PHYTOSOMES AN EMERGING TECHNOLOGY FOR HERBAL DRUG …
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PHYTOSOMES AN EMERGING TECHNOLOGY FOR HERBAL DRUG
DELIVERY: AN APPROACH TO HEPATOPROTECTION
Chandraprakash Dwivedi*, Surbhi Kesharwani , Sandip Prasad Tiwari,
Trilochan Satapathy, Amit Roy
Columbia Institute of Pharmacy, Tekari, Near Vidhansabha Raipur, C.G., 493111, India.
ABSTRACT
Phytoconstituents, despite having excellent bioactivity in vitro,
demonstrate less or no in vivo actions due to their poor lipid solubility
or improper molecular size or both, resulting in poor absorption and
poor bioavailability. Lipid solubility and molecular size are the major
limiting factors for molecules to pass the biological membrane and to
be absorbed systematically following oral or topical administration.
Some phytoconstituents are destroyed in the gastric environment when
taken orally. The term “phyto” means plant, while “some” means cell-
like. Therefore, phytosome is a “phytophospholipid complex”
resembling a small cell. Phytosomes are produced by a patented
process whereby standardized plant extracts or their constituents are
bound to phospholipids, mainly phosphatidylcholine, producing a lipid-compatible molecular
complex. Phytosomes exhibit a better pharmacokinetic and pharmacodynamic profile than
conventional herbal extracts. The phytosome technology markedly enhances the
bioavailability of phytomedicine and has effectively 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. .the focus of this review is to elucidate the concept of hepatotoxicity, including
its causes, pathogenesis and prevention. The article also reviews the scope of herbal plants as
well as novel delivery systems like phytosomes for the treatment of hepatotoxicity and liver
related disorders. It has a lot of potential in the field of medicine, pharmaceuticals and
cosmetics.
Key words: Drug delivery, phosphatidylcholine, phytoconstituents, hepatotoxicity, Herbal.
World Journal of Pharmaceutical ReseaRch
Volume 3, Issue 2, 3443-3461. Review Article ISSN 2277 – 7105
Article Received on 12 January 2014, Revised on 26 January2014, Accepted on 17 February 2014
*Correspondence for
Author
Chandraprakash Dwivedi
Columbia Institute of
Pharmacy, Tekari, Near
Vidhansabha Raipur, C.G.,
India.
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INTRODUCTION
Medicinal plants have been acknowledged and are extremely valued all over the world as a
prosperous source of bioactives for the prevention and treatment of ailments. Herbal
medicines are being used by about 80% of the world population primarily in the developing
countries for primary health care. They have stood the test of time for their safety, efficacy,
cultural acceptability and minimal side effects, liver an imperative organ has a crucial in the
metabolism of xenobiotics that causes it to succumb to numerous hepatic diseases. Synthetic
drugs exploited in the treatment of liver diseases are incompetent and may sometimes lead to
serious side-effects. In this context, herbal therapy has emerged as a proficient approach with
good values in treating hepatic diseases.1, 2developing a satisfactory herbal therapy to treat
severe liver diseases requires systematic investigation of properties such as antiviral action
(hepatitis b, hepatitis c), anti-hepatotoxicity (antioxidants), stimulation of liver regeneration
and choleretic activity. The focus of this review is to elucidate the concept of hepatotoxicity,
including its causes, pathogenesis and prevention. The article also reviews the scope of herbal
plants as well as novel delivery systems like phytosomes for the treatment of hepatotoxicity
and liver related disorders.medicinal herbs are significant source of hepatoprotective drugs. It
has been reported that about 170 phytoconstituents isolated from 110 plants belonging to 55
families do possess hepatoprotective activity.liver protective herbal drugs contain a variety
of chemical constituents like phenols, coumarins, curcuminoids, lignans, essential oils and
terpenoids.3,4 The phytosomes hasmore ability to carry the herbal extract of hydrophilic
nature through the lipid bilayer and thus it is more bioavailable compared to simple extract.
