journal of biologically active products from nature volume 2 issue 2 2012 [doi...

7/21/2019 Journal of Biologically Active Products From Nature Volume 2 Issue 2 2012 [Doi 10.1080%2F22311866.2012.10719…

http://slidepdf.com/reader/full/journal-of-biologically-active-products-from-nature-volume-2-issue-2-2012-doi 1/14

This article was downloaded by: ["Queen's University Libraries, Kingston"]On: 03 September 2013, At: 04:09Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House37-41 Mortimer Street, London W1T 3JH, UK

Journal of Biologically Active Products from NaturePublication details, including instructions for authors and subscription information:

http://www.tandfonline.com/loi/tbap20

Phytosomes: Complexation, Utilisation and Commeric

StatusApoorva Agarwal

a , Prithviraj Chakraborty

a , Debarupa D. Chakraborty

a & Vikas Anand

Saharana

a Department of Pharmaceutical Sciences , Sardar Bhagwan Singh P. G. Institute of

Biomedical Sciences and Research, Balawala , Dehradun , 248161 , Uttarakhand , India

Published online: 24 Jun 2013.

To cite this article: Apoorva Agarwal , Prithviraj Chakraborty , Debarupa D. Chakraborty & Vikas Anand Saharan (2012)

Phytosomes: Complexation, Utilisation and Commerical Status, Journal of Biologically Active Products from Nature, 2:2,

65-77, DOI: 10.1080/22311866.2012.10719111

To link to this article: http://dx.doi.org/10.1080/22311866.2012.10719111

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) containedin the publications on our platform. However, Taylor & Francis, our agents, and our licensors make norepresentations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of tContent. Any opinions and views expressed in this publication are the opinions and views of the authors, and

are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon ashould be independently verified with primary sources of information. Taylor and Francis shall not be liable forany losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoeveor howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any substantial or systematicreproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in anyform to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

http://dx.doi.org/10.1080/22311866.2012.10719111

http://www.tandfonline.com/action/showCitFormats?doi=10.1080/22311866.2012.10719111

http://www.tandfonline.com/page/terms-and-conditions

http://www.tandfonline.com/page/terms-and-conditions

http://dx.doi.org/10.1080/22311866.2012.10719111

http://www.tandfonline.com/action/showCitFormats?doi=10.1080/22311866.2012.10719111

http://www.tandfonline.com/loi/tbap20



Phytosomes: Complexation, Utilisation and Commerical Status

Apoorva Agarwal*, Prithviraj Chakraborty, Debarupa D. Chakraborty, Vikas Anand Saharan

Department of Pharmaceutical Sciences, Sardar Bhagwan Singh P.G. Institute of

Biomedical Sciences and Research, Balawala, Dehradun-248161, Uttarakhand, India

Abstract: In past few decades numerous studies have been conducted to explore the nature’s gift of

invaluable medicinal compounds. Herbs and botanicals have been extensively reviewed by researchers

worldwide. However, the bioavailability of natural compounds is still under question. Various techniques areemployed to overcome the same of which phytosomes technology appears to be very promising. Phytosomes

have shown marked enhancement in bioavailability and established clinical efficacy. This is due to increased

solubilization of drug in intestinal milieu along with the ability to cross lipoidal biomembranes. This literature

reviews the basics for preparation, mechanism of drug-phospholipid complexation and subsequent utilisation.

Some of the major herbal extracts which have shown proven improvement in bioavailability are also studied.

In vitro lipid digestion model is assessed which provides an indication for the in vivo performance of the

commercial product. Various marketed products and leading marketing companies are also surveyed.

Key words: Phytosomes, polyphenols, bioavailability, phospholipids, lipolysis.

Introduction

With the advent of 21st century, people have become much more concerned about their health

and fitness. Towards this, popularity of herbal

active extracts have emerged a lot owing to its

established clinical efficacy and minimum side

effects. It has been estimated that about 40-70 %

of the new compounds discovered pose a

challenge due to their low bioavailability limited

by poor aqueous solubility 1,2. Drug discovery by

intricate chemical scaffolds and manifold high

throughput activity screens often lead to finding

of potent but hydrophobic drugs 3. This calls for

development of effective and robust techniquesto endow them with higher bioavailability. Lipid

based formulations is one such approach which

rationalizes drug absorption 4 by various ancillary

mechanisms. This includes inhibition of cyto-

chrome enzymes 5 and P-gp mediated efflux 6,

increased membrane permeability

7

and enhanced lymphatic transport 8,9 to bypass presystemic

metabolism.

Herbal plant extracts have reported therapeutic

benefit. But extraction of individual compound

from the extract often exhibits limited clinical

utility as the synergistic effect of various natural

ingredients get lost 10. To surmount such barrier,

Phytosome technology first emerged in 1989 11

when a group of Italian researchers found that oral

intake of polyphenols and flavanoids have poor

bioavailability as such but show marked enhance-

ment on complexing it with phospholipids. Thiswas confirmed by histological examination

depicting high binding affinity of polyphenolic

compounds to phospholipids in living plant tissue12. Most of the herbal extracts constitute

*Corresponding author (Apoorva Agarwal)

E-mail: < [email protected] > © 2012, Har Krishan Bhalla & Sons

Journal of Biologically Active Products from Nature

ISSN Print : 2231-1866 Online: 2231-1874

www.jbappn.com

JBAPN 2 (2) 2012 pp 65 - 77 65

Received 24 November 2011; accepted in revised form 12 January 2012



polyphenols and flavanoids which show poor

absorption 13 due to their multiple ring structures

unsuitable for passive diffusion or lack of carrier

mediated transport or poor miscibility in water/

lipids. Phytosomes differ from liposomes in

various aspects pointed in table 1. Unlikeliposomes, phytosomes involve chemical bonding

between act ive principle and phospholipids.

