phytosomes an emerging technology for herbal drug …

www.wjpr.net Vol 3, Issue 2, 2014.

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Dwivedi et al. World Journal of Pharmaceutical Research

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


3446


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


3451


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.


3452


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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