Phytosomes - A New Herbal Drug Delivery System - International ...

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701____________________________________________Review ArticlePhytosomes - A New Herbal Drug Delivery SystemSandip Sarjerao ShelkeShree Ambabai Talim Sanstha's Diploma In Pharmacy College, Sangli- Miraj road,walnesswadi, Miraj, Dist- Sangli, Tal- Miraj, Maharashtra, India.1) Herbal Medicine1.1) IntroductionHerbal medicines are the synthesis of therapeuticexperiences of generations of practicing physicians ofindigenous systems of medicine for over hundreds ofyears 1 . The World Health Organisation (WHO) hasrecently defined traditional medicine including herbaldrugs as therapeutic practices that have been inexistence for hundreds of years before thedevelopment and spread of modern medicine and arestill in use today. The traditional preparationscomprise of medicinal plants, minerals and organicmatter. Herbal drugs constitute only those traditionalmedicines which are primarily used as medicinalplant preparations for therapy 2 . Herbal medicines arealso termed as phytotherapeutic agents orphytomedicines. These phytomedicines are alsoavailable as standardized herbal preparationsconsisting of complex mixtures of one or moreplants, which are used in many countries 3 .1.2) Importance of Herbal MedicineThe use of medicinal plants for health reasons startedthousands of years ago and is still a part of medicalpractice in China, Egypt, India and other developingcountries. Over the centuries, the use of medicinalherbs has become an important part of daily life inthe western world despite significant progress inmodern medicine and pharmaceutical research.Increasing knowledge of metabolic processes andeffects of plants on human physiology has enlargedthe range of application of medicinal plants 4 .WHO estimates that 4 billion people, i.e. about 80 %of the world population, presently use herbalmedicine for some aspect of primary health care?Major pharmaceutical companies are currentlyconducting extensive research on plant materialsgathered from the rain forests and other places fortheir potential medicinal value.Substances derived from the plants remain the basisfor a large proportion of the commercial medicationsused today for the treatment of heart disease, highblood pressure, pain, asthma, and other problems. Forexample, Ephedra is an herb used in TraditionalChinese Medicine for more than two thousand yearsto treat asthma and other respiratory problems.Ephedrine, an active ingredient in Ephedra, is used inthe commercial pharmaceutical preparations for therelief of asthma symptoms and other respiratoryproblems. It helps the patients to breathe more easily.Another example of the use of the herbal preparationin modern medicine is the foxglove plant. This herbhad been in use since 1775. At present the powderedleaf of this plant is known as the cardiac stimulantdigitalis to the millions of heart patients.Herbal medicine can be broadly classified intovarious basic systems: Traditional Chinese herbalism,which is part of Traditional Oriental Medicine,Ayurvedic herbalism, which is derived fromayurveda, and Western herbalism, which originallycame from Greece and Rome to Europe and thenspread to North and South AmericaThere are some Ayurvedic herbs that are useful forreducing cholesterol, diabetes etc. Similarly thepopularity of Ginseng and Ginkgo biloba (Ginkgo) isrising due to its effects like immunomodulatory 5 .Herbal medicines have stood the test of time for theirsafety, efficacy, cultural acceptability and lesser sideeffects 2 .In comparison to well defined synthetic drugs, herbalmedicines exhibit some marked differences 6 viz1. Long history of use and better patienttolerance2. Renewable resource3. Environment friendly4. Local availability5. Important recent breakthrough6. Major source of new lead generationApart from this, they also offer therapeutics for agerelateddisorders like memory loss, osteoporosis,immune disorders, diabetes, cancer etc; for whichmodern medicine has no complete cure. Herbals,mainly in developing countries, are known for theirbetter cultural acceptability and lesser side effects 2 .2) PhytosomesThe term "phyto" means plant while "some" meanscell-like. Phytosome are created when thestandardized extract and active ingredients of an herbare bound to the phospholipids on a molecular level.Vol. 3 (4) Oct – Dec 2012 www.ijrpbsonline.com 1709

