Bhattacharya S Phytosomes

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Open Access
Review Article Online Journal

Phytosomes: The New Technology for Enhancement

of Bioavailability of Botanicals and Nutraceuticals

Received: 19-Dec-08 Revised: 08-Dec-08 Accepted: 11-Jan-09

Abstract
Lipid solubility and molecular size are the major limiting
factors for molecules to pass the biological membrane to be
absorbed systematically following oral or topical
administration. Several plant extracts and phytoconstituents,
despite having excellent bio-activity in vitro demonstrate less
or no in vivo actions due to their poor lipid solubility or
improper molecular size or both, resulting poor absorption Sanjib Bhattacharya
and poor bioavailability. It is often found that, when individual
Bengal School of Technology,
constituents are isolated from the plant extract there is loss of Sugandha, Hooghly 712102, West
specific bio-activity. Sometimes some constituents of the Bengal, India
multi-constituent plant extract are destroyed in gastric
environment when taken orally. Phytosomes are advanced
forms of herbal formulations that are better absorbed, and as
a result produce better bioavailability and actions than the
conventional herbal extracts. They are produced by a For Correspondence:
patented process whereby the standardized plant extract or
its constituents are bound to phospholipids, mainly Tel: +91 9874331777
phosphatidylcholine, producing a lipid compatible molecular
complex. This phyto-phospholipid complex (phytosome) Email: [email protected]
resembles a little cell. Phytosomes exhibit better
pharmacokinetic and pharmacodynamic profile than
conventional herbal extracts. Phytosome technology has
been effectively used to enhanced the bioavailability of many
popular herbal extracts including milk thistle, Ginkgo biloba,
grape seed, green tea, hawthorn, ginseng etc and can be
developed for various therapeutic uses or dietary
supplements.

Keywords: Phytosomes, plant extract, bioavailability

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 Bhattacharya S Phytosomes

Introduction both fat-miscible and water miscible

nutrients. They are miscible both in water
Over the past century, phytochemical and and in lipid environments, and are well
phytopharmacological sciences established absorbed orally. The phospholipid mainly
the compositions, biological activities and employed to make phytosomes, is
health promoting benefits of numerous phosphatidylcholine, derived form soybean
3
botanical products. Most of the biologically (Glycine max) . Phytosomes are more
active constituents of plants are polar or bioavailable as compared to conventional
water soluble molecules. However, water herbal extracts owing to their enhanced
soluble phytoconstituents (like flavonoids, capacity to cross the lipoidal biomembrane
tannins, terpenoids etc) are poorly absorbed and finally reaching the systemic circulation.
either due to their large moleculer size Phytosome has been an emerging trend in
which can not absorb by passive diffusion, delivery of herbal drugs and nutraceuticals.
or due to their poor lipid solubility; severely
limiting their ability to pass across the lipid- Phytosome Technology
rich biological membranes, resulting poor
1
bioavailability . It has often been observed The flavonoid and terpenoid constituents of
that the isolation and purification of the plant extracts lend themselves quite well for
constituents of an extract may lead to a the direct binding to phosphatidylcholine.
partial or total loss of specific bio-activity for Phytosomes results from the reaction of a
the purified constituent - the natural stoichiometric amount of the phospholipid
constituent synergy becomes lost. Very often (phosphatidylcholine) with the standardized
the chemical complexity of the crude or extract or polyphenolic constituents (like
2
partially purified extract seems to be simple flavonoids) in a non polar solvent .
essential for the bioavailability of the active Phosphatidylcholine is a bifunctional
constituents. Extracts when taken orally compound, the phosphatidyl moiety being
some constituents may be destroyed in the lipophilic and the choline moiety being
gastric environment. As standardized hydrophilic in nature. Specifically the choline
extracts are established, poor bioavailability head of the phosphatidylcholine molecule
often limits their clinical utility due to above binds to these compounds while the lipid
said reasons. It has been observed that soluble phosphatidyl portion comprising the
complexation with certain other clinically body and tail which then envelopes the
useful nutrients substantially improves the choline bound material. Hence, the
bioavailability of such extracts and their phytoconstituents produce a lipid compatible
individual constituents. The nutrients so molecular complex with phospholipids, also
helpful for enhancing the absorption are the called as phyto-phospholipid complex.
phospholipids. Phytosome is a patented Molecules are anchored through chemical
technology developed by a leading bonds to the polar choline head of the
manufacturer of drugs and nutraceuticals, to phospholipids, as can be demonstrated by
4,5
incorporate standardized plant extracts or specific spectroscopic techniques . Precise
water soluble phytoconstituents into chemical analysis indicates the unit
phospholipids to produce lipid compatible phytosome is usually a flavonoid molecule
molecular complexes, called as phytosomes linked with at least one phosphatidylcholine
and so vastly improve their absorption and molecule. The result is a little micro sphere
2
bioavailability . or cell is produced. The term “phyto” means
plant while “some” means cell-like. The
Phospholipids are complex molecules that phytosome technology produces a little cell,
are used in all known life forms to make cell whereby the plant extract or its active
membranes. In humans and other higher constituent is protected from destruction by
animals the phospholipids are also employed gastric secretions and gut bacteria owing to
as natural digestive aids and as carriers for

