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Supramolecular Phospholipids–polyphenolics Interactions: The Phytosome< Sup>® Strategy To Improve The Bioavailability Of Phytochemicals

Supramolecular phospholipids–polyphenolics interactions: The PHYTOSOME< sup>® strategy to improve the bioavailability of phytochemicals

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  See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/38095660 Supramolecular phospholipids-polyphenolicsinteractions: The PHYTOSOME (R) strategy toimprove the...  Article   in  Fitoterapia · November 2009 DOI: 10.1016/j.fitote.2009.11.001 · Source: PubMed CITATIONS 82 READS 302 4 authors , including:Ajay SemaltyHemwati Nandan Bahuguna Garhwal Univers… 77   PUBLICATIONS   833   CITATIONS   SEE PROFILE Mona B SemaltyHemwati Nandan Bahuguna Garhwal Univer… 67   PUBLICATIONS   775   CITATIONS   SEE PROFILE Federico FranceschiIndena S.p.A. 33   PUBLICATIONS   578   CITATIONS   SEE PROFILE All content following this page was uploaded by Ajay Semalty on 05 June 2015. The user has requested enhancement of the downloaded file.  This article appeared in a journal published by Elsevier. The attachedcopy is furnished to the author for internal non-commercial researchand education use, including for instruction at the authors institutionand sharing with colleagues.Other uses, including reproduction and distribution, or selling orlicensing copies, or posting to personal, institutional or third partywebsites are prohibited.In most cases authors are permitted to post their version of thearticle (e.g. in Word or Tex form) to their personal website orinstitutional repository. Authors requiring further informationregarding Elsevier’s archiving and manuscript policies areencouraged to visit:http://www.elsevier.com/copyright  Author's personal copy Review Supramolecular phospholipids – polyphenolics interactions: ThePHYTOSOME ® strategy to improve the bioavailability of phytochemicals Ajay Semalty a, ⁎ , Mona Semalty a , Mohan Singh Maniyari Rawat b , Federico Franceschi c, ⁎ a Department of Pharmaceutical Sciences, H.N.B. Garhwal University Srinagar (Garhwal), India b Department of Chemistry, H.N.B. Garhwal University Srinagar (Garhwal), India c Research and Development Laboratories, Indena S.p.A. (Settala), Italy a r t i c l e i n f o a b s t r a c t  Article history: Received 20 October 2009Accepted in revised form 3 November 2009Available online 14 November 2009 The poor and/or erratic oral bioavailability of polyphenolics can be improved using thePHYTOSOME ®1 delivery system, a strategy that enhances the rate and the extent of solubilizationinto aqueous intestinal  󿬂 uids and the capacity to cross biomembranes. Phospholipids show af  󿬁 nityfor polyphenolics, and form supramolecular adducts having a de 󿬁 nite stoichiometry. This articlereviews the preparation and characterization of PHYTOSOME ® complexes and their activity invarious medicinal (cardiovascular, anti-in 󿬂 ammatory, hepatoprotective, anticancer) and cosmetic(skin aging) realms of application.© 2009 Elsevier B.V. All rights reserved. Keywords: FlavonoidBioavailabilityPHYTOSOME ® Herbal drugsPhospholipid complex Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3072. Physical and chemical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3073. Methods of preparation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3084. Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3084.1. Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3084.2. Thermal gravimetric analysis (TGA)/differential scanning calorimetry (DSC). . . . . . . . . . . . . . . . . . . . . 3085. Biological pro 󿬁 le of PHYTOSOME ® adducts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3095.1. Cardiovascular properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3095.2. Anti-in 󿬂 ammatory properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3095.3. Anti-aging properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3105.4. Hepatoprotective properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3105.5. Anticancer properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3125.6. Weight management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3136. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Fitoterapia 81 (2010) 306 – 314 ⁎  Corresponding authors. Semalty is to be contacted at Department of Pharmaceutical Sciences, PB No.-32, H.N.B. Garhwal University Srinagar (Garhwal)-246174,India. Franceschi, Indena S.p.A., via Don Minzoni 6, 20090 Settala (MI), Italy. E-mail addresses:  [email protected] (A. Semalty), [email protected] (F. Franceschi). 1 PHYTOSOME ® is a registered trademark of Indena S.p.A. Milan, Italy.0367-326X/$  –  see front matter © 2009 Elsevier B.V. All rights reserved.doi:10.1016/j. 