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Indian Journal of Experimental BiologyVol. 45, February 2007, pp. 133-159

Review Article

Self-assembled surfactant nano-structures important in drug delivery: A review

Giddi Hema Sagar 1 M A Arunagirinathan 1 & Jayesh R Bellare 1, 2* 1Department of Chemical Engineering and 2School of Biosciences and Bioengineering,

Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India

Role of self assembled structures as a vehicle is significant over the years. Their applications have been found for allroutes of drug delivery. These micro and nano structures are containers loaded with drugs, ideal for targeted and sustainedrelease of the drug. Drug efficacy depends on the drug loaded into the vehicle, temperature, drug solubility, pH, releasecharacteristics, additives and most significantly, the vehicle morphology. This in turn suggests that the same vehicle cannot

be used with high efficiency for all types of drugs and locations where the drug delivery has to take place. The status ofvarious self assembled structures and their applications in drug delivery is reviewed in this communication.

Keywords : Drug delivery, Self assembled surfactant nano-structure

There are several important packaged drugs which usemicro and nano structures for packaging and ascarriers for drug delivery. The reason to do so is thatthese drugs have specific controlled, sustained andtargeted release characteristics. This is especially truein the case of poorly soluble drugs 1, which have poor

bioavailability when given orally. In parenteralapplications, higher concentrations can readily beachieved with the use of harsh solvents. The surface

area in contact affects the performance of the drugdelivered at the location. Increased surface areaimproves the solubility and therefore bioavailability.

Nanostructures have many important applications in bioengineering 2 and in particular for healthcaretechnologies. Nanostructures demonstrate tremendousincrease in surface area, which suggests that lesscompact structures and shapes may increasecirculation time and additionally favour solubility.Equilibrium structures, which have considerable

potential as delivery systems 3 for a wide range ofdrugs have been thoroughly explained in this review.

The so-called bottom-up design of biomimeticassemblies 4 and the rules that could be used to predictthe type of self-aggregated structure formed frommolecules in a controlled fashion is covered.

This paper focuses on the numerous micro andnano structures formed when a surfactant is dissolvedin various solvents that are already in use as drug

vehicles, and also those, which could be used asfuture generation vehicles. We have encompassed thevarious types of drugs that can be delivered usingconventional vehicles as well as new ones. Liquidcrystalline structures 5 as well as newer structures arealso considered as potential drug delivery vehicles.Structural characteristics of drug vehicles are alsodiscussed in general. Despite the extensive usage ofconventional liposomes 6, micelles and niosomes as

vehicles over the years, these vehicles were not foundto be useful for certain drugs in terms of bioavailability, specific targeting and controlled drugrelease. This opened the doors for exploring a newergeneration of self-assembled structures. An attempthas been mad here to explore the origin, conditionsand different sources of lipids which lead to theformation of these newer nano and microstructuresviz. ribbon, cochleate, high axial ratio microstructures(HARM), icosahedra, cage like, fiber, ribbon,

bicontinuous structures and myelin figures.

Surfactant: Self assembly and bio-degradabilityAmphiphiles are anionic, cationic, zwitterionic or

nonionic depending on the charge accumulated by thehead group. In solution, they self assemble to form avariety of structures which are of the order of nano tomicro ranges. Self-assembled structures change insize and shape with concentration, pH, temperatureand pressure. Surfactants self assemble by bottomup approach into various structures governed bycritical packing number as discussed later. Thedifferent characterization methods used to determine

________________Correspondent author

Phone: +91-22-25767207Fax: +91-22-25726895E-mail: [email protected]

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INDIAN J EXP BIOL, FEBRUARY 2007134

the structural properties of self assembled structuresare briefly elucidated.

Surfactants and lipids associate into a variety of

structures in water and other solvents. In a moreconcentrated system, the equilibrium structure isdetermined by the strength of the interaction forces

between the aggregates. Thus the forces that holdamphiphilic molecules together in micelles and

bilayers are not strong covalent or ionic bonds but theweaker van der Waals forces, hydrophobicattractions, hydrogen bonding and screenedelectrostatic interactions. Surfactants are well knownto exert a wide range of biological, pharmacologicaland toxicological effects on the human body 7, hencenonionic surfactants like Span, Tween series andCremaphor and zwitterionic lipids are preferred.

The biodegradability of a surfactant is governedonly by the molecular structure of the hydrophobicgroup 7. However, the poly (glycol) hydrophilic groupthat is present in ethoxylate nonionic surfactants alsoinfluences biodegradability. For a given alkyl chainlength, the larger the number of glycol units, theeasier the biodegradation. Surfactants must provideeasy and continuous access in all sorts of environmentand physical and chemical conditions likely to beexperienced during storage and in physiological use.In addition, surfactant vehicles must be resistant tomicrobial degradation and also suitable for cellgrowth and propagation 8.

Packing parameterA general method to predict the type of self

assembled structure that will form considers the

packing parameter 9 of the monomer. A collection ofmonomers of the amphiphile arranges itself to formthe most favoured structures. The packing parameter

depends on the optimal area of the head group a 0, volume of the hydrocarbon chain or chains v, and theextended hydrocarbon chain length l0.

Packing number =00la

v (1)

Packing number stresses the importance of thesurfactant head group in predicting the shape and sizeof the aggregates, however, the surfactant tail alsocontrols the equilibrium aggregate formation.Although the equilibrium area is directly dependenton the interaction parameter of the head group and notthe tail, the tail plays a role in the formation ofspherical micelles, rod like micelles and spherical

bilayer vesicles. In cylindrical aggregates, the taildoes not affect the equilibrium area; its influence can

be seen only in sphere-to-rod transitions 11 . A simpletechnique to control the packing parameter is bychanging the tail length or varying the head groupwith the use of ions. The value of the dimensionless

packing number determines whether the aggregateswill form spherical micelles, non-spherical micelles,vesicles, bilayers or inverted micelles (Fig 1), as theseaggregates will have minimum free energy. The

packing parameter can be calculated for lipidmixtures 12, and this is a reasonable model foradditives like cholesterol which when added to

phosphatidylcholine, forms complementary molecularshapes like bilayer structures 13.

Fig. 1 Classification of structures formed by Self-association of lipids based on critical packing parameter. Modified from [13].

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SAGAR et al .: NANO-STRUCTURES IMPORTANT IN DRUG DELIVERY 135

Characterization methodsThe most fundamental characterization includes

structure and surface morphology comprising size,

size distribution, shape and three-dimensionalstructure. For surfactant structures that are small(below the resolution of an optical microscope),special techniques are needed. Furthermore, suchstructures are naturally labile and occur within acertain concentration regime, temperature and phase.The mode of characterization of nano andmicrostructures is broadly classified into direct andindirect techniques (Table 1). These techniques play akey role and each of them has its constraintsdepending upon the type of sample and the sourcefrom which it is derived i.e. synthetic, biological or

polymers.Optical and confocal microscopy 14 are relatively

free from artifacts, handling is convenient, sample preparation is easy, and are therefore preferred for biological samples. Transient structures and dynamicchanges in the system can also be studied. However,these techniques are not useful for determining thesize, shape and internal morphology of structures inthe sub-micron range. For this, Scanning ElectronMicroscopy (SEM) 15, Transmission ElectronMicroscopy (TEM) 16 and Cryo-TEM are to be used.Care should be taken that the sample is prepared

properly 17. Temperature sensitive samples that cannot be studied at room temperature can be done usingcryo mode by Cryo-TEM and Cryo-SEM 18. In these

techniques, a sample is vitrified in the fully hydratedcondition, by plunging it into liquid ethane, propaneand nitrogen from a temperature-controlledenvironment. By Cryo-TEM, the structuralcharacteristics of liquid and gel samples are very wellevaluated. Indirect methods of characterization basedon the scattering of light or X-rays are dynamic lightscattering (DLS) 19, small angle X-ray scattering(SAXS) 20 and its analogue, small angle neutronscattering (SANS), all of which reveal informationlike particle size distribution and polydispersitythrough model-dependent interpretations.

MicellesThe self association of an amphiphile occurs in a

stepwise manner with one monomer added to theaggregate at a time. For long chain amphiphiles, theassociation is strongly cooperative and results in largeaggregate micelles. Many thermodynamic transportand spectroscopic properties show a distinct change in

behaviour at critical micelle concentration (CMC).Micelles have a closely spherical shape in a wideconcentration range above CMC, with no markedchange in shape until the surfactant solubility limit is

Table 1 Characteristics of characterization techniques used for surfactant micro and nano structures

TechniqueCharacteristics Size (min)

(nm)Sample Source Comments

Optical microscopy Dynamic systems , livesamples 200

Liquid and solid Halogen lamp Direct technique withoutartifacts, needs no sample

preparationConfocalmicroscopy

Dynamic systems , livesamples and structures insingle plane

200Biological,fluorescence, liquidand solid samples

Laser Direct method,fluorescent samples,without artifacts

Scanning electronmicroscopy

(SEM)

Surface and externalmorphology 2

Solid Electron beam Sample preparation iseasy, sample thickness

does not matterTransmissionelectron microscopy(TEM)

Internal, externalmorphology and diffraction

patterns, crystallography 0.2

Solid Electron beam Specific Sample preparation needed,sample thickness lessthan 100 nm

Cryo-TEM Internal, externalmorphology and diffraction

patterns, crystallography0.2

Liquid Electron beam Temperature sensitivesamples

Dynamic lightscattering (DLS)

Particle size and sizedistributions 3

Gels, liquid suspensionand solid dispersion

Laser Indirect technique,Sample in suspension

SAXS Size, shape, and subatomicordering 5

Liquid, solid, gel and biological

X-ray Indirect technique,sample preparation iseasy.