The phytosome technology has been reported to effectively enhance the bioavailability of
many popular herbal extracts including milk thistle, ginkgo biloba, grape seed, green tea,
hawthorn, ginseng turmeric, centella, ammi etc and can further be developed for various
therapeutic uses or dietary supplements. The focus of this review is to elucidate the concept
of hepatotoxicity, novel delivery systems like phytosomes for the treatment of hepatotoxicity
and liver related disorders. Including its causes, pathogenesis and prevention .5, 6
PHOSPHATIDYLCHOLINE AND HERBAL EXTRACT
Phospholipids are a class of lipids and are a major component of all cell membrane. In
humans and other higher animals the phospholipids are also employed as natural digestive
aids and as carriers for both fat-miscible and water miscible nutrients. They are a major
component of biological membrane and can be isolated from either egg yolk or soy beans
from which they are mechanically extracted or chemically extracted using hexane.
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Phosphatidylcholine is a bifunctional compound, the phosphatidyl moiety being lipophilic
and the choline moiety being hydrophilic in nature. Specifically the choline head of the
phosphatidylcholine molecule binds to the components of herbal extract while the lipid
soluble phosphatidyl portion then envelopes the choline bound material that results in a little
micro sphere or cell is produced. The term "phyto" means plant while "some" means cell-
like. What the Phytosome process produces is a microsphere cell that protects valuable
components of the herbal extract from destruction by digestive secretions and gut bacteria.6, 7, 8
Figure 1. Structure of Phosphatidylcholine(PC)
Many popular standardized herbal extracts comprising of flavanoids, polyphenolics, terpenes,
alkaloids, volatile oils are employed for the preparation of phytosomes. The hypothesis of an
interaction with phospholipids originated from a histochemical finding indicating that
anthocyanosides from Vaccinium myrtillus L. showed a strong affinity for specific cellular
structures rich in phospholipids. Evidence that flavonoids as well as saponins and triterpenic
acids, do form real complexes with phospholipids was obtained about years ago when these
complexes could be prepared and chemically standardized. Mainly flavanoids and
polyphenolics are complexed with the phospholipids molecules and forms phytosomes. More
than 4,000 naturally occurring flavonoids have been identified, each with its own distinctive
molecular structure and 3-D shape. Flavonoids are part of a broader class of dietary
antioxidants called polyphenols and are distinctive for their triple ring structures. 9, 10 the poor
absorption of polyphenolics is likely due to two main factors. First, these are multiple-ring
molecules not quite small enough to be absorbed from the intestine into the blood by simple
diffusion nor does the intestinal lining actively absorb them, as occurs with some vitamins
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and minerals. Second, they typically have poor miscibility with oils and other lipids. This
severely limits their ability to pass across the lipid-rich outer membranes of the enterocytes,
the cells that line the small intestine. PC is miscible both in the water phase and in oil/lipid
phases, and is excellently absorbed when taken by mouth. The molecular properties of PC
and precise chemical analysis indicate the unit phytosome is usually a herbal extract molecule
linked with at least one PC molecule. A bond is formed between the two molecules to create
a hybrid molecule. This hybrid is highly lipid - miscible, better suited to merge into the lipid
phase of the enterocyte’s outer cell membrane. Once there, it can cross the enterocyte and
reach the circulating blood.11, 12
Figure 2. Hepatotoxicity and its mechanism
Figure 3. Role of hepatotoxic mediators and hepatoprotective mediators
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Herbal plant used for hepato-protective 8, 9
Figure 4.structure of hepetoprotective plant
Figure 5.structure of hepetoprotective plants8,9, 10
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Carrier systems for herbal drug
Delivery in liver
Drug delivery is a preliminary requirement. Emphasis needs to be laid in developing vehicles
that can transport bioactives to the liver with reduced access to non-specific tissues.
Phytosomes
Phospholipids are complex molecules used in all known life forms to build cell membranes.
The term “phyto” implies plant while “some” means cell-like. Water-soluble
phytoconstituent molecules (mainly polyphenoles) can be converted into lipid - compatible
molecular complexes, which are called phytosomes. Phytosomes may augment
bioavailability as compared to simple herbal extracts owing to their enhanced capacity to
cross the lipid rich biomembranes and finally enter the systemic circulation the blood.
