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Comparative bioavailability of curcumin, turmericand Biocurcumax� in traditional vehiclesusing non-everted rat intestinal sac model

Shishu*, Manjul Maheshwari1

University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India

A R T I C L E I N F O

Article history:

Received 18 August 2009

Received in revised form

27 January 2010

Accepted 28 January 2010

Available online 21 February 2010

Keywords:

Curcumin

Permeability

Non-everted intestinal sac

Biocurcumax�Bioavailability

Solubility

1756-4646/$ - see front matter � 2010 Elsevidoi:10.1016/j.jff.2010.01.004

* Corresponding author: Tel.: +91 172 2534281E-mail addresses: shishugoindi@yahoo.c

wari).1 Tel.: +91 172 2534281 (O), +91 9872319234

A B S T R A C T

The bioavailability of curcumin from turmeric, Biocurcumax� and as plain curcumin was

investigated using conventional vehicles by a non-everted rat intestinal model. Results of

ex vivo intestinal permeability studies showed an enhancement in the permeability of cur-

cumin with increase in lipophilicity of the vehicle used. Maximum permeability of curcu-

min was obtained from corn oil (13.4%) followed by clarified butter (9.82%), milk (4.24%)

and aqueous suspension (1.66%) in 8 h. Another very interesting and important observation

was that the permeation of curcumin was more from turmeric and Biocurcumax� than

from plain curcumin. These studies strongly suggest that curcumin may be consumed as

turmeric/Biocurcumax� in lipophilic vehicles instead of plain curcumin for maximum ben-

eficial effects.

� 2010 Elsevier Ltd. All rights reserved.

1. Introduction

The dried powdered rhizomes of Curcuma longa L. (Zingibera-

ceae), commonly known as turmeric, have extensively been

used for centuries as a spice, food preservative, and a yellow

colourant for food, drugs, and cosmetics (Nadkarni, 1976). Cur-

cumin (diferuloylmethane; 1,7-bis[4-hydroxy-3-methoxy-

phenyl]-1,6-heptadiene-3,5-dione) along with its mono- and

bisdemethoxy derivatives, collectively called curcuminoids,

constitute the major orange-yellow colouring matter and the

biologically active constituents of turmeric. Natural curcumin,

isolated from C. longa, contains curcumin I (diferuloylme-

thane, 94%), curcumin II (demethoxycurcumin, 6%), and cur-

cumin III (bisdemethoxycurcumin, 0.3%) and curcumin is

er Ltd. All rights reserved

(O), +91 172 2782099 (R)o.in, goindi@satyam.net

(M); fax: +91 172 2541142

responsible for most of the pharmacological actions of tur-

meric. A number of studies have highlighted antioxidant

(Jayaprakasha et al., 2006; Sandur et al., 2007), anti-inflamma-

tory (Aggarwal et al., 2006; Chen et al., 2008), anticancer

(Hatcher et al., 2008; Johnson & Mukhtar, 2007), nephroprotec-

tive (Cekmen et al., 2009), hypolipidemic (Manjunatha &

Srinivasan, 2007), hepatoprotective (Naik et al., 2004) and

immunomodulatory (Gao et al., 2004) properties of curcumin.

Curcumin has also been reported to combat various types of

rheumatoid arthritis and Alzheimer’s disease (Ringman

et al., 2005). Curcumin modulates various molecular targets,

including transcription factors, cytokines, cell cycle proteins

and a multitude of enzymes (COX-II), receptors and cell sur-

face adhesion molecules (Shishodia et al., 2005). In traditional

.

; fax: +91 172 2541142..in (Shishu), manjul_maheshwari2007@yahoo.co.in (M. Mahesh-

.

J O U R N A L O F F U N C T I O N A L F O O D S 2 ( 2 0 1 0 ) 6 0 – 6 5 61

system of medicine, turmeric has been used as an antiseptic, a

cure for poisoning, for treating dyspepsia and respiratory dis-

orders, to eliminate body wastes, wound healing and as a cure

for some skin diseases, and as a household remedy for treat-

ing sprains and swellings caused by injury (Ammon & Wahl,

1991). Many animal and clinical studies have proven that it

is a non-toxic and highly safe compound with a wide range

of pharmacological properties and doses as high as 8–10 g

per day have been shown to be well tolerated in humans

(Lao et al., 2006). However, clinical application of curcumin is

limited because of its poor bioavailability (Yang et al., 2007)

due to its poor solubility in water and poor absorption. Poor

absorption from the gut and avid metabolism in the body are

cited as the reasons for the lack of systemic availability. While

the major portion of ingested curcumin is excreted unmetab-

olized through the faeces, a small portion that is absorbed is

extensively converted to its water-soluble metabolites, glucu-

ronides and sulphate, and excreted. This seriously limits cur-

cumin to reach targets distant from the gut and exert its

beneficial action (Christopher et al., 2002). Preclinical and clin-

ical pilot studies with this dietary phytochemical suggest that

concentrations of curcumin achieved in plasma and target tis-

sues are very low (Anand et al., 2007; Sharma et al., 2007).

