDM were 94 times greater than for the unformulated
95% curcumin (391.5 §86.42 vs 4.16 §1.25 ng-ml/h) at the
same 400-mg dose of material (Table 3). However, when the
data were normalized with respect to the amount of curcumin
ingested (64.6 mg for the CLDM vs 323 mg for 95% curcumin),
the AUC/mg of total curcumin for the study product was
522 times greater than for the 95% curcumin, denoting a vastly
greater absorption of total curcumin from the CLDM.
Responder rates were also calculated and compared.
Response was dened as a C
of 20 ng/ml or greater. No
unformulated 95% curcumin subjects attained this C
, but 11
out of 12 CLDM subjects attained this response. Corrected chi-
square analysis showed a signicant difference for percentage
of responders for the CLDM (p<0.0001) compared to the
95% curcumin.
The results of this study demonstrate that a novel proprietary
liquid droplet micromicellar formulation of curcumin facili-
tates absorption and produces exceedingly high plasma levels
of both conjugated and total curcumin compared to unformu-
lated 95% curcumin. Taken together, the C
and AUC data
based on the actual amount of curcumin ingested demonstrate
a marked superiority with respect to absorption and the plasma
levels achieved with the novel proprietary curcumin formula-
tion compared to the unformulated 95% curcumin. The CLDM
had been absorbed on hydroxypropyl cellulose to yield a ow-
able powder in order to facilitate capsule lling to match the
Table 2. T
and T
Values for unformulated 95% curcumin and BioCurc.
95% Curcumin BioCurc
Free Sulfate Glucuronide Total Free Sulfate Glucuronide Total
n7 9 1 9 10 12 11 12
(h) 4.0 4.0 4.0 8.6 3.8 1.6 1.6 1.5
SEM 1.67 1.32 0.00 4.84 2.38 0.08 0.11 0.07
(ng/ml¢h) 0.126 0.363 0.300 0.310 0.429 3.912 141.9 33.66
(h) 5.5 1.9 2.3 2.2 1.6 0.18 0.005 0.021
SEM Dstandard error of the mean.
Each value is the mean of 12 subjects.
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appearance of the unformulated 95% curcumin comparator
product. As noted above, due to the poor absorption of curcu-
min, various formulations have been developed to enhance the
bioavailability of curcumin (1238).
In general, in order for a substance such as curcumin to
exert a systemic physiological response, it must be absorbed,
and pharmacokinetic studies are conducted to assess the extent
of absorption and the metabolic fate of the substance in ques-
tion. The novel CLDM formulation of curcumin assessed in
this study demonstrated greatly enhanced absorption compared
to unformulated 95% curcumin. The relative importance of the
blood levels of free curcumin and its glucuronide and sulfate
conjugates as opposed to total curcumin with respect to physio-
logical effects has yet to be determined.
Curcumin is physiologically more active than its conjugated
forms and therefore it is assumed that blood levels of free cur-
cumin reect greater physiological activity (5,1114). This
study has demonstrated measurable levels of free curcumin
associated with the novel proprietary curcumin formulation as
well as high levels of curcumin conjugates. Whether increased
and measurable blood levels of free curcumin are reected in
enhanced tissue levels and greater physiological responses
remain to be determined, and subsequent studies are required
to address these questions.
The presence of an initial free curcumin peak at 1.5 hours
after administration of the CLDM study product followed by a
second peak at 12 hours and a third peak at 24 hours provides
new and interesting information (Figure 2C). How the novel
composition of the product inuences the formation and
occurrence of these 3 peaks and subsequent physiological
responses remains to be determined. The second and third
peaks may reect lymphatic uptake and enterohepatic recycling
with deconjugation, respectively (5,6).
It is exceedingly difcult to make direct pharmacokinetic
comparisons between various curcumin formulations that
contain widely differing amounts of curcumin, are delivered
in markedly differing amounts of total product mass, and
exhibit wide variations in the amount of curcumin absorbed
(1232,38,39). For comparative purposes, published phar-
macokinetic data (C
and AUC) for 95% curcumin and
various enhanced absorption formulations are presented in
Table 3. The data have been normalized and are presented
as C
/mg curcumin and AUC/mg curcumin (Table 3),
permitting a more direct and simplied comparison with
respect to absorption and bioavailability and comparing the
amount of curcumin given to the subjects in these studies
with the amount occurring in the blood. Douglass and
Clouatre (12) developed a previous approach to this prob-
lem that involved equations for determining relative molar
absorption and relative mass efciency that took into con-
sideration not only the relative amount of curcumin
administered but also the mass of the formulation.
Table 3 summarizes pharmacokinetic data from studies with
various formulations including micronized curcuminoids plus
turmeric oil (BCM-95); curcuminoids formulated with phos-
phatidylcholine from soy lecithin and microcrystalline cellulose
(Meriva); coadministered with piperine (Curcumin C
plex); complexed with fenugreek-derived galactomannan ber
Table 3. Comparison of pharmacokinetic properties of various curcumin formulations.