󿬁 tote.2009.11.001 Contents lists available at ScienceDirect Fitoterapia  journal homepage: www.elsevier.com/locate/fitote  Author's personal copy 1. Introduction For good bioavailability, natural products must have a goodbalance between hydrophilicity (for dissolving into the gastro-intestinal  󿬂 uids) and lipophilicity (to cross lipidic biomem-branes). Many phytoconstituents like polyphenolics have goodwater solubility, but are, nevertheless, poorly absorbed [1]becauseoftheirlargesize,incompatiblewithaprocessofpassivediffusion and/or their poor miscibility with oils and other lipids.As a result, the ability of   󿬂 avonoids to cross the lipid-rich outermembrane of small intestine enterocytes is severely limited.Water-soluble phytoconstituents (mainly polyphenolics)can be converted into a lipid-compatible molecular complexknown as PHYTOSOME ® . A PHYTOSOME ® is generally morebioavailable than a simple herbal extract due to its enhancedcapacity to cross the lipid-rich biomembranes and reachcirculation [2 – 5]. Phospholipids are small lipid moleculeswhere glycerol is bonded to two fatty acids, with the thirdhydroxyl, normally one of the two primary methylenes,bearing a phosphate group [6]. Phospholipids from soy,mainly phosphatidylcholine, are lipophilic substances andreadily complex polyphenolics. In this context, phosphatidyl-choline, the major molecular building block of cell mem-branesandacompoundmiscibleinbothwaterandinoil/lipidenvironments, is well absorbed orally, and has the potentialto act as a chaperon for polyphenolics, accompanying themthrough biological membranes [7].PHYTOSOME ® complexes were developed at Indena(Milan, Italy) in the late Eighties. Many popular standardizedherbal extracts [e. g.  Ginkgo biloba  L., grape ( Vitis vinifera  L.)seeds, milk thistle ( Silybum marianum  (L.) Gaertn), green tea( Camellia sinensis  (L.) O. Kuntze), ginseng ( Panax ginseng   C.A.Meyer), licorice ( Glycyrrhiza glabra  L.), horse chestnut(  Aesculus hippocastanum  L.),  Centella asiatica  (L.) Urban,olive ( Olea europea  L.),  Terminalia sericea  Burch. Ex. DC,  Amnivisnaga  (L.) Lam, turmeric ( Curcuma longa  L.) and hawthorn( Crataegus spp. )] are currently commercially available in thePHYTOSOME ® form (see Table 1). Flavonoids and terpenoidsfrom herbal extracts undergo different absorption pathwayswhenboundtophospholipids,andthisarticlereviewsvariousaspects and the latest trends of PHYTOSOME ® research,highlighting recent advances in their therapeutic potential. 2. Physical and chemical properties The  󿬁 rst PHYTOSOME ® generation was prepared bycombining selected polyphenols or polyphenol extractswith phospholipids in non-polar solvents [2], but, morerecently, a newer PHYTOSOME ® generation was developedusinghydro-ethanolicsolvents.Productsobtainedinthiswaycomplywithcurrent food speci 󿬁 cations[8,9], andexpandthePHYTOSOME ® ' potential from the pharma/cosmetic  󿬁 eld tothe health-food one.A PHYTOSOME ® is an amphiphilic substance with ade 󿬁 nite melting point, generally soluble in nonpolar solvents(whereitshydrophilicmoietyisnot),andmoderatelysolublein fats. The low solubility in aqueous media makes theformation of stable emulsions and creams possible (Fig. 1),improving the biopharmaceutical properties of both highlylipid insoluble and poorly water-soluble phytoconstituents.The PHYTOSOME ® formulation increases the absorption of active ingredients when topically applied on the skin [10 – 19],and improves systemic bioavailability when administeredorally [20 – 24]. In water medium, a PHYTOSOME ® will assumea micellar shape, forming a liposome-like structure. Funda-mentaldifferencesexit,however,betweenaPHYTOSOME ® anda liposome. In liposomes, the active principles are dissolved inthe central part of the cavity, with no possibility of molecularinteraction between the surrounding lipid and a hydrophilicsubstance. On the contrary, the PHYTOSOME ® complex cansomewhat be compared to an integral part of the lipidmembrane (Fig. 2), where the polar functionalities of thelipophilic guest interact via hydrogen bonds with the polarheadofaphospholipid(i.e.phosphateandammoniumgroups),forming a unique arrangement that can be evidenced byspectroscopy [10,11,18,25 – 28].Thus,IRandmulti-nuclearspectroscopicstudiesshowthataPHYTOSOME ® isnotamechanicalmixtureoftwoconstituents,  Table 1 Available PHYTOSOME ® complexes on the market. PHYTOSOME® and all other trademarks are owned by Indena S.p.A. Milan, Italy.Trade name Phytoconstituent complexed with phospholipid IndicationEscin  ß  -sitosterol Phytosome ® Escin  ß  -sitosterol from horse chestnut fruit Anti-oedemaSiliphos ® Silybin from milk thistle seed Hepatocyte protectionSilymarin Phytosome ® Silymarin from milk thistle seed AntihepatotoxicMeriva ™  Curcuminoids from turmeric rhizomeVirtiva ® Ginkgo 󿬂 avonglucosides, ginkgolides, bilobalide