Biocurcumax� is a synergistic product of sesquiterpenoids

(volatile oils) and the curcuminoids present in turmeric re-

cently developed and patented by Arjuna Natural Extracts

Ltd. (Patent No. 200430), Edayar, India (Antony et al., 2005). It

is a reconstituted turmeric extract standardized with not less

than 95% curcuminoids (‘‘curcuminoid’’ is a mixture of curcu-

min, demethoxycurcumin and bisdidemethoxycurcumin,

wherein curcumin is the major component of the curcumi-

noid and comprises about 95% of the curcuminoid, and,

demethoxycurcumin and bisdidemethoxycurcumin are min-

or components of the curcuminoid). It has been reported to

be more bioavailable than curcumin (Antony, 2006). Similarly,

there are numerous other reports on attempts to enhance the

bioavailability of this promising bioactive phytoconstituent.

Some recent investigations suggest the use of piperine as an

adjuvant (Bhutani et al., 2009), liposomal curcumin (Li et al.,

2005), curcumin nanoparticles (Shaikh et al., 2009), gastrore-

tentive tablets (Shishu et al., 2008), curcumin phospholipid

complex (Liu et al., 2006), self-microemulsifying drug delivery

system (Cui et al., 2009) and solid lipid microparticles (Yadav

et al., 2009) for enhancing the bioavailability of curcumin.

In the traditional Indian system of medicine turmeric pow-

der is administered orally as a dispersion in milk or in a mix-

ture of clarified butter and milk. As a dietary component it is

generally consumed as curry ingredient where it is dispersed/

dissolved in cooking media like oils or clarified butter. The

aim of the present investigation was to explore and compare

the bioavailability of curcumin from turmeric (natural dietary

form), Biocurcumax� (a patented product with enhanced bio-

availability) and as plain curcumin and also to check the bio-

availability of curcumin from different conventional vehicles

such as milk, clarified butter and corn oil using non-everted

rat intestinal model. The permeability of drug candidates

across the intestinal mucosa is one of the most important fac-

tors in defining their bioavailability and biological activity.

Non-everted intestinal rat sac method is an excellent tech-

nique that may be employed to predict in vivo human absorp-

tion and bioavailability of promising natural compounds with

poor water solubility, poor permeability and/or poor stability

(Ruan et al., 2006). Therefore, this technique was used to as-

sess the bioavailability of curcumin.

2. Materials and methods

2.1. Materials

Curcumin and BCM-95� CG (Biocurcumax�: 95% curcumi-

noids) were obtained as gift from Arjuna Natural Extracts

Ltd., Edayar, India. Turmeric powder (MDH-Haldi powder,

Lot number: DLHP/91-NR/10/GS/08-L; curcumin content

3.4%), desi ghee/clarified butter (Verka� ghee) and corn oil

(Saffola� refined oil) were purchased from a local market in

Chandigarh, India. All other reagents and chemicals used

were of analytical reagent grade.

2.2. Analytical technique

The samples were analyzed using a UV–visible double beam

spectrophotometer (Shimadzu, Kyoto, Japan). The methodol-

ogy and data were validated for linearity, accuracy and preci-

sion in the drug concentration range of 1–10 lg/ml. The

equation for linearity was observed to be y = 1.113E � 01x with

r2 = 0.9999 and E1%1cm = 1113 at kmax 422 nm.

2.3. Solubility studies

The solubility of curcumin and Biocurcumax� was deter-

mined in water, desi ghee (clarified butter) and corn oil. An

excess amount of curcumin was added to 2 ml of each se-

lected vehicle and was kept at 37 ± 1 �C in a thermostated

shaking water bath (Narang Scientific Works, New Delhi, In-

dia) for 48 h. Then contents were then filtered through

0.22 lm filter and the filtrate was analyzed spectrophotomet-

rically at kmax 422 nm after appropriate dilution with

methanol.