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 Bhattacharya S Phytosomes

the gastroprotective property of phospha- medium. Silybin and phospholipids were

6
tidylcholine . resolved into the medium, after the organic
solvent was removed under vacuum
condition, silybin-phospholipid complex was
12
formed .

LIPOSOME

Figure 1: Organization of the phytosome

molecular complex. A flavonoid molecule (lower
right) is enveloped by a phospholipid molecule.

Likewise phytosomes, a liposome is formed

by mixing a water soluble substance with
phosphatidylcholine in definite ratio under
specific conditions. Here, no chemical bond
is formed; the phosphatidylcholine molecules
surround the water soluble substance. There
may be hundreds or even thousands of
phosphatidylcholine molecules surrounding
the water-soluble compound. In contrast,
with the phytosome process the Figure 2: Major difference between liposome and
phosphatidylcholine and the plant phytosome. The molecular organization of the
components actually form a 1:1 or a 2:1 liposome (upper segment) versus many individual
molecular complex depending on the phytosomes (lower segment).
substance(s) complexed, involving chemical
bonds. This difference results in phytosome Advantages of phytosomes
being much better absorbed than liposomes
showing better bioavailability. Phytosomes Phytosomes have the following advantages
have also been found superior to liposomes 13-15
.
7
in topical and skin care products
• It enhances the absorption of lipid
Methods of preparation insoluble polar phytoconstituents through
oral as well as topical route showing
Phytosomes are prepared by complexing better bioavailability, hence significantly
polyphenolic phytoconstituents in 1:2 or 1:1 greater therapeutic benefit.
ratio with phosphatidylcholine. Marena and • As the absorption of active constituent(s)
Lampertico, Jiang et al, Maiti et al. reported is improved, its dose requirement is also
8-11
the methods of phytosome prepration . reduced.
Yanyu et al prepared silybin-phospholipid
complex using ethanol as a reaction

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 Bhattacharya S Phytosomes

• Phosphatidylcholine used in preparation Grange et al. conducted a series of studies