Phytosomes have the active principle intercalated

in the layers of phospholipids rather than

entrapped in core as in liposomes (Fig.1).

Preparation of phytosomes

Drug

Active principles selected are generally poorly

Table 1. Phytosomes v/s Liposomes

Property Phytosomes Liposomes

Drug: phospholipid ratio 14, 15 1:1 or 2:1 molecular complex Aggregate of 1000’s of phospho-lipid molecules around the drug

Nature of bond 16 Chemical bonding No chemical bond

(hydrogen bonds)Route of administration 16 Oral and topical Topical and parenteral (oral

delivery is not evidenced)Drug position17 Intercalated in phospholipids Hydrophilic drug in core

layers and lipophilic drug in outer layer Nature of drug 17 Usually little soluble in water Both hydrophilic and lipophilic

and lipids

Bioavailability 18 Higher Lower than phytosomes

Fig.1 Molecular organisation of liposomes (upper segment) and phytosomes (lower segment) 16

soluble both in water and lipids. These are selected

from group consisting of quercetin, kaempferol,

quercretin-3, rhamnoglucoside, quercetin-3-

rhamnoside, hyperoside, vitexine, diosmine, 3-

rhamnoside, (+) catechin, (-) epicatechin,

apigenin-7-glucoside, luteolin, luteolinglucoside,ginkgonetine, isoginkgonetine and bilobetine 19.

Phytosomes formed operate in a solvent having

reduced dielectric constant. Marked changes in

physicochemical properties occur indicating

formation of a true stable complex 20.

Phospholipids

Phospholipids are mainly classified as phospho-

sphingolipids and phosphoglycerides. Phospho-

Apoorva Agarwal et al. / JBAPN 2 (2) 2012 pp 65 - 77 66



sphingolipids are mainly used in topicals eg.

Ceramide. However, phosphoglyceride is lecithin

which is a mixture of phosphatidylcholine,

phosphatidylethanolamine, phosphatidylinositol,

phosphatidylserine etc. Of these, phosphatidyl-

choline is the material of choice as it is anexcellent oil/water emulsifier and soluble in both

water and lipids 21. It is a zwitterionic molecule

having a positively charged headgroup and

negatively charged tailgroups which allows slight

salt formation with divalent cations 12 .

Commercial sources are vegetable oil seeds such

as soy bean. Apart from this, milk and egg yolk is

also gained importance 21.

Drug-phospholipid complex

The drug: phospholipid ratio ranges from 0.5-

2, most preferable being 22. Phytosomes are novelvesicle systems prepared by reacting drug in an

aprotic solvent such as dioxane or ethanol having

dissolved phospholipids (Fig.2). After solubili-

sation, this mixture is concentrated to ensure

bonding of reactants. Complex thus formed is

isolated by solvent removal under vacuum, by

lyophilisation or by precipitation with non-

solvents 23, 24.

Add phospholipids to organic

solvent containing drug

Solution of drug-Phosholipids in solvent

Drying under vacuum

Isolation of complex by

precipitation or lyophilisation

Retrieval of complexes

Fig. 2. Steps in Drug-Phospholipid

complex preparation 25

Mechanism of complexation

Phytosomes result by reacting a stoichiometric

ratio of standardised herbal extract and

phospholipids in a non polar solvent 23. Being an

amphipathic molecule, phosphatidylcholine

consists of both lipophilic moiety i.e. phosphatidyl

and hydrophilic entity i.e. choline. On reaction,

the polar choline head interacts and chemically binds to polar functionalities of drug molecule

while the non polar phosphatidyl portion envelops

the choline bound drug to form body and tail 26,

27. Hence, these are also referred to as phyto-

phosphol ipid complex result ing in a li tt le

microsphere or cell in which drug is intercalated

in phospholipid layers.

Properties of complex

Among the physicochemical properties,

phytosome exhibit clear and sharp melting point,

moderately soluble in fats and freely soluble innon polar solvents in which individual precursors

were not soluble 28, 29. On treatment with water,

they assume a micellar shape resembling liposome

like structure 30. Again, hydrogen bonds between

drug and phospholipids were demonstrated by

spectroscopic techniques 31, 32.

Biologically, phytosomes are better absorbed

and more bioavailable 33 than conventional herbal

extracts as revealed by pharmacokinetic and

pharmacodynamic studies in experimental

animals and human volunteers26

.

Merits of Phytosomes

Phytosome technology offers numerous

advantages over conventional dosage forms some

of which are listed above:

a) It enhances the absorption of poorly water

soluble compounds and results in greater bio-

availability 34 which results in reduced dose 35 and

low risk profile 36.

b) It is safe 37, biodegradable and biocompatible

dosage forms.

c) In addition to this, they are used to target liver 38 protecting compounds. Phosphatidyl choline

offers a synergistic effect because it itself is

hepatoprotective 39.

d) It also offers improved penetration through skin

providing potential application in cosmetics,

transdermals and topicals 40.

e) Good entrapment efficiency is an added




advantage.

f) Better stability profile than liposomes due

chemical bonding between drug and phospho-

lipids 41.

g) They offer non invasive route of administration

eg. Oral and dermal delivery.h) Attractive market value 42 of phytosomes due

to simple manufacturing method, low investment

and ease of scale up 17 is appreciable.