Phytosomes are better able to transit a hydrophilic environment into the lipid-friendly
environment of the enterocyte cell membrane and from there into the cell, finally reaching
the blood. Chemical analysis indicates that in phytosome is usually a flavonoid molecule
linked with at least one phosphatidylcholine molecule. A bond is formed between these two
molecules, creating a hybrid molecule.the phytosomal preparations that have been
demonstrated safe and effective in live .11,12,13
Figure 6.Structure of Phytosomes
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PREPARATION OF PHYTOSOME- THE PHYTOSOME TECHNOLOGY
1. Phytosomes are novel complexes which are prepared by reacting from 3-2 moles but
preferably with one mole of a natural or synthetic phospholipid, such as
phosphatidylcholine, phosphatidylethanolamine or phosphatidyiserine with one mole of
component for example- flavolignanans, either alone or in the natural mixture in aprotic
solvent such as dioxane or acetone from which complex can be isolated by precipitation
with non solvent such as aliphatic hydrocarbons or lyophilization or by spray drying. In
the complex formation of phytosomes the ratio between these two moieties is in the range
from 0.5- 2.0 moles. The most preferable ratio of phospholipid to flavonoids is 1:1.
2. Naringenin–pc complex was prepared by taking naringenin with an equimolar
concentration of phosphatidylcholine (pc). The equimolar concentration of pc and
naringenin were placed in a 100 ml round bottom flask and refluxed in dichloromethane
for 3 h. On concentrating the solution to 5–10 ml, 30 ml of n-hexane was added to get the
complex as a precipitate followed by filtration. The precipitate was collected and placed
in vacuum desiccators .14
3. The required amounts of drug and phospholipids were placed in a 100 ml round-bottom
flask and dissolved in anhydrous ethanol. After ethanol was evaporated off under vacuum
at 40 ◦c, the dried residues were gathered and placed in desiccators overnight, then
crushed in the mortar and sieved with a 100 mesh. The resultant silybin-phospholipid
complex was transferred into a glass bottle, flushed with nitrogen and stored in the room
temperature.
4. The flavonoid and terpenoid constituents of plant extracts lend themselves quite well for
the direct binding to phosphatidylcholine. Phytosomes results from the reaction of
stoichiometric amount of the phospholipid (phosphatidylcholine) with the standardized
extract or polyphenolic constituents (like simple flavonoids) in a non polar solvent.
Phosphatidylcholine is a bifunctional compound, the phosphatidyl moiety being lipophilic
and the choline moiety being hydrophilic in nature. Specifically the choline head of the
phosphatidylcholine molecule binds to these compounds while the lipid soluble
phosphatidyl portion comprising the body and tail which then envelopes the choline
bound material13,14
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Phospholipids dissolved in organic solvent containing
Drug/extract
step 2
Drying of solution of phospholipids in organic solvent
With drug/extract
Step 3
formation of thin film
Step 4
Hydration of thin film
Step 5
Formation of phytosomal suspension
Improved Bioavailability Of Herbal Extract With Improved
RESULTS
The phytosome process has been applied to many popular herbal extracts including Ginkgo
biloba, grape seed, hawthorn, milk thistle, green tea, and ginseng and recent research shows
improved absorption and bioavailability with phytosomes as compared to the conventional
means. Many standardized extract containing flavanoids and polyphenolics have been
reported with improved bioavailability when incorporated in photosomal preparation.