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reached, where a liquid crystalline phase generallyseparates out. The formation of rod like micelles anddisk shaped micelles is promoted by increasing the

surfactant concentration.Non-polymeric micelles

Micelles are association polymers that are indynamic equilibrium with monomers present insolution. This makes their structure tuneable withchanges in the surrounding medium. The cooperativeself association of an ionic amphiphile like sodiumdodecyl sulphate (SDS) into micelles results inaccumulation of charge on the aggregate structure.This leads to the binding of counter ions to themicelle by electrostatic attraction. Counter ionrepulsion, its influence on hydration and subsequent

solubilization has a marked influence on micelle size,shape and further phase transformation.

The combination of an ionic surfactant such asSDS with drugs such as diphenhydramine, tetracaineand amitriptyline in aqueous media, has been studiedextensively to investigate their sustained releasecharacteristics 20. A mixture of SDS and positivelycharged drugs forms similar phases as traditionalcatanionic mixtures. This may prove useful inobtaining functional controlled-release systems whenusing gels as drug carriers 21. Drug solubility andstability were studied for camptothecin (CPT) by

incorporating it in SDS (Fig 2), and then transformed by passing it through an agarose gel preparation. Thesolubility of CPT in water increased when SDS wasadded beyond CMC, while the drugs solubility in themicelles increased due to their hydrophobic core 22.The release characteristics of the drug from the gelslowed down with SDS concentration. The effect ofSDS concentration was also studied for

polyquaternium-4 (PQ-4) which is used in cosmeticsand topical drug delivery applications 23.

Nonionic surfactants like Tween 80 (Polysorbate80) and Cremophor-EL are used for controlled andtargeted delivery (Table 2). The low solubility of the

drug itazigrel was addressed using Tween 80 micellesas vehicle. On the co-administration of esterase withthe formulation, the absorption of itazigrel across theepithelial surface was accelerated 24. On addingCremophor-EL in ethanol and water to the drug

paclitaxel, the formulation reduced the average bladder tissue concentration but could not alter therate of penetration across the bladder wall 25.Polymeric micelles

The new generation drug delivery micelle consistsof biodegradable polymers prepared from diblockcopolymers and tri block copolymers. Block

copolymers consist of soluble and insoluble segmentscovalently bonded together. Diblock copolymers havetwo segments, one soluble and the other insoluble.Block copolymers in suitable solvents self assembleinto a wide variety of structures with well-definedmorphology, well-defined size, and with high stabilityto harsh environments. The soluble segment of the

block forms the corona and the insoluble segmentaggregates into a dense micellar core, as observed formost diblock copolymers.

Triblock copolymers which are composed of three polymeric blocks in which one of the polymer block

is soluble whereas the remaining two are insoluble ortwo are soluble and other is insoluble in the solvent.They exhibit a wide variety of nano- andmicrostructures. The structures observed for tri blockcopolymers include onion like micelles 26, pHsensitive micelles, janus micelles 27, vesicles, and shellcross linked micelles 28. Polymeric micelles preparedfrom block or tri-block polymers mostly consist ofPEO or PEG as the hydrophilic part. The othersegments of the block are varied based on property

Fig. 2 (a) Cryo-TEM pictures of micelles for catanionic mixture of cationic drug tetracaine and anionic surfactant SDS. Scale barindicates 200 nm [21] (b) Fluorescence microscopy image of drug Triametrene, loaded into worm like micelles [50] (c) Fluorescencemicroscopy images of pH-sensitive liposomes loaded with HPTS/DPX and infected J774 cell after 7 min post incubation [84].

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like biodegradable and non toxic behaviour for drugdelivery. Polyethylene glycol (PEG) and polyethyleneoxide (PEO) are polymers having an identical structure

except for chain length and end groups, and are themost commercially important polyether. Polyethyleneglycol refers to an oligomer or polymer with lowmolecular weight while polyethylene oxide is used forhigher molecular weights formulation.

Polymeric micelles are based on the hydrophobicgroup or its derivatives with various combinations ofhydrophilic groups (Table 2). The one mostcommonly used is (PEG) with phosphatidylethanolamine (PE) 29, methoxy (PEG)-b-poly (5-

benzyloxy-trimethylene) 30 for the delivery ofanticancer drugs. The amount of protein adsorption onmicelles was found to be minimal and insignificant

but micelles as a delivery vehicle may be stronglyinfluenced by protein- drug interaction 29. Variousspecific targeting ligand molecules can be attached atthe surface of the lipid micelles for targeting cells 30.Copolymers have the ability to assemble intonanoscopic structures in an aqueous environment.This makes them potential candidates for genetransfection. Also there is no cytotoxicity and thetransfection efficiency increases three fold in cells 31.

Copolymers form micelles spontaneously.Significantly, they increase the solubility of poorlywater-soluble drugs. The release of drugs from

micelles can be achieved by using a hydrophobicagent. A sink can be developed for the drug, therebyincreasing as much as ten times the total amount of

drug incorporated into polymeric micelles32

. For agastric acid formulation of copolymer micelles, a twofold increase in maximum concentration wasachieved, which made it a good candidate for oraldrug delivery 33. Feasibility studies were conductedwith copolymers prepared from polyethylene oxide(PEO) and PPO (propylene oxide) as a vehicle: a

block of PEO-b-PPO showed pseudo zero-ordersustained release for percutaneous administration. Adecrease in the apparent permeability and apparentrelease flux 34 of the drug were observed, whereas the

biological activity of the drug incorporated micelleswas fully retained for copolymer of poly(caprolactone) and PEO 35. With poloxamer and poly(epsilon-caprolactone) vehicles for amphotericin B(AMB), a decrease in the antifungal activity of AMBwas observed, but this apparent disadvantage can besimply overcome by usage of higher concentrations ofdrug or higher doses of formulations owing toreduced toxicity 35.

pH sensitive micellesIn recent years, micelles formed from amphiphilic

block copolymers have been receiving attention as potential drug carriers. The size of these nano

Table 2 Drugs delivered using micelles

Surfactant Size(nm) Drug Ref. Non-Polymeric micellesSDS

200Diphenhydramine, TetracaineCamptothecin (CPT)

21,22,23

Polysorbate 80 - Itazigrel 24Cremophor - Paclitaxel(PTX) 25Polymeric micellesMethoxy(PEG)-block-poly(5-benzyloxy-trimethylene carbonate) 96 Ellipticine 29PEG-PE(phosphatidyl ethanolamine) Anticancer drug 30Poly(p-Dioxanone-co-L-Lactide)-b-PEG(PPDO/PLLA-b-PEG) 60-165

Beta-glactosidase 31

PEG-block-poly(phenylalanine) (PEG-b-PPhe) 55-58 Paclitaxel (PTX) 32Methoxy(PEG)-poly(caprolactone/trimethylene carbonate) DiblockPEG-poly(CL-co-TMC) -

Risperidone 33

Poly(ethylene oxide)poly(propylene oxide)Poly(ethylene oxide) (PEOPPOPEO)

50Fentanyl 34

Poly(caprolactone) b-poly(ethylene oxide)(PCL-b-PEO)

500600Dihydrotestosterone (DHT) 35

Poly(epsilon-caprolactone) (poloxamer 188),Poly(ethyleneoxide)-b-PBLA (PEO-b-PBLA) -

Amphotericin B (AMB) 36, 37

Cholesterol end capped PEO -b-Cholesterol-end-capped poly(2-methacryloyloxyethyl phosphorylcholine) (CEPEO-b-CMPC) -

Adriamycin (ADR) 38

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containers, typically between 20-100 nm, was shownto be effective not only in avoiding renal exclusionand reticuloendothelial uptake, but also enabled them

to selectively target certain tissues such as tumors,due to their high vascular permeability. In addition, ithas been proposed that cells via an endocytosis

process may take up such assemblies. Rapid changesin the micelle structures with change in pH ascompared to conventional polymers made them workeffectively under acidic and alkaline condition.

An important issue determining the effectiveness ofa micellar drug carrier is the ability to control the timeover which drug release takes place, and to trigger thedrug release at a specific location and time. Themildly acidic pH encountered in tumors, inflamma-

tory tissues ( pH 6.8), different compartments of cells( pH 56) and blood plasma ( pH 7.4) provides a potential means of drug release when the drug reachesthese targets. Bond cleavage occurs when pHsensitive micelles are subjected to acidic and neutralconditions 39. This has enhanced the understanding of

polymers constituting the micelle. There have beenrelatively few copolymer-based systems describedthat are capable of releasing their contents undermildly acidic conditions. These systems havetitrateable groups as the basis for their pH sensitivity.Table 3 shows pH sensitive micelles reported in the

literature for various drugs.

There is a need for a carrier which can have atriggered release in endosomes ( pH 6.0), as well as

provide a high concentration of the drug in the

console and nucleus, for multi-drug resistant cancercells. A block copolymer of PolyHisPoly (1-histidine)-b-PEG, poly (lactide) (PLLA)-b-PEG) 39,PEO-b-poly (ally glycidyl ether (PAGE) and triblock

polymer PLLA-PEO z-PLLA poly (l-lactide)-b-poly(2-ethyl-2-oxazoline)-b-poly (l-lactide) 41 micelles was

prepared for delivery of the drug DOX doxorubicin.Polymer micelles are stable at pH 7.4, whereas below7.0 they are unstable. In order to decrease theworkable pH range, the micelles were prepared usingfolate. DOX doxorubicin loading was found to be 75-85%, which was three times greater as compared tofree DOX, with faster 39 drug release at pH 5.0 than at

pH 7.4 40, 41 .

