Available online at www.sciencedirect.com

International Journal of Pharmaceutics 345 (2007) 925

Review

Stable drug encapsulation in micelles and microemulsionsAjit S. Narang a,1, David Delmarre b,1, Danchen Gao c,,1

a

b

Abstract

Oral absodissolutionhigh drug endrug-relatedprecipitationproblems cocould be use 2007 Else

Keywords:microemulsif

Contents

1. Intro1.1.1.2.1.3.1.4.1.5.

2. Drug2.1.2.2.2.3.

3. Drug3.1.3.2.3.3.3.4.3.5.3.6.

CorresponE-mail ad

1 FormerlyVernon Hills,

0378-5173/$doi:10.1016/jBiopharmaceutics R&D, Bristol-Myers Squibb, PO Box 191, Mail Stop 85A-167A, New Brunswick, NJ 08903, USACapsugel Pharmaceutical R&D Center, Parc dInnovation, Rue Tobias Stimmer, B.P. 30442, 67412 Illkirch Graffenstaden Cedex, France

c Anchen Pharmaceuticals, Inc., 5 Goodyear, Irvine, CA 92618, USAReceived 8 June 2007; received in revised form 26 August 2007; accepted 30 August 2007

Available online 8 September 2007

rption of hydrophobic drugs can be significantly improved using lipid-based non-particulate drug delivery systems, which avoid thestep. Micellar and microemulsion systems, being the most dispersed of all, appear the most promising. While these systems showtrapment and release under sink conditions, the improvement in oral drug bioavailability is often unpredictable. The formulation andbiopharmaceutical aspects of these systems that govern oral absorption have been widely studied. Among these, preventing drugupon aqueous dilution could play a predominant role in many cases. Predictive ability and quick methods for assessment of such

uld be very useful to the formulators in selecting lead formulations. This review will attempt to summarize the research work thatful in developing these tools.vier B.V. All rights reserved.

Bioavailability; Hydrophobic drugs; Micelles; Microemulsions; Precipitation; SEDDS; SMEDDS; Self-emulsifying; Solubilization; Self-ying

duction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Solutions, emulsions, microemulsions, and micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Components of micelles and microemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Characterization of microemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Drug entrapment and structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Microemulsions for protein and peptide delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

loading capacity in micelles and microemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Solubilization capacity in reverse micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Dilutability as monophasic systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Solubilization capacity in diluted microemulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

precipitation and solute crystallization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17In vivo drug precipitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Prediction of in vivo drug precipitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Avoiding in vivo drug precipitation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Mechanism of solute crystallization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Preventing drug crystallization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Combined use of solubilization approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

ding author. Tel.: +1 949 639 8143.dress: danchen.gao@anchen.com (D. Gao).at Morton Grove Pharmaceuticals, Inc., 50 Lakeview Pkwy #127,IL 60061, USA.

see front matter 2007 Elsevier B.V. All rights reserved..ijpharm.2007.08.057

10 A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925

4. Other factors influencing bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214.1. Lymphatic transport and lipolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224.2. Inhibition of drug efflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224.3. . . . .

5. Conc . . . .Ackn . . . . .Refer . . . .

1. Introdu

Oral liquespecially aopment, anmanagemestability offerred, e.g.solubility (are the limas emulsionDiprivanous mediae.g., Augmtion, e.g., Zsoft gelatingelatin capalso be fordrug deliveaddition ofe.g., Sandim

Emulsioas a dispertively. Theand showdynamic indo not shoor separatilower dispthem transpbe formulanon-aqueoureverse micwith wateras it is andthey formcentrates asystems (Soffer furthenificantly rthat simpleSMEDDSa soft gelacontainingstomach.