from  Ginkgo biloba  leaf VasokineticGinkgoselect ® Phytosome ® Ginkgo 󿬂 avonglucosides, ginkgolides, bilobalide from  Ginkgo biloba  leaf VasokineticGinselect ® Phytosome ® Ginsenosides from  Panax ginseng   rhizome Skin elasticity improver, adaptogenicLeucoselect ® Phytosome ® Polyphenols from grape seed Antioxidant, capillarotropicCentella Phytosome ® Triterpenes from  Centella asiatica  leaf Cicatrizing, trophodermic18  ß  -glycyrrhetinic acid Phytosome ® 18  ß  -glycyrrhetinic acid from licorice rhizome SoothingCrataegus Phytosome ® Vitexin-2 ″ -O-rhamnoside from Hawthorn  󿬂 ower AntioxidantGinkgo biloba Dimeric FlavonoidsPhytosome ® Dimeric  󿬂 avonoids from  Ginkgo biloba  leaf Lipolytic, vasokineticGinkgo biloba Terpenes Phytosome ® Ginkgolides and bilobalide from  Ginkgo biloba  leaf SoothingSericoside Phytosome ® Sericoside from  Terminalia sericea  bark root Anti-wrinklesGreenselect ® Phytosome ® Polyphenols from green tea leaf Prevention of free radical-mediated tissuedamages and weight managementVisnadex ® Visnadin from  Amni visnaga  umbel VasokineticPA 2  Phytosome ® Proanthocyanidin A 2  from horse chestnut bark Anti-wrinkles, UV protectant307  A. Semalty et al. / Fitoterapia 81 (2010) 306  –  314  Author's personal copy but a speci 󿬁 c complex between a hydrophilic guest and alipophilic hostcharacterized byspeci 󿬁 c dipolar interactions,inaccordance with the spectroscopic differences between aPHYTOSOMEandamechanicalmixtureofitstwoconstituents. 3. Methods of preparation APHYTOSOME ® ispreparedbycomplexingapolyphenolicphytoconstituent or mixture with a phospholipid. Dependingon the product, mass ratios in the 1:1.5 – 1:4 are observed.Various preparation methods for a PHYTOSOME ® [3,8,9,12 – 16,19,29 – 33] and the resulting complex can be differentdepending on the protocol employed. Thus, the phospholipidcomplex of curcumin [34] prepared in an aprotic solvent [35] showed remarkable differences from the one prepared in aprotic solvent [8], and three different silybin – phospholipidcomplexeshavebeenreported.Twoofthemwerepreparedinaprotic solvent [Silipide (IdB 1016) [30], a pharma-gradePHYTOSOME ® whichhasbeenextensivelycharacterized[27],and Siliphos ® ], while a third silybin – phospholipid complexwas obtained in protic solvents [32]. Different phospholipidsafford different complexes, as found for  G. biloba  extracts,whose PHYTOSOME ® extract with phosphatidylserine com-plex is known as Virtiva ® , while the standard phosphatidyl-choline complex is known as Ginkgoselect ® PHYTOSOME ® )[31]. 4. Characterization 4.1. Spectroscopy Complexation and molecular interactions between phy-toconstituents and phosphatidylcholine in solution havebeen studied by  1 H-NMR  [2,8,10,25 – 27],  13 C-NMR [2,8,10,27],  31 P-NMR, [8 – 10] as well as by IR spectroscopy[18]. Complex formation is associated with changes of chemical shift and line broadening of some characteristicsignalsinNMRspectraandwithappearanceofnewbandsinIR spectra. 4.2. Thermal gravimetric analysis (TGA)/differential scanning calorimetry (DSC) Detection and measurement of thermal effects such asfusion, solid – solid transitions, glass transitions, loss of solvent, and decomposition, can be used to characterize asolid PHYTOSOME ® .TheTG/DTanalysesoftwocomplexesandthemechanicalmixtures of phytoconstituentand phospholipidcomponentsare reported in Fig. 3 [36]. The DT pro 󿬁 le of SilymarinPHYTOSOME ® (green solid line in Fig. 3a) shows anendothermic peak with a maximum at about 173 °C, cor-responding to a ca. 3% weight loss, and a less intense andbroader endothermic signal with a maximum at about148 °C. The TG pro 󿬁 le (blue solid line in Fig. 3a) of somePHYTOSOME ® adducts shows an initial loss on drying below100 °C (about 4%), and a massive weight loss starting atabout 175 °C due to degradation. The TG/DT pro 󿬁 les of thephytoconstituent/phospholipid mechanical mixture(dashed lines) show two broad endothermic peaks, the 󿬁 rstonewithamaximumatabout146 °Candcorrespondingto a weight loss of ca. 2%, and the second one at about 167 °Cwithalossofweightofca.3%followedbythemassiveweightloss expected for degradation. Fig. 3b shows the TG/DTpro 󿬁 le of Ginkgoselect ® PHYTOSOME ® and the one of aGinkgoselect ® /phospholipid mechanical mixture. The DTpro 󿬁 le of the PHYTOSOME ® (green solid line in Fig. 3b)shows only an endothermic peak with a maximum at about179 °C,linkedtoaweightlossofabout2%.Conversely,theTGpro 󿬁 le(bluesolid line) showsaninitiallossondryingbelow100 °C(about2%)andamassiveweightlossstartingatabout180 °C due to degradation. Fig. 1.  Electron-microscopic examination of lyophilized microdispersion of Ginselect ® PHYTOSOME ® 0.1% in water. Magni 󿬁 cation 1×4000. Fig. 2.  Major difference between liposome and PHYTOSOME ® .308  A. Semalty et al. / Fitoterapia 81 (2010) 306  –  314