of phytosomes, besides acting as a on silymarin phytosome, containing a
carrier also acts as a hepatoprotective, standardized extract from the seeds of S.
hence giving the synergistic effect when marianum, administered orally and found
hepatoprotective substances are that it could protect the fetus from maternally
20
employed. ingested ethanol .
• Chemical bonds are formed between
phosphatidylcholine molecule and Bombardelli et al. reported Silymarin
phytoconstituent, so the phytosomes phytosomes, in which silymarin (a
show better stability profile. standardized mixture of flavanolignans
• Added nutritional benefit of extracted from the fruits of S. marianum) was
phospholipids. complexed with phospholipids. Phytosomes
showed much higher specific activity and a
Enhanced bioavailability longer lasting action than the single
constituents, with respect to percent
Recent research shows improved absorption reduction of odema, inhibition of
and bioavailability with phytosomes as myeloperoxidase activity, antioxidant and
15
compared to the conventional means. Most free radical scavenging properties .
of the phytosomal studies are focused to
Silybum marianum (milk thistle) which Barzaghi et al. conducted a human study
contains premier liver-protectant flavonoids. designed to assess the absorption of silybin
The fruit of the milk thistle plant contains when directly bound to phosphatadylcholine.
flavonoids known for hepatoprotective Plasma silybin levels were determined after
effects
16,17
. Silybin is the chief and most administration of single oral doses of silybin
potent constituent of silymarin, the flavonoid phytosome and a similar amount of silybin
complex from milk thistle. A standardized from milk thistle in healthy volunteers. The
extract from Silybum marianum (milk thistle) results indicated that the absorption of silybin
is an excellent liver protectant but very poorly from silybin phytosome is approximately
absorbed orally. seven times greater compared to the
absorption of silybin from regular milk thistle
21
Yanyu et al. prepared the silymarin extract (70-80 % silymarin content) .
phytosome and studied its pharmacokinetics
in rats. In the study the bioavailability of Moscarella et al. investigated in one study of
silybin in rats was increased remarkably after 232 patients with chronic hepatitis (viral,
oral administration of prepared silybin- alcohol or drug induced) treated with silybin
phospholipid complex due to an impressive phytosome at a dose of 120 mg either twice
improvement of the lipophilic property of daily or thrice daily for up to 120 days, liver
silybin-phospholipid complex and function returned to normal faster in patients
improvement of the biological effect of taking silybin phytosome compared to a
12
silybin . group of controls (49 treated with
commercially available silymarin, 117
22
Tedesco et al. reported silymarin phytosome untreated or given placebo) .
show better anti-hepatotoxic activity than
silymarin alone and can provide protection Studies have shown ginkgo phytosome
against the toxic effects of aflatoxin B1 on (prepared from the standardized extract of
18
performance of broiler chicks . Busby et al Ginkgo biloba leaves) produced better
reported that the use of a silymarin results compared to the conventional
phytosome showed a better fetoprotectant standardized extract from the plant (GBE, 24
activity from ethanol-induced behavioral % ginkgo flavone glycoside and 6 % terpene
deficits than uncomplexed silymarin .
19 lactones). In a bioavailability study
conducted with healthy human volunteers

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 Bhattacharya S Phytosomes

the levels of GBE constituents (flavonoids phytosome once daily for 5 days. The blood
and terpenes) from the phytosomal form TRAP (Total Radical-trapping Antioxidant
peaked after 3 hours and persisted longer for Parameter) was measured at several time
st th
at least 5 hours after oral administration. It intervals during 1 day, then also on 5 day.
st
was found that the phytosomal GBE Already by 30 mins after administration on 1
produced a 2-4 times greater plasma day, blood TRAP levels were significantly
concentration of terpenes than did the non- elevated over the control which received
phytosomal GBE. Its major indications are conventional standardized grape seed
25
cerebral insufficiency and peripheral vascular extract .
disorders, and it also can ameliorate reduced
cerebral circulation. Its improved oral Green tea extract generally contains a totally
bioavailability and good tolerability makes it standardized polyphenolic fraction (not less
the ideal Ginkgo product even for long term than 66.5 %, containing epigallocatechin and
treatment. In studies with ginkgo phytosome its derivatives ) obtained from green tea
in patients with peripheral vascular disease leaves (Thea sinensis) and mainly
(e.g. Raynaud’s disease and intermittent characterized by the presence of
circulation) it was shown to produce a 30-60 epigallocatechin 3-O-gallate, the key
% greater improvement compared to regular compound. These compounds are potent
7,23
standardized GBE . modulators of several biochemical processes
linked to the breakdown of homeostasis in
Grape seed phytosome is composed of major chronic-degenerative diseases such
oligomeric polyphenols (grape as cancer and atherosclerosis. Green tea
proanthocyanidins or procyanidins from has got several long term benificial activities
grape seed extract, Vitis vinifera) of varying such as antioxidant, anticarcinogenic,
molecular size, complexed with antimutagenic, antiatherosclerotic, hypocho-
phospholipids. The main properties of lesterolemic, cardioprotective, antibacterial
procyanidin flavonoids of grape seed are an and anticariogenic effects. Despite such
increase in total antioxidant capacity and potential actions green tea polyphenols have
stimulation of physiological antioxidant very poor oral bioavailability from
defenses of plasma, protection against conventional extracts. The complexation of
ischemia/reperfusion induced damages in green tea polyphenols with phospholipids
the heart, protective effects against strongly improves their poor oral
atherosclerosis thereby offering marked bioavailability. A study on absorption of
protection for the cardiovascular system and phytosomal preparations was performed in
other organs through a network of healthy human volunteers along with non
mechanisms that extend beyond their great complexed green tea extract following oral
24
antioxidant potency . administration. Over the study period of 6
hours the plasma concentration of total
In a study where rabbits were fed a high flavonoids was more than doubled when
cholesterol diet for 6 weeks, to markedly coming from the phytosomal versus the non-
elevate their blood cholesterol and induce phytosomal extract. Antioxidant capacity was
atherosclerotic lesions in their aortas and measured as TRAP (Total Radical-trapping
carotid arteries. One group of rabbits Antioxidant Parameter). The peak
received grape seed phytosome in their feed antioxidant effect was a 20% enhancement
for the first 6 weeks, then 4 weeks of the and it showed that the phytosome
high-cholesterol diet. These developed formulation had about double the total
7, 26
significantly less aortic plaque than did the antioxidant effect .
control groups which received conventional
standardized grape seed extract in similar Maiti et al. developed the quercetin-
regimen. In a randomized human trial, young phospholipid phytosomal complex by a
healthy volunteers received grape seed