Source Curcumin Dose (mg) Material Dose (mg) C
(ng/ml) C
/mg Curcumin AUC (ng¢h/ml) AUC/mg Curcumin Reference
95% Curcuminoids 323 400 1.22 0.0038 4.16 0.0104 Current
95% Curcuminoids 318 411 13.4 0.0421 49.9 0.1568 21
95% Curcuminoids 81 103 9.10 0.1129 14.3 0.1774 21
95% Curcumin 30 30 1.8 0.0600 4.1 0.1367 22
95% Curcuminoids 2920 4000 57 0.0195 929 0.3182 25
95% Curcumin 1900 2000 150 0.0789 462 0.2437 26
95% Curcuminoids 1295 1894 9.0 0.0069 122.5 0.0878 31
95% Curcuminoids 1350 1895 2.3 0.0017 10.8 0.0080 29
95% Curcuminoids 1774 1945 2.3 0.0013 19.7 0.0111 32
95% Curcuminoids 3240 3600 <1 NA NA NA 33, 34, 35
95% Curcuminoids CPiperine 9000 12,000 <1ND ND 38
BioCurc 64.6 400 282 4.3653 351 5.4334 Current
Theracurmin 30 Drink 25.8 0.8600 121 4.0333 28
Theracurmin 30 250 29.5 0.9833 113 3.7667 22
Theracurmin 182 1500 231.5 1.2692 693 3.7993 27
Theracurmin 200 1667 222 1.1100 NA NA 24
Theracurmin 400 3330 511 1.2775 NA NA 24
CurQfen 97.7 250 341 3.4995 963 9.8567 21
CurQfen 391 1000 579 1.4808 2274 5.8159 21
Cavacurmin 371 2000 87.0 0.2342 389 1.0463 32
Longvida 163 650 22.4 0.1374 95.3 0.5828 30
CurcuWIN 376 1567 34.9 0.0928 380 1.011 29
BCM-95 279 500 45.0 0.1611 NA NA 27
BCM-95 376 NA 0.5 0.0013 5.8 0.0154 29
BCM-95 392 NA 1.1 0.0028 12.1 0.0309 32
BCM-95 1718 2000 573 0.3335 3588 2.0888 26
Meriva 152.5 58.5 0.3856 NA NA 27
Meriva 209 1110 69 0.3301 640 2.7948 31
Meriva 376 2000 207 0.6037 1336 3.5532 31
Meriva 376 8.7 0.0231 65.3 0.1737 29
Meriva 382 18.0 0.0471 86.9 0.2274 32
Meriva 303 2000 71 0.2343 785 2.591 25
NA Ddata not available, ND Dnot detected at 1 ng/mL.
Downloaded by [] at 08:52 18 October 2017
(CurQfen); complexed with a hydrophobic carrier, cellulosic
derivatives, and natural antioxidants (CurcuWIN); use of
microparticle and surface-controlled colloidal dispersion tech-
nology using ghatti gum and glycerin (Theracurmin); com-
plexed with g-cyclodextrin (Cavacurmin); and a solid lipid
curcumin particle (Longvida). The results of published phar-
macokinetic studies involving these formulations are compared
with the novel CLDM formulation used is the current study as
well as with the results from various studies using unformu-
lated 95% curcumin.
When one compares the C
/mg curcumin and AUC/mg
curcumin administered from the various pharmacokinetic
studies presented in Table 3, the data indicate that greatest
absorption and bioavailability are produced with the novel
CLDM formulation used in the current study. The products
that provide the closest absorption per milligram of curcumin
to the CLDM study product are the microparticle and surface-
controlled colloidal dispersion technology product using ghatti
gum and glycerin (Theracurmin) and the complex with fenu-
greek-derived galactomannan ber (CurQfen). These products
are discussed in more detail below. The following are pharma-
cokinetic comparisons between the novel CLDM and various
other formulations based on published pharmacokinetic data.
The average C
/mg curcumin for the product based on
surface-controlled colloidal dispersion with ghatti gum and
glycerin (Theracurmin) from various studies is approximately
1.17 (2224,29) compared to 4.37 for the new CLDM, suggest-
ing that the novel study product is approximately 3.7 times
more readily absorbable. Based on several studies for which
data are available, the AUC/mg curcumin administered is
approximately 5.43 for the CLDM compared to 3.9 for the
ghatti gumglycerin-dispersed product (22,29), a factor of over
1.4 times.