The uselimited byexcipients.

y bers aty wsolvof codditspecn oritatioilabiagellarent

to-usyea

ed tofor tmplporinvase

fewerciaents,le imrecip

quiy useeviewbe us

oluti

plepoleater.er c

solvly cn be

acisoluDispersion size of emulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .lusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .owledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ction

id dosage forms are often required of new molecules,t the discovery and pre-clinical stages of drug devel-

d of existing molecules as a part of product life-cyclent. When permitted by the aqueous solubility andthe drug substance, a simple solution in water is pre-, Prozac oral solution. More often, however, drugin relation to its required concentration) and stabilityiting factors. Hydrophobic drugs may be formulateds and suspensions, e.g., Megace ES suspension and

emulsion. Drugs that show rapid degradation in aque-can be formulated as either powder for suspension,entin, Amoxil, and Zegerid; powder for solu-erit; oily solution, e.g., Aquasol E (Vitamin E)capsules; or oily suspension, e.g., Accutane soft

sules. Hydrolysis-sensitive hydrophobic drugs maymulated as oily concentrates called self-emulsifyingry systems (SEDDS) that form an emulsion uponwater or an aqueous solution with mild agitation,mune oral solution.

ns and suspensions allow the drug to be administeredsed oil solution or as suspended particles, respec-se dosage forms, however, have particulate naturephase separation upon storage due to their thermo-stability. In contrast, micelles and microemulsions

w the physical instability in terms of agglomerationon of the dispersed phase. These systems also haveersed phase size (200 nm) than emulsions, givingarency. Also, these dosage forms allow the drug toted as both ready-to-use aqueous solutions and ass concentrates. The concentrate may be a solution,ellar solution, or a microemulsion, which is dilutedimmediately before administration, or administeredgets diluted with gastric fluids in vivo. In cases wheretransparent microemulsions upon dilution, the con-re known as the self-microemulsifying drug deliveryMEDDS). SEDDS, SMEDDS, and micellar systemsr advantage over conventional emulsions in the sig-

educed energy requirement for their preparation, suchmixing is enough for their formation. SEDDS and

and mamulatocapaciand corange

In awith redilutioprecipbioavaadvanta micedependready-least 2expecttution

Exacyclos(FortoVerycomm

excipidictabdrug pity andbe verThis rcould

1.1. S

Simand diing wof lowsolutetitativepH caweaklydipolemay also be administered as concentrates, e.g., intin capsule, and expected to form solubilized drugmicelles or microemulsions in vivo upon dilution in

of SEDDS, SMEDDS, and micellar systems istheir drug loading capacity and the usage level ofSurfactants and cosolvents can be toxic at high doses

the dielectinteractionubility maa hydrophi(HPBCD).to drug enwater. In a. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

limited in their daily and per-dose uptake levels. For-im to develop systems with maximum drug loadinghile using minimum possible amounts of surfactantsents. These limitations lead formulators to a limitedmpositions.ion, micelles and microemulsions can be metastablet to drug solubility and show drug precipitation uponcrystallization over a period of storage. In vivo drugn upon dilution in stomach can lead to failure inlity enhancement and compromise the competitiveof this dosage form. In vitro drug crystallization insolution or microemulsion could be very slow andon temperature and handling of the formulation. Thee formulations are expected to have a shelf life of atrs, while concentrates (SEDDS and SMEDDS) arebe physically and chemically stable after reconsti-

he duration of the therapy or until administration.es of commercialized SMEDDS formulations includee (Neoral), ritonavir (Norvir), and saquinavir) (Cooney et al., 1998, Porter and Charman, 2001).