2.4. Ex vivo intestinal permeation studies

Ex vivo permeation studies of curcumin, turmeric and Bio-

curcumax� from different vehicles were carried out using

non-everted gut sac technique. A total number of 20 male

Wistar rats (weighing 200–250 g) were used for the complete

study. Animals were sacrificed by spinal dislocation after

overnight fasting. The small intestine was removed by cutting

across the upper end of the duodenum and the lower end of

the ileum and manually stripping the mesentery. The small

intestine was washed out carefully with cold normal oxygen-

ated saline solution (0.9%, w/v, NaCl) using a syringe equipped

with blunt end. The clean intestinal tract was prepared into

8 ± 0.2 cm long sacs having a diameter of 3.0 ± 0.5 mm. Each

sac was filled with 0.5 ml of curcumin formulation (equivalent

to 0.5 mg of curcumin) via a blunt needle, and the two sides of

the intestine were tied tightly with thread. Each non-everted

intestinal sac was placed in a glass conical flask containing

50 ml of a mixture of Krebs Ringer phosphate buffer saline

pH 7.4 [containing sodium chloride (0.67%, w/v), potassium

0

5

10

15

20

25

30

0 2 4 6 8 10Time (h)

Am

ount

per

mea

ted/

area

(µ

g/cm

2 ) in

8h

Aq. Susp. Milk Clarified Butter Corn oil

Fig. 1 – Plot of cumulative amount of curcumin permeated

per unit area vs time in different vehicles.

62 J O U R N A L O F F U N C T I O N A L F O O D S 2 ( 2 0 1 0 ) 6 0 – 6 5

chloride (0.034%, w/v), magnesium sulphate (0.059%, w/v),

calcium chloride (0.011%, w/v), sodium dihydrogen phosphate

(0.234%, w/v) and glucose (0.18%, w/v) in distilled water] and

isopropyl alcohol in the ratio of 7:3 (v/v). The entire system

was maintained at 37 �C in a shaking water bath operating

at 50 rpm and aerated with oxygen (10–15 bubble/min) using

laboratory aerator. From outside of the sac 2 ml samples were

withdrawn every 30 min for 8 h and replaced with fresh 2 ml

of medium. The samples were analyzed at kmax 422 nm using

a UV–visible spectrophotometer (Shimadzu, Kyoto, Japan).

The cumulative amount released per unit area of sac (lg/

cm2), flux (lg/cm2/h) and percent drug permeation in the

receptor compartment were calculated (Ruan et al., 2006).

Studies were performed in four replicates and all data were

statistically analyzed by one-way analysis of variance (ANO-

VA) followed by Dunnett’s test and P value <0.05 was consid-

ered significant.

3. Results and discussion

3.1. Solubility studies

Solubility of a bioactive compound is an important physical

parameter that affects its absorption and bioavailability.

Therefore, the solubility of curcumin was determined in dif-

ferent vehicles used traditionally for administration (Table 1).

In corn oil the solubility curcumin was found to be highest

(0.426 ± 0.009 mg/ml) followed by clarified butter

(0.330 ± 0.007 mg/ml) and water (0.00564 ± 0.0006 mg/ml). Cur-

cumin from Biocurcumax� showed similar solubility behav-

iour in corn oil (0.458 ± 0.008 mg/ml) and in clarified butter

(0.351 ± 0.010 mg/ml). However, the aqueous solubility of cur-

cumin from Biocurcumax� (0.027 ± 0.001 mg/ml) was found

to be significantly higher (5.4 times) than solubility of plain

curcumin in water (P < 0.05). Greater solubility of curcumin

in Biocurcumax� may be due to the presence of some other

chemical constituents in this bioavailability enhanced

preparation.

3.2. Influence of vehicles on ex vivo permeation of plaincurcumin

Fig. 1 depicts the ex vivo permeation profiles of curcumin from

different vehicles using non-everted rodent gut sac tech-

nique. From aqueous suspension curcumin showed low per-

meation, i.e., only 1.513 ± 0.214 lg/cm2 (1.66%) in 8 h which

may be due to poor solubility of curcumin in water. Whereas,

an increase in permeability of curcumin was observed, when

it was incorporated into lipophilic vehicles employed tradi-

tionally for administration. The amount of curcumin released

Table 1 – Solubility profile of curcumin andBiocurcumaxTM.