In Vivo fate of phytosome formulations

Drug-phospholipid complexes are prepared

with an objective to circumvent the hurdle of poor

bioavailabil ity of botanical extracts which is

otherwise not achieved using conventional

formulation techniques. Drug absorption from

these formulations depends on dispersion pattern,

lipid digestion and subsequent solubilisation43

.On oral administration, formulation lipids

stimulate secretion of gastric lipase from chief

cells in gastric mucosal lining 44, 45 and secretion

of pancreatic lipase and co-lipase from pancreas46. Together, they result in partial digestion of

triglycerides 47, 48 forming a crude emulsion which

then enters the small intestine. In small intestine,

phospholipase A2hydrolyses phosphatidylcholine

to lysophosphatidylcholine and fatty acid 49, 50.

Exogenous lipids stimulates secretion of

endogenous bile salts, phospholipids and

cholesterol from gall bladder 51 further facilitatinglipid digestion and forming colloidal structures

i.e. micelles, mixed micelles and multi/unilamellar

vesicles 43. These colloids favour solubilisation

of drug in aqueous unstirred layer, thereby

promoting lipid and drug absorption from the

brush border membrane of enterocytes 52.

Characterisation of phytosomes

Physical characterisation of phytosomes include

shape, size, distribution, entrapment efficiency,

chemical composition 53 etc. Major techniques

include:

Visualisation

This is done by using Transmission electron

microscopy and scanning electron microscopy 54.

Vesicle size & Zeta potential

This is deter-mined by Dynamic light scattering

and photon correlation spectroscopy 25.

Entrapment Efficiency

It is measured by ultra centrifugation technique55.

Transition temperature

It is determined using differential scanning

calorimetry.

Surface tension activity measurement

It can be measured by ring method in a Du Nouy

ring tensiometer 56.

Vesicle stability

Mean size is measured by DLS and structural

changes are monitored by TEM 57.

Drug content

It is quantified by HPTLC or spectroscopic 58

techniques.

Spectroscopy

Formation of drug-phospholipid complex is

verified by comparing spectral data of individual

precursors and final complex. H1 NMR, C13 NMR,

FTIR spectrums 26 are thoroughly reviewed to

confirm the complex formation by matching

signal peaks and molecular imaging 12.

In Vitro Lipolysis

Dynamic lipolysis models (Fig.3) are beneficial

in investigating the effect of simulated lipid

digestion on drug solubilization and release from

marketed phytosomal lipid preparations 1. This is

conducted in a continuously agitating dissolution

vessel having a mixture of bile salts, phospho-

lipids in buffered aqueous solution equilibriated

at 37°C 59. Pancreatic lipase initiates the lipid

digestion which causes a drop in pH due to fatty

acid liberation. pH drop is quantified by pH-stat

meter controller and is again maintained usingequimolar solution of NaOH through autoburette.

During this process, samples are withdrawn and

ultracentrifuged to separate the digest into poorly

dispersed oil phase, a highly dispersed aqueous

phase and a precipitated pellet phase. This helps in

quantification and gives an indication of the in vivo

performance of phytosomal formulations 43, 60.




Fig. 3. Schematic Diagram for in vitro Lipolysis model

Landmarks in phytosome technology

Phytosome technology has recently attracted

the attention of many researchers due to its

capacity of successful and effective delivery of

potential therapeutics and dietary supplements.

Such formulations of some curative extractsdiscussed below have set a milestone in this

field.

SiliphosTM milk thistle phytosomes

The first commercial phytosome preparation 12

was made using flavonolignan silybin, a major

constituent of Silymarin marianum (fam.

Asteraceae), and a liver support remedy for past

2000 years 61. These preparations were initially

named IDB 1016 or Siliphide 62, 63 which was later

recasted as Siliphos® PhytosomesTM 64

. Silybinis an effective hepatoprotective agent conserving

liver glutathione level along with preventing the

oxidative damage 61. It also lowers serum ferritin65 and shows promising anti-cancer 66 and anti-

inflammatory 67 potential. Siliphos® has been a

breakthrough for phytosomes offering four times

more exposure of silybin to liver than traditional

preparations 68.

Merivaselect® phytosomes

Curcumin polyphenols69, obtained from

Curcuma longa family Zingiberaceae, are powerful scavengers of superoxide and hydroxyl

free radicals 70. They also lower the incidence of

mutations and genetic disorders by the ability to

prevent DNA oxidative damage 71. Potential effect

in cancer chemoprevention 72, inflammation 73 and

neuro-degenerative diseases 74 is also under study.

The bioavailability of curcumin phytosomes

preparations (Meriva®) is found greater than non

phytosome preparations 75.

Greenselect® phytosome

Green tea catechins and polyphenols, procured

from Camellia sinensis family Theaceae, are potent anti-oxidant 76 and anti-inflammatory 77.

Green tea extract (GTC) also helps in weight loss

reduction 78. It also favours good cardiovascular

health 79 and fights against cancer 80. Ability to

cross blood brain barrier along with its gene

modulating and cell signalling activities, GTC

serves as a significant CNS protectant 81.

Leucoselect® phytosomes

Grape seed extract consists of oligomeric

proanthocyanidins from Vitis vinifera. Apart fromdecreasing lipid peroxidation 82 and delaying

hemolysis, they are quenchers of superoxide,

hydroxyl, peroxyl and peroxynitrite radicals 83.

They also provide CVS protection by minimising

post-prandial oxidative stress by decreasing pro-

oxidant levels 84.

Gingkoselect® phytosomes

Gingko biloba dimeric flavanoids induces

lipolysis by inhibiting cAMP phosphodiesterase

and improves microcirculation 85. It also shows

greater activity and slower release than noncomplexed extracts 86. Terpenes of Gingko biloba

have been evaluated for use in allergic contact

dermatitis and results show statistically significant

reduction of skin reactivity intensity 87.