SEDDS and SMEDDS formulations have beenlized because of limitations in the usage level ofe.g., surfactants and cosolvents, and the unpre-

provement of oral bioavailability due to possibility ofitation upon aqueous dilution in vivo. Predictive abil-ck methods for assessment of such problems couldful to the formulators in selecting lead formulations.

will attempt to summarize the research work thateful in developing these tools.

ons, emulsions, microemulsions, and micelles

aqueous drug solutions involve hydrogen-bondinginteractions of drug molecules with the surround-Hydrophobic drugs have low solubility becauseapacity for these interactions. In such cases, theent interactions can be qualitatively as well as quan-

hanged to improve the drug solubility. For example,adjusted with buffers to increase ionization of a

dic or a weakly basic drug, resulting in higher ion-tesolvent interactions. Cosolvent addition reduces

ric constant of water and facilitates hydrophobics of drug molecules with the solvent system. Sol-y also be increased by drug complexation withlic compound, e.g., hydroxypropyl--cyclodextrinHydrophobic and/or specific ionic interactions leadtrapment in HPBCD, which, in turn, is soluble inddition, incorporation of amphiphilic surfactants in

A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925 11

aqueous solutions can solubilize hydrophobic drugs by differentmechanisms.

Surfactaand are ch(HLB) valunantly hydwhile surfand form wform aquemolecules.

Surfactaconcentratiregions forCMC, surfmicelles wihydrophobing its solusurfactantssions, wheWhen theglobules armicroemulon the inteof drug solactions witdiffer fromin the amousions oftentheir forma

Both miaqueous sohave summthese syste2006; GursLawrence aThe physicment, as wedetermine tity during s

1.2. Comp

Pharmaoil and surfand/or a coponents ofin aqueousSMEDDSfor hydrolypacking int

The surionic or noof the hydrThus, whilhydrogen bon its hydrstabilized b

concentration on the stability of an emulsion or a microemulsionis more profound in the case of ionic surfactant than nonionic

antsantsroemmphfacta

actanl HLot bees onurfacyste

ss tharallolveeaseed phobncrequeizatieou

entse lisactancatioS00exci

cturf miant/cmilales

strucdeteitionhob

mentroem. Ththat

diaggle rregiof motheaxisompter,, 19

emulres aondes o

ion ints have both hydrophilic and lipophilic propertiesaracterized by their hydrophilelipophile balancees. Surfactants with an HLB value >10 are predomi-rophilic and favor the formation of o/w emulsions,actants with HLB values

12 A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925

Table 1Examples of surfactants, cosurfactants, and cosolvents used in commercial lipid-based formulations

Excipient name (commercial name) Examples of commercial products in which it has been usedSurfactants/cosurfactants

Polysorbate 20 (Tween 20) Targretin soft gelatin capsulePolysorbate 80 (Tween 80) Gengraf hard gelatin capsuleSorbitan monooleate (Span 80) Gengraf hard gelatin capsulePolyoxyl-35-castor oil (Cremophor EL) Gengraf hard gelatin capsule, Ritonavir soft gelatin capsulePolyoxyl-40-hydrogenated castor oil (Cremophor RH40) Neoral soft gelatin capsule, Ritonavir oral solutionPolyoxyethylated glycerides (Labrafil M 2125Cs) Sandimmune soft gelatin capsulesPolyoxyethylated oleic glycerides (Labrafil M 1944Cs) Sandimmune oral solutiond--Tocopheryl polyethylene glycol 1000 succinate (TPGS) Agenerase soft gelatin capsule, Agenerase oral solution

CosolventsEthanol Neoral soft gelatin capsule, Neoral oral solution, Gengraf hard gelatin capsule,

Sandimmune soft gelatin capsule, Sandimmune oral solutionGlycerin Neoral soft gelatin capsule, Sandimmune soft gelatin capsulePropylene glycol Neoral soft gelatin capsule, Neoral oral solution, Lamprene soft gelatin capsule,

Agenerase soft gelatin capsule, Agenerase oral solution, Gengraf hard gelatincapsule

Polyethylene glycol Targretin soft gelatin capsule, Gengraf hard gelatin capsule, Agenerase soft gelatincapsule, Agenerase oral solution