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701Phytosome structures contain the active ingredientsof the herb surrounded by the phospholipids. Thephospholipid molecular structure includes a watersolublehead and two fat-soluble tails, because of thisdual solubility, the phospholipid acts as an effectiveemulsifier, which is also one of the chief componentsof the membranes in our cells. Phytosomes areadvanced forms of herbal products that are betterabsorbed, utilized, and as a result produce betterresults than conventional herbal extracts.2.1) IntroductionPreparations of plants or parts of them were widelyused in popular medicine since ancient times and tilltoday the use of phytomedicines are widespread inmost of the world’s population. During the lastcentury chemical and pharmacological studies havebeen performed on a lot of plant extracts in order toknow their chemical composition and confirm theindications of traditional medicine. The Phytosomeprocess produces a little cell because of that thevaluable components of the herbal extract areprotected from destruction by digestive secretionsand gut bacteria. Phytosomes are better able totransition from a hydrophilic environment into thelipid-friendly environment of the enterocyte cellmembrane and from there into the cell 7 , finallyreaching the blood. Most of the bioactive constituentsof phytomedicines are flavonoids (e.g.,anthocyanidins from bilberry, catechins from greentea, silymarin from milk thistle). However, manyflavonoids are poorly absorbed the poor absorption offlavonoid nutrients is likely due to two factors. First,they are having multiple-ring molecules that are toolarge to be absorbed by simple diffusion. Secondlyflavonoid molecules typically have poor miscibilitywith oils and other lipids, which limited their abilityto pass across the lipid-rich outer membranes of theenterocytes of the small intestine. Water-solubleflavonoid molecules can be converted into lipidcompatiblemolecular complexes, aptly calledphytosomes. The lipid-phase substances employed tomake flavonoids lipid-compatible are phospholipidsfrom soy, mainly phosphatidylcholine (PC).Phosphatidylcholine is the principal molecularbuilding block of cell membranes miscible both inwater and in oil environments, and is well absorbedwhen taken by mouth. Chemical analysis indicatesthat in phytosome is usually a flavonoid moleculelinked with at least one phosphatidylcholinemolecule. A bond is formed between these twomolecules, creating a hybrid molecule. This highlylipid-miscible hybrid bond is better suited to mergeinto the lipid phase of the enterocyte's outer cellmembrane. Phosphatidylcholine is not merely apassive "carrier" for the bioactive flavonoids of thephytosomes, but is itself a bioactive nutrient withdocumented clinical efficacy for liver disease,including alcoholic hepatic steatosis, drug-inducedliver damage, and hepatitis. The intakes ofphytosome preparations sufficient to provide reliableclinical benefit often also provide substantialphosphatidylcholine intakes. The phytosome processhas been applied to many popular herbal extractsincluding Ginkgo biloba, grape seed, hawthorn, milkthistle, green tea, and ginseng. The flavonoid andterpenoid components of these herbal extracts lendthemselves quite well for the direct binding tophosphatidylcholine. Specifically, the choline head ofthe phosphatidylcholine molecule binds to thesecompounds while the fat-soluble phosphatidylportion comprising the body and tail then envelopesthe choline-bound material. The result is a little microsphere or cell is produced 8 . Phytosomes haveimproved pharmacokinetic and pharmacologicalparameter which in result can advantageously be usedin the treatment of the acute and chronic liver diseaseof toxic metabolic or infective origin or ofdegenerative nature. It can also be used in antiinflammatoryactivity as well as in pharmaceuticaland cosmetic compositions 8.2.2) Preparation of PhytosomePhytosomes are novel complexes which are preparedby reacting from 3-2 moles but preferably with onemole of a natural or synthetic phospholipid, such asphosphatidylcholine, phosphatidylethanolamine orphosphatidyiserine with one mole of component forexample- flavolignanans, either alone or in thenatural mixture in aprotic solvent such as- dioxane oracetone from which complex can be isolated byprecipitation with non solvent such as aliphatichydrocarbons or lyophilization or by spary drying. Inthe complex formation of phytosomes the ratiobetween these two moieties is in the range from 0.5-2.0 moles. The most preferable ratio of phospholipidto flavonoids is 1:1 9 .In the phytosome preparations, phospholipids areselected from the group consisting of soy lecithin,from bovine or swine brain or dermis,phosphatidylcholine, phosphatidylethanolamine,phosphatidyiserine in which acyl group may be sameor different and mostly derived from palmitic, stearic,oleic and linoleic acid. Selection of flavonoids aredone from the 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 andbilobetine. Some liposomal drugs complex operate inthe presence of the water or buffer solution where asVol. 3 (4) Oct – Dec 2012 www.ijrpbsonline.com 1710

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701phytosomes operate with the solvent having areduced dielectric constant. Starting material ofcomponent like flavonoids are insoluble inchloroform, ethyl ether or benzene. They becomeextremely soluble in these solvents after formingphytosomes. This chemical and physical propertychange is due to the formation of a true stablecomplex 10 .2.3) Properties of Phytosomes2.3.1) Chemical propertiesPhytosomes is a complex between a natural productand natural phospholipids, like soy phospholipids.Such a complex is obtained by reaction ofstoichiometric amounts of phospholipid and thesubstrate in an appropriate solvent. On the basis ofspectroscopic data it has been shown that the mainphospholipid-substrate interaction is due to theformation of hydrogen bonds between the polar headof phospholipids (i.e. phosphate and ammoniumgroups) and the polar functionalities of the substrate.When treated with water, phytosomes assumes amicellar shape forming liposomial-like structures, inliposomes the active principle is dissolved in theinternal pocket or it is floating in the layermembrane, while in phytosomes the active principleis anchored to the polar head of phospholipids,becoming an integral part of the membrane forexample in the case of thecatechindistearoylphosphatidylcholine complex, inthis there is the formation of H-bonds between thephenolic hydroxyls of the flavone moiety and thephosphate ion on the phosphatidylcholine side.PhosphatidylcholineThis can be deduced from the comparison of theNMR of the complex with those of the pureprecursors. The signals of the fatty chain are almostunchanged. Such evidences inferred that the two longaliphatics chains are wrapped around the activeprinciple, producing a lipophilic envelope, whichshields the polar head of the phospholipid and thecatechin 11.Vol. 3 (4) Oct – Dec 2012 www.ijrpbsonline.com 1711