Apart from this, various other compounds are

also formulated using this technology listed in

Table 2.




T a b l e 2 . L i s t o f m a r k e t e d p h

y t o s o m e p r e p a r a t i o n s a n d t h e i r a p p l i c a t i o n s 1 0 , 2 3 , 9 2 - 9 6

N o .

P r o d u c t

A c t i v e P r i n c i p l e

D o s e

C a t e g o r y

T h e r a p e u t i c u s e

1

S i l i p h o s ®

S i l y b i n f r o m

1 2 0 m g

P h a r m a c e u t

i c a l ,

H e p a t o p r o t e c t i v e , A n t i - o x i d a n t

h e a l t h f o o d

,

S i l y b u m m a r i a n u m

c o s m e t i c

2

L e u c o s e l e c t ®

P r o c y a n i d i n s f r o m

5 0 - 1 0 0 m g

H e a l t h f o o d

, c o s m e t i c

A n t i o x i d a n t , a n t i c

a n c e r

V i t i s v i n i f e r a

3

G i n s e n g ® P h y t o s o m e s

G i n s e n o s i d e s f r o m

1 5 0 m g

C o s m e t i c

I m m u n o m o d u l a t o

r

P a n a x g i n s e n g

4

E c s i n - b e t a - s i t o s t e r o l s

E c s i n - b e t a - s i t o s t e r o l

-

C o s m e t i c

A n t i o e d e m a

P h y t o s o m e

f r o m h o r s e c h e s t n u t f r

u i t

5

O l e a s e l e c t P h y t o s o m e s

P o l y p h e n o l s f r o m

-

-

A n t i h y p e r l i p i d e m

i c ,

O l e a e u r o p e a

a n t i - i n f l a m m a t o r y

6

E s c u l o s i d e P h y t o

s o m e s

E s c u l o s i d e f r o m

-

-

V a s o a c t i v e , a n t i c e

l l u l i t e

A e s c u l u s h i p p o c a s t a n u

m

7

M e r t o s e l e c t P h y t

o s o m e s

A n t h o c y a n o s i d e s f r o m

-

-

A n t i o x i d a n t , i m p r

o v e s c a p i l l a r y

V a c c i n i u m m y r t i l l u s

t o n e

8

Z a n t h a l e n e P h y t o

s o m e s

Z a n t h a l e n e f r o m

-

-

S o o t h i n g , a n t i i r r i t a n t , a n t i - i t c h i n g

Z a n t h o x y l u m b u n g e a n u

m

9

V i s n a d e x ® P h y t o s o m e s

V i s n a d i n e f r o m

-

C o s m e t i c

V a s o k i n e t i c , c i r c u l a t i o n i m p r o v e r

A m m i V i s n a g a

1 0

C e n t e l l a P h y t o s o

m e s

T e r p e n e s f r o m

-

H e a l t h f o o d

, c o s m e t i c

B r a i n t o n i c , v e i n & s k i n d i s e a s e s

C e n t e l l a a s i a t i c a

1 1

G l y c y r r h i z a P h y t o s o m e s

1 8 - b e t a g l y c y r r h e t i n i c

a c i d

-

C o s m e t i c

A n t i i n f l a m m a t o r y , s o o t h i n g

f r o m G l y c y r r h i z a g l a b r a

1 2

L y m p h a s e l e c t ® P

h y t o s o m e s T r i t e r p e n e s f r o m

-

-

H y p o t e n s i v e , i n s o

m n i a

M e l i o t u s o f f i c i n a l i s

1 3

M e r i v a s e l e c t ® P h y t o s o m e s

P o l y p h e n o l s f r o m

2 0 0 - 3 0 0 m g

H e a l t h f o o d

, c o s m e t i c

C a n c e r c h e m o p r e v e n t i v e

C u r c u m a l o n g a

1 4

P A 2

P h y t o s o m e s

P r o a n t h o c y a n i d i n s A 2 f r o m

-

H e a l t h f o o d

, c o s m e t i c

A n t i w r i n k l e , U V

p r o t e c t a n t

h o r s e c h e s t n u t b a r k




t a b l e . ( c o n t i n u e d ) .

N o .