If one uses the average C
/mg for the studies that exam-
ined the pharmacokinetic properties of the micronized curcu-
min with turmeric oil (BCM-95) (27,28), the C
curcumin for the novel study product is approximately 29 times
greater, and the AUC/mg curcumin is approximately 5.6 times
greater. A similar comparison with the phosphatidylcholine
formulated curcumin product (Meriva) indicated that the
/mg curcumin for the CLDM study product was approxi-
mately 8.6 times greater and the AUC/mg curcumin consumed
was approximately 2.2 t imes greater (Table 3).
Another absorption-enhanced product that is available is
composed of 20% curcumin, a hydrophilic carrier, cellulose
derivatives and antioxidants (CurcuWIN) (29). This product is
reported to have 46 times greater absorption than 95% curcu-
min (12,29). When comparing the C
/mg curcumin of this
product with that of the CLDM used in this study, the results
indicate that the CLDM produced a maximum concentration
that was approximately 47 times greater per milligrams of
ingested curcumin. When comparing the AUC/mg curcumin
administered, the value for the CNDL study product was
approximately 5.4 times greater (Table 3).
When the study product is compared to curcumin com-
plexed with g-cyclodextrin (Cavacurmin) (32), the C
and AUC/mg ingested curcumin for the novel study product
were approximately 18.7 and 5.2 times, respectively, greater for
the novel CLDM product (Table 3). Similarly, when comparing
the pharmacokinetic properties of a solid lipid curcumin parti-
cle (Longvida) with the CLDM study product, the C
/mg cur-
cumin and AUC/mg administered curcumin were
approximately 32 and 9.2 times greater for the study product,
An inverted doseresponse effect was observed with the cur-
cumingalactomannan complex (CurQfen) (21). Another
pharmacokinetic study should be conducted with this product
to clarify the issue. When comparing the average of the 2 doses
of curcumin to the study product, the C
/mg curcumin and
AUC/mg curcumin values for the study product were approxi-
mately 1.9 times and equivalent, respectively. Several studies
have examined the pharmacokinetic properties of curcumin
coadministered with piperine (C
Complex) (33,34). The
results suggest that the C
/mg and the AUC/mg may be 22
and 1.9 times greater, respectively, for the novel CLDM study
product compared to this product.
When one examines the C
/mg curcumin and AUC/mg
curcumin values for unformulated 95% curcumin from various
studies (21,22,2529,31,32,3841), wide variations occur in the
values obtained (Table 3). Various reasons may exist for these
disparate results based on differences in the analytical protocols
including differences in doses given, manner of administration
(with or without food), extraction procedures, analytical and
quantitation methods, sample storage conditions, analytes
determined, and how end-points were calculated. Furthermore,
differences in sensitivity and specicity of the assay methods
may contribute to these widely varying results. With relatively
few exceptions (30,3337), plasma samples in these studies
were enzymatically hydrolyzed resulting in the release of conju-
gated and bound curcumin. The average C
/mg curcumin
value for the 9 studies involving unformulated 95% curcumin
was approximately 0.03 ng/mL/mg total curcumin. In compari-
son, when free curcumin plus sulfate and glucuronide conju-
gated curcumin were analyzed without enzymatic hydrolysis as
was done in the current study, the C
observed for unformu-
lated 95% curcumin was only 0.003 ng/mL/mg curcumin.
The reason for this difference is not clear but may be due to
the effects of enzymatic hydrolysis and release of tissue-bound
curcumin. Similar results were observed regarding the AUC/
mg administered curcumin with respect to unformulated 95%
curcumin (Table 3). When one compares the average values for
/mg curcumin and AUC/mg ingested curcumin for unfor-
mulated 95% curcumin with the values for the CLDM study
product, the values for the study product are approximately
119 and 48 times greater, respectively. As a consequence, it can
be concluded that the novel study product exhibits much
greater absorbability per milligram of administered curcumin.
The results suggest that enzymatic hydrolysis of plasma
samples prior to analysis inuences the analytical results and
does not provide any information regarding the amount of free
curcumin in the blood. Free, unconjugated curcumin and its
analogs compared to conjugated curcuminoids have been
shown to possess greater anti-inammatory, antioxidant, tissue
protectant, and antiproliferative activities (5,42,43) and, as a
consequence, formulations that result in higher levels of free
curcumin may be expected to yield greater physiological effects.
A strength of the study was the use of the same subjects
under the identical experimental conditions to compare the
Downloaded by [] at 08:52 18 October 2017
absorption of the novel study product with 95% curcumin. In
addition, free curcumin, curcumin glucuronide, and curcumin
sulfate were analyzed without enzymatic hydrolysis, specically
allowing quantitation of each of these 3 components. Most
other pharmacokinetic studies resort to enzymatic hydrolysis
to free curcumin from its conjugates and therefore the amounts
of each of the free and conjugated forms that are present in
plasma are not known (1341). The total curcumin in the
plasma was calculated, allowing for the glucuronide and sulfate
components. The composition of the novel product involves
components that are all generally recognized as safe and there-
fore can be used in dietary supplements and food products.