Micelles have also been prepared from selfassembling amphiphlic block polymers that aresensitive to pH changes. The block copolymers weresynthesized containing an oligomer of PEG (polyethylene glycol) or derivatives of the PEG hydrophilicgroup which is coupled with a hydrophobic polymer.Diblock polymers prepared for drug delivery include

poly ethylene glycol-poly aspartate hydrazone (PEG-PEH) 42, polyethylene glycol-phosphatidyl-ethanola-mine (PEG-PE) 43, and PEG- b-poly aspartic acid 44. It

was found that PCL (polycaprolactone)-PEG45

micelles could stably preserve drugs underTable 3 pH sensitive micelles and various drugs delivered

Surfactant Micelle size (nm), pH Drug Ref.

PolyHis-b-PEG-folatePoly(l-lactide)(PLLA)-b-PEG-folatePHSM/f, PHSM, PHIM/f and PHIM

55-70, pH 6.8 Doxorubicin (DOX) 39

PEO-b-(poly(allyl gly acidyl ether)(PEO-b-PAGE)

pH 5.0 DOX 40

Poly(l-lactide)-b-poly(2-ethyl-2-oxazoline)-b-poly(l-lactide)(PLLA-PEOB zB-PLLA)

150-400, pH 5.8

DOX 41

PEG-poly(aspartatehydrazone) pH 7.4 Adriamycin 42(PEG-PE)phosphatidylethanolamine 7-35 Anticancer drug 43PEG-b-poly(aspartic acid) 55 , pH 5.0 Dendrimerzinc porphyrin 44Poly(caprolactone)-poly(ethylene glycol)-PCL,PCL/PEG/PCL

100 Indomethacin 45

Ethyl methacrylate and tert-butyl methacrylate-PEGmethacrylate.

11-40, Acidic to basic Progesterone 46

Mono-methoxy (MPEG), poly (D,L-lactide) (PDLLA),sulfamethazine oligomer (OSM)

pH 7.2-8.4 Paclitaxel (PTX) 47

Pluronic P-105 pH 5.5 anthracyclin drug ruboxyl 48Terminally-alkylated(N-isopropylacrylamide) (NIPAM)copolymers

pH 5.7 Anticancer photo sensitizeraluminum chloride

phthalocyanine

49

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physiological conditions. For the anti tumor drugadriamycin, pH sensitive micelles was found to beoptimal drug vehicles in terms of functional and

structural properties for cancer therapy and forintractable cancers with limited vasculature 42.Micelles were prepared by varying the molecular

length of PEG in a PEG-PE conjugate, which led thesystem to form stable, long circulating micelles. Suchmicelles were found to be effective in accumulatingspecific, poorly soluble anticancer drugs at the tumorsite upon administration in mice 43. Micelles werefound to be stable for dendrimer zinc porphyrinincorporated in poly aspartic acid block in a salinesolution at a pH of 6.2 to 7.4. The high stability isthought to be due to hydrogen bonding in the micelle

core, which can be broken in the presence of urea,suggesting that drug release occurs in an acidic pH of544.

Another source for preparing block polymers isderivatives of poly ethylene oxide which are used forspecific drugs. In this technique, blocks are preparedusing ethyl methacrylate and tert -butyl methacrylateand hydrophilic poly (ethylene glycol) methacrylate 46

for in vitro release studies of progesterone. Theincrease in pH results in ionization of acidfunctionalities present in the polymer chains, which inturn enhances the release rate of the hydrophobic

drug. Mono-methoxy poly ethylene glycol (MPEG), poly (D, L-lactide) (PDLLA) and sulfamethazineoligomer (OSM) 47 biodegradable copolymers had alow CMC due to the strong hydrophobic nature.Block polymer micelles were pH sensitive due to theOSM transition from ionized to non-ionized state. The

block showed high encapsulation efficiency for paclitaxel and stability for two days. Since no organicsolvent is used in this formulation technique, it could

be an important tool for delivery of protein drugs andhydrophobic drugs.

Other formulations for preparing pH sensitive

micelles include using Pluronic P-105 which is adifunctional block copolymer with primary hydroxylgroups and non-toxic in nature. Anthracyclin drugruboxyl (Rb) accumulation took place in cell nuclei 48.The uptake of drug incorporated pluronic micelleswas increased by ultrasound in PBS solution ascompared to vesicles. A two fold increase in thefluorescence intensity of a test fluorescent label wasobserved at pH 7.4 than at pH 5.5, demonstrating the

pH sensitivity. Using alkylated N-isopropy-lacrylamide (NIPAM) copolymers and hydrophilic

vinyl pyrrolidone, cytotoxicity and localization intumors were enhanced; this also lowered the phasetransition pH of the copolymers without affecting the

onset of micellization49

.Worm like micelles

Polymeric spherical micelles have already provento be extremely useful for therapeutic applications.Worm like micelles, (also known as thread-likemicelles) (Fig. 2) could be used as they have a muchlarger core volume for encapsulation. They can flowreadily through nano pores 50 and circulate muchlonger than vesicles. One seemingly novel strategywould be to generate, spherical micelles fromdegradable worm micelles. The effect of adding analcohol ethoxylate nonionic surfactant (C 18E18) toaqueous solutions of a cationic surfactant, erucyl bis(hydroxyethyl) methyl ammonium chloride, wasobserved. This cationic surfactant has the ability toself-assemble into giant wormlike micelles in

presence of an electrolyte, such as KCl. In salt-freesolutions, the mixture of the two surfactants gave riseto spherical micelles 51. Addition of a nonionicsurfactant to the system is a way to control the lengthof worm like micelle.

Visualization of worm-like micelles can beachieved by fluorescence microscopy 50 afterincorporating fluorescent dyes in the micelle core 52.Increasing the molecular weight of the copolymersincreases both, the diameter of the worm-like micelles(from about 10 to 40 nm), as well as their stiffness.Some drugs may affect the bilayers and thereby affectthe resultant morphology of the micelle. For example,a long alkylboladiamine such as spermine disrupts thelipid bilayer by perturbing the local organization ofthe phospholipids. With increasing concentration ofspermine, worm-like micelles (WLM) that are formedinitially 53 transform finally to spherical (globular)micelles 54.

For drug delivery, worm-like micelles of modified

PEO were shown to be able to incorporate a range ofhydrophobic drugs in the core of the worm-likemicelles 55, and methods were provided to chemicallymodify the ends of the PEO blocks that make theworm-like micelles specifically bind to particularsurfaces and cells. Worm-like micelles were preparedwith blends of PEO-PLA (Poly lactic acid) and PEO-PEE (polyethylene) for the drug Triamterene. Theloading efficiency was in a range that does not give aninitial toxic burst of the drug 50. Worm-like micellescan encapsulate one or more active agents, which

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include drugs, therapeutic compounds, dyes, nutrients,sugars, vitamins, proteins, protein fragments, salts,electrolytes, genes or gene fragments, products of

genetic engineering, steroids, adjuvants, biosealants,gases, or ferro fluids. Polymeric worm micelles canachieve targeted delivery 52.

Disk shaped micellesA disc shaped micelle is thought to be composed of

a bilayer with its edge having a hemi cylindricalstructure. When the surfactant concentration isincreased, spherical micelles transform into diskshaped micelles. Bilayers with mixed catanionicsurfactants also exhibit disks in certain concentrationranges. When lecithin vesicles were solubilized inalkyl sulfate surfactants, small globular and mixedmicelles were observed at higher concentrations.However, a decrease in salt concentration results indisk shaped micelles 56.

As the PEG concentration was increased for 1, 2-distearoylphosphatidylcholine (DSPC), and 1, 2-dipalmitoylphosphatidylcholine (DPPC), initiallyliposomes were observed and then at 5 mol %, diskshaped micelles were seen. With a further increase inPEG concentration, spherical micelles were observed.Variation in temperature had little effect on theaggregate structure 57. Disk shaped micelles formed bynonionic surfactants are 12-60 micron in size whichenabled them for high encapsulation of the drugtimolol maleate. The formulation showed a sustainedactivity profile upon administration into the ocularcavity; however, systemic absorption was minimizedto a negligible level. These so-called discomes werefound to be promising for controlled ocularadministration of water-soluble drugs 58. It was foundthat large discoid structures existed under certainconditions of the phase, which when sonicated,

produced discoidal vesicles (discomes), accompanied by a slow increase in particle size of the dispersionimmediately after sonication 59.

Vesicles and liposomesVesicles prepared from phospholipids have been

widely investigated as drug delivery vehicles for awide variety of drugs. Here we have focused ondifferent types of liposomes, as vehicles for drugtransport, namely liposomes, pH-sensitive liposomes,magnetic liposomes, niosomes, proniosomes,

polyhedral niosomes and a dry formulation ofniosomes.

LiposomesLiposomes are bilayered closed structures made of

natural or synthetic surfactants, often lipids. They were

discovered in the mid 1960s(ref. 60) and originallystudied as cell membrane models. They have sincegained recognition in the field of drug delivery.Liposomes are described as lipid bilayers surroundingan aqueous space. They are classified based on thenumber of lipid bilayers surrounding the aqueous core.Liposomes are formed by the self-assembly of

phospholipid molecules in an aqueous environment.The amphiphilic phospholipid molecules form a closed

bilayer sphere in an attempt to shield their hydrophobicgroups from an aqueous environment, while stillmaintaining contact with the aqueous phase via thehydrophilic head group. The resulting closed sphereencapsulates aqueous soluble drugs within its centralaqueous compartment, or it encapsulates lipid solubledrugs within the bilayer membrane that forms the wall.Alternatively, lipid soluble drugs may be complexedwith cyclodextrin and subsequently encapsulatedwithin the liposome aqueous compartment. Theassociation of drugs with liposomes or theencapsulation of drugs within liposomes alters drug

pharmacokinetics. This phenomenon may be exploitedto achieve targeted therapies. It is necessary to alter thesurface of the liposome in order to optimize liposomaldrug targeting. Surfactant liposomes and vesicles havealso been used for respiratory distress syndrometherapy 61, 62 .