Lipid ingredientsCorn oil mono-, di-, tri-glycerides Neoral soft gelatin capsule, Neoral oral solutiondl--Tocopherol Neoral oral solution, Fortovase soft gelatin capsuleFractionated triglyceride of coconut oil (medium-chain triglyceride) Rocaltrol soft gelatin capsule, Hectorol soft gelatin capsuleFractionated triglyceride of palm seed oil (medium chain triglyceride) Rocaltrol oral solutionMixture of mono- and di-glycerides of caprylic/capric acid Avodart soft gelatin capsuleMedium chain mono- and di-glycerides Fortovase soft gelatin capsuleCorn oil Sandimmune soft gelatin capsule, Depakene capsuleOlive oil Sandimmune oral solutionOleic acid Ritonavir soft gelatin capsule, Norvir soft gelatin capsuleSesame oil Marinol soft gelatin capsuleHydrogenated soybean oil Accutane soft gelatin capsule, Vesanoid soft gelatin capsuleHydrogenated vegetable oils Accutane soft gelatin capsule, Vesanoid soft gelatin capsuleSoybean oil Accutane soft gelatin capsulePeanut oil Prometrium soft gelatin capsuleBeeswax Vesanoid soft gelatin capsule

Fig. 1. (A) A hypothetical ternary phase diagram representing three components of the system (water, emulsifier (E), and oil) as three axis of an equilateral triangle.Different compositions of the formulation result in the formation of different phase structures: normal micellar solution, inverted micellar solution, macroemulsions oremulsions, o/w microemulsions, w/o microemulsions, and various transition phases represented by cylinders and lamellae structures. The conventionally designatedL1 phase consists of micelles and o/w microemulsions while the L2 phase consists of inverted micelles and w/o microemulsions (Prince, 1975). (B) Schematicrepresentation of the dispersed phase structure of micelles, reverse micelles, o/w microemulsions, and w/o microemulsions.

A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925 13

intermediate liquid crystalline phases, which are viscoelasticgels composed of hexagonal array of water cylinders adjacentto the w/oleaflets adjare charactmicroemulration of coregion. Coof aqueousmonophasi

1.3. Chara

Charactmicroemulto oral liqustability ofdensity, cotial of theof the com2004). Addprovides innents and pemployedet al., 2005sions has b(PCS) and(Malcolmsstatic lightand small-phase sizeof the hartions in coShukla ethave beennance (SD2004) and2006).

Duringphase diagmix with otransparenc(Moreno eistics andPhase stabierated testset al., 200phase of thmatographand microematographof capacityin microemtition coeffidosage formtion or crysstorage at

upon dilution with water to form o/w microemulsions, which canbe done by dropwise addition, static serial dilution, or dynamic

on (Lre a

ao edrugnt co

gs con tEDDhob

olutirentma

ross

permor us

rter

rug

atios o

cedsualce-a

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atton, 19o thactandinene macids phylal0). FizatiFurenterepensurfma

entintewhied ples.ted,s cuneoug captitionintephase and a lamellar phase of swollen bimolecularacent to the o/w phase (Prince, 1975). These phaseserized by the presence of birefringence, as opposed tosion regions which are optically isotropic. Incorpo-surfactant and/or cosolvent increases the one-phase

nstruction of phase diagrams enables determinationdilutability and range of compositions that form a

c region.

cterization of microemulsions

erization of reverse micelles, SMEDDS, andsions involves the physical and chemical tests relatedid dosage forms, e.g., assay, uniformity of content,the active (impurities), appearance, pH, viscosity,

nductivity, surface tension, size and zeta poten-dispersed phase, etc. with respect to the effectposition on physical parameters (Podlogar et al.,itionally, differential scanning calorimetry (DSC)formation on the interactions of different compo-olarization microscopy using crossed polarizers is

to confirm isotropicity of the formulation (Neubert). Size of the dispersed phase in o/w microemul-een measured by photon correlation spectroscopytotal-intensity light scattering (TILS) techniques

on et al., 2002). The use of scattering techniques, e.g.,scattering (SLS), dynamic light scattering (DLS),angle neutron scattering (SANS), for dispersedmeasurement requires correction for non-ideality