Silymarin is some of the most studied drug for the better delivery of silybin by forming
silybinphospholipid complex. Yanyu et al. prepared the silymarin phytosome and studied its
pharmacokinetics in rats. In the study the bioavailability of silybin in rats was increased
remarkably after oral administration due to an improvement of the lipophilic property of
silybin-phospholipid complex.15, 16
Siliphos milk thistle phytosome
Silybin is the chief and most potent constituent of silymarin, the flavonoid complex from
milk thistle. A standardized extract from silybum marianum (milk thistle) is an excellent
liver protectant but very poorly absorbed orally. Silymarin phytosomes studied for its
pharmacokinetics in rats and bioavailability of silybin in rats was remarkably increased after
oral administration of prepared silybin-phospholipid complex possibly due to improved
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lipophilic property of silybin-phospholipid complex and subsequent biological effect of
silybin.in a similar study demonstrated that silymarin phytosome exerted a better anti-
hepatotoxic activity than silymarin alone and provided protection against the toxic effects of
aflatoxin on performance of broiler chicks. Silymarin phytosomes, in which silymarin (a
standardized mixture of flavanolignans extracted from the fruits of s. Marianum) was
complexed with phospholipids showed much higher specific activity and a longer lasting
action than the single constituent, with respect to percent reduction of odema, inhibition of
myeloperoxidase activity, antioxidant and free radical scavenging properties.16,17
Ginkgoselect phytosome
Ginkgoselect phytosomes (gsp) were prepared via complexation of ginkgo biloba extract with
soy phospholipids (1:2 w/w). Liver damage was induced in wistar rats by administering
rifampicin simultaneously and gsp were administered orally for 30 days/daily to rmp treated
rats. Level of marker enzymes (sgot, sgpt and salp), albumin (alb) and total proteins (tp) were
assessed in serum. Treatments with gbp50 as well as silymarin decreased the sgot, sgpt and
salp elevated by rmp and increased the alb and tp levels. Sgot and sgpt levels were nearly
restored to normal in the gbp50 treated group.19, 20, 21
Quercetin phytosomes
The quercetin-phospholipid phytosomal complex developed showed that the formulation
exerted better therapeutic efficacy than the molecule in rat liver injury induced by carbon
tetrachloride. Level of marker enzymes (sgot, sgpt and salp), albumin (alb) and total proteins
(tp) were assessed in serum. Treatments with quercetin phytosomes decreased the sgot, sgpt
and salp elevated by ccl4 and increased the alb and tp levels.22,23
PROPERTIES OF PHYTOSOMES
Physico-chemical properties
As previously discussed, phytosomes are prepared by reaction of stoichiometric amount
of phospholipid with the standardized plant extract as substrate. The spectroscopic data
reveals that the phopspholipid- substrate interaction is due to the formation of hydrogen
bond between the polar head (i.e., phosphate and ammonium group) and the polar
functionalities of the substrate.
The size of phytosome varies from 50 nm to a few hundred µm.
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Phytosomes when treated with water, they assume a micellar shape resembling liposome
and photon correlation spectroscopy (pcs) reveals these liposomal structures acquired by
phytosomes.
Regarding the solubility of phytosomes, the complexes are often freely soluble in aprotic
solvents, moderately soluble in fats, insoluble in water and relatively unstable in alcohol.
But the phytosomes of certain lipophilic phytoconstituents like curcumin has shown
increased water solubility upon complexation with phospholipids which has been
discussed later in this paper.25,26,27
Biological properties
Phytosomes are novel complexes which are better absorbed and utilized; hence they produce
more bioavailability and better result than the conventional herbal extract or non-complexed
extracts, which has been demonstrated by pharmacokinetic studies or by pharmacodynamic
tests in experimental animals and in human subjects28. Phytosomes express their behaviour in
physical or biological system because of their physical size, membrane permeability,
percentage entrapment, chemical composition, quantity and purity of the materials used. The
phytosomes should not be confused with liposomes where hydrophilic drug molecules are
entrapped within a cavity or spaces between the membranes. The liposomes may involve
several hundred phospholipid molecules for this entrapment and are usually now being used
for cosmetic purposes. Instead, the phytosomes involves interaction of 1- 4 phospholipid
molecules with the phytoconstituents which are chemically anchored to each other. Several
researches have shown the phytosomes to be a better alternative for liposomes in terms of
membrane permeability and stability. Fig.5 illustrates a comparative account of phytosomes
with liposomes.28, 29
Novel Approaches For Delivery Of Herbal Constituents
Liposomes
Liposomes are artificial microscopic vesicles consistiong of an aqueous core enclosed in one
or more phospholipid layers, used to convey vaccines, drugs, enzymesor other substances to
target cells or organs.30, 31
Nanoparticles
Nanoparticles are particles of less than 100nm in diameter that exhibit new or enhanced
sizedependent properties compared with larger particles of same material.