Multilamellar vesicles (MLV) consist of severallayers of lipid separated from one another by a layer ofaqueous solution. These vesicles are of the size rangefrom nanometers to microns. Small unilamellarvesicles (SUV) surrounded by a single lipid bilayer arein the size range of 20-60 nm, where as largeunilamellar vesicles (LUV) surrounded by a singlelipid layer are of nanometer to cell dimension. Over theyears phospholipids have played the role of vehicles fordrugs (Table 4). Several lipids have been used informulations, keeping in view that they have propertiessimilar to those of natural phospholipids. They areconsidered non toxic, biodegradable and non-immunogenic.

A series of biocompatible PEGylated amphiphiliccopolymers have been deduced, which have themicellization potential to form nano-sized micelles inan aqueous environment. This enabled them toincorporate hydrophobic drugs in micelles and thusregulate the release of the drug 63. Liposomes

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improved the therapeutic index with increaseddelivery of antibiotics to liver and spleen 64 andmacrophages 65. Halothane and chloroform mediated

formulations do not show a significant change in physicochemical properties 66. Studies for the releaserate of Azelaic acid conducted with formulations of

phospholipids with and without ethanol solutionindicated a more rapid release from ethosomal (withethanol) solution than with liposomal solution.However the trends were comparable with viscous

forms 67.Derivatives of phosphatidylcholine (PC) and the

source of PC affect drug release and loading. Soya-PC

based liposomes showed greater sensitivity comparedto dimyristoyl PC (DMPC). Vitamin-containing Soya-PC liposomes were found to be most compatible 68.Oral administration of mono phasic vesicles of egg-PC to rats substantially reduced or eliminated thegastric and intestinal ulceration normally associatedwith the ingestion of the drug 69. Similar to an egg-PC

Table 4 Liposomes as drug carrier

Surfactant/Additives Size (nm), pH Drug Ref.

Liposomes

Phosphatidylcholine(PC),Dioleoylphosphatidylcholine (DOPC) - Fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) 63

(PC)/ cholesterol (chol) - Ampicillin 64Phosphatidylcholine (PC) - Vancomycin, Teicoplanin 65PC/chol 200-300 AMPB(2-4'-amino-3'-methylphenyl

benzothiazole)66

Soya- PC 200-400 Azelaic acid (AA) 67Dimyristoyl(dm-PC), Soya-PC - Vitamin E 68Egg phosphatidylcholine (EPC) - Indomethacin 69EPC,Distearoylphosphatidylcholine(DSPC)

100 - 130 DOX 70

DSPC -chol- N-biotinoyldistearoyl phosphoethanolamine-alpha tocopherol

136 Avidin 71

EPC, Phosphatidylglycerol(PG),Dipalmitoylphosphatidylcholine (DPPC),

- Paclitaxel (Taxol), 2-succiny l,2-methyl pyridinium acetate

72

DPPC - Sugar Phosphates 73DPPC, Bile salt/cholesterol - Insulin 74,75DOPC, Dioleoylphosphatidylglycerol(DOPG)

- Lipophilic drug compound (RS-93522, dihydropyridine Ca 2+ channel

blocker)

76

Dioleoyl trimethylammonium propane,(DOTAP)-DOPC, DOPG-DOPC

600 Gene delivery 77

Fusogenic liposomes 300-380 Diphtheria toxin A (DTA) 78Tween80/Stearylalcohol, cholesterol,Span /Stearylalcholol, cholestrol

- Petrolatum 79

DC-6-14,O,O0-ditetradecanoyl-N-(alpha-trimethylammonioacetyl)diethanolamine chloride;Dioleoylphosphatidylethanolamine(DOPE)/chol, Cationic Gemini surfactant

100 Gene tranfer, DNA 81,83

DOTAP,DOPE, DC/Chol - Plasmid DNA 82DOPE: Cholesterolhemisuccinate(CHEMS)

380 Etanidazole (ETZ) 84

Triton X-100/Amylalcohol 100-200 Peptide and Oligonucleotide 85PC/CHOL 192-498 5-carboxyfluorescein (CF) 86

pH sensitive liposomes

CHEMS - Indomethacin 69EPC-CHEMS-T-80-OAlc 100, pH 5.0 Calcein 87DOPE:CHEMS 380, pH 8.5 Etanidazole (ETZ) 88PC-DDAB-CHEMS,PC-DDAB-CHEMS-Tween-80, DDAB-CHEMS-folate-PEG-PE

pH 4.0- pH 7.4 Calcein, Plasmid DNA 89

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formulation that was sterically stabilized and studiedin rats 70, it was found that sterically stabilizedcompounds were best suited for administration of

DOX. Liposomes from distearoyl PC was comparedwith biotin coated liposomes in an area where lymphnode targeting was desired. Aggregation of avidintook place for biotin coated liposomes 71. Cremophorand PEG coated liposomes have been used clinicallyfor the treatment of ovarian and breast cancer 72.

The effect of sugar phosphate mixtures on thetransition temperature of dehydrated dioleoyl-

phosphocholine (DOPC) formulations has beenevaluated. Sucrosephosphate mixtures provide aninteresting alternative to pure saccharide formulationsdue to their high glass transition temperatures and

their increased ability to maintain a low meltingtransition temperature in the presence of smallamounts of water 73. Surface coated liposomes wereinvestigated for oral drug delivery of peptide drugssuch as insulin. Liposomes prepared from DPPC-cholformulation which were coated with PEG had slowerrelease characteristics for insulin compared toconventional liposomes 74. When a mixture ofdioleoylphosphocholine (DOPC) anddioleoylphosphatidylglycerol (DOPG) was used as anintravenous drug carrier for a lipophilic drug, it

produced a physically and chemically stable

preparation that solubilized the drug76

. Liposomescomposed of cationic lipid and phospholipids werestudied as vehicles for gene delivery. The effect of thecationic lipid dioleoyl trimethylammonium propane(DOTAP) was studied on the physical properties ofliposomes such as their size and membrane domainstructure. It was found that DOTAP exerted asignificant effect on the acyl chain mobility of DPPCcontaining liposomes 77. Feasibility studies offusogenic liposomes as an effective antigen deliverysystem were reviewed 78. Fusogenic liposomes are

prepared by fusing conventional liposomes with an

ultraviolet inactivated sendai virus.The effect of two bases, vaseline and a white

petrolatum base, on drug release from liposomes wasstudied 79. The liposomes consisted of stearyl alcohol,cholesterol, Tween 80 and Span. Diffusion studiesrevealed that the drug release rate decreased 2.5 timeswhen liposomes were incorporated in vaseline as a

base. Liposomes have promising biocompatibility forgene delivery. In particular, cationic liposomes have

been found to be particularly effective 80. Ultrasoundtechnique for gene transfer is being used for using

cationic and neutral lipids. Using an ultrasoundfrequency of 1 MHz with the prepared formulations,transfection at intensity of 0.5 and with a duty factor

of 100 was demonstrated 81

. For plasmid DNA genetherapy, DOTAP-DOPE liposomes were found tohave myotoxicity which was independent ofconcentration 82.

pH sensitive liposomes pH sensitive liposomes can be used in treating

human diseases. However, it is important toemphasize that pH triggered release may not be

beneficial for all applications of drug delivery.Liposomes are mostly prepared from cationic, anionicor mixture of cationic and anionic surfactants(Table 4). pH sensitive liposomes exploit the acidicenvironment of tumors in order to triggerdestabilization of liposomal membranes and releasetheir contents. They release a larger proportion oftheir contents than non- pH sensitive liposomes. This

phenomenon is seen when the pH of the environmentdecreases from physiological pH of 7.4 to a pH

between 3.5 and 6.5. Liposomes are internalised bycells via the endocytotic pathway, and are exposed inthe endosome to a decreasing pH. Liposomes can betargeted to cells using appropriate ligands such asantibodies directed to epitopes on cells of interest.Many tumors tend to have a pH 5.8 to 6.5. It is

possible to make liposomes that are stable only at a pH 7.4 and unstable at other pH, they can be used fortargeted delivery. Liposomal drug formulations arehence preferred for targeting tumors which are moreacidic than the surrounding normal tissue, such astumors with pH of about 6.5 or less, and even

preferably around pH 6.It was also found that the tuneable pH-sensitive

liposomes composed of cationic and anionic lipidsmay be of utility in drug delivery applications. pHsensitive liposomes of hydroxypyrene-1,3,6-trisulfonic acid (HPTS)-p-xylene-bis-pyridinium

bromide (DPX) are shown in Fig 2. It is alsosuggested that the ability of cationic lipids to adoptinverted non bilayer structures when combined withanionic lipids, may be due to their ability of cationiclipids to facilitate the intracellular delivery ofmacromolecules 87. Low molecular weight drugsloaded in pH sensitive liposomes were designed forselective delivery to the cytoplasm of phagocyticcells. These combinations showed 72 % selectivitycompared to a free dose, thus enhancing the efficacyof poorly active molecules 88. Liposomes were also

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used in combination with non-steroidal anti-inflammatory drugs, and were found to have minimalgastrointestinal side effects 69. Catanionic surfactants

which are prepared by addition of Tween 80 to drugsused in anti-tumor therapy 88 and gene transfer, showedan improved stability at neutral buffer, and delayedthe release of calcein.