P r o d u c t

A c t i v e P r i n c i p l e

D o s e

C a t e g o r y

T h e r a p e u t i c u s e

1 5

S a b a l s e l e c t P h y t o s o m e s

F a t t y a c i d s , a l c o h o l s ,

-

-

A n t i o x i d a n t , b e n

i g n p r o s t a t e

s t e r o l s f r o m S e r e n o a r e p e n s

h y p e r p l a s i a

1 6

G r e e n s e l e c t ® P h

y t o s o m e s

E p i g a l l o c a t e c h i n f r o m

5 0 - 1 0 0 m g

H e a l t h f o o d

A n t i c a n c e r , a n t i o x i d a n t

T h e a s i n e n s i s

1 7

X i m i l e n e & X i m

e n o i l

X i m i l e n e & X i m e n o i l f r o m

-

-

S k i n s m o o t h n e r a

n d s o o t h e r

P h y t o s o m e s

S a n t a l u m a l b u m

1 8

G i n g k o s e l e c t ® P

h y t o s o m e s

F l a v a n o i d s f r o m

1 2 0 m g

H e a l t h f o o d

, c o s m e t i c

A n t i - a g e i n g , p r o t e c t s b r a i n ,

G i n g k o b i l o b a

v a s o k i n e t i c

1 9

R u s c o g e n i n P h y t o s o m e s

S t e r o i d s a p o n i n s f r o m

-

-

A n t i - i n f l a m m a t o r y , i m p r o v e s

R u s c u s a c u l e a t u s

c i r c u l a t i o n

2 0

E c h i n a c e a P h y t o

s o m e s

E c h i n a c o s i d e s f r o m

-

-

I m m u n o m o d u l a t o

r y ,

E c h i n a c e a a n g u s t i f o l i a

n e u t r a c e u t i c a l

2 1

S e r i c o s i d e P h y t o

s o m e s

S e r i c o s i d e s f r o m

-

C o s m e t i c

S k i n v i t a l i z e r , a n t i - w r i n k l e

T e r m i n a l i a s e r i c e a

2 2

C u r b i l e n e P h y t o s o m e s

C u r b i l e n e f r o m

-

-

S k i n c a r e , m a t t i n g a g e n t

C u c u r b i t a p e p o s e e d s

2 3

H a w t h o r n P h y t o

s o m e s

F l a v a n o i d s f r o m

1 0 0 m g

H e a l t h f o o d

A n t i h y p e r t e n s i v e , c a r d i o

C r a t a e g u s s p p .

p r o t e c t i v e

2 4

B o s w e l l T M P

h y t o

s o m e s

B o s w e l l i c a c i d f r o m

-

H e a l t h f o o d

, c o s m e t i c

A n t i i n f l a m m a t o r

y

B o s w e l l i a s e r r a t a r e s i n




Commercial aspects and market status

According to a recent survey, of all the drug

products marketed in 3 major global economies

i.e. UK, USA & Japan, 2-4 % comprises of oral

lipid based formulations 88. The Phytosome®

Technology was developed by Indena S.p.A of Italy to augment the absorption and utilisation of

poorly available phytomedicines 89. Indena is one

of the world’s leading companies in lieu of

exploring the nature’s riches and development of

suitable dosage forms using the herbs & botanicals90. Apart from Indena, Natural Factors (Canada)

and Nature’s Herbs (USA) 91 too manufacture

phytosomal preparations. Some of the available

marketed products are listed in table 2 along with

their active principle, dose and therapeutic use.

Despite its distinct advantages, simple manu-

facturing process and ease of upgrading

phytosome ® technology to industrial scale

favours its rapid commercialisation. Phytosomes

offer the suitability to be formulated both for oral

and topical delivery. Indena 90 suggest the most

effective means of formulation so as to ensure its

best performance.

Soft gelatin capsules

It is the most ideal solution in which phytosomal

complex is dispersed in vegetable or semi-

synthetic oil to get an oleaginous suspension for filling into soft gelatin capsules. However,

selection of vehicle governs the behaviour and

remains critical.

Hard gelatin capsules

Direct volumetric filling of the material without

undergoing precompression is best known

method. A preliminary dry granulation can further

result in better performance.

Tablets

Dry granulation is the ideal manufacturing

process for high strength unit doses. For low

strength units, 60-70 % excipients are added to

cover poor flow and low density challenges

followed by direct compression. Wet granulation

is strictly avoided due to instability of the complex

on exposure to water and heat.

Topicals

To be applied topically, phytosome complex is

dispersed either in lipidic or watery phase and thenadded to already prepared emulsion at temperature

not exceeding 40°C.

Conclusion

In nutshell, Phytosomes® serves as a boon for

poorly bioavailable natural extracts with well

established processing techniques and developed

analytical methods. It offers a myriad spectrum

of advantages over other traditional forms of

medicine. Numerous drug products are available

in the market with registered patents. This litera-ture shows that Phytosomes® have added a new

dimension in pharmaceutical research & develop-

ment having abundant potential yet to be explored.

Reference

1. Hauss, D.J. (2007). Oral lipid-based formulations. Advanced Drug Delivery Reviews, 59: 667-

676.

2. Gursoy, R.N., Benita, S. (2004). Self-emulsifying drug delivery systems (SEDDS) for improved

oral delivery of lipophilic drugs. Biomedicine and Pharmacotherapeutics, 58(3): 173-182.

3. Lipinski, C.A. (2000). Drug-like properties and the causes of poor solubility and poor permeability.

Journal of Pharmacological and Toxicological Methods, 44: 235-249.

4. Vonderscher, J., Meinzer, A. (1994). Rationale for the development of Sandimmune Neoral.Transplant Proceedings, 26: 2925-2927.

5. Wandel, C., Kim, R.B., Stein, M. (2003). “Inactive” excipients such as Cremophor can affect in

vivo drug disposition. Clinical Pharmacology and Therapeutics, 73(5): 394-396.

6. Cornaire, G., Woodley, J., Hermann, P., Cloare, A., Arellano, C., Houin, G. (2004). Impact of

excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. International Journal

of Pharmaceutics, 278: 119-131.

7. Rege, B., Kao, J., Polli, J. (1992) Effects of nonionic surfactants on membrane transporters in




Caco-2 cell monolayers. Journal of Pharmaceutical Sciences, 16: 237-246.

8. Charman, W.N. (1992). Lipid vehicle and formulation effects on intestinal lymphatic drug

transport, In: W.N. Charman, V.J. Stella (Eds.), Lymphatic Transport of Drugs, CRC Press, Boca

Raton, 113-179.

9. Hauss, D.J., Fogal, S.E., Ficorilli, J.V. (1998). Lipid-based delivery systems for improving the

bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. Journal of Pharmaceutical Sciences, 87: 164-169.

10. Bhattacharya, S., Ghosh, A. (2009). Phytosomes: the Emerging Technology for Enhancement

of Bioavailability of Botanicals and Nutraceuticals. International Journal of Health Research,

2(3): 225-232.

11. Bombardelli, E., Curri, S.B., Della Loggia, R. et al. (1989). Complexes between phospholipids

and vegetal derivatives of biological interest. Fitoterapia, 60: 1-9.