d sphere model arising from interparticle interac-ncentrated microemulsions (Shukla et al., 2002;al., 2003). Structural features of microemulsionsstudied using self-diffusion nuclear magnetic reso-NMR) (Spernath et al., 2003; Johannessen et al.,small-angle X-ray scattering (SAXS) (Garti et al.,

the development of these systems, pseudo-ternaryrams are constructed by titrating a reverse micellene of the components and observing visually fory and through crosspolarizers for optical isotropy

t al., 2003). Maintenance of monophasic character-drug solubility is tested upon dilution with water.lity of formed microemulsions is evaluated by accel-such as centrifugation or freeze thaw cycles (Brime

2). Partitioning behavior of drug in the dispersedese systems has been studied by electrokinetic chro-y (EKC) for both micelles (Ishihama et al., 1994)mulsions (Huie, 2006), and by gel permeation chro-y (GPC) in micelles (Scherlund et al., 2000). The logfactor obtained by EKC of hydrophobic compoundsulsions correlated well with their octanol water par-cients (log P) (Mrestani et al., 1998). In addition, this

is tested to evaluate the tendency for drug precipita-tallization by physical observation upon undisturbedroom temperature and refrigerated conditions, and

injectifor motion (Gof thediffere2001).

Druinversiin SMhydropdrug stranspastudiescell aca semi2003)ing (Po

1.4. D

LocdependEnhantems uinterfashape oof hyd(AOT)and HHattonleads tcosurfl-histiisooctaaminoaqueoul-phenal., 200solubilsions (at the ision das a co

Thedependon thephase,dispersmolecufacilitataneouspontaloadin

Parby thei et al., 1998). Modified in vitro tests can be usedccurate assessment of tendency for drug precipita-t al., 2004; Gao et al., 2003). Solubilization capacityis measured by saturation solubility evaluation in

mponents and component mixtures (Aramaki et al.,

an be incorporated in microemulsions by the phaseemperature (PIT) method (Brime et al., 2002) andS by dissolving the drug in the hydrophilic or the

ic component(s). The PIT method involves mixingon with microemulsions and applying heat to formdrug loaded systems. In addition, drug release rate

y be carried out, when desired, in Franz diffusionthe donor and acceptor compartments separated byeable membrane (Peltola et al., 2003; Spiclin et al.,ing US Pharmacopeial methods for dissolution test-and Charman, 2001).

entrapment and structure

n of the solubilized drug in microemulsion systemsn the hydrophobicity and structure of the solute.drug solubility in microemulsion and micellar sys-ly arises from the solubilization at the interface. Thessociated solute, in turn, may affect the size and

microemulsion droplets. For example, incorporationobic amino acids in di-2-ethylhexyl sulfosuccinaterse micelles (Leodidis and Hatton, 1990a; Leodidis, 1990b; Leodidis and Hatton, 1991a; Leodidis and91b) and w/o microemulsions (Yano et al., 2000)eir association at the interface, and they may act asts. Upon comparing the solubilization of glycine,

, and l-phenylalanine in AOT stabilized water-in-icroemulsions, Yano et al. observed that hydrophilicglycine was solubilized primarily in the dispersed

ase while hydrophobic amino acids, l-histidine andanine, migrated to the AOT interface layer (Yano eturedi-Milhofer et al. obtained similar results with theon of aspartame in water/isooctane/AOT microemul-di-Milhofer et al., 2003). Aspartame was solubilizedface and resulted in a sharp reduction of surface ten-ding on aspartame concentration, indicating its roleactant.ximum amount of solubilized hydrophobic drug ison the curvature of the interface. Surfactant layerrface has a positive curvature towards the dispersedch is determined both by the relative volume ofhase and the spontaneous curvature of surfactantEntrapment of drug molecules in the interface isleading to higher drug loading capacity, if the spon-rvature is lower than the actual curvature. Highers curvature, on the other hand, leads to lower drugacity at the