Magnetic liposomesMagnetic liposomes are prepared by adding

magnetic particles to the liposome formulation. Themagnetic particles themselves may be ferromagneticor superparamagnetic. They get magnetized byapplying an external magnetic field and can be usedfor targeted delivery to brain capillaries and forneurological disease. The effect of

phosphatidylcholine (PC) on the synthesis ofmagnetite nanoparticles and magnetoliposomes andtheir properties were studied 89. Immunomagneticliposomes prepared from lipid formulation of PC cholesterol in presence of dodecanal in the bilayersfacilitated the binding of antibodies to the surface ofthe liposomes 90. Magnetic liposomes incorporatedwith adriamycin showed greater antitumor activitywhen used under magnetic force, than mereintravenous administration of ADR solution andmagnetic ADR liposomes without the use of magneticforce. ADR administered as magnetic liposomeseliminated weight loss of hamsters, one of the sideeffects produced by ADR. Interestingly, magneticliposomes (without incorporated ADR) undermagnetic force also suppressed tumor growth 91.

A magnetic liposome formulation containing phosphatidylserine (PS), PC and cholesterol wasstudied with the model drug diclofenac sodium 93. Itshowed selective uptake with 5.95 fold increasecompared to free drug, and 7.58 fold increase incomparison to non-magnetic formulation, while RGD

peptide coated magnetic liposomes showed even better results 92 (Fig 3). Additionally, the formulationsignificantly bypassed liver uptake mediated byradiation and was helpful in controlled drugdelivery 93.

NiosomeThe success achieved with liposomal systems

stimulated the search for other vesicle formingamphiphiles, a system that could combine theadvantage of liposomes with the ability to increasemembrane permeability, low cost, greater stability,and ease of storage as compared to liposomes. Non-

ionic surfactants were among the first alternativematerials studied. A large number of surfactants havesince been found to self assemble into closed bilayer

vesicles which are used for drug delivery. Niosome formation requires the presence of anonionic amphiphile and an aqueous solvent.Stabilizers like cholesterol (CH), polyoxyethyleneether (Solulan C-24) stabilize formulations against theformation of aggregates by repulsive, steric andelectrostatic effects. A large number of niosomalformulations containing cholesterol with a little decyl

phosphate (DCP) incorporated in the bilayer werefound to prevent the aggregation of vesicles. Also theaddition of DCP to the formulation increased thesurface charge. Vesicles containing 100 % surfactanthave the highest entrapment efficiency for niosomes,

Fig. 3 Fluorescence microscopy image of T.S. of brain of albinorat after 4 h of administration of 6-carboxyfluorescein loaded: (a)RGD-coated magnetic liposomes; (b) RGD-coated non-magneticliposomes (600x) [92].

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but are least stable and readily release their contentsas compared to 1:1 molar ratio of cholesterol andsurfactant whose entrapment efficiency is less with a

stable formulation. In fact, preferred niosomeformulations (Table 5) consist of cholesterol andsurfactant in a 1:1 molar ratio.

The encapsulation efficiency can be modified bysurfactants containing different types of head groupshaving a higher gel to liquid crystalline phasetransition temperature. Several surfactants such assorbitan ester (Span), ethoxylated sorbitan ester(Tween) surfactants and sucrose esters are alreadywell established for use in formulations used for drugdelivery. Depending on the surfactant used in theabove series, the drug entrapment will vary because of

different Hydrophilic Lipophilic Balance (HLB). TheHLB scale which is a measure of surfactant solubilityin the solvent, ranges from 0.5 to 19.5.

Niosome size varies depending on the method of preparation. Preparation methods could be sonication,extrusion, sonication and filtration, micro fluidization,thin film hydration and high pressure homogenization.

Niosomes less than 60 nm in size was obtained when prepared with a micro fluidizer. Vesicle size isimportant for the target. Niosomes are said to have adesirable interaction with human skin when applied ina topical preparation. They improve the characteristicsof the horny layer of skin, both by reducingtransepidermal water loss and by increasing skinsmoothness by replenishing lost lipids. Niosomes

Table 5 Niosomes prepared from a range of surfactants and drug used for studies

Surfactant/Additives Size Drug Ref.

Niosomes

Nonionic surfactant 3.72 m Carboplatin (CBP) 94Tween 80 (polyethoxy sorbitan monooleate),Span 60( Sorbitan monostearate), Tween 20(polyethoxysorbitan monolaurate)Span 80 (Sorbitan monooleate)

600 to 1000 nm Cytarabine hydrochloride 95

Span 20 / Chol (cholestrol), Span 60/ Chol, Span 80 /Chol 1.5-3.0 m Nimesulide 96Soya-PC and hydrogenated Soya phosphatidylcholine,Span40/Chol/DCP, Span 60/Chol/DCP, Brij 30/Chol/DCP,TrCG110 (Triton 110)/Chol/DCP

100 -400 nm Tretinoin 97

Span 20/Chol/PA - Amarogentin 98Span 60 /Chol / (Solulan C-24) Cholesteryl-

polyoxyethylene ether20 m 5,6-carboxyfluorescein (CF),

Haemagglutinin (HA)100

Hexadecylpoly-5-oxyethylene ether (CB 16BEOB 5B);Octadecyl poly-5-oxyethylene ether (CB 18BEOB 5B);Hexadecyl diglycerol ether (CB 16BGB 2B); Span 40 andSpan 60

235 nm N-(2-Hydroxypropyl)methacrylamide (HPMA)copolymer-Doxorubicin

101

Span / cholesterol 565-571 nm Camptothecin 102(PMA) Palmitoyl muramic acid/Chol, Span60/ poly-24-oxyethylene cholesterol ether

250 nm Doxorubicin (DOX) 103

DMPC/Chol,Soybean PC/Chol, Egg/PC/Chol,Span40/Chol,Span60/Chol,Span60/DCP, Span60/CH-DCP

- Enoxacin 104

Span40, Span20, Span60, Span80/Chol - Colchicine, 5-fluorouracil 105Span 60/Chol,PC/Chol 4-5 m Dithranol 106Soya lecithin-akyl polyglucosid (ASP), Soyalecithin-

Glycerol monoleate (GM),Lyso Soya lecithin-akyl polyglucosid (ASP)

- Ketoprofen (KP) 107

Sucrose esters/ chol/DCP. 0.5 m Ovalbumin 108

Proniosomes

Span 40-Egg PC/Cholesterol, Span 40/DCP-Cholesterol,Span 40/Cholesterol

- Levonorgestrel (LN) 109

Sorbitols - Maltodextrin 110Span 60-Lecithin/Cholesterol,Tween 20-Lecithin/Cholesterol

4.4-6.6 nm Ketorolac 111

Span surfactant/Lecithin/Cholesterol, Tweensurfactant/Lecithin/Cholestrol,

447-971 nm Estradiol 112

Span60/CH-DCP 6000 nm CF 113

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which were prepared with the anti tumor drugcarboplatin (CBP) for targeting lung carcinoma inmice had an entrapment efficiency of 29 % and were

stable for 3 months. CBP incorporated in niosomeshad better targeting efficiency compared to freeCBP 94. Large multilamellar vesicles prepared for thedrug doxorubicin from C 16 triglyceryl ester with andwithout cholesterol were administered to S-180 tumor

bearing mice. Administration of cholesterolcontaining niosomes was found to be more effectivein reducing tumor growth.

Niosome vesicles prepared from Tween20, Tween80 for the drug cytarabine hydrochloride 95 which had80% entrapment efficiency, exhibited a prolongedrelease over a period of 16 hr as compared to

formulations prepared from span 60 and span 80which had 67.5 % entrapment efficiency. Nimesulidewas incorporated in niosomes by changing the HLBusing Tweens and Spans but keeping the cholesterolconcentration constant. Highest entrapment of 39 %was obtained at HLB of 8.6 while the drugentrapment was found to decrease with decrease inHLB from 8.6 to 1.8. It was also observed that for agiven formulation, on increasing the surfactant tocholesterol ratio from 2 to 3.33, the drug entrapmentincreased approximately from 65 to 90 %(ref. 96) Invitro studies showed prolonged release of nimesulide

gel as compared to plain drug gel96

.From MLV to LUV to SUV, there was an increase

in drug entrapment efficiency for Tretinoin (TRA),with the slowest release seen at the transitiontemperature for SUV, unlike MLV and LUV. SUV

prepared from Span 60 had a higher entrapmentsimilar to Span 40(ref. 97). Non hydrogenated soya

phosphatidylcholine (P90) liposomes are capable ofdelivering higher amounts of TRA with respect to

both hydrogenated soya phosphatidylcholine (P90H)liposomes and niosomes. This could be due to ahigher bilayer permeability of P90 liposomes as they

are made up of pure enriched Soya phosphatidylcholine (90%) with highly unsaturatedand polyunsaturated fatty acid content that canincrease the bilayer fluidity 97.

Varying the structure and or bilayer composition ofvesicle dispersions the delivery of the lipophilic drugTRA can modulate. Vesicles made from Triton CG110 appear to be suitable carriers of TRA becausethey showed good stability especially when prepared

by the thin film method 97. The effect of amarogentinas an antileishmanial agent was studied in three

forms: as a free drug and incorporated in liposomes orniosomes. The study was on hamsters infected for 30days with Lesihmania donovani . There was

suppression of the parasite in the spleen to the extentof 34 % for free drug , 69% for liposomes, and 90%for niosomes 98.