A weakness of the study was the lack of determination of the
derivatives of curcumin, including demethoxycurcuin, bis-
demethoxycurcumin, dihydrocurcumin, tetrahydrocurcumin,
and hexahydrocurcumin. These metabolites of curcumin are
not determined in most studies. A need exists for a determina-
tion of the plasma levels of these constituents in order to better
understand the relationships between curcuminoid pharmaco-
kinetics and physiological/pharmacological effects. Further-
more, studies are required to assess the effects of the enhanced
absorption of curcumin associated with the CLDM product rel-
ative to specic physiological outcomes.
In summary, the novel CLDM product developed and
used in the current study exhibits very high gastrointestinal
absorption, which in general is greater than a variety of
enhanced absorption products for which pharmacokinetic
data are available. The AUC/mg administered curcumin
was approximately 417 times greater for the study product
than for unformulated 95% curcumin administered to the
same subjects and under the same experimental conditions.
This represents absorption greater than for any of the
known available products. Additional studies are needed to
conrm the results of this study and determine how the
enhanced absorption of this novel highly bioavailable form
of curcumin inuences the effects of curcumin with respect
to specic health conditions as well as general health and
Conict of interest
S.J.S. and L.R.B. serve as consultants for Boston BioPharm Inc.
This study was funded by Healthy Directions, LLC (a Helen of Troy
Company), Bethesda, Maryland, and Boston BioPharm Inc., Boston,
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... Moreover, our previous treatment of MT-COMP mice with turmeric (curcumin, an active ingredient of turmeric) suggested that purified curcumin might reduce the accumulation of mutant-COMP [24]. CurQ+ is a unique coconut oil-based dispersion of curcumin that dramatically increases absorption (up to 65-fold) over powdered curcumin [40]. This study assessed whether CurQ+ dampened the MT-COMP growth plate pathology. ...
... CurQ+ was selected based on a long history of safe human consumption of curcumin/turmeric, and because curcumin has been shown to reduce joint degeneration in OA [37,49,55,56] and cellular stresses that are involved in the mutant-COMP pathology [18,20,24,26,32]. Moreover, CurQ+, a formulation of curcumin, was specifically evaluated because it is more absorbable compared to 95% powdered curcumin [40]. ...
... CurQ+ was selected based on a long history of safe human consumption of curcumin/turmeric, and because curcumin has been shown to reduce joint degeneration in OA [37,49,55,56] and cellular stresses that are involved in the mutant-COMP pathology [18,20,24,26,32]. Moreover, CurQ+, a formulation of curcumin, was specifically evaluated because it is more absorbable compared to 95% powdered curcumin [40]. The current working model of PSACH growth plate chondrocyte pathology is a selfperpetuating loop initiated by the retention of mutant-COMP in the ER of chondrocytes that stimulates severe and unrelenting cellular stress resulting in chondrocyte death. ...
Full-text available
Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable formulation of curcumin, was tested in MT-COMP mice at doses of 82.3 (1X) and 164.6 mg/kg (2X). CurQ+ treatment of MT-COMP mice from 1 to 4 weeks postnatally decreased mutant COMP intracellular retention, inflammation, restoring both autophagy and chondrocyte proliferation. CurQ+ reduction of cellular stress in growth plate chondrocytes dramatically reduced chondrocyte death, normalized femur length at 2X 164.6 mg/kg and recovered 60% of lost limb growth at 1X 82.3 mg/kg. These results indicate that CurQ+ is a potential therapy for COMPopathy-associated lost limb growth, joint degeneration, and other conditions involving persistent inflammation, oxidative stress, and a block of autophagy.
... Several of these enhanced-absorption preparations are commercially available under different registered brand names. Bioavailabilities of curcumin in human studies of example branded products are presented in Table 3 [19,22,42], [45,46,47,48,49], [49,50,51,52,53,54,55,56],. ...
... BioCurc® is a liquid droplet micellar formulation of curcumin. It has been shown to raise bioavailability of curcumin by 94-fold [45]. BCM-95® is a mixture of turmeric essential oils and curcumin. ...
... For the majority of products, comparisons of bioavailabilities among different studies are inexact due to varying study designs, analytical techniques, pharmacokinetic parameters, dosages, and other relevant details of each formulation. In spite of these drawbacks, literature reports reveal clear trends, with several products exhibiting over 100-fold higher bioavailability relative to standard unformulated curcumin [42,54,61] or close it [45,50]. ...