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Microemulsion
A thermodynamically stable dispersion of two immiscible liquids, stabilized by surfactants. A
microemulsion is an emulsion whose particles are less than 1 micron in size.
Phytosome
It is a newly introduced patented technology developed to incorporate standardized plant
extracts or water soluble phytoconstituents into phospholipids to produce lipid compatible
molecular complexes they are also known as herbosome.32,33
Transfersomes
A transfersomes carrier is an artificially designed to be like cell vesicle or a cell engaged in
exocytosis and thus suitable for controlled and potentially targeted drug delivery.
Transfersome consist of phosphatidylcholine and cholate and are ultra deformable vesicles
with enhanced skin penetrating properties. 34, 35
Figure 7 .organisation of phytosome complex
Difference between phytosome and liposome the molecular organization of liposome
upper segment the molecular organization of phytosome lower segment
Liposomes are prepared by same procedure as phytosomes. A liposome is formed by mixing
a water soluble substance with phosphatidylcholine in definite ratio under specific conditions.
The main differences between liposomes and phytomes are
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1. Main difference is that in liposomes no chemical bond is formed and the
phosphatidylcholine molecules surround the water soluble substance. In a liposome, the
material is simply
emulsified.
2. There may be hundreds or even thousands of phosphatidylcholine molecules surrounding
the water-soluble compound. In contrast, with the phytosome process the
phosphatidylcholine and the plant components actually form a 1:1 or a 2:1 molecular
complex depending on the substance (s) complexes, involving chemical bonds. This
difference results in better absorption of phytosomes than liposomes showing better
bioavailability. Phytosomes have also been found superior to liposomes in topical and
skin care products another difference is size of liposomes. Liposomes, although composed
of phosphatidylcholine, are much larger.
3. Fundamental differences are that in liposomes, the active constituents are dissolved in the
central part of the cavity, with no possibility of molecular interaction between the
surrounding lipid and a hydrophilic substance35,36. On the other hand the phytosome
complex can somewhat be compared to an integral part of the lipid membrane, where the
polar functionalities of the lipophilic molecule interact via hydrogen bonds with the polar
head of a phospholipids (i.e. Phosphate and ammonium groups), forming a unique pattern
which can be characterized by spectroscopy. This difference results in phytosome being
much better absorbed than liposomes showing better bioavailability.
4. Phytosomes are also superior to liposomes in skin care products while the liposome is an
aggregate of many phospholipids molecules that can enclose other phytoactive molecules
but without specifically bonding to them.
5. liposomes are touted delivery vehicles, but for dietary supplements, they are very less
efficient. But for phytosome products numerous studies prove they are markedly better
absorbed and have substantially greater clinical efficacy.
6. some liposomal drug complexes operate in the presence of the water or buffer solution
whereas phytosomes operate with the solvent having a reduced dielectric constant.
Starting material of component like flavonoids is insoluble in chloroform, ethyl ether or
benzene. They become extremely soluble in these solvents after forming phytosomes.
This chemical and physical property change is due to the formation of a true stable
complex.37,38,39
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Marketed Preparations Of Phytosomes
Silymarin phytosome
Most of the phytosomal studies are focused on silybum marianum (milk thistles) which
contains premier liver protectant flavonoids. Yanyu et al. (2006) prepared silymarin
phytosome and studies its pharmacokinetic in rats. In the studies, the bioavailability of silybin
in rat was increased remarkably after oral administration of silybin-phospholipid complex
due to an impressive improvement of the lipophilic properties of silybinphospholipid
complex and improvement of biological effect of silybin . 39, 40
Curcumin phytosome
Maiti et al. (2006) developed the phytosomes of curcumin (flavonoid from curcuma longa,
turmeric) and naringenin (flavonoid from grape fruit, vitis vinifera) in two different studies.