Sorbitan monostearate Span 60 niosomes wereused as drug delivery vehicles for antigens. 5, 6-carboxyfluorescein (CF), bovine serum albumin(BSA) and haemagglutinin (HA) were used as modelantigens in depot and immunogenic studies. Albumin

being both biocompatible and biodegradable has adistinct advantage as a vehicle of drug delivery.Therefore, aspirin loaded albumin nanoparticles

prepared by coacervation method were found useful

in ophthalmic drug delivery99

. In contrast to a simpledrug solution, whose concentration peaks with in to1 hr, a nanoparticle formulation releases aspirin at asustained rate for a prolonged duration: 50% totalcumulative percentage at the end of 20 hr, 90% at 72hr. In vivo studies done on balb mice lead to theconclusion that the v/w/o gel showed depot propertiesfor over 48 hr following intramuscular administration.Both the w/o and v/w/o gels demonstratedimmunoadjuvant characteristics and enhanced the

primary and secondary humeral immune responses toheamagglutinin antigen 100 .

Factors affecting the encapsulation efficiency andsize of niosomes were studied for N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-doxorubicin. Niosomes prepared by using Span 40and Span 60, by dehydration method had a highencapsulation efficiency of 60 % (ref. 101) due to thelarger vesicles which were formed when thehydrophilic portion of the molecule was decreasedrelative to the hydrophobic portion. Thus a largerhead group would also increase membrane curvatureand decrease vesicle size 101 .

Niosomes loaded with camptothecin, which were

prepared from Span and cholesterol, were spherical inshape similar to phospholipid vesicles, withunilamellar bilayers. The niosome formulation hadnarrow size distributions and higher entrapmentefficiency. The antitumor activity was better than freecamptothecin 102 . Palmitoyl muramic acid (PMA)vesicles were found to avoid liver uptake but notspleen uptake when compared to DOX loadedsorbitan monostearate (Span 60) niosomes. DOX

plasma levels at 5 h after the administration of DOXPMA vesicles represented 0.20% of the administered

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dose and 0.10% in the case of DOX Span 103 .Encapsulation percentage in all the formulations wasmore than liposomes (DMPC, PC). Niosomes

prepared with Span 40 and CH had the highestencapsulation. Skin permeation for formulationscontaining Span 60 and DCP was 57 %, which wasattributed to the fact that DCP decreased

permeation 104 . This was evident from in vitro studiesconducted on nude mouse skin using Franz diffusioncells.

Niosomes were prepared by evaporation-sonicationmethod for formulation of Span 60 and cholesterol.The release studies of colchicine and 5-fluorouracil(5-FU) in vitro from niosomes showed a prolongedrelease profile over a period of 24 hr 105. Altering the

proportion of phosphatidylcholine and cholesterol inthe formulation the entrapment efficiency of dithranolin liposomes optimized. Hydration and permeationmediums were also established, keeping in view the

poor solubility and stability of dithranol. The meanliposome and niosomes sizes were 4 and 5 micron,respectively. Drug-leakage study carried out atdifferent temperatures over a period of two monthsaffirmed that drug leakage increased withtemperature 106.

ProniosomeOn storage, niosomes exhibit aggregation, fusion,

leakage or hydrolysis of entrapped drugs. Thisreduces the life of the dispersion. On dehydration,niosomes produce proniosomes which is a dry, freely

flowing, granular product. The dry product dissolvedin aqueous media to form a multilamellar niosomesuspension. As compared to niosomes, proniosomes

have a better shape and encapsulation efficiency(Fig 4).Transdermal drug delivery systems based on

proniosomes were studied with Span 40 surfactantwith and without DCP, with different sources of PCsuch as egg PC and soya PC in ethanol, propanol,isopropanol and butanol for the drug levonorgestrel(LN). Niosomes containing isopropanol and butanolwere formed more spontaneously than niosomescontaining propanol and ethanol perhaps due to faster

phase separation of isopropanol and butanol due totheir lower solubility 109. In vitro studies on drugloading, rate of hydration (spontaneity), vesicle size,

polydispersity, entrapment efficiency and drugdiffusion across rat skin were also studied in detail.The effect of formulation composition, amount ofdrug, type of Spans, alcohols and sonication time ontransdermal permeation profile was identified.Stability studies performed at 48 C and at roomtemperature demonstrated the utility of a proniosomaltransdermal patch containing levonorgestrel as aneffective contraceptive 109 . Table 5 shows in brief thedifferent drugs and proniosome formulations whichare used for drug delivery.

Surfactant/sorbitol/maltodextrin-based systems can promote proniosomes as a potentially scalable methodto produce niosomes for delivery of hydrophobic oramphiphilic drugs 110 . Studies were performed to

Fig. 4 (a) Photomicrograph of dithranol loaded niosomes (DNS4) [106] (b) Photomicrograph of polyhedral niosomes formed byC16EO 5: Solulan C24 in water at room temperature. [116] Electron micrograph of (c) Conventional niosomes (d) Proniosomes derivedfrom SP/CH/DCP. Scale bars represent 10 m [113].

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compare formulations of the same drug with differentHLB number. It was found that proniosomes preparedwith Span 60 provided a higher ketorolac flux across

the skin than did those prepared with Tween 20(ref.111). No significant difference was observed in theencapsulation efficiency and skin permeation ofestradiol from proniosomes prepared containingcholesterol and proniosomes without cholesterol forSpan and Tween series 112 . The effect of particle size,formulation and entrapment efficiency was studied insynthetic gastric and intestinal fluid. Although thesize distributions are approximately the same, theaverage particle size of a proniosome-derivedniosome is approximately 6 microns while that of aconventional niosome is about 14 microns 113 .

Polyhedral niosomeIn aqueous media, nonionic surfactants self

assemble into spherical vesicles, tubular, disk-likevesicles and vesicles with faceted edges which areknown as polyhedral niosomes. Polyhedralniosomes 114, 115 with faceted edges were observed incertain mixed surfactant compositions (Fig 4). Forexample, mixtures of hexadecyl diglycerol etherC16G2-Cholesterol- Solulan C24 were found to formspherical, tubular, polyhedral and disk-like vesiclesdepending on the molar ratio of the constituents 115 .The morphology of polyhedral niosomes wasdependent on temperature as well as cholesterolcontent. On heating above their phase transitiontemperature, polyhedral niosomes undergo reversibleshape transformation into spherical structures Theviscosity of polyhedral niosomes at room temperatureis higher than their spherical counterparts due to theirfaceted and relatively rigid shape. Polyhedralniosomes are more permeable at room temperature

because of lack of or low levels of cholesterol in theirmembranes 116 . Polyhedral niosomes are potential drugdelivery vehicles as they are permeable and show

prominent thermo responsive behaviour if the size andshape can be tuned in line with the pore size of theactive sites.

Liquid crystalline structuresWhen the volume fraction of a surfactant in a

micellar solution is increased above a certainthreshold, a series of structures are commonlyencountered. As the concentration increases, thenumber of micellar aggregates increases. In spite ofthe repulsive interactions between micelle surfaces,micelles get closer. Surfactant aggregates change their

shape and size as concentration is increased, therebyleading to the formation of a series of structuresknown as mesophases or lyotropic (solvent-induced)

liquid crystals.The main phases associated with two-component

surfactant/water systems are hexagonal (normal orinverted), lamellar, several cubic phases andassociated structures. The release of a drug fromliquid crystalline phases is governed by factors suchas drug concentration, diffusion constant, solubility ofthe drug, structural characteristics, porosity, stabilityof structure in presence of the drug, and size of thedrug molecule entrapped in the structure. Initialdiscussions focused on the lamellar phase which isgenerally used for transdermal routes. This was

followed by hexagonal and reverse hexagonal phasesand finally on the cubic phase which can be used forvaginal, mucosal and to some extent parenteral route.An attempt was made to relate the structure of drugsand their carriers in the context of transmembranedelivery.

LamellarLamellar lyotropic liquid crystalline systems are

thermodynamically stable, optically isotropic oranisotropic are formed spontaneously. They can bestored for long periods without phase separation.

Depending on the concentration of the solvent(generally water or an aqueous solution) and on the polarity of the solvated mesogen, these systems canundergo various phase transitions. Lamellar structuresconsist of lipophilic bilayers alternately arranged withhydrophilic layers that contain interlamellar water.The formation of a lamellar liquid crystalline phase(Fig. 5) is dependent on the water content andtemperature. A lamellar phase exhibits interestingsolubility properties which make it a good choice as avehicle. Lamellar phases possess one dimensionalorder with hydrophobic and hydrophilic layers, so it is

possible to incorporate water soluble, oil soluble aswell as amphiphilic drugs within the structuredlamellar layers.

As lamellar liquid-crystalline systems contain alarge proportion of incorporated water in thesandwich layers between hydrophilic domains,evaporation of water is less than that from traditionalwater-in-oil creams. Their moisture content is retainedfor a long time, so the transepidermal water loss isreplaced by long-lasting hydration according to theneeds of the skin. New possibilities for the

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development of controlled drug delivery systems areinherent in these systems because of their stability andspecial skin-friendly structure.

Lamellar structures that display the greatestsimilarity with intercellular lipid membranes are usedfor transdermal drug delivery of various drugs(Table 6). Sustained drug release can be manipulated

by increasing the hydrocarbon chain disorder as wasobserved in lamellar phase with 20 % (w/w) of thedrug 117 . A mixture of Myverol18-92(glycerolmonlinoleate) and Myverol 18-99 (monooleate) wasused to study the effect of dissolution in media and

additives on drug release 118 . Bioavailibility studies ofcyclosporine on rats, suggested the lamellar phase as a

potential vehicle for clinical use 119 . The potential of a

glyceryl monooleatewater system as a buccaladhesive delivery system for the peptide drugDADLE was investigated by in vitro studies. Drugrelease was found to be dependent on the initial watercontent present in the liquid crystalline phase,temperature. Drug release was found to be slow incomparison to the immersion method 120 .