Full-text available
Curcumin, from the rhizome of turmeric (Curcuma longa L.), has a wide variety of biological activities. Unfortunately, its poor water-solubility greatly limits its bioavailability. The purpose of this study was to evaluate CUMINUP60®, a novel preparation utilizing a solvent-free, co-grinding method designed to improve curcumin’s bioavailability. We performed a single-center crossover experiment to compare the new product with standard 95% curcumin in the blood plasma of twelve healthy adults (10 males, 2 females). Total bioavailability of curcumin and its sulfate and glucuronide conjugates from the test product, measured by their areas under the curve over 12 h (AUC0-T), showed a combined increase of 178-fold over standard curcumin and its conjugates from the reference product. The new product represents a significant improvement for providing greater bioavailability of curcumin, as compared with several other branded preparations. It therefore has broad applications for preparing curcumin as a more effective health ingredient in functional foods, beverages, and nutraceuticals.
... Activa el receptor activado por el proliferador de peroxisoma y la vía de señalización Nrf2, dando como resultado una regulación negativa de interleucina-6, resistina, leptina y proteína quimiotáctica monocítica, además de favorecer la adiponectina. Este efecto pleiotrópico justifica la amplia gama de efectos biológicos que se le atribuyen (Stohs et al. 2018). ...
... En otro estudio realizado en humanos se utilizó una formulación micromicelar de gota líquida de curcumina, dando como resultado de 522 veces mejor en contraste de la curcumina nativa, la cual sigue siendo congruente con estudios previos (Stohs et al. 2018). ...
Full-text available
Curcumin is the main bioactive component of Curcuma longa, this biomolecule has anti-inflammatory, antioxidant and nephroprotective properties. The main disadvantage of this molecule is its low bioavailability. The objective of this project was to evaluate the nephroprotective effect of curcumin by the synthesis of a nanocomposite of gold nanoparticles with curcumin, and evaluate the nephroprotective effect in a murine model of nephrotoxicity induced by gentamicin. This low bioavailability is due to its poor absorption, apparent rapid metabolism, inactivity of final metabolism products, rapid elimination, limited tissue distribution and a short half-life. One way to increase absorption, bioavailability and half-life in plasma is through the use of nanoparticle-based release systems. In this project, the nephroprotective effect of curcumin was evaluated by treatment-improvement with nanocomposite of gold nanoparticles with curcumin. We synthesize the nanocomposite by a green method, and characterize it with UV-vis, TEM and FTIR. Rats were randomly separated in 9 experimental groups with seven days-treatment, each group had 6 Wistar rats weighting between 220-250 g, group 1 healthy rats, group 2 native curcumin, group 3 gold nanoparticles, group 4 nanocomposite, group 5 rats with gentamicin-induced kidney damage (this model of nephrotoxicity will be used for groups 5, 6, 7, 8), group 6 + native curcumin, group 7 + gold nanoparticles, group 8 + nanocomposite, group 9 were pretreated rats for 7 days with nanocomposite, on day 8 gentamicin model was used + nanocomposite for 7 more days. The lethal dose 50 was determined for the nanocomposite. Serum renal biomarkers creatinine and BUN were measured. Histopathological study with hematoxylin-eosin stain was performed to detect changes in tubular necrosis, tubular dilatation, glomerulus structure, edema, infiltration of mononuclear cells and formation of hyaline drops in tubular cells. Our nanocomposite maintained normal levels of kidney function biomarkers.
... 154 Another study showed that a polysorbate formulation of curcumin named BioCurc/CLDM (85% curcumin, 13% desmethoxycurcumin, 2% bisdemethoxycurcumin, lauryl macrogol-32 glycerides, polysorbate-20, DL-alphatocopherol, hydroxy prolyl cellulose) (6 tablets, cross-over study) possess excellent absorption and bioavailability and safety in healthy individuals. 155 In addition, cyclodextrin formulation of curcumin known as Cavacurcumin along with omega-3 fatty acids (ω-3 FA), astaxanthin, gamma linoleic GLA, tocotrienols, hydroxy tyrosol, and vitamin D3 resulted in substantial reduction of hs-CRP, and SBP in healthy volunteers. This regimen was also well-tolerated without any adverse side effects. ...
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Curcumin has been credited with a wide spectrum of pharmacological properties for the prevention and treatment of several chronic diseases such as arthritis, autoimmune diseases, cancer, cardiovascular diseases, diabetes, hemoglobinopathies, hypertension, infectious diseases, inflammation, metabolic syndrome, neurological diseases, obesity, and skin diseases. However, due to its weak solubility and bioavailability, it has limited potential as an oral medication. Numerous factors including low water solubility, poor intestinal permeability, instability at alkaline pH, and fast metabolism contribute to curcumin's limited oral bioavailability. In order to improve its oral bioavailability, different formulation techniques such as coadministration with piperine, incorporation into micelles, micro/nanoemulsions, nanoparticles, liposomes, solid dispersions, spray drying, and noncovalent complex formation with galactomannosides have been investigated with in vitro cell culture models, in vivo animal models, and humans. In the current study, we extensively reviewed clinical trials on various generations of curcumin formulations and their safety and efficacy in the treatment of many diseases. We also summarized the dose, duration, and mechanism of action of these formulations. We have also critically reviewed the advantages and limitations of each of these formulations compared to various placebo and/or available standard care therapies for these ailments. The highlighted integrative concept embodied in the development of next-generation formulations helps to minimize bioavailability and safety issues with least or no adverse side effects and the provisional new dimensions presented in this direction may add value in the prevention and cure of complex chronic diseases.