Vehicle Solubility ofcurcumin (mg/ml)

Solubility ofBiocurcumax� (mg/ml)

Water 0.005 ± 0.0006 0.027 ± 0.001

Clarified butter 0.330 ± 0.007 0.351 ± 0.010

Corn oil 0.426 ± 0.009 0.458 ± 0.008

per unit area from milk, corn oil and clarified butter was

found to be 3.86 ± 0.428 (4.24%), 8.93 ± 0.642 (9.82%) and

12.18 ± 0.428 lg/cm2 (13.40%) in 8 h, respectively, which was

significantly different and higher than that from the aqueous

suspension at P < 0.05. The rate of permeation (flux) of curcu-

min from aqueous suspension, milk, clarified butter and corn

oil was observed to be 0.129 ± 0.045, 0.908 ± 0.107,

1.804 ± 0.0275 and 3.033 ± 0.099 lg/cm2/h, respectively

(Fig. 5). More than 23-fold increase in flux from corn oil 14-

fold increase from clarified butter and 7-fold increase in flux

were achieved from milk when values were compared with

flux values from aqueous suspension. Such a high degree of

enhancement in the permeability of curcumin from the lipo-

philic vehicles may be attributed to the greater solubility of

curcumin in these vehicles and subsequent favourable

partitioning.

3.3. Influence of vehicles on ex vivo permeation ofcurcumin from turmeric

Like plain curcumin the amount of curcumin permeated per

unit area from turmeric (Fig. 2) using lipophilic vehicles like

milk, corn oil and clarified butter (5.14 ± 0.454 lg/cm2; 5.32%,

13.1 ± 0.681 lg/cm2; 13.57% and 19.2 ± 0.909 lg/cm2; 19.9% in

8 h, respectively) was found to be significantly greater than

that from aqueous suspension (1.76 ± 0.227 lg/cm2; 1.83%).

Similarly, the order of rate of permeation of curcumin from

turmeric was as follows: aqueous suspension

(0.183 ± 0.016 lg/cm2/h) < milk (1.062 ± 0.173 lg/cm2/h) < clari-

fied butter (3.134 ± 0.025 lg/cm2/h) < corn oil (5.079 ± 0.221 lg/

cm2/h). More than 27-fold increase in flux from corn oil, 17-

fold increase in flux from clarified butter and 6-fold increase

in flux was achieved from milk when compared with aqueous

suspension of turmeric (Fig. 5). Turmeric is reported to con-

tain volatile oils (sesquiterpene ketones or tumerons, includ-

ing a-tumerone, b-tumerone, artumerone, a-atlantone,

curlone, zinziberene, curcumol); curcuminoids (curcumin,

demethoxycurcumin, bisdemethoxycurcumin); 1,5-diaryl-

penta-1,4-dien-3-on-derivatives; and sugars (Uehara et al.,

1992). Higher permeation of curcumin from turmeric as com-

pared to plain curcumin may be due permeation enhancing

effects of volatile components present in the turmeric.

0

5

10

15

20

25

30

0 2 4 6 8 10Time (h)

Am

ount

per

mea

ted/

area

(µ

g/cm

2 ) in

8h

Aq. Susp Milk Clarified Butter Corn oil

Fig. 2 – Plot of cumulative amount of curcumin permeated

per unit area vs time from turmeric using different vehicles.

J O U R N A L O F F U N C T I O N A L F O O D S 2 ( 2 0 1 0 ) 6 0 – 6 5 63

3.4. Influence of vehicles on ex vivo permeation ofcurcumin from Biocurcumax�

Biocurcumax�, a patented product of Arjuna Naturals is a

reconstituted, purified and standardized turmeric extract with

enhanced bioavailability (Antony, 2006). Results of ex vivo per-

meation studies of curcumin from Biocurcumax� using rat

intestinal sac are shown in Fig. 3. Like plain curcumin and tur-

meric the cumulative amount of curcumin permeated per unit

area from Biocurcumax� using corn oil was the highest

(20.94 ± 0.375 lg/cm2; 26.3%) followed by clarified butter

(13.52 ± 0.468 lg/cm2; 16.98%), milk (5.43 ± 0.468 lg/cm2;

6.82%) and aqueous suspension (2.05 ± 0.187 lg/cm2; 2.58%).

Similarly the order of rate of permeation of curcumin from

Biocurcumax� (Fig. 5) was corn oil (4.303 ± 0.0155 lg/cm2/

h) > clarified butter (2.47 ± 0.030 lg/cm2/h) > milk (0.977 ±

0.079 lg/cm2/h) > aqueous suspension (0.147 ± 0.033 lg/cm2/

h). Biocurcumax� contains a blend of the sesquiterpenoids

and the curcuminoids present in turmeric (Antony et al.,

2005). Like turmeric higher permeation values as compared

to plain curcumin may be due to the presence of the sesquit-

erpenoids/volatile oils that might have influenced the perme-

ability of curcumin through intestinal membrane.

0

5

10

15

20

25

30

0 2 4 6 8 10Time (h)

Am

ount

per

mea

ted/

area

(µg

/cm

2 ) in

8h

Aq. Susp Milk Clarified Butter Corn oil

Fig. 3 – Plot of cumulative amount of curcumin permeated

per unit area vs time from Biocurcumax� using different

vehicles.