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-37012.3.2) Biological PropertiesPhytosome are advanced forms of herbal productsthat are better absorbed, utilized and as a resultproduce better results than conventional herbalextracts the increased bioavailability of thephytosome over the non complexed botanicalderivatives has been demonstrated bypharmacokinetics studies or by pharmacodynamictests in experimental animals and in human subjects12 .2.4) Characterization of PhytosomesThe behavior of phytosomes in both physical andbiological system is governed by the factors such asphysical size membrane permeability; percententrapped solutes, chemical composition as well asthe quantity and purity of the starting materials.Therefore, the phytosomes are characterized forphysical attributes i.e. shape, size, its distribution,percentage drug capture entrapped volume,percentage drug released and chemical composition13 .2.5) Difference between Phytosome and liposomeLiposomes are used primarily in cosmeticsto deliver water-soluble substances to theskin. Mixing a water-soluble substance withphosphatidylcholine forms a liposome. Nochemical bond is formed and there may behundreds or even thousands ofphosphatidylcholine molecules surroundingthe water-soluble compound. In contrast,with the Phytosome process thephosphatidylcholine and the individual plantcomponents actually from a 1:1 or a 2:1complex depending on the substance 17.Phytosomes are not liposome - structurally,the two are distinctly different as shown infig. no.1. The phytosome is a unit of a fewmolecules this makes difference so thephytosomes being much better absorbed thatliposomes. Not surprisingly, Phytosomes arealso superior to liposomes in skin careproducts while the liposome is an aggregateof many phospholipid molecules that canenclose other phytoactive molecules butVol. 3 (4) Oct – Dec 2012 www.ijrpbsonline.com 1712

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701without specifically bonding to them.Liposomes are touted delivery vehicles, butfor dietary supplements their promise hasnot been fulfilled. But for phytosomeproducts numerous studies prove they aremarkedly better absorbed and havesubstantially greater clinical efficacy.Companies have successfully applied thistechnology to a number of standardizedflavonoid preparations.The phytosomes technology is abreakthrough model for 18.· Marked enhancement of bioavailability· Significantly greater clinical benefit· Assured delivery to the tissues· No compromise of nutrient safety2.6) Advantages over the conventionaldosage form,The various advantages of phytosome arementioned below;1.Phytosome are better bioavailablebotanical extracts, dramaticallyenhance bioavailability due to theircomplex with phospholipids anddelivers faster and improvedabsorption in intestinal tract.2. Phytosome permeates the nonlipophillicbotanical extract to bebetter absorbed in intestinal lumen.3. Phytosome will be given in smallquantity and desired results can beachieved.4. Phytosome is widely used incosmetics due to there more skinpenetration and have a high lipidprofile.5. Phytosome are been used to giveliver protectant flavonoids becausethey were easily bioavailable.Phytosomes Herbal Support 14-19The Phytosome process has been applied tomany popular herbal extracts includingGinkgo biloba, grape seed, hawthorn, milkthistle, green tea, and ginseng. Theflavonoid and terpenoid components ofthese herbal extracts lend themselves quitewell for the direct binding tophosphatidylcholine. Specifically, thecholine head of the phosphatidylcholinemolecule binds to these compounds whilethe fat-soluble phosphatidyl portioncomprising the body and tail then envelopesthe choline-bound material. The result is alittle micro sphere or cell is produced. Whatthe Phytosome process produces is a littlecell whereby the valuable components of theherbal extract are protected from destructionby digestive secretions and gut bacteria.The effectiveness of any herbal product (ormedication) is dependent upon delivering aneffective level of the active compounds. Formilk thistle, this means delivering aneffective level of silybin for Pan ax ginsengit’s the compounds known as ginsenosidesfor Ginkgo biloba extract it is the flavonoidsand the terpenes; and for green tea it isepigallocatechin 3-O- gallate. It only makessense that if you can increase the absorptionand utilization of these components that youwill see better results. And, that is exactlywhat has been shown in several studies withvarious Phytosomes.For example, several clinical studies havealso shown SILYBIN PHYTOSOME ismore effective and produces better resultscompared to regular milk thistle extracts. Inone study of 232 patients with chronichepatitis (viral, alcohol, or drug induced)treated with SILYBIN PHYTOSOME at adosage either 120 mg twice daily or 120 mgthree times daily for up to 120 days, liverfunction returned to normal faster in thepatients taking SILYBIN PHYTOSOME compared to a group of controls (49 treatedwith a commercially available silymarin;117 untreated or given placebo).Preliminary studies have also shown GinkgoPhytosome and Grape Seed Phytosome toproduce better results compared to theconventional extract forms of these plants.Vol. 3 (4) Oct – Dec 2012 www.ijrpbsonline.com 1713