... Several other studies involving the administration of curcumin and its formulations in healthy humans also showed high absorption and bioavailability 59, 126, [144][145][146][147][148][149][150][151] . Moreover, curcumin supplementation in combination with ferrous sulfate was shown to enhance serum levels of iron, TIBC, and hemoglobin in healthy subjects 152 . ...
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Turmeric (Curcuma longa) has been used for thousands of years for the prevention and treatment of various chronic diseases. Curcumin is just one of >200 ingredients in turmeric. Almost 7000 scientific papers on turmeric and almost 20,000 on curcumin have been published in PubMed. Scientific reports based on cell culture or animal studies are often not reproducible in humans. Therefore, human clinical trials are the best indicators for the prevention and treatment of a disease using a given agent/drug. Herein, we conducted an extensive literature survey on PubMed and Scopus following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The keywords "turmeric and clinical trials" and "curcumin and clinical trials" were considered for data mining. A total of 148 references were found to be relevant for the key term "turmeric and clinical trials", of which 70 were common in both PubMed and Scopus, 44 were unique to PubMed, and 34 were unique to Scopus. Similarly, for the search term "curcumin and clinical trials", 440 references were found to be relevant, of which 70 were unique to PubMed, 110 were unique to Scopus, and 260 were common to both databases. These studies show that the golden spice has enormous health and medicinal benefits for humans. This Review will extract and summarize the lessons learned about turmeric and curcumin in the prevention and treatment of chronic diseases based on clinical trials.
Since the COVID-19 pandemic in 2020, many reports have highlighted several potential anti-SARS-CoV-2 drug candidates, including phenolic compounds. Therefore, this study aimed to evaluate the anti-SARS-CoV-2 activity of nine common phenolic compounds found in plants using the in vitro cellular infection model. The anti-SARS-CoV-2 activity of curcumin, quercetin, gallic acid, catechin, rutin, kaempferol, naringenin, coumaric acid and caffeic acid were evaluated on SARS-CoV-2-infected Vero E6 cells by using a cytopathic effect (CPE)-based assay. The anti-SARS-CoV-2 activity in human lung cells, A549 expressing human ACE2 and TMPRSS2, was evaluated by the RT-qPCR technique. S1-ACE2 interaction and 3CL protease activity assays were also performed for the potent compound. Of the nine phenolic compounds, only curcumin inhibited the SARS-CoV-2 induced CPE activity (EC 50 of 13.63 µM) in Vero E6 cells, but with a low selective index (SI) value. Interestingly, curcumin exhibited potent anti-SARS-CoV-2 activity in A549 cells with an EC 50 of 4.57 µM and an SI value of 7.96. S1-ACE2 interaction and 3CL protease inhibitory activities of curcumin were also observed. In conclusion, curcumin showed a moderate in vitro anti-SARS-CoV-2 activity. The true potential of curcumin as an anti-SARS-CoV-2 candidate could be further evaluated in a COVID-19 animal model.
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Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies.
Background: Curcumin supplementation may promote weight loss and ameliorate obesity-related complications through its anti-oxidative and anti-inflammatory properties. Objective: An umbrella review and updated meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the effect of curcumin supplementation on anthropometric indices. Methods: Systematic reviews and meta-analyses (SRMAs) of RCTs were identified from electronic databases (Medline, Scopus, Cochrane and Google Scholar) up to 31st March 2022 without language restriction. SRMAs were included if they assessed curcumin supplementation on any of body mass index (BMI), body weight (BW), or waist circumference (WC). Subgroup analyses were performed, stratifying by patient types, severity of obesity and curcumin formula. The study protocol was a priori registered (PROSPERO; CRD42022321112) RESULTS: From an umbrella review, fourteen SRMAs with 39 individual RCTs were included with a high degree of overlap. Additionally, searching was updated from the last search of included SRMAs in April, 2021 up to 31st March 2022, and we found 11 additional RCTs, bringing the total up to 50 RCTs included in the updated MA. Of these, 21 RCTs were classified as high risk of bias. Curcumin supplementation significantly reduced BMI, BW, and WC with mean differences (MD) of -0.24 kg/m2 (95% CI: -0.32, -0.16), -0.59 kg (95% CI: -0.81, -0.36) and -1.32 cm (95% CI: -1.95, -0.69), respectively. The bioavailability-enhanced form reduced BMI, BW and WC more with MD of -0.26 kg/m2 (95% CI: -0.38, -0.13), -0.80 kg (95% CI: -1.38, -0.23) and -1.41cm (95% CI: -2.24, -0.58), respectively. Significant effects were also seen in subgroups of patients, especially in adults with obesity and diabetes. Conclusions: Curcumin supplementation significantly reduces anthropometric indices and bioavailability-enhanced formulas are preferred. Augmenting curcumin supplement with lifestyle modification should be an option for weight reduction.