3.5. Comparison of bioavailability of curcumin fromturmeric, Biocurcumax� and as plain curcumin

The bioavailability of curcumin as plain curcumin, from tur-

meric and Biocurcumax� was assessed using a non-everted

rat intestinal sac model. It was observed that from all the four

different vehicles used in the study plain curcumin showed

the least permeation. Almost 1.2–1.7 times enhancement in

permeation was obtained from turmeric and Biocurcumax�(Figs. 4 and 5). There was a statistically significant difference

in cumulative amount permeated per unit area in 8 h between

Biocurcumax� and plain curcumin, and turmeric and plain

curcumin when the permeation studies were carried out using

clarified butter and corn oil at P < 0.05. This difference in per-

meation profile may be due to the presence of volatile oils (ses-

quiterpenoids) in both turmeric and Biocurcumax� which

might be responsible for the enhanced permeation of curcu-

min through intestinal membrane. Results also indicate that

turmeric and Biocurcumax� showed equivalent performance

in the lipophilic vehicles and there was no statistically signif-

icant difference at P < 0.05. From aqueous suspension, the

cumulative amount released per unit area from plain curcu-

min, turmeric and Biocurcumax� was 1.51 ± 0.107,

1.76 ± 0.227 and 2.05 ± 0.187 lg/cm2 in 8 h, respectively, was

negligible because of poor water solubility characteristics of

curcumin. Slightly higher permeation of curcumin from Bio-

curcumax� aqueous suspension in comparison to plain cur-

cumin may be due to greater water solubility of curcumin

present in Biocurcumax� (Table 1). On comparison of flux data

of plain curcumin with turmeric and Biocurcumax� from dif-

ferent vehicles, it was observed that significantly higher val-

ues were obtained in case of permeation studies carried out

using clarified butter and corn oil at P < 0.05 and values were

not statistically significantly different in case of aqueous sus-

pension and milk. Although there was no statistically signifi-

cant difference between turmeric and Biocurcumax� in total

amount of permeated per unit area in 8 h using clarified butter

and corn oil at P < 0.05, significantly higher values of rate of

permeation (flux) were found in turmeric when comparison

was done with Biocurcumax�, suggesting that in the natural

form turmeric, there were some other constituents such as

sugars in addition to volatile oils which were influencing the

solubility and permeation behaviour of curcumin.

0

5

10

15

20

25

Am

ount

per

mea

ted/

area

(µg

/cm

2 ) in

8

h

Aq. Susp Milk Clarified butter Corn oil

Curcumin Turmeric Biocurcumax

Fig. 4 – Comparison of cumulative amount of curcumin

permeated per unit area from turmeric, Biocurcumax� and

as plain curcumin using different vehicles.

0

1

2

3

4

5

6

Flu

x (µ

g/cm

2 /h)

Aq. Susp Milk Clarified butter Corn oil

Curcumin Turmeric Biocurcumax

Fig. 5 – Comparison of flux of curcumin from turmeric,

Biocurcumax� and as plain curcumin using different

vehicles.

64 J O U R N A L O F F U N C T I O N A L F O O D S 2 ( 2 0 1 0 ) 6 0 – 6 5

4. Conclusions

Curcumin, a polyphenol from dietary spice turmeric is cur-

rently one of the most actively and extensively investigated

natural compound for its broad spectrum of pharmacological

activities. However, the fact that it is poorly absorbed after oral

administration limits full exploitation of this potential candi-

date against a wide spectrum of therapeutic powers it pos-

sesses to treat various ailments. Turmeric is extensively

used in traditional Indian system of medicine and as a home

remedy for various diseases. Therefore, in the present investi-

gations the solubility behaviour in different traditional vehi-

cles like milk, clarified butter and corn oil which are usually

used for administration of turmeric was studied. Curcumin

being lipophilic showed higher solubility in these traditional

vehicles and hence showed greater permeation through intes-

tinal membrane. Further, it was also observed that permeation

of curcumin from Biocurcumax� and turmeric containing vol-

atile sesquiterpenoids was substantially higher than plain cur-

cumin. Although these are only preliminary investigations

using ex vivo rat intestinal sac model, these studies do suggest

that by using traditional lipophilic vehicles and using the nat-

ural dietary form, i.e., turmeric and Biocurcumax� instead of

plain curcumin, higher absorption and greater therapeutic

levels of this highly promising molecule can be achieved.

Acknowledgements

The authors gratefully acknowledge the financial assistance

from the University Grants Commission, India. The authors

are also thankful to Arjuna naturals, Kerala for providing

the gift sample of curcumin and Biocurcumax�.

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