Skin-compliant lyotropic liquid crystals withrelatively low emulsifier concentration were

Fig. 5 Optical micrographs of (a) Lamellar phase in Tween 85/water system (b) Hexagonal phase in Triton X-100/water system (c)Isotropic cubic phase in AOT/water system

Table 6 Drug related studies in lamellar and hexagonal phase

Surfactant Conc. Drug Ref.

LamellarGyceryl monooleate (GMO) 85-90 % w/w Salicylic acid 117Myverol 18-92 Chlorpheniramine maleate (CPM), propranolol(PPL) HCL 118Monoglyceride 62% w/w Cyclosporine 119GMO 16% w/w D-Ala2, D-Leu5enkephalin (DADLE) 120Brij30 -Brij 35 - Octyl methoxycinnamate, Benzophenone-4 (sunscreen) 121Polyoxyethylene(10) oleyl ether(Brij 96V)

Less than 30 w/w Cream 122

Fatty acid/Cholesterol 55-20% w/w 5-fluorouracil 123Soybean lecithin 6% w/w Diclofenac diethyl amine 124Dihexadecylphosphatidylethanolarnine (DHPE)Dipalmitoylphosphatidylethanolamine (DPPE)

Less than 1 mM Sucrose, maltose 125

Synperonic A7 PEGB 7B CB 13 15B)

50-80% w/w Chlorhexidine diacetate 126

Oleic acid 2-10% w/w Cosmetic and pharmaceutical Product 127DOPC,DOTAP 3:1 mol ratio DNA 128DODAB/cholesterol - DNA 129

Hexagonal Brij30 -Brij 35 - Octylmethoxycinnamate, Benzophenone-4 (sunscreen) 121Synperonic A7 PEG7C1315) 30-50 % w/w Chlorhexidine diacetate 126

DOPE,DOTAP 3:1 mol ratio DNA 128GMO-TSP(trisodium phosphate) 60-80 % w/w Furosemide 130Lipopolyamine - DNA 131DGMO-GDO-F127 2.25-2.25-0.5 (w/w) D-alpha-tocopheryl poly(ethylene glycol) 132

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developed using nonionic surfactants for controlleddrug delivery systems. A mixture of Brij30 withBrij35 had the highest diffusion for the hydro soluble

sunscreen benzophenone-4 Diffusion was found to begreatly dependent on the physicochemical propertiesof the solute. These formulations had good

penetration and diffusion of drug through skin due tovery low interfacial tension arising at the oil/water

boundary surface 121. Addition of paraffin andglycerol to Brij 96V did not significantly change thestructure of lamellar liquid crystals. The presence oflamellar phase with multi components at a lowersurfactant concentration made it suitable fortransdermal use 122 .

Hydrophilic drugs such as 5-fluorouracil and

oestradiol were found to have a high absorption ratewhen incorporated in formulations prepared from amixture of fatty acids 123 . The diffusion profileexamined for drug using lamellar phospholipids asvehicle had high diffusion as compared to liposomes

prepared from same formulation 124 . An expandedlamellar gel phase was observed for surfactantdispersion in sucrose, maltose and trehalose 125 . Therelation between the structure and kinetics of drugrelease for chlorohexidine diacetate from lamellar

phase was understood to be anomalous (non-Fickian)transport 126 .

Cationic and anionic surfactants have been used fordrug and gene transfer. However due to the toxicity ofanionic surfactants; lower concentrations had to beused 127 than that needed for liquid crystals. Lamellar

phase has been used for gene transfer using cationicsurfactant and delivery of plasmid DNA 128 by anionicsurfactant where a complex between DNA andsurfactant clusters were formed which encapsulatedthe transfer agents within the lamellae of theaggregated multilamellar structures 129 .

Hexagonal phase

The hexagonal phase is composed of an array ofclosely packed long cylindrical micelles arranged in ahexagonal pattern (Fig. 5). The micelles may be eithernormal in water, (H1) i.e. with the hydrophilic headgroups located on the outer surface of the cylinder; orinverted (H2). Hexagonal and lamellar phases wereobserved for the system 126 when the surfactantconcentration was 50 % w/w (Table 6). The release ofchlorhexidine diacetate from the lamellar liquidcrystalline systems was less than thrice that of thehexagonal mesophases. The chlorhexidine diacetate

release from hexagonal liquid crystalline preparationswas characterized by zero-order release kinetics. Theresults indicate that drug release kinetics is strongly

dependent on the liquid crystalline structure. With anincrease in surfactant concentration, a transitionoccurs from hexagonal to cubic phase. Besides,addition of more than 5% tri sodium phosphatetransforms the cubic phase into a reverse hexagonal

phase 130 . The diffusion of sunscreens within liquidcrystals was found to be strongly dependent on thestructure of the liquid crystal and physicochemical

properties of the solute 121 .The transfection activity of complexes prepared

from a mixture of DOPE, DOTAP at different molarratios, was used for delivering plasmid DNA in vivo studies for HeLa cervical carcinoma cells 128 . Theaddition of DNA to an ethanolic solution oflipopolyamine forms tubular micelles which getfurther transformed into hexagonal structures thatcould be used for gene transfer 131 .

Cubic phaseThe structure of the cubic phase is unique. It

consists of a curved bicontinuous lipid bilayerextending in three dimensions, separating twocongruent networks of water channels. The micellarcubic phases I 1 and I 2 are built up by a regular packingof small micelles (or reversed micelles in the case ofI2). The micelles are short prolate ellipsoids arrangedin a body-centered, cubic, close-packed array. The

bicontinuous cubic phases V 1 and V 2 are ratherextended, porous, connected structures in threedimensions. They are considered to be formed byeither connected rod-like micelles, similar to branchedmicelles, or bilayer structures (Fig 5). Denoted V 1 andV2, they can be normal or reverse structures and are

positioned between H 1 and L- alpha and between L alpha and H 2 respectively. In addition to the L 1 region, thereare three single-phase liquid crystalline regions: thelamellar liquid crystalline phase, or L alpha and the two

bicontinuous cubic liquid crystalline phases: thePn3m (diamond) and the Ia3d (gyroid).

The concept of functionalization is to control theloading and release properties of the activecomponent by changing the properties of the cubic

phase. Functionalization is achieved by incorporatingamphiphilic molecules into the liquid crystal; thehydrophobic portion of the amphiphile inserts into the

bilayers of the cubic phase and the hydrophilic portions extend into the water channels. Bycustomizing the specific properties of the hydrophilic

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Monoolein is available in different commercialgrades as unsaturated glycerol monooleate Myverol18-92 and Myverol 18-99. A liquid crystalline gel of

Myverol 18-99 is available for vaginal delivery ofantimuscarinic drugs 139 . A mixture of Myverol 18-92and 18-99 is a low viscous formulation. Onadministration, it became highly viscous and showeda phase change which slowed down release of thedrug 140 . Dissolution and additive inclusion in theformulation affects drug release characteristics 118 .Mono glyceride-triglycerides when dissolved inmedia behave similar to monoolein in different mediaand upon oil addition. On comparison with glycerideand triglyceride based vehicles, the dietary lipid inconjunction with nonionic surfactant based isotropic

formulation enhanced the oral bioavailability andreduced inter individual variability of cyclosporine 119 .Adding lipidic penetration enhancers in the

formulation can enhance penetration of cyclosporineinto skin. This increases both transdermal as well astopical delivery 131. Drugs that partition into lipid

bilayers have their lipophilic parts screened by the bilayer. Shorter equilibration time for partition can beattained by heating the sample, or by increasing theinterfacial area between the cubic phase andcoexisting aqueous phase, both of which would speedup the diffusion of the drug. It has also been observed

that incorporation of DOPC in GMO enhances the bilayer affinity for 4-phenybutylamine 142 . Additivesdo play an effective role in increasing the drugloading and in improving the release characteristics ofthe drug from cubic phase. The solubility of drug inGMO is enhanced by additives like Tween 80, PEG,trisodium phosphate 130 , DODMAC, DEEDAC 143

without affecting the formation of cubic phase.

Newer structuresIn this section we focus on newer types of Nano

and Microstructures like icosahedra, cage-like

structures, myelin tubes and High Axial RatioMicrostructures (HARM) including ribbon andcochleate structures. Some of these are already beingused as vehicles. Others may play such a role infuture.

IcosahedraA mixture of anionic and cationic surfactants that

are made salt free self assemble into hollowaggregates (Fig 6) like regular icosahedra shape 144 with pores at the vertices. Icosahedra formed in the

region of 0.5< r < 0.75 (excess anionic surfactant) forMyristic acid Cetyltrimethylammonium hydroxide(CTAOH) sample were 1 micron in size. When the

cationic component was present in excess, nano discswere formed by rejection of excess charge towardsthe edges 145 . When the anionic component was inexcess, vesicles were formed at higher temperature 146 .The icosahedral structures can be used for drug orcosmetic delivery. It may be particularly useful for

permeation of creams through the skin in suchapplications. The nano-holes present at vertices ofthese icosahedra enhance the controlled release ofdrugs and genes.

Cage like structures

Nanocages were prepared from shell cross linkedmicelles 28 comprising of various diblock copolymers.