The antioxidant activity of the complex was significantly higher than pure curcumin in all
dose level tested. In the other study the developed phytosome of naringenin produced better
antioxidant activity than the free compound with a prolonged duration of action, which may
due to decrease in the rapid elimination of the molecule from body .40, 41, 42
Evaluation Of Phytosomes
I. Characterization technique
1. Visualization: Visualization of phytosomes can be achieved using transmission electron
microscopy (tem) and by scanning electron microscopy (sem) .42
2. Entrapment efficiency: The entrapment efficiency of a drug by phytosomes can be
measured by the ultracentrifugation technique.
3. Transition temperature: The transition temperature of the vesicular lipid systems can be
determined by differential scanning calorimetric .43
4. Surface tension activity measurement: The surface tension activity of the drug in
aqueous solution can be measured by the ring method in a du nouy ring densitometer.
5. Vesicle stability: The stability of vesicles can be determined by assessing the size and
structure of the vesicles over time. The mean size is measured by dls and structural changes
are monitored by tem.
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6. Drug content: The amount of drug can be quantified by a modified high performance
liquid chromatographic method or by a suitable spectroscopic Method.44, 45
Ii. Spectroscopic evaluations
To confirm the formation of a complex or to study the reciprocal interaction between the
phytoconstituent and the phospholipids, the following Spectroscopic methods are used .46,
47
1.1HNMR
2. 13CNMR
3. FTIR
Specific Agents And Their Effects On The Liver 48, 49, 50
Acetaminophen: Cytochrome p-450-2e1 generates a toxic metabolite napqi and this
produces hepatic necrosis.
Amoxicillin: Moderate rise in sgot and sgpt level, hepatic dysfunction including jaundice,
hepatic cholestasis and acute cytolytic hepatitis.
Chlorpromazine: Infectious hepatitis with laboratory features of obstructive jaundice.
Ciprofloxacin: Cholestatic jaundice, elevated sgpt, sgot and alkaline phosphatase level.
Diclofenac: Elevation of alt and ast level, liver necrosis, jaundice and fulminant hepatitis.
Erythromycin: Increased level of sgpt, sgot, hepatocellular and/or cholestatic hepatitis with
or without jaundice.
Fluconazole: Elevated transaminase level, hepatitis, cholestasis and fulminant hepatic
failure.
Isoniazid: Elevation of serum transaminase level, severe and fatal hepatitis.51, 52, 53
Phytosomes 54,55,56,57
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Table 1: Marketed Preparations
Phytosomes Phytoconstituent complexed with
phosphatidylcholine Indication Dose
Mg
Silybin phytosome
Tm
Siybin from silymarin marinum
Nutraceutical, antioxidant 120
Ginkgo phytosome
Tm
24% ginkgo flavonoids from Ginkgo biloba
Protects brain and vascular Lining
120
Greentea Phytosome tm
Epigallocatechin 3-o-gallate from
Camellia sinesis
Anticancer,systemic Antioxidant
50- 100
Olive oil Phytosometm
Poluphenols from olea europaea
Oil
Anti-oxidant,anti inflammatory -
Centella Phytosometm Terpenes Vein and skin
disorders51 -
CONCLUSION
Modern society has innate knowledge about the herbal treatment of liver disease from many
cultures. Research into plants traditionally used in the treatment of liver disease has
significantly advanced in the past 15 years, and much of what has been discovered supports
traditional knowledge. There continues to be a need for safe, effective treatments of liver
disease. An assortment of botanical medicines such as milk thistle, turmeric, green tea,
licorice, tinospora cordifolia, andographis paniculata and picrorhiza, are the best-researched
plants for the treatment of liver disease, with many human therapeutic trials available to the
practicing physician to assess their potential effectiveness. Plant drugs (combinations or
individual drug) for liver diseases should possess sufficient efficacy to cure severe liver
diseases caused by toxic chemicals, viruses (hepatitis b, hepatitis c, etc.), excess alcohol
intake, etc. A single drug cannot be effective against all types of severe liver diseases.
Effective formulations have to be developed using indigenous medicinal plants,with proper
pharmacological experiments and clinical trials. The manufacture of plant products should
be governed by standards of safety and efficacy.
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