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 Bhattacharya S Phytosomes

6, 7, 23
Table 1: Commercial phytosome products

Phytoconstituents
S/N Phytosomes Dose Indications
complexed
TM
1 Silybin Phytosome Silybin from Silybum 120 mg Hepatoprotective,
marianum antioxidant for liver and
skin
TM
2 Ginkgo Phytosome 24 % ginkgoflavonoids 120 mg Protects brain and
from Ginkgo biloba vascular linings, anti-
skin ageing
TM
3 Ginseng Phytosome 37.5 % ginsenosides 150 mg Nutraceutical,
from Panax ginseng immunomodulator
4 Green Tea Epigallocatechin from 50-100 Nutraceutical, systemic
TM
Phytosome Thea sinensis mg antioxidant, anti-cancer
5 Grape Seed Procyanidins from Vitis 50-100 Nutraceutical, systemic
TM
Phytosome vinifera mg antioxidant, cardio-
protective.
TM
6 Hawthorn Phytosome Flavonoids from 100 mg Nutraceutical, cardio-
Crataegus sp. protective and
antihypertensive
7 Olive oil Phytosome Polyphenols from Olea - Antioxidant, anti-
europaea oil inflammatory,
anti-hyperlipidemic
8 Echinacea Phytosome Echinacosides from - Nutraceutical,
Echinacea angustifolia immunomodulator

simple and reproducible method and also Conclusion

showed that the formulation exerted better
therapeutic efficacy than the molecule in rat In recent times the emerging technology of
27
liver injury induced by carbon tetrachloride . drug delivery and drug targeting is also being
applied to phytopharmaceuticals. Botanicals
Recently Maiti et al. developed the have enormous therapeutic potential which
phytosomes of curcumin (flavonoid from should be explored through some value
turmeric, Curcuma longa) and naringenin added drug delivery systems. Standardized
(flavonoid from grape fruit, Vitis vinifera) in plant extracts or mainly polar
10,11
two different studies . The antioxidant phytoconstituents like flavonoids, terpenoids,
activity of the complex was significantly tannins, xanthones when complexed with
higher than pure curcumin in all dose levels phospholipids like phosphatidylcholine give
tested. In the other study the developed rise to a new drug delivery technology called
phytosome of naringenin produced better phytosome showing much better absorption
antioxidant activity than the free compound profile following oral administration owing to
with a prolonged duration of action, which improved lipid solubility which enables them
may be due to decrease in the rapid to cross the biological membrane, resulting
elimination of the molecule from body. enhanced bioavailability i.e. more amount of
active principle in the systemic circulation.
In this way different phytosome products This means more amount of active
(Table 1) have demonstrated significant constituent becomes present at the site of
therapeutic or health giving effects when action (liver, brain, heart, kidney etc) at
compared with the conventional plant similar or less dose as compared to the
extracts. conventional plant extract. Hence, the
therapeutic action becomes enhanced, more

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 Bhattacharya S Phytosomes

detectable and prolonged. Several excellent 9. Jiang YN, Yu ZP, Yan ZM, Chen JM. Studies on
preparation of herba epimedii flavanoid
phytoconstituents have been successfully
phytosomes and their pharmaceutics. Zhongguo
delivered in this way exhibiting remarkable Zhong Yao Za Zhi 2001; 26 (2): 105-8.
therapeutic efficacy in animal as well as in 10. Maiti K, Mukherjee K, Gantait A, Saha BP,
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28 pharmacokinetic study in rats. Int J Pharm 2007;
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