Cancer is considered as the major public health scourge of the 21st century. Though remarkable strides were made for developing targeted therapeutics, these therapies suffer from lack of efficacy, high cost, and debilitating side effects. Therefore, the search for safe, highly efficacious, and affordable therapies is paramount for establishing a treatment regimen for this deadly disease. Curcumin, a known natural, bioactive polyphenol compound from the spice turmeric (Curcuma longa), has been well documented for its wide range of pharmacological and biological activities. A plethora of literature indicates its potency as an anti-inflammatory and anti-cancer agent. Curcumin exhibits anti-neoplastic attributes via regulating a wide array of biological cascades involved in mutagenesis, proliferation, apoptosis, oncogene expression, tumorigenesis, and metastasis. Curcumin has shown a wide range of pleiotropic anti-proliferative effects in multiple cancers and is a known inhibitor of varied oncogenic elements, including NF-κB, c-myc, cyclin D1, Bcl-2, VEGF, COX-2, NOS, TNF-α, interleukins, and MMP-9. Further, curcumin targets different growth factor receptors and cell adhesion molecules involved in tumor growth and progression, making it a most promising nutraceutical for cancer therapy. To date, curcumin-based therapeutics have completed more than 50 clinical trials for cancer. Though creative experimentation is still elucidating the immense potential of curcumin, systematic validation by proper randomized clinical trials warrants its transition from lab to bedside. Therefore, this chapter summarizes the outcome of diverse clinical trials of curcumin in various cancer types
Curcumin, one of the 3 principal curcuminoids found within turmeric rhizomes, has long been associated with numerous physiologically beneficial effects; however, its efficacy is limited by its inherently low bioavailability. Several novel formulations of curcumin extracts have been prepared in recent years to increase the systemic availability of curcumin; Longvida®, a solid lipid curcumin particle preparation, is one such formulation that has shown enhanced bioavailability compared with standard curcuminoid extracts. As part of a safety assessment of Longvida® for use as a food ingredient, a bacterial reverse mutation test (OECD TG 471) and mammalian cell erythrocyte micronucleus test (OECD TG 474) were conducted to assess its genotoxic potential. In the bacterial reverse mutation test, Longvida® did not induce base‐pair or frame‐shift mutations at the histidine locus in the genome of Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537, in the presence or absence of exogenous metabolic activation. Additionally, two gavage doses (24 hours apart) of Longvida® to Swiss albino mice at 500, 1000, or 2000 mg/kg body weight/day did not cause structural or numerical chromosomal damage in somatic cells in the mammalian erythrocyte micronucleus test. It was therefore concluded that Longvida® is non‐genotoxic. The genotoxic potential of a solid lipid curcumin particle preparation (Longvida®), which provides a more bioavailable source of curcuminoids compared with standard curcumin extracts, was assessed using a bacterial reverse mutation test (Ames test) and mammalian cell erythrocyte micronucleus test. Longvida® did not induce base‐pair or frame‐shift mutations in the Ames test and did not cause structural or numerical chromosomal damage in somatic cells in the mammalian erythrocyte micronucleus test. It was therefore concluded that Longvida® is non‐genotoxic.
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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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Curcumin, a plant-derived polyphenolic compound, naturally present in turmeric (Curcuma longa), has been the subject of intensive investigations on account of its various activities. The implementation of safe, beneficial and highly functional compounds from natural sources in human nutrition/prevention/therapy requires some modifications in order to achieve their multi-functionality, improve their bioavailability and delivery strategies, with the main aim to enhance their effectiveness. The low aqueous solubility of curcumin, its rapid metabolism and elimination from the body, and consequently, poor bioavailability, constitute major obstacles to its application. The main objectives of this review are related to reported strategies to overcome these limitations and, thereby, improve the solubility, stability and bioavailability of curcumin. The effectiveness of curcumin could be greatly improved by using nanoparticle-based carriers. The significance of the quality of a substance delivery system is reflected in the fact that carrying curcumin as a food additive/nutrition also means carrying the active biological product/drug. This review summarizes the state of the art, and highlights some examples and the most significant advances in the field of curcumin research.
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Cancer chemoprevention involves the use of different natural or biologic agents to inhibit or reverse tumor growth. Epidemiological and pre-clinical data suggest that various natural phytochemicals and dietary compounds possess chemopreventive properties, and in-vitro and animal studies support that these compounds may modulate signaling pathways involved in cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials and have shown variable results. In this review, we summarize the data regarding select phytochemicals including curcumin, resveratrol, lycopene, folates and tea polyphenols with emphasis on the clinical evidence supporting the efficacy of these compounds in high-risk populations.