12. Kidd, P.M. (2009). Bioavailability and Activity of Phytosome Complexes from Botanical

Polyphenols: The Silymarin, Curcumin, Green Tea, and Grape Seed Extracts. Alternative Medicine

Review, 14(3): 226-246.

13. Manach, C., Scalbert, A., Morand, C. et al. (2004). Polyphenols: food sources and bioavailability,

American Journal of Clinical Nutrition, 79: 727-747.

14. Jose, M.M., Bombardelli, E. (1987). U.S. Patent No- EPO209037. Pharmaceutical compositions

containing flavanolignans and phospholipida active principles.

15. Semalty, A., Semalty, M., Singh, D., Rawat, MSM. (2009). Preparation and characterization of

phospholipid complexes of naringenin for effective drug delivery. Journal of Inclusion Phenomena

and Macrocyclic Chemistry, DOI 10.1007/s10847-009-9705-8.

16. Awasthi, R., Kulkarni, G.T., Pawar, V.K. (2011). Phytosomes: an approach to increase the bio-

availability of plant extracts. International Journal of Pharmacy and Pharmaceutical Sciences,

3(2): 1-3.

17. Kumar, V.S., Kesari, A. (2011). Herbosome: A novel carrier for herbal drug delivery. International

Journal of Current Pharmaceutical Research, 3(3): 36-41.

18. Bombardelli, E. (1994). Phytosome in functional cosmetics. Fitoterapia, LXV (5): 387-401.

19. Saonere Suryawanshi, J.A. (2011). Phytosome: An emerging trend in herbal drug treatment.Journal of Medical Genetics and Genomics, 3(6): 109-114.

20. Sharma, S., Sikarwar, M. (2005). Phytosome: A Review. Planta. Indica, 1(2): 1-3.

21. Stuchlik, M., Zak, S. (2001). Lipid based vehicle for oral drug delivery. Biomedical papers,

145(2): 17-26.

22. Magistretti, M.J., Bombardelli, E. (1987). U.S. Patent No-EPO209037. Phamaceutical compo-

sitions containing flavanolignans and phospholipida active principles.

23. Raju, T.P., Reddy, M.S., Reddy, V.P. (2011). Phytosomes: A novel phyto-phospholipid carriers

for herbal drug delivery. International Research Journal of Pharmacy. 2(6): 28-33.

24. Mascarella, S. (1993). Therapeutic & antilipoperoxidant effects of silybin phosphatidyl choline

complex in chronic liver disease. Current Therapeutic Research, 53: 98-102.

25. Fry, D.W. (1978). White JC. Goldman ID. Rapid secretion of low molecular weight solutes from

liposomes without dilution. Analytical Biochemistry, 90: 809-815.26. Franco, P.G. (1998). US Patent No-EPO 275005. Bombardelli E. Complex coppouns of bioflavan-

oids with phospholipids, their preparation and uses and pharmaceutical and cosmetic compo-

sitions containing them.

27. Bombardelli, E., Giuseppe, M. (1991). U.S.Patent No. EPO 441279 B1. Bilobalide phospholipide

complex, their applications and formulation containing them.

28. Semalty, A., Semalty, M., Rawat, M.S.M. (2007). The phytophospholipid complexes phyto-

somes: A potential therapeutic approach for herbal hepatoprotective drug delivery. Pharmacognosy




Reviews, 1: 369-374.

29. Vasanti, S. (2008). Phytosomes: A short review. http://www.biology-online.org/articles/phyto

somes-short-review. html.

30. Liposomes: A Practical Approach, Preparation of liposomes and size determination. (1990).

New RRC (Ed.), Oxford University Press, 36-39.

31. Bombardelli, E. (1991). Phytosome: a new cosmetic delivery system. Boll Chim Farm. 130:431-438.

32. Bombardelli, E., Spelta, M. (1991). Phospholipid-polyphenol complexes: A new concept in

skin care ingredients. Cosmetics and Toiletries, 106: 69-76.

33. Dubey, D., Shrivastava, S., Kapoor, S. (2007). Phytosome: a novel dosage structure. http://

www.pharmainfo.net/reviews/

34. Kingdom, A.D. (2001).Pharmacognosy in 21st century. Journal of Pharmacognosy and Pharma-

cology, 53: 135-148.

35. Kidd, P., Head, K. (2005). A review of bioavailability and clinical efficacy of milk thistle phyto-

some: a silybin phosphatidylcholine complex. Alternative Medicine Reviews, 10(3): 193-203.

36. Bombardelli, E., Spelta, M., Loggia Della, R., Sosa, S., Tubaro, A. (1991). Aging skin: Protective

effect of silymarin-Phytosome. Fitoterapia, 62(2): 115-22.

37. Gupta, A., Ashawal, M.S., Saraf, S. (2007). Phytosomes: A novel approach towards functionalcosmetics. Journal of Plant Science, 644-649.

38. Marena, C., Lampertico, M. (1991). Preliminary clinical development of silipide: A new complex

of silybin in toxic liver disorders. Planta Medica. 57: A124-A125.

39. Kidd, P.M. (2002). Phosphatidylcholine. In: Czap K, Miller AL, Head KA et al. eds. Alternative

Medicine Review Monographs Volume One. Dover, ID: Thorne Research, Inc., 310-315.

40. Dayan, N., Touitou, E. (2002). Carrier for skin delivery of trihexyphenidyl HCl: ethosomes vs

liposomes. Biomaterials, 21: 1879-1885.

41. Citernesi, U., Sciacchitano, M. (1995). Phospholipids/active ingredient complexes. Cosmetics

& Toiletries, 110: 57-68.