Nano cages possessing carbonyl groups on theirinternal surfaces and acrylic acid residues throughouttheir structure were prepared and functionalized. Thiswas done either by Schiff-base chemistry i.e.covalently attaching phosphatidylethanolamine-basedlipids within the nanocage; or by carbodiamide-mediated coupling, to covalently attach lipidsthroughout the shell (Fig. 6). Schiff basefunctionalized nanostructures can enhance the pHresponse and increased uptake of hydrophobic

guests147

.High axial ratio microstructures (HARM)Double chain amphiphilies self assemble into

Fig. 6 (a) Freeze fracture micrograph of icosahedra obtainedfrom myristic acid-CTAOH sample Scale bar represents 250 nm[144] (b) TEM Micrograph for PtBA-b-PI, PAA-b-PI diblock(Scale bar 100 nm) [147].

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tubules, twisted ribbons, and helices, which areexamples of high axial ratio microstructures (HARM).These result from intrinsic bending of rectangular

bilayer lipid sheets due to chiral packing of moleculesin the membrane. These HARM structures are potential drug delivery vehicles. They can play asignificant role in safe targeted delivery of drugs.HARM structures were observed in amphiphileshaving different head groups like sphingolipids 148,149 and peptides, in the presence of glutamic acid dialkylamides 150 . When suspended in media, amphiphilesorganized to form a wide variety of HARM asdiscussed in the following sections. Table 8 showsHARM based on the source of surfactant. The methodof preparation governs the type of HARM (Fig. 7)formed, different type of HARM like ribbon, tube,cochleates were observed when NFA-Galcer in DMF-water was prepared using pyridine evaporationmethod, thermal cycle and freeze-thaw cycle.Fibers

Fibers are newer generation delivery vehicles for

delicate compounds such as proteins which showlower encapsulation efficiency and decreased

bioactivity in conventional drug carriers. Fibers are

made from complexes of cationic and anionic polyelectrolytes. A chitosan-alginate complex formsfiber like structures (Fig. 7) that can control therelease rate of drugs. When entrapped in chitosan-alginate fibers, the release times of drugs have beenfine-tuned. For example, for dexamethasone therelease time was 2 hr with an initial burst, and forcompounds like bovine serum albumin, plateletderived growth factor (PDGF-bb) and avidin, therelease time span was 3 weeks without an initial burst.The release kinetics can also be controlled by usingvarious ratios of cationic to anionic polyelectrolytes,as well as alginate/heparin ratio at constant cationic

polyelectrolyte concentration 151.Typical fiber fabrication involves the use of high

temperature or organic solvents, rendering themunsuitable for protein encapsulation. However,

polyelectrolyte complexation as mentioned above

Fig. 7 (a) Transmission electron microscopy images of negatively stained HFA-GalCer [148] (b) SEM images of chitosan-alginatefibers at x1000 [151] (c) Freeze fracture electron micrograph of cochleate cylinders. Scale bar represents 275 nm [154] (d) Opticalmicrograph of myelin tubes in brij30/water system

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does not require harsh solvents. Furthermore, possibilities of protein encapsulation in fibers, orincorporation of growth factors into the fibrous

scaffold, can help orchestrate the growth of newtissue, particularly in a spatially defined manner dueto the fibrous orientation. Fibers of chitosan-poly(acrylic acid), chitosan-gellan and poly (alpha L-glutamic acid)-(poly (L-lysine) which are used intextiles 151 can also be used as drug carriers.Polyglycolic acid fiber based tubes stabilized by poly(L-lactic acid) (PLLA) and a copolymer of poly (D,L-lactic-co-glycolic acid) (PLGA) has been studied intissue engineering which resulted in enhancedcompression strength 152. A triblock copolymer ofPLGA-PEG-PLGA has been studied for sustainedrelease of insulin 153.

CochleatesCochleates are continuous, solid, lipid bilayer

sheets rolled up in a spiral, with no internal aqueousspace (Fig. 7). Calcium ions maintain the cochleate inits rolled form, bridging each successive layer throughionic interaction. Cochleates can be stored in calciumcontaining buffer, as the entire cochleate structure is aseries of solid layers. The components within theinterior of the cochleate structure remain intact evenwhen exposed to a harsh environment. Cochleates arecomposed of naturally occurring materials like

phosphatidylserine (PS), cholesterol and calciummade into a stable phospholipidcalcium precipitate.Cochleates made from the surfactantdioleoylphosphatidylserine (DOPS) containing AMBwas used for drug delivery. It was found that for allcochleate-AMB doses there was complete clearanceof the organism from lungs, unlike other modes ofAMB delivery like liposomes (LAMB) and micelles(DAMB) 154,155 . Because of the hydrophobic nature ofAmphotericin B (AMB) molecules, they get localizedin the lipid bilayers of the cochleates. This protects

AMB from degradation on exposure to harshenvironmental conditions. The delivery of some anti

bacterial drugs such as clofazimine, aminoglycosides,

beta-lactam, vancomycin could benefit fromcochleates, by reducing their toxicity and improving bactericidal activity.

Clofazimine cochleate was prepared by thetrapping method. Its safety and efficacy wereanalyzed in cell cultures by vero cells. Clofaziminecochleate was found to be 500 times less toxic thanfree clofazimine 156 . Protein and DNA cochleates werehighly effective as vaccines when given via mucosal,

parental and oral routes. A comparison study wasdone for liposomes and cochleates prepared from PSformulation and PG formulation 157 . It indicated thatthe PS cochleate vaccine induced responses at aslower rate than liposome based vaccine, but theresponse remained higher. The response inducedusing encochleated DNA was much stronger than thatinduced by proteoliposome-encapsulated DNA 157 .Cochelates were prepared using different sources oflipids (Table 8).

Ribbon like structures were observed for lipid withAmphotericin B 158 in 1988. The lipid complexcontains a much higher amount of Amphotericin Band is described as a mixture of dimyristoylphos-

phatidylcholine and dimyristoylphosphatidyl glycerol(7:3). It has lower toxicity with less hemolytic activitycompared to conventional liposomal AMB 159 .Liposomes encapsulated with drugs 160 were also

prepared using cochleates as precursors.

Myelin figuresMyelin figures are finger like extrusions (Fig. 7)

having concentrically arranged alternating aqueouslayers and surfactant bilayers around a central core ofwater. The growth of myelin figures is due to achemical potential difference caused by aconcentration gradient along the radial direction

Table 8 Different types of HARM structures and surfactants

Vehicles Surfactant Drug Ref.

Fiber, amorphous, cochleate,tube, ribbon, liposome, Helicalribbon, tubules, rod likeaggregates

Psychosine, Sphingosine, Ceramide, NFA Galcer, HFA-Gal cer, Gal-cer,Peptide-Glu-(NHC nH2n+1 )2 n=12,14,16

- 148,149,150

Cochleate Dimyristoylphosphatidylcholine(DMPC) and PhosphatidylglycerolDimyristoylphosphatidylglycerol,Sphingosine, Phosphatidylserine (PS)and DOPS, HFA-Galcer(galactocerebroside)

Amphotericin B (AMB),DNA, Protein

154,155,156,157,158,160

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perpendicular to the long axes of myelin figures 155.This non equilibrium structure was observed inanionic, cationic, nonionic and zwitterionic

surfactants viz. bis-2-ethylhexylsulfosuccinate,sodiumdodecylsulphate, dodecylbenzene sulphonicacid/magnesium nitrate, dialkylphospate,dialkylammonium salts, oleic acid/hydrazine,cholesterol/ sodium oleate, Sterols/water solublesurfactants and phosphatidylcholine 161.

Myelin figures are found to emerge from aninsoluble lamellar phase that has been formed when asurfactant like PC, AOT 162 , comes into contact withan aqueous phase. Eroded myelin figures were alsoobserved for Tween 85/water system 163 . It hassometimes been observed that onion like structuresformed from a sheared surfactant system likeAOT/brine, instead of myelin structures 164 .

Concluding summaryA wide range of spontaneous, self assembling

surfactant structures in the size range spanning from afew nanometers to tens of micrometers have beenreported. Of these, some structures like liposomes,micelles and cubic liquid crystalline structures haveconventionally been used for drug delivery. Unusualmicro and nanostructures such as high axial ratiomicrostructures (HARM), which include ribbon type,fiber, twisted ribbons, tube and cochleate, have anincreased interfacial area. Their supramolecularlyorganized architecture imparts enhanced stability toan entrapped drug. This safeguards drug moleculesfrom physiologically harsh conditions. Hence, HARMstructures are encouraging as drug delivery vehicles,especially for vaccines. The tight packing ofaggregates in HARM may prove useful forentrapment of lipophilic drugs and their constant,sustained release via dissolution and clearance. We

predict that in the near future other nano-structuressuch as nanocages, icosahedral structures havingholes at the vertices, and non-equilibrium structures

like myelins, will be important drug delivery systemsfor controlled sustained drug release. Lamellar andhexagonal phases have also been used for drugdelivery; however their potential has not been wellexplored. Apart from concentrated surfactant systems,dilute systems will also play a dominant role in drugdelivery, such as polymeric micelles which wererecently identified as candidates for delivery ofanticancer drugs. The oral delivery of proteins isindeed a challenging task. This is because acids andenzymes present in the gastrointestinal tract denature

proteins, and as of now there is no efficient vehiclethat can resist denaturation. It will be of immensevalue if pH sensitive vehicles with enzyme resistant

architecture could be developed. pH sensitive micellesand amide based fibrous structures could play a rolein oral delivery of amino acid and protein baseddrugs. Research should focus on the fact that nonequilibrium structures that undergo dynamicmicrostructural transformations while attainingequilibrium subsequent to dissolution fromconcentrated formulations may prove useful astransient vehicles for drug delivery. It is felt that non-equilibrium structures could be important deliveryvehicles of the future.

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