Curcumin is a natural plant-derived compound that has attracted a lot of attention for its anti-cancer activities. Curcumin can slow proliferation of and induce apoptosis in cancer cell lines, but the precise mechanisms of these effects are not fully understood. However, many lines of evidence suggested that curcumin has a potent impact on gene expression profiles; thus, functional genomics should be the key to understanding how curcumin exerts its anti-cancer activities. Here, we review the published functional genomic studies of curcumin focusing on cancer. Typically, a cancer cell line or a grafted tumor were exposed to curcumin and profiled with microarrays, methylation assays, or RNA-seq. Crucially, these studies are in agreement that curcumin has a powerful effect on gene expression. In the majority of the studies, among differentially expressed genes we found genes involved in cell signaling, apoptosis, and the control of cell cycle. Curcumin can also induce specific methylation changes, and is a powerful regulator of the expression of microRNAs which control oncogenesis. We also reflect on how the broader technological progress in transcriptomics has been reflected on the field of curcumin. We conclude by discussing the areas where more functional genomic studies are highly desirable. Integrated OMICS approaches will clearly be the key to understanding curcumin's anticancer and chemopreventive effects. Such strategies may become a template for elucidating the mode of action of other natural products; many natural products have pleiotropic effects that are well suited for a systems-level analysis.
Cancer is still a major cause of death all over the world. Its incidence and prevalence are increasing drastically. Cancer treatment imposes high socioeconomic burden with little impact especially on aggressive types of cancer. Reversing or delaying carcinogenesis "cancer chemoprevention" by purified or extracted natural products is a cost-effective alternative. Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects. These properties make curcumin a leading chemopreventive agent. Despite its effective anticarcinogenesis properties, curcumin's poor solubility, instability, and extensive metabolism result in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that resist metabolism while retaining curcumin's pharmacological properties, and adding another natural product that has bioenhancing properties to curcumin or combination of two of these strategies. This review comprehensively explores curcumin's chemistry and pharmacology followed by comparing and contrasting a vast number of strategies designed to enhance curcumin's bioavailability and its therapeutic effects. The review provides insights into which curcumin formulation strategies have the greatest promise to reach clinical application.
Curcumin, a yellow pigment in the Indian spice Turmeric (Curcuma longa), which is chemically known as diferuloylmethane, was first isolated exactly two centuries ago in 1815 by two German Scientists, Vogel and Pelletier. However, according to the pubmed database, the first study on its biological activity as an antibacterial agent was published in 1949 in Nature and the first clinical trial was reported in The Lancet in 1937. Although the current database indicates almost 9000 publications on curcumin, until 1990 there were less than 100 papers published on this nutraceutical. At the molecular level, this multitargeted agent has been shown to exhibit anti-inflammatory activity through the suppression of numerous cell signalling pathways including NF-κB, STAT3, Nrf2, ROS and COX-2. Numerous studies have indicated that curcumin is a highly potent antimicrobial agent and has been shown to be active against various chronic diseases including various types of cancers, diabetes, obesity, cardiovascular, pulmonary, neurological and autoimmune diseases. Furthermore, this compound has also been shown to be synergistic with other nutraceuticals such as resveratrol, piperine, catechins, quercetin and genistein. To date, over 100 different clinical trials have been completed with curcumin, which clearly show its safety, tolerability and its effectiveness against various chronic diseases in humans. However, more clinical trials in different populations are necessary to prove its potential against different chronic diseases in humans. This review's primary focus is on lessons learnt about curcumin from clinical trials. Linked articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit
Curcumin is poorly absorbed driving interest in new preparations. However, little is known about pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the two formulations. Phosphatidylcholine curcumin extract yielded only 20–30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady-state in both plasma and rectal tissues. This article is protected by copyright. All rights reserved
In recent years, several drugs have been developed deriving from traditional products and current drug research is actively investigating the possible therapeutic roles of many Ayruvedic and Traditional Indian medicinal therapies. Among those being investigated is Turmeric. Its most important active ingredient is curcuminoids. Curcuminoids are phenolic compounds commonly used as a spice, pigment and additive also utilized as a therapeutic agent used in several foods. Comprehensive research over the last century has revealed several important functions of curcuminoids. Various preclinical cell culture and animals studies suggest that curcuminoids have extensive biological activity as an antioxidant, neuroprotective, antitumor, anti-inflammatory, anti-acidogenic, radioprotective and arthritis. Different clinical trials also suggest a potential therapeutic role for curcuminoids in numerous chronic diseases such as colon cancer, lung cancer, breast cancer, inflammatory bowel diseases. The aim of this review is to summarize the chemistry, analog, metal complex, formulations of curcuminoids and their biological activities.