42. Patel, J., Patel, R., Khambholjab, K., Patel, N. (2009). An overview of phytosomes as an

advanced herbal drug delivery system. Asian Journal of Pharmaceutical Sciences, 4(6): 363-371.43. Porter, C.J.H., Trevaskis, N.L., Charman, W.N. (2007). Lipids and lipid-based formulations:

optimizing the oral delivery of lipophilic drugs. Nature Reviews Drug Discovery, 6: 231-248.

44. Borovicka, J. et al . (1997). Regulation of gastric and pancreatic lipase secretion by CCK and

cholinergic mechanisms in humans. American Journal of Physiology, 273: G374-G380.

45. Moreau, H. et al . (1989). Immunocytolocalization of human gastric lipase in chief cells of the

fundic mucosa. Histochemistry, 91: 419-423.

46. Thomson, A.B.R., Keelan, M., Garg, M.L., Clandinin, M.T. (1989). Intestinal aspects of lipid

absorption: in review. Canadian Journal of Physiology and Pharmacology, 67: 179-191.

47. Hamosh, M. et al. (1981). Fat digestion in the newborn- Characterization of lipase in gastric

aspirates of premature and term infants. Journal of Clinical Investigation, 67: 838-846.

48. Abrams, C.K. et al . (1988). Gastric lipase: localization in the human stomach. Gastroenterology,

95: 1460-1464.49. Van den Bosch, H., Postema, N.M., De Haas, G.H., Van Deenen, L.L. (1965). On the positional

specificity of phospholipase A from pancreas. Biochimica et Biophysica Acta, 98: 657-659.

50. Borgstrom, B., Dahlqvist, A., Lundh, G., Sjovall, J. (1957). Studies of intestinal digestion and

absorption in the human. Journal of Clinical Investigation, 36: 1521-1536.

51. Duane, W.C., Ginsberg, R.L., Bennion, L.J. (1976). Effects of fasting on bile acid metabolism

and biliary lipid composition in man. Journal of Lipid Research, 17: 211-219.

52. Thomson, A.B., Schoeller, C., Keelan, M., Smith, L., Clandinin, M. (1993). Lipid absorption:




passing through the unstirred layers, brush-border membrane, and beyond. Canadian Journal of

Physiology and Pharmacology, 71: 531-555.

53. Jain, N.K. (2005). Liposomes as drug carriers, controlled and novel drug delivery. 1st edition,

CBS publisher, 321-326.

54. Maghraby, G.M.M., Williams, A.C., Barry, B.W. (2000). Oestradiol skin delivery from

ultradeformable liposomes: refinement of surfactant concentration. International Journal of Pharmaceutics, 196: 63-74.

55. Pandey, S., Patel, K. (2010). Phytosomes: Technical revolution in phytomedicine. International

Journal of PharmaTech Research, 2: 627-631.

56. Berge BAI, V., Swartzendruber, V.A.B., Geest, J. (1997). Development of an optimal protocol

for the ultrastructural examination of skin by transmission electron microscopy. Journal of

Microscopy, 187: 125-133.

57. Chauhan, N.S., Gowtham, R., Gopalkrishna, B. (2009). Phytosomes: A potential Phyto-

phospholipid carriers for herbal drug delivery. Journal of Pharmacy Research, 2: 1267-70.

58. Facino, R.M., Carini, M., Aldini, G. (1994). Free radicals sea action and anti-enzyme activities

of procyanidines vitis vinifera-a mechanism for their capillary protection. Arzneimittelforschung,

44: 592-601.

59. Porter, C.J.H., Charman, W.N. (2001). In vitro assessment of oral lipid based formulations.Advanced Drug Delivery Reviews, 50: S127-S147.

60. Christensen, J.O. , Schultz, K., Mollgaard, B., Kristensen, H.G., Mullertz, A. (2004).

Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain

triacylglycerols. European Journal of Pharmaceutical Sciences, 23: 287-296.

61. Kidd, P.M. (2002). Glutathione. In: Czap K, Miller AL, Head KA, et al, eds. Alternative Medicine

Review Monographs, Volume One. Dover, ID: Thorne Research, Inc, 184-192.

62. Malandrino, S., Pifferi, G. (1990). IdB-1016. Drugs Future, 15: 226-227.

63. Barzaghi, N., Crema, F., Gatti, G. (1990). Pharmacokinetic studies on IdB 1016, a silybin-

phosphatidylcholine complex, in healthy human subjects. European Journal of Drug Metabolism

and Pharmacokinetics, 15: 333-338.

64. www.indena.com/pdf/ephytosome.pdf Accessed- Oct 11, 2011.65. Bares, J.M., Berger, J., Nelson, J.E. et al. (2008). Silybin treatment is associated with reduction

in serum ferritin in patients with chronic hepatitis C. Journal of clinical Gastroenterology, 42:

937-944.

66. Ramasamy, K., Agarwal, R. (2008). Multitargeted therapy of cancer by silymarin. Cancer Letters,

269: 352-362.

67. Manna, S.K., Mudkopadhyay, A., Van, N.T., Aggarwal, B.B. (1999). Silymarin suppresses

TNF-induced activation of NF-kappaB, c-Jun N-terminal kinase, and apoptosis. Journal of

Immunology, 163: 6800-6809.

68. Schandalik, R., Gatti, G., Perucca, E. (1992). Pharmacokinetics of silybin in bile following

administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschung, 42:

964-968.

69. Goel, A., Kunnumakkara, A.B., Aggarwal, B.B. (2008). Curcumin as “Curecumin”: from kitchento clinic. Biochemical Pharmacology, 75: 787-809.