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701For example in studies with GinkgoPhytosome in peripheral vascular disease(e.g., Raynaud’s disease and intermittentclaudication) Ginkgo Phytosome was shownto produce a 30-60% greater improvement compared toregular Ginkgo biloba extract (24% ginkgoflavone glycoside and 6% terpene lactones).CONCLUSIONPhytosomes are novel compoundscomprising of lipophillic complexes ofcomponents of various plants like SilybumMarianum, Ginkgo Biloba, ginseng etc withphospholipids. Phytosome prepration isdone by non-convectional method.Absorption of phytosome in gastro-intestinaltract is appreciably greater resulting inincreased plasma level than the individualcomponent. Complex formation ratio ofcomponent and phospholipids is 1:1 and 2:1.Phytosomes are used as a medicament andhave wide scope in cosmetology. Manyareas of phytosome are to be revealed infuture in the prospect of pharmaceuticalapplication. Phytosomes forms a bridgebetween the convectional delivery systemand novel delivery system.REFERENCES1. Houdret J., A Visual Dictionary ofHerbs, South water. 2000, 1.2. Kambhoj V.P., Current Science,2000, 1 (10), 35.3. Calixio J.B., Braz. J. Med. Boil.Res., 2000, 33(2), 179.4. Bentley R. and Trimet H., MedicinalPlants, International BookDistributors, 1992, 1, 1079.5. Samanta M.K., Mukherjee P.K.,Prasad N.K. and Suresh B., theEastern Pharmacist., 2000, 23.6. Mascarella S., 1993, Therapeutic andantilipoperoxidant effects of silybinphosphatidylcholinecomplex inchronic liver disease, Preliminaryresults. Curr Ther.Res., 53(1), 98-102.7. .Magistretti Maria Jose, BombardelliEzio, 1987, U.S. Patent No-EPO209037 Pharmaceuticalcompositionscontainingflavanolignans and phospholipidaactive principles.8. Sharma Shalini, Sikarwar Mukesh,Phytosome: a review, Planta Indica,Vol.1, No. 2, April 2005, 1-3.9. Bombardelli Ezio, MustichGiuseppe, 1991, U.S. PatentNo.EPO-275005 bilobalidephospholipid comlex, their uses andformulation contaning them.10. Franco P.G., Bombardelli, Ezio,1998, U.S. Patent No-EPO 275005,Complex coppouns of bioflavonoidswith phospholipids, their preparationand uses and pharmaceutical andcosmatic compositions containingthem.11. Jain N.K, Controlled and novel drugdelivery, 1 st edition, CBS publisher,2005, 321-326.12. U.S. Department of Health andhuman Services, CosmeticHandbook, U.S. GovernmentPrinting Office.13. Bombardelli Ezio, Phytosome infunctional cosmetics, FitoterapiaLXV (5): 1994, 387-401.14. Parris Kidd, Kathleen H, A review ofthe bioavailibility and clinicalefficacy of milk thiatle phytosome: asilybin-phosphatidylcholinecomplex, Altern Med Rev 2005;10(3): 193-203.15. Kingom A.D., Pharmacognosy in 21stcentury, Journal ofPharmacognosy and pharmacology,2001, 53,135-148.16. Gabetta Bruno, Bombardelli Ezio,Pifferi Giorgia, 1986, U.S. PatentNo- 4764508 Complexes ofVol. 3 (4) Oct – Dec 2012 www.ijrpbsonline.com 1714

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701flavanolignans with phospholipids,preparation there of and associatedpharmaceutical compositions.17. Schandalik R, Gatti G, and PeruccaE: Pharmacokinetics of silybin inbile following administration ofsilipide and silymarin incholecystectomy patients. ArzneimForsch 1992; 42(7):964-8.18. Barzaghi N, et al.: Pharmacokineticstudies on IdB 1016, a silybinphosphatidylcholinecomplex, inhealthy human subjects. Eur J DrugMetab Pharmacokinet 1990;15(4):333-8.19. www.natural-wellness.com.Vol. 3 (4) Oct – Dec 2012 www.ijrpbsonline.com 1715