Review Article Pharmacosomes: An Emerging Novel Vesicular Drug Delivery...

Hindawi Publishing CorporationISRN PharmaceuticsVolume 2013 Article ID 348186 10 pageshttpdxdoiorg1011552013348186

Review ArticlePharmacosomes An Emerging Novel Vesicular Drug DeliverySystem for Poorly Soluble Synthetic and Herbal Drugs

Archana Pandita and Pooja Sharma

Nanomedical Research Centre ISF College of Pharmacy Ferozepur GT Road Ghal Kalan Moga Punjab 142001 India

Correspondence should be addressed to Archana Pandita zyeshthasandygmailcom

Received 2 July 2013 Accepted 1 August 2013

Academic Editors F-R Chang J V de Julian-Ortiz J Lee and H Mucke

Copyright copy 2013 A Pandita and P Sharma This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

In the arena of solubility enhancement several problems are encountered A novel approach based on lipid drug delivery systemhas evolved pharmacosomes Pharmacosomes are colloidal nanometric size micelles vesicles or may be in the form of hexagonalassembly of colloidal drug dispersions attached covalently to the phospholipid They act as befitting carrier for delivery of drugsquite precisely owing to their unique properties like small size amphiphilicity active drug loading high entrapment efficiency andstability They help in controlled release of drug at the site of action as well as in reduction in cost of therapy drug leakage andtoxicity increased bioavailability of poorly soluble drugs and restorative effects There has been advancement in the scope of thisdelivery system for a number of drugs used for inflammation heart diseases cancer and protein delivery along with a large numberof herbal drugs Hence pharmacosomes open new challenges and opportunities for improved novel vesicular drug delivery system

1 Introduction

Thenovel drug delivery system has been exploited a lot in thepast few decades and attention is also being paid to furtherdevelop this system The two ideal requirements for a systemto be novel are

(1) drug delivery at a predetermined rate and for pre-determined span of time

(2) conveying the active entity to the target site

At this point of time there is no such system that can fulfilall these requirements So a lot of efforts are required toaccomplish them using novel approaches These goals arebeing achieved by concentrating attention either on drugdistribution by unifying drug into a carrier systemmodifyingmolecular drug construct or by restraining drug release inthe bioenvironment to ascertain assigned distribution profileNovel drug delivery attempts to minimize the side effects andmaintain relatively unvarying and potent levels of drug inthe body The carriers or chemical derivatization may help tolocalize the drug action spatially in diseased tissue or organ oradjacent to it [1] Among the different pharmaceutical carriers

(Figure 1) the vesicular carriers are extremely organizedassemblies of bilayers of lipid that may be single or concentricin nature formed when the building blocks (amphipathic)of these bilayers encounter water [2] The clinical use ofmany drugs particularly chemotherapeutic agents is limitedbecause of their narrow therapeutic window [1] So the novelapproaches in drug delivery serve as a helping hand to achieveall these imperative goals

The advantages of novel drug delivery system includes [2]

(1) incorporation of therapeutic dose at controlled rate

(2) sustaining drug concentration within an optimalrange

(3) optimum dose at right time and at right location

(4) relationship between maximum efficacy and the doseof drug

(5) minimizes adverse or toxic effects

(6) freedom from frequent dose intake

(7) improved patient compliance

2 ISRN Pharmaceutics

Cellular

Polymeric

Macromolecular

Pharmaceutical carriers

Particulate

Figure 1 Different types of pharmaceutical carriers

2 Vesicular Drug Delivery System

Vesicular drug delivery system is one of the systems that canimprove the bioavailability of the drug and the reductionin toxicity by drug targeting to the specific site Binghampioneered the biologic origin of vesicular systems in 1965 andhence named them Bingham bodies [3] As a consequence alarge account of vesicular systems like liposome [4] noisome[5] and pharmacosome [6] came into existence As the drugreaches directly to the site of action there is a reduction indrug toxicity and no conflicting effects are seen

3 Advantages of Vesicular System [7]

(1) It is an efficient method for reducing the drug toxicityand targeting it to the site of action

(2) It is capable of consolidating hydrophilic andhydrophobic drugs

(3) It helps to reduce the expense of treatment(4) It improved bioavailability of poorly soluble drugs(5) It sustained release by receding the time of drug

elimination of rapidly metabolizable drugs(6) It overcomes the complications regarding stability

solubility and degradation of the drug(7) It acts as drug reservoir by encapsulating the drug

and overcoming the problems of conventional dosageforms

(8) These carriers correspond to the structure and func-tion of biomolecules and hence are biocompatible andbiodegradable

The properties of the vesicle depend on its varying configu-ration composition shape entrapment apparent charge andconcentration ldquoThe vesicular carrier systems have observed anumber of applications in various fields (Figure 2)rdquo All thosepreparations that load the drugs passively like microemul-sions or carriers that are temperature pH or magneticallysensitive consequently lead to less drug loading and leakageof the drug in formulation [8ndash11]

Some vesicular system associated problems are shown inFigure 3 [2 12]

Themajor complications that arise withmost of the drugsare their poor solubility that results in poor bioavailabilitybecause the rate of absorption as well as the extent of drug

absorbed depends on solubility of the drug For this purposeGordon Amidon and his collaborators in 1995 introduceda classification system for the drugs based on their solubilityand permeability called the Biopharmaceutics ClassificationSystem (BCS) [13] There are four classes according to thissystem Class I drugs substances showed high permeabilityand high solubility Class II drugs showed high permeabilityand low solubility Class III drugs exhibited low perme-ability and high solubility whereas Class IV drugs showedlow permeability and low solubility So dissolution was alimiting factor of Class II and Class IV drugs accordingto BCS system [14] The rate of drug release depends onthe intrinsic solubility which in turn relies on the size ofparticles structural order of the drug derivatized form ofthe drug and so forth So a number of concepts have beenapplied to enhance the solubility of such poorly solubledrugs like size reduction solubilising in a surfactant formingdrug derivative that is water-soluble conversion of liquidmedications into dry free flowing powders changing solidstate of the drug and forming solid dispersion and complexeswith agents for example metals cyclodextrin [15]The use oflipids as carrier based systems has recently shown to improvethe solubility of drugs that are poorly soluble in water as theincrease in solubility will result in enhanced bioavailabilityThe lipid nanoparticles have the property to adhere likethe gastrointestinal tract and once they adhere they canrelease the drug at appropriate site of action Solid lipidnanoparticles and nanolipid carrier systems have been usedfor the purpose [16 17] Another technique for improvingsolubility using complexation of the drug with phospholipidshas demonstrated enhancement in absorption along withthe permeation of lipid-complexed drug molecule [11 18]Development in the field of vesicular system has led to drugtargeting sustained release and reduction in toxicity of thedrugs [19] Owing to the advantages associated with thepharmacosomes it will be a landmark in the field of vesiculardrug delivery system

4 Pharmacosomes

Pharmacosome may be defined as a neutral molecule pos-sessing both positive and negative charge water-loving andfat-loving properties and an optimum ratio of polyphenolwith phospholipids in a complex formThe drugs are presentin a dispersion form in these lipoidal drug delivery sys-tem conjugated by electron pair sharings and electrostatic

ISRN Pharmaceutics 3

Vesicular carrier systems

Immunology Membrane Diagnostic Genetic engineering

Figure 2 Applications of vesicular carrier systems

Liposomes

Expensive preparation

Deterioration of lipids by oxidation

Settling of vesicles in suspension

Drug leakage from vesicles

Niosomes

Shelf life of aqueous suspension limited due to aggregation leaching or hydrolysis of entrapped drug

Time consuming inefficient and instable

Transfersomes

Expensive

Chemically unstable due to oxidative degradation

Lack of purity of natural phospholipids

Lack of pureness of crude phospholipid

Figure 3 Complications with various vesicular systems

forces or by forming a hydrogen bond with lipids [20]Pharmacosome is derived from theword ldquoPharmakonrdquowhichmeans drug and ldquosomardquo meaning carrier It means a vesicularsystem in which the drug is associated with the carrierTheselipid conjugated vesicles may exist as colloidal nanometricsize micelles vesicles or may be in the form of hexagonalassembly enjoying a functional hydrogen atom banking uponthe architecture of the complex The drug molecule witha free carboxylic or functional hydrogen atom like amino

hydroxyl groups is converted to an ester with the help ofthe hydroxyl moiety of the lipid resulting in the formationof a prodrug A spacer chain may or may not be used forthis purpose The prodrug possesses both hydrophilic andlipophilic properties Despite these properties prodrugs havethe capability to reduce interfacial tension increase the areaof contact and hence improve bioavailability They aid thedeportation through the cell membrane cell wall and tissuesIf the concentration is increased beyond a level it may existin an intermediate state between liquid and crystal [21] Oncontact with water these prodrugs assemble into a single ormultiple layers resulting in the formation of pharmacosomesThis system is developed by keeping the surface propertiesas well as the bulk properties of the drug-lipid conjugate inconsideration [11]

41 Salient Features of Pharmacosomes [31]

(a) The physical and chemical traits of the conjugatecontrol the stability of the whole system

(b) As they consist of both water-loving and fat-lovingproperties they have an ease of passing through thecell membrane walls or tissues either by the actionof endocytosis or exocytosis

(c) The rate of degradation relies on size nature offunctional group present in the drug molecule fattyacid chain length in lipids presence or absence ofspacer All these factors can be varied to optimize invivo pharmacokinetic behaviour

(d) They can be administered via topical oral extra- orintravascular route

42 Materials for Pharmacosomes [21 32 33] The followingcomponents may be utilised for the preparation of pharma-cosomes (Table 1)

5 Preparation of Pharmacosomes

Initially for the formation of pharmacosomes there is a needof drug-lipid conjugate For this purpose the salt form ofthe drug is converted into the acidic form to expose thefunctional hydrogen atom to form a complex The aqueoussolution of the drug is acidified extracted using chloroformand subsequently recrystallised Then equimolar phospho-lipid concentration is taken and dissolved in an organic


Table 1 Components of pharmacosomes

Component Requirement

Drugs Functional hydrogen atom from aminocarboxyl or hydroxyl group that can be esterified

Solvents High purity volatile and intermediate polarity

Lipid Phospholipids-phosphoglyceride orsphingolipids

solvent which is then evaporated under vacuum at a definitetemperature The complex is then collected as a dry residueafter placing it in a dessicator overnight

Generally two methods are followed for the preparationof pharmacosomes They areas follows

51 Solvent Evaporation Technique

(a) Hand-shaking method In this technique the drug-lipid conjugate is mixed with an organic solventwhich under the conditions of vacuumdeposits a thinfilm on the walls of round-bottom flask and yieldsa vesicular suspension when hydrated with aqueousmedium

(b) Rotary evaporator

52 Ether-Injection Technique In this technique the drug-lipid complex is dissolved in an organic solventThis mixtureis then slowly injected into a heated aqueous agent result-ing in the formation of vesicles The state of amphiphilesdepends on the concentration When the concentration isless amphiphiles introduce a monomer state but as theconcentration is increased variety of structures may beformed that is round cylindrical disc cubic or hexagontype Mantelli and collaborators studied the comparativeeffect of prodrug of diglyceride with a standard surfactantdodecylamine hydrochloride on the interfacial tension Itwas concluded that above the critical micellar concentrationlong cylinders were observed in hexagonal arrangement andprodrug exhibited liquid-crystalline phase exhibiting largemolecular structures [11 22 23]

53 Other Approaches

(a) Another approach for producing pharmacosomes isto incorporate a hydrophobic drug into a polymerfabricated from a glycol and aspartic acid derivativeresulting in formation of a biodegradablemicelle drugconjunct Being a water soluble monomeric conjunctof drug the chances of precipitation of drug ondilution are reduced [11 34]

(b) A modified technique involving diluted lyotropicliquid crystals of amphiphilic drugs was used by Goy-mann and collaborators for developing fenoprofendrug based pharmacosomes [11 35]

Despite these conjugations drug can also be markedto glyceride-containing groups where the amphiphilic

molecules can be dispersed spontaneously [11 36] Singhand Jain formulated ldquovesicular constructsrdquo with the help ofstoichiometric concentrations of phosphatidylethanolaminealong with phosphatidylcholine and small amount of choles-terol to encapsulate antibiotic amoxicillin in aqueous domainwhich significantly enhanced cytoprotection [37]

Li and colleagues [38] studied the physicochemicalproperties of puerarin and its lipid conjugate prepared bytraditional method like solvent evaporation freeze thawingand particle size reduction technique along with technologyof super-critical fluid Puerarin is an isoflavone used in con-ditions like high temperature aches diabetes heart diseaserespiratory infections like measles and bowel disturbanceslike diarrhoea Initially the conjugate was prepared by addingsolution of both phospholipid and drug in the reactionvessel at a pressure of 100 bar and a temperature maintainedat 38∘C which was then left for approximately 3 hoursFor the complete removal of residual solvent the flow ofcarbon dioxide was regulated at 25mLmin The complexesprepared by using the SCF technology demonstrated morerapid dissolution and better particle size and morphology

6 Characterisation of Pharmacosomes[2 11 21 32 33 39]

61 Complex Determination With the help of FTIR spec-trum the formation of the complex or the conjugate canbe determined by correlating spectrum observed in complexsample with that of discrete constituents and also with theirmixture

62 Stability of Pharmacosomes Correlating the spectrumof complex at various points of time in the solid statewith spectrum of a dispersion in water consisting of smallparticles once the product has been lyophilized is used toevaluate the stability of the system

63 Scanning Electron MicroscopyTransmission ElectronMicroscopy These techniques can be utilised for studyingthe surface order of pharmacosomes The purity grades ofthe lipid being used and few variables observed duringoperation (method of preparation vacuum assigned androtational speed) alter the shape and size of pharmacosomesPharmacosomes are formed of greasy nature if preparedusing lower purity grades of lipids resulting in large aggregateformation and those fabricated using lipids of more than90 purity grade show susceptibility to degradation due tooxidation which affects complex stability So 80 puritygrade is the commonly used phospholipid grade

64 Solubility The modification in solubility caused bycomplexation can be evaluated using shake-flask techniqueIn this technique the organic phase that is 1-octanol andaqueous phase that is buffer solution at appropriate pHconsisting of drug-phospholipid conjugate are consortedand after constant shaking equilibrium is maintained at atemperature of 37∘C for 1 dayThe aqueous phase is separated


Table 2 Therapeutic applications of drugs incorporated in pharmacosomes [22 23]

Drugs ResultsAmoxicillin Enhanced protection of cells treatment of peptic ulcers in male ratsBupranolol hydrochloride Augmented lymphatic transport and affect intraocular pressureCytarabin Biological activity was enhancedDermatan sulphate Biological activity was enhanced and improved bioavailabityPindolol diglyceride Plasma concentration improved up to three to five foldsTaxol Biological activity was enhanced

and then concentration is determined using UV or HPLCtechnique

65 Drug-Lipid Compatibility Differential scanning calori-metry is a thermoanalytical technique utilised to determinedrug-lipid compatibility and their interactions if any Thethermal response is studied using separate samples andheating them in a sample pan which is closed The nitrogengas is purged and the temperature is maintained in a definiterange with a specific heating rate

66 Crystalline State Measurement The crystalline nature ofdrug can be determined using X-ray diffraction techniqueThe tube voltages and tube current can be regulated in theX-ray generator Copper lines may be used as the sourceof radiation The scan angle can be regulated The overallcombined intensity of all reflection peaks is projected by areaunder curve of X-ray powder diffraction pattern that specifiesthe specimen attributes

67 Dissolution Studies Dissolution studies in vitro are doneusing various models available for the purpose The resultsare assessed on the basis of apprehended activity of the activeconstituents therapeutically

7 Advantages of Pharmacosomes [11 40 41]

(a) Membrane fluidity does not control the release rateas the drug is covalently bound The release rate isaffected by the transition temperature of conjugate

(b) The release of the drug from pharmacosomes ishydrolysis based which includes enzymatic hydrol-ysis also After absorption their rate of degradationrelies on the size nature of functional group fatty acidchain length and presence or absence of spacer chain

(c) As the carrier is covalently bound there are nochances of drug leakage

(d) Being amphiphilic in nature it can incorporatehydrophilic as well as lipophilic drugs

(e) Entrapment efficiency is quite high and predeter-mined because of covalent linkage of drug and carrierIt remains unaffected by the volume of inclusion

(f) Unlike liposomes there is no need to remove theunentrapped drug

(g) There is a reduction in transferexchange of phospho-lipids and low solubility is envisaged by high densitylipoproteins

(h) The bioavailability of drugs that are poorly soluble isimproved

(i) They targeted delivery to the site of infection

(j) They reduced cost of therapy

(k) Reduction in adverse effects and toxicity

71 Advantages of Pharmacosomes over Other Vesicular Sys-tems [11 32 33 42 43]

(a) They are less tedious and time consuming thanliposomes

(b) The process of drug release is hydrolysis rather thanbilayer diffusion surface desorption or degradationas in case of liposomes

(c) Unlike liposomes the entrapment efficiency of phar-macosomes remain unaffected by the volume ofinclusion

(d) The membrane fluidity of pharmacosomes is depen-dent on conjugate phase transition temperature anddoes not affect the release rate of pharmacosomes dueto covalent binding of drug and lipid However incase of liposomes drug release and system stabilityare governed by membrane fluidity which in turn isdependent on lipid composition

(e) There is no drug leakage or sedimentation due tocovalent binding of the drug to the carrier

8 Limitations of Pharmacosomes [12]

(a) A compound can be synthesised depending on theamphiphilic nature

(b) They require superficial as well as mass drug-lipidinteraction

(c) Covalent type of bond is required to restrict drugleakage

(d) Pharmacosomes are susceptible to get fused aggre-gate or hydrolyse by chemicals on storage


Table 3 Various Phytosomes of different herbal constituents

Phytosomes Phytoconstituent complexed Indication

Silybin phytosome Silybin Nutraceutical hepatoprotective and antioxidant forskin

Ginkgo phytosome 24 ginkgo flavonoids Lipolytic vasokinetic and slowing aging process

Green Tea phytosome Epigallocatechin gallate Provides nutrition anticancer and nutraceutical andprevents systemic oxidation

Olive oil Polyphenols Prevents oxidation inflammation and elevated lipidlevels

Grape Seed Procyanidins Protects heart provides nutrition capillarotropic andprevents systemic oxidation

Haw thorn phytosome Flavanoids Protects heart and provides nutrition antihypertensiveCentella phytosome Terpenoids Venous disorders and skin disordersEchinacea Echinocytes Provides nutrition and improves immunityGinseng phytosome Ginsenosides Provides nutrition and improves immunityLicorice phytosome 18 120573-glycyrrhetinic acid Relieving effectBoswellia phytosome Boswellic acid Reduction in inflammationCrataegus phytosome Vitexin-210158401015840-O-rhamnoside AntioxidantEscin phytosome Escin 120573-sitosterol Antioedema

Ginkgoselect phytosomeGinkgoFlavonglycosides ginkgolides andbilobalide

Improved blood circulation

Ginkgo biloba terpenes Ginkgolides bilobalide Relaxing and calmingCurcumin phytosomes Curcuminoids Anti-inflammatoryPA2 phytosome Proanthocyanidin A2 Antiageing protection against UVResveratrol phytosome Resveratrol rhizome AntioxidantSericoside phytosome Sericoside bark root AntiageingVisnadex Visnadin VasokineticLeucoselect phytosome Procyanidolic oligomers Systemic antioxidant antidiabetic cardioprotective

Mirtoselect phytosome Anthocyanoside Antioxidant to manage blood vessels of retina andvenous insufficiency

Sabalselect Alcohol fatty acid and sterol groups Protects heart and prevents enlargement of cancerousas well as noncancerous prostate

Polinacea phytosome Echinacosides and HMWpolysaccharides Immunomodulator

Lymphaselect phytosome Extracts of lymphaselect roots and barks Chronic venous disorders and insufficiency of lowerlimbs

9 Applications of Pharmacosomes

(a) Pharmacosomes demonstrate a wider stability profileand greater shelf life

(b) Pharmacosomes have the capacity to augment drugabsorption and its transport Using response surfacedesign Yue et al [44] and colleagues optimised theformulated geniposide pharmacosomes and exam-ined their attributes The ratio of phospholipid todrug temperature of reactionmixture and concentra-tion of drug were found to be 3 50∘C and 55mgmLrespectively

(c) Pharmacosomes can improve the rate of permeationby improving the membrane fluidity The transitiontemperature of vesicles in the form of vesicles andmicelles might pose an evident effect on vesicular

interaction with biomembrane hence improving thetransfer of drug across membrane

(d) Khare [45] demonstrated the prominent effect of cas-cade fusion system of pharmacosomes at appropriatetemperature on drug targeting in an organism byapplying heating and cooling phenomenon on tissues

(e) Pharmacosomes have achieved a new level by enhanc-ing therapeutic effects of several drugs (Table 2) likepindolol derivative taxol bupranolol acid derivativecytarabin amoxicillin dermatan sulphate and soforth [31 44 46]

(f) Pharmacosomes the amphiphilic lipid vesicular sys-tem can be used for the development of novel oph-thalmic dosage forms Amphiphilic prodrug formspharmacosomes when diluted with tear [47] and


Table 4 Various patents related to phytosomes

Research Innovation Patent number ReferenceOlive extracted from leaves or fruits complexedwith phospholipids Improved bioavailability EP1844785 [24]

Ginkgo biloba derivatives for treatment ofasthma and allergy Asthma and allergy treated EP1813280 [25]

Cosmetic and dermatological composition forthe treatment of aging or photodamaged skin

Development of a topical skin treatmentcomprising a substance that stimulates collagensynthesis

EP1640041 [26]

Use of thymosin for skin treatment and woundhealing

Use of thymosin 120573-4 for the treatment of skinand repair of wound US20070015698 [27]

Isoflavone characteristics Solubility colour taste and textural attributesimproved WO2004045541 [28]

A herbal pant extract based antioxidant forcirculatory and adiposity issues Antioxidant treatment of circulatory problems EP1214084 [29]

Saponin phospholipid complex along withcosmeceutical and pharmaceuticalcompositions in them

High lipophilicity improved bioavailabilitypharmaceutical dermatologic and cosmeticadvantages

EPO283713 [30]

modify corneal drug transport and release profile[48]

(g) Pharmacosomes have greater degree of selectivity foraction on specific target cells Raikhman et al [49]described pharmacosomes as building particles capa-ble in the transport of biologically active substancesincluding nucleic acids and proteins

(h) Semalty and colleagues [21] studied the develop-ment of pharmacosomes of aceclofenac and evaluatedthem A higher drug content was 9188 (ww) for1 1 aceclofenac phospholipid complex and 8903(ww) for 2 1 aceclofenac phospholipid complexThesolubility was higher in case of aceclofenac pharma-cosomes than aceclofenac Moreover the drug releaseover 4 hrs of dissolution study was only 6869 incase of free aceclofenac while it was 7978 for1 1 aceclofenac pharmacosome and 7617 for 2 1aceclofenac pharmacosomes for the same span oftime

(i) Semalty et al [50] studied the development ofdiclofenac pharmacosome and it was found that solu-bility was enhanced in pharmacosomes (221120583gmL)as compared to diclofenac (105120583gmL) Drug releasewas also improved from 604 of diclofenac to 878of diclofenac pharmacosomes after 10 hrs of disso-lution study Observed drug content of diclofenacpharmacosomes was 962 plusmn 1

(j) Han and colleagues [51] optimized the prepara-tion of 20(S)-protopanaxadiol pharmacosomes andobserved the encapsulation efficiency of pharmaco-some which was 8084 plusmn 053 for a diameter of1001 nm and 7276plusmn063 for the diameter of 1173 nm

(k) Ping et al [41] prepared didanosine pharmacosomesusing tetrahydrofuran injection method and studiedthe in vivo behaviour in rats It was found thatpharmacosomes may be a potential delivery system

for prolonged effects in targeted tissues and livertargeting

(l) Zhang et al [52] using central composite design reg-ulated pharmacosomes of 3101584051015840-dioctanoyl-5-fluoro-21015840-deoxyuridine and observed good targeting effi-ciency of pharmacosomes in vivo and improved drugpotential to pass through blood brain barrier

(m) Yi-Guang et al [53] prepared acyclovir pharmaco-somes and observed that the plasma proteins inblood absorbed pharmacosomes and interfered withthe interactions of erythrocytes and hence reducedhaemolytic reaction

(n) Semalty et al [33] prepared aspirin-phospholipidcomplex (1 1 molar ratio) and observed the enhancedbioavailability of aspirin and reduced gastrointestinaltoxicity

10 Phytosomes A Novel Drug DeliverySystem for Herbal Drugs

Pharmacosomes are also commonly known as phytosomesconsisting of drug-phospholipid complexes (see Supplemen-taryMaterial available online at httpdxdoiorg1011552013348186 Figure S1) and having herbal active ingredient [5455]

101 Properties of Phytosomes [56ndash60]

(1) Phytosomes may be defined as a conglomerate ofa herbal drug and lipids like soya lecithin thatare developed using stoichiometric ratios of lipidand the herbal constituent in a particular solventThe spectroscopic analysis explained the interactionbetween the polar functional groups of substrate andphosphate as well as ammonium groups of polarhead of phospholipid by forming hydrogen bond


Here the phytoconstituent gets anchored with phos-pholipid polar head It therefore amalgamates withmembrane For example in case of phosphatidyl-choline and catechin complex there is a formation ofhydrogen bond between hydroxyl group in phenolsof the flavones moiety and phosphate group of phos-phatidylcholine When the nuclear magnetic studieswere performed for the complex and compared withpure precursors there was no change in fatty acidchain signals It suggested that the active principle gotenclosed into two long chains aliphatic in natureThisresulted in a lipophilic envelope that shields the polarphase of phospholipid as well as the constituent [57]

(2) Based on pharmacokinetic as well as pharmaco-dynamic trials performed in animals as well ashuman beings phytosomes are known to improve thebioavailability and absorption of herbal extracts ascompared to noncomplexed ones [58]

(3) Phytosomes are lipophilic in nature having a definitemelting point free solubility in nonpolar solventsand moderate solubility in fats

(4) There are some elementary differences between lipo-somes and phytosomes otherwise they also adapt amicellar construct on treating with water

102 Merits [61ndash65]

(1) Phytosomes improve the bioavailability and stabilityprofiles by improving drug absorption to the intesti-nal tract as compared to unbound phytoconstituent aswell as forming a stable complex with phospholipids

(2) Phytosomes can be used for liver targeting as theyincrease the solubility in the bile salts

(3) There is a reduction in drug dose due to betterabsorption of active phytoconstituents

(4) PC gives a synergistic hepatoprotective effect withphytosomes besides acting as a carrier

(5) Phytosomes may be used in cosmetic industry due totheir improved skin penetration andhigh lipid profile

11 Applications of Phytosomes [57 59 66ndash70]The phytosomes may be used for the development of severalherbal extract (Table 3) complexes to provide beneficialeffects using natural products

12 Patented TechnologiesRelated to Phytosomes

A number of herbal extract complexes have been developedand are being patented (Table 4) to solve the issues thatrestrict the use of herbal products

13 Conclusion

Vesicular systems are the emerging carrier systems in thepharmaceutical industry Despite having disadvantages ofgetting fused aggregated they still serve as a vital tool fortargeting ans sustained drug release With the improvementin spacer groups and linkages further drug fate and biologicalactivity may be modified Yet greater efforts are requiredtowards exploring the mechanism of action and investigatingnonbilayer phases Hence pharmacosomes have immensepotential in improving the drug delivery in case of bothnatural and synthetic active constituents Current researchtrends include cellular targeting using different approacheslike PEGylation biotinylation and so forth

Conflict of Interests

The authors certify that there is no conflict of interests withany financial organisation regarding thematerial discussed inthe paper

Acknowledgment

The authors are highly thankful to ISF College of PharmacyMoga for their immense support and contribution to makethis work successful

References

[1] J L Patel and P D Bharadia ldquoA review on pharamacosomes asa novel vesicular drug delivery systemrdquo WJPR vol 1 pp 456ndash469 2012

[2] K De Pintu and De Arnab ldquoPharmacosomes a potential drugdelivery systemrdquo International Research Journal of Pharmacyvol 3 pp 102ndash105 2012

[3] S Saraf R Rathi C D Kaur and S Saraf ldquoColloidosomes anadvanced vesicular system in drug deliveryrdquo Asian Journal ofScientific Research vol 4 no 1 pp 1ndash15 2011

[4] A Deepti R Madhukar R Jukanti B Suresh P Reddy andV Reddy ldquoProvesicular drug delivery systems an overview andappraisalrdquo Scholars Research Library vol 2 no 4 pp 135ndash1462010

[5] R K Kesarvani A K Sharma M D Ayaz and R K Keshar-wani ldquoReview novel drug delivery system for the vesiculardelivery of drug by the niosomesrdquo International Journal ofResearch in Controlled Release vol 1 pp 1ndash8 2011

[6] S Gupta R P Singh P Lokwani S Yadav and S KGupta ldquoVesicular system as targeted drug delivery system anoverviewrdquo International Journal of Pharmacy and Technologyvol 3 no 2 pp 987ndash1021 2011

[7] R C Doijad D S Bhambere M V Fakirappa and N VDeshmukh ldquoFormulation and characterization of vesiculardrug delivery system for anti-HIV drugrdquo Journal of GlobalPharma Technology vol 1 no 1 pp 94ndash100 2009

[8] M J Pozansky and R L Juliano ldquoBiological approaches to thecontrolled delivery of drugs a critical reviewrdquo PharmacologicalReviews vol 36 no 4 pp 277ndash336 1983


[9] A D Bangham M M Standish and G Weissmann ldquoTheaction of steroids and streptolysin S on the permeability of phos-pholipid structures to cationsrdquo Journal ofMolecular Biology vol13 no 1 pp 253ndash259 1965

[10] U Ogihara T Sasaki H Toyama O M Sneha and H Nishig-ori ldquoRapid diagnostic imaging of cancer using radiolabeledliposomesrdquoCancer Detection and Prevention Journal vol 21 pp490ndash496 1997

[11] D Kavitha J Naga Sowjanya and S Panaganti ldquoPharmaco-somes an emerging vesicular systemrdquo International Journal ofPharmaceutical Sciences Review and Research vol 5 no 3 pp168ndash171 2010

[12] S Biju S Talegaonkar P Mishra and R Khar ldquoVesicular sys-tems an overviewrdquo Indian Journal of Pharmaceutical Sciencesvol 71 pp 421ndash427 2009

[13] M P Wagh and J S Patel ldquoBiopharmaceutical classificationsystem scientific basis for biowaiver extensionsrdquo InternationalJournal of Pharmacy and Pharmaceutical Sciences vol 2 no 1pp 12ndash19 2010

[14] R Lobenberg and G L Amidon ldquoModern bioavailability bioe-quivalence and biopharmaceutics classification system Newscientific approaches to international regulatory standardsrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol50 no 1 pp 3ndash12 2000

[15] J Varshosaz R Talari S AMostafavi and A Nokhodchi ldquoDis-solution enhancement of gliclazide using in situ micronizationby solvent change methodrdquo Powder Technology vol 187 no 3pp 222ndash230 2008

[16] V E Ivanov Y S Moshkovskii and L M Raikhman ldquoEffectsof temperature on cascade systems of pharmacosome fusionrdquoPharmaceutical Chemistry Journal vol 15 no 9 pp 619ndash6211981

[17] M K Rawat A Jain and S Singh ldquoIn vivo and cytotoxicityevaluation of repaglinide-loaded binary solid lipid nanoparti-cles after oral administration to ratsrdquo Journal of PharmaceuticalSciences vol 100 no 6 pp 2406ndash2417 2011

[18] NK JainAdvances in Controlled andNovel DrugDelivery CBS2003

[19] S Sharma L Mishra I Grover A Gupta and K Kaur ldquoLipo-somes vesicular system an overviewrdquo International Journal ofPharmacy and Pharmaceutical Sciences vol 2 no 4 pp 15ndash212010

[20] A Semalty M Semalty B S Rawat D Singh and M S MRawat ldquoPharmacosomes the lipid-based new drug deliverysystemrdquo Expert Opinion on Drug Delivery vol 6 no 6 pp 599ndash612 2009

[21] A Semalty M Semalty B S Rawat D Singh and M S MRawat ldquoDevelopment and evaluation of pharmacosomes ofaceclofenacrdquo Indian Journal of Pharmaceutical Sciences vol 72no 5 pp 576ndash581 2010

[22] A Steve ldquoLipophilic drug derivatives for use in liposomesrdquo USPatent S 534 499 (C1 S14-25 A61K3170) 1996

[23] I Taskintuna A S Banker M Flores-Aguilar et al ldquoEvaluationof a novel lipid prodrug for intraocular drug delivery effectof acyclovir diphosphate dimyristoylglycerol in a rabbit modelwith herpes simplex virus-1 retinitisrdquo Retina vol 17 no 1 pp57ndash64 1997

[24] F Franceschi and A Giori A Phospholipid Complex of OliveFruits or Leaves Extracts Having Improved BioavailabilityEP1844785 2007

[25] F Di Pierro Compositions Comprising Gingko Biloba Deriva-tives for the Treatment of Asthmatic and Allergic ConditionsEP1813280 2007

[26] T Doering A Traeger and M Waldmann-Laue Cosmeticand Dermatological Composition For the Treatment of Aging orPhotodamaged Skin EP1640041 2006

[27] E Bombardelli G F Patri and R Pozzi Complexes of SaponinsWith Phospholipids and Pharmaceutical and Cosmetic Composi-tions Containing Them EP0283713 1988

[28] H K Kleinman and A L Goldstein Treatment of skinand wound repair with thymosin beta-4 US Patent No-20070015698 2007

[29] H K Kleinman and A L Goldstein Treatment of skinand wound repair with thymosin beta 4 USPatentNo-20070015698 2007 KhareAB Soluble isoflavone compositionsWO2004 045541 2004

[30] G Merizzi An Anti-Oxidant Preparation Based on PlantExtracts for the Treatment of Circulation andAdiposity ProblemsEP1214084 2002

[31] M O Vaizoglu and P P Speiser ldquoPharmacosomesmdasha noveldrug delivery systemrdquo Acta Pharmaceutica Suecica vol 23 no3 pp 163ndash172 1986

[32] I P Kaur andMKanwar ldquoOcular preparations the formulationapproachrdquoDrug Development and Industrial Pharmacy vol 28no 5 pp 473ndash493 2002

[33] A Semalty M Semalty D Singh and M S M RawatldquoPreparation and characterization of phospholipid complexesof naringenin for effective drug deliveryrdquo Journal of InclusionPhenomena and Macrocyclic Chemistry vol 67 no 3 pp 253ndash260 2010

[34] M J Lawrence ldquoSurfactant systems their use in drug deliveryrdquoChemical Society Reviews vol 23 no 6 pp 417ndash424 1994

[35] C C Muller-Goymann and H-J Hamann ldquoPharmacosomesmdashmultilamellar vesicles consisting of pure drugrdquo European Jour-nal of Pharmaceutics and Biopharmaceutics vol 37 no 2 pp113ndash117 1991

[36] J S Valentino andN CWilliam Lymphatic Transport of DrugsCRC Press Boca Raton Fla USA 1992

[37] A Singh and R Jain ldquoTargeted Vesicular Constructs forcryoprotection and treatment of HPylori infectionsrdquo US Patent6576 625 2003

[38] Y Li D J Yang S L Chen S B Chen and A S C ChanldquoComparative physicochemical characterization of phospho-lipids complex of puerarin formulated by conventional andsupercritical methodsrdquo Pharmaceutical Research vol 25 no 3pp 563ndash577 2008

[39] E Bombardelli and M Spelta ldquoPhospholipid-polyphenol com-plexes a new concept in skin care ingredientsrdquo Cosmetics ampToiletries vol 106 pp 69ndash76 1991

[40] E P Goldberg Targeted Drugs Wiley Newyork 1983[41] A Ping Y Jin and C Da-wei ldquoPreparation and in vivo

behaviour of didanosinepharmacosomes in ratsrdquo Journal ofChinese Pharmaceutical vol 3 pp 227ndash235 2005

[42] S K P Rajapati S Kumar V K Sahu and G PrakashldquoProniosomal gel of flurbiprofen formulation and evaluationrdquoJournal of Drug Delivery andTherapeutics vol 2 no 1 pp 105ndash114 2012

[43] S P Vyas V Jaitely and P Kanaujia ldquoSynthesis and char-acterisation of palymitoyl propanolol hydrochloride auto-lymphotrophs for oral administrationrdquo International Journal ofPharmaceutics vol 186 no 2 pp 177ndash189 1999


[44] P-F Yue Q Zheng B Wu et al ldquoProcess optimizationby response surface design and characterization study ongeniposide pharmacosomesrdquo Pharmaceutical Development andTechnology vol 17 no 1 pp 94ndash102 2012

[45] A B Khare ldquoSoluble isoflavone compositionsrdquoWO2004045541 2004

[46] H A Lieberman M M Rieger and G S S Banker Pharma-ceutical Dosage Forms Disperse Systems Informa HealthcareLondon UK 1998

[47] BMMithalOcularDosage Forms Text Book of PharmaceuticalFormulations VallabhPrakashan New Delhi India 1997

[48] F La Torre and A P Nicolal ldquoAmikacin gel administration inthe treatment of peristomal dermatitisrdquoDrugs under experimen-tal and clinical research vol 24 no 3 pp 153ndash157 1998

[49] L M Raikhman Y S Moshkovskii and L A PiruzyanldquoPharmacosome concept a new approach to drug preparationrdquoPharmaceutical Chemistry Journal vol 12 no 4 pp 431ndash4341978

[50] A Semalty M Semalty D Singh and M S M Rawat ldquoDevel-opment and physicochemical evaluation of pharmacosomes ofdiclofenacrdquo Acta Pharmaceutica vol 59 no 3 pp 335ndash3442009

[51] M Han J Chen S Chen and X Wang ldquoPreparation andstudy in vitro of 20(S) protopanaxadiolpharmacosomesrdquo ChinaJournal of Pharmaceutics vol 35 pp 842ndash846 2010

[52] Z-R Zhang J-X Wang and J Lu ldquoOptimization of thepreparation of 3rsquo5rsquo-dioctanoyl-5-fluoro-2rsquo-deoxyuridine phar-macosomes using central composite designrdquo Yaoxue Xuebaovol 36 no 6 pp 456ndash461 2001

[53] J Yi-Guang A I Ping L I Miao and H Xin-Pu ldquoPreparationand properties of Acyclovir pharmacosomesrdquo Chinese Journalof Pharmaceuticals vol 36 no 10 pp 617ndash620 2005

[54] S Shalini andR K Roy ldquoPhytosomes an emerging technologyrdquoInternational Journal of Pharmaceutical Research and Develop-ment vol 2 pp 14ndash15 2010

[55] P Shivanand and P Kinjal ldquoPhytosomes technical revolution inphytomedicinerdquo International Journal of PharmTech Researchvol 2 no 1 pp 627ndash631 2010

[56] E Bombardelli and G Mustich ldquobilobalidephosphalipid com-plex their uses and formulation containing themrdquo US PatentNo EPO-275005 1991

[57] D Murray ldquoPhytosomes-increase the absorption herbal ext-ractrdquo httpdoctormurraycomphytosomes-herbal-support-increase-the-absorption-of-herbal-extracts

[58] C Marena and M Lampertico ldquoPreliminary clinical devel-opment of silipide a new complex of silybin in toxic liverdisordersrdquo Planta Medica vol 57 no 2 pp A124ndashA125 1991

[59] N S Chauhan R Gowtham and B Gopalkrishna ldquoPhyto-somes a potential Phytophospholipid carriers for herbal drugdeliveryrdquo Journal of Pharmacy Research vol 2 pp 1267ndash12702009

[60] N K Jain Controlled and Novel Drug Delivery CBS New YorkNY USA 1st edition 2005

[61] A Semalty M Semalty and M S Rawat ldquoThe Phytophospho-lipid complexes phytosomes a potential therapeutic approachfor hepatoprotective drug deliveryrdquoPharmacognosy Review vol1 no 2 pp 369ndash374 2007

[62] A D Kingom ldquoPharmacognosy in 21 st centuryrdquoThe Journal ofPharmacy and Pharmacology vol 53 no 2 pp 135ndash148 2001

[63] B Gabetta E Bombardelli and G Pifferi ldquoComplexes offlavanolignans with phospholipids preparation thereof and

associated pharmaceutical compositionsrdquo U S Patent no-4764508 1986

[64] E Bombardelli M Spelta R Della Loggia S Sosa and ATubaro ldquoAging skin protective effect of Silymarin-phytosomerdquoFitoterapia vol 62 no 2 pp 115ndash122 1991

[65] E Bombardelli A Cristoni and P Morazzoni ldquoPhytosomes infunctional cosmeticsrdquo Fitoterapia vol 65 no 5 pp 387ndash4011994

[66] S Sharma andM Sikarwar ldquoPhytosome a reviewrdquo Plant Indicavol 1 pp 1ndash3 2005

[67] S Bhattacharya ldquoPhytosomes emerging strategy in delivery ofherbal drugs and nutraceuticalsrdquo Pharma Times vol 41 no 3pp 9ndash12 2009

[68] S Bhattacharya ldquoPhytosomes the new technology for enhance-ment of bioavailability of botanicals and nutraceuticalsrdquo Inter-national Journal of Health Research vol 2 no 3 pp 225ndash2322009

[69] PM Kidd PHYTOSOMESHighly Bioavailable Plant Extractshttpwwwdockiddcompdf2LinksPhytosomeInd5 10 04pdf

[70] A Joshi S Chaturvedi and V Kumar Phytosomes-A Revolutionin Herbal Drugs Pharma Review Kongposh publications 2008

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


Cellular

Polymeric

Macromolecular

Pharmaceutical carriers

Particulate

Figure 1 Different types of pharmaceutical carriers

2 Vesicular Drug Delivery System

Vesicular drug delivery system is one of the systems that canimprove the bioavailability of the drug and the reductionin toxicity by drug targeting to the specific site Binghampioneered the biologic origin of vesicular systems in 1965 andhence named them Bingham bodies [3] As a consequence alarge account of vesicular systems like liposome [4] noisome[5] and pharmacosome [6] came into existence As the drugreaches directly to the site of action there is a reduction indrug toxicity and no conflicting effects are seen

3 Advantages of Vesicular System [7]

(1) It is an efficient method for reducing the drug toxicityand targeting it to the site of action

(2) It is capable of consolidating hydrophilic andhydrophobic drugs

(3) It helps to reduce the expense of treatment(4) It improved bioavailability of poorly soluble drugs(5) It sustained release by receding the time of drug

elimination of rapidly metabolizable drugs(6) It overcomes the complications regarding stability

solubility and degradation of the drug(7) It acts as drug reservoir by encapsulating the drug

and overcoming the problems of conventional dosageforms

(8) These carriers correspond to the structure and func-tion of biomolecules and hence are biocompatible andbiodegradable

The properties of the vesicle depend on its varying configu-ration composition shape entrapment apparent charge andconcentration ldquoThe vesicular carrier systems have observed anumber of applications in various fields (Figure 2)rdquo All thosepreparations that load the drugs passively like microemul-sions or carriers that are temperature pH or magneticallysensitive consequently lead to less drug loading and leakageof the drug in formulation [8ndash11]

Some vesicular system associated problems are shown inFigure 3 [2 12]

Themajor complications that arise withmost of the drugsare their poor solubility that results in poor bioavailabilitybecause the rate of absorption as well as the extent of drug

absorbed depends on solubility of the drug For this purposeGordon Amidon and his collaborators in 1995 introduceda classification system for the drugs based on their solubilityand permeability called the Biopharmaceutics ClassificationSystem (BCS) [13] There are four classes according to thissystem Class I drugs substances showed high permeabilityand high solubility Class II drugs showed high permeabilityand low solubility Class III drugs exhibited low perme-ability and high solubility whereas Class IV drugs showedlow permeability and low solubility So dissolution was alimiting factor of Class II and Class IV drugs accordingto BCS system [14] The rate of drug release depends onthe intrinsic solubility which in turn relies on the size ofparticles structural order of the drug derivatized form ofthe drug and so forth So a number of concepts have beenapplied to enhance the solubility of such poorly solubledrugs like size reduction solubilising in a surfactant formingdrug derivative that is water-soluble conversion of liquidmedications into dry free flowing powders changing solidstate of the drug and forming solid dispersion and complexeswith agents for example metals cyclodextrin [15]The use oflipids as carrier based systems has recently shown to improvethe solubility of drugs that are poorly soluble in water as theincrease in solubility will result in enhanced bioavailabilityThe lipid nanoparticles have the property to adhere likethe gastrointestinal tract and once they adhere they canrelease the drug at appropriate site of action Solid lipidnanoparticles and nanolipid carrier systems have been usedfor the purpose [16 17] Another technique for improvingsolubility using complexation of the drug with phospholipidshas demonstrated enhancement in absorption along withthe permeation of lipid-complexed drug molecule [11 18]Development in the field of vesicular system has led to drugtargeting sustained release and reduction in toxicity of thedrugs [19] Owing to the advantages associated with thepharmacosomes it will be a landmark in the field of vesiculardrug delivery system

4 Pharmacosomes

Pharmacosome may be defined as a neutral molecule pos-sessing both positive and negative charge water-loving andfat-loving properties and an optimum ratio of polyphenolwith phospholipids in a complex formThe drugs are presentin a dispersion form in these lipoidal drug delivery sys-tem conjugated by electron pair sharings and electrostatic





Liposomes





Niosomes



Transfersomes

Expensive



























53 Other Approaches







































































EP1640041 [26]







EPO283713 [30]





























13 Conclusion




Acknowledgment


References














































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





Liposomes





Niosomes



Transfersomes

Expensive



























53 Other Approaches







































































EP1640041 [26]







EPO283713 [30]





























13 Conclusion




Acknowledgment


References














































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of













53 Other Approaches







































































EP1640041 [26]







EPO283713 [30]





























13 Conclusion




Acknowledgment


References














































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





























































EP1640041 [26]







EPO283713 [30]





























13 Conclusion




Acknowledgment


References














































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of















13 Conclusion




Acknowledgment


References














































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

Review Article Pharmacosomes: An Emerging Novel Vesicular Drug Delivery...

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Transcript of Review Article Pharmacosomes: An Emerging Novel Vesicular Drug Delivery...