70. Soni, K.B., Kuttan, R. (1992). Effect of oral curcumin administration on serum peroxides and

cholesterol levels in human volunteers. Indian Journal of Physiology and Pharmacology, 36:

273-275.

71. Garcea, G., Berry, D.P., Jones, D.J. (2005). Consumption of the putative chemopreventive

agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their

pharmacodynamic consequences. Cancer Epidemiology, Biomarkers and Prevention, 14: 120-




125.

72. Villegas, I., Sanchez-Fidalgo, S., Alarcon de la Lastra, C. (2008). New mechanisms and thera-

peutic potential of curcumin for colorectal cancer. Molecular Nutrition and Food Research, 52:

1040-1061.

73. Strimpakos, A.S., Sharma, R.A. (2008). Curcumin: preventive and therapeutic properties in

laboratory studies and clinical trials. Antioxidants and Redox Signaling, 10: 511-545.74. Begum, A.N., Jones, M.R., Lim, G.P. (2008). Curcumin structure-function, bioavailability, and

efficacy in models of neuroinflammation and Alzheimer’s disease. Journal of Pharmacology and

Experimental Therapeutics, 326: 196-208.

75. Marczylo, T.H., Verschoyle, R.D., Cooke, D.N. (2007). Comparison of systemic availability of

curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemotherapy

and Pharmacology, 60: 171-177.

76. Coyle, C.H., Philips, B.J., Morrisroe, S.N. (2008). Antioxidant effects of green tea and its

polyphenols on bladder cells. Life Sciences, 83: 12-18.

77. Krahwinkel, T., Willershausen, B. (2000). The effect of sugar-free green tea chew candies on

the degree of inflammation of the gingiva. European Journal of Medical Research, 5: 463-467.

78. Di Pierro, F., Menghi, A.B., Barreca, A. (2009). Greenselect® phytosome as an adjunct to a

low-calorie diet for treatment of obesity: a clinical trial. Alternative Medicine Reviews , 14:154-160.

79. Zhao, B., Guo, Q., Xin, W. (2001). Free radical scavenging by green tea polyphenols. Methods

in Enzymology, 335: 217-231.

80. Khan, N., Afaq, F., Saleem, M. (2006). Targeting multiple signaling pathways by green tea

polyphenol (-)-epigallocatechin-3-gallate. Cancer Research, 66: 2500-2505.

81. Mandel, S.A., Avramovich-Tirosh, Y., Reznichenko, L. (2005). Multifunctional activities of

green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative

stress and PKC signalling pathway. Neurosignals, 14: 46-60.

82. Simonetti, P., Ciappellano, S., Gardana, C. (2002). Procyanidins from Vitis vinifera seeds: in

vivo effects on oxidative stress. Journal of Agricultural and Food Chemistry, 50: 6217-6221.

83. Maffei Facino, R., Carini, M., Aldini, G. (1994). Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis vinifera. A mechanism for their capillary protective

action. Arzneimittelforschung, 44: 592-601.

84. Natella, F., Belelli, F., Gentili, V. (2002). Grape seed proanthocyanidins prevent plasma post-

prandial oxidative stress in humans. Journal of Agricultural and Food Chemistry, 50: 7720-7725.

85. Morazzoni, P., Cristoni, A., Bombardelli, E., Saponara, R., Bosisio, E. (0000). Inhibition of

phosphodiesterases by Ginkgo Biloba Dimeric Flavonoids and modulation of skin microcirculation

and adipocytes lipolysis-Proceedings of the 20th IFSCC Congress.

86. Indena. Gingko biloba Dimeric flavanoids Phytosomes®, Available at: http://www.indena.com/

pdf/GBDFPhytosome.pdf. Accessed- Oct 11, 2011.

87. Indena. Gingko biloba Terpenes Phytosomes®, Available at: http://www.indena.it/pdf/

gbterpenesphytosome.pdf. Accessed- Oct 11, 2011.

88. For the United States of America:www.rxlist.com, www.fda.gov/cder, www.accessdata.fda.gov/scripts/cder/iig/index.cfm; For the United Kingdom: http://emc.medicines.org.uk/; For Japan:

http://www.e-search.ne.jp/~jpr/jprdb/eindex.htmlAccessed Oct 11, 2011.

89. Phytosomes: A technical revolution in phytomedicine. Available at: http:// www.indena.com.

Accessed- Oct 11, 2011.

90. Indena. Formulating Phytosomes®, Available at: http://www.phytosomes.info/public/

formulating_phytosome.asp. Accessed- Oct 11, 2011.

91. Sindhumol, P.G., Thomas, M., Mohanachandran, P.S. (2010). Phytosomes: A novel dosage




form for enhancement of bioavailability of botanicals and neutraceuticals. International Journal

of Pharmacy and Pharmaceutical Sciences, 2(4): 10-14.

92. Murray. Phytosomes-Increase the absorption of herbal extract,Available at: www. doctor

murray.com/articles/silybin.htm Accessed- Oct 11, 2011.

93. Vitamedics, Phytosome Products, Available at http://www.vitaemedics.com. Accessed- Oct 11,

2011.94. Mukherjee, P.K., Maiti, K., Kumar, V. (2007). Value added drug delivery systems with botani-

cals: Approach for Dosage development from natural resources. Pharma Reviews, 6: 57-60.

95. Joshi, A., Chaturvedi, S., Kumar, V. (2007-08). Phytosomes-A revolution in herbal drugs. Pharma

Review, Kongposh Publications.

96. Indena. Phytosomes®: More bioavailable, Available at: http://www.indena.it/pdf/phytosome.pdf.

Accessed- Oct 11, 2011.


journal of biologically active products from nature volume 2 issue 2 2012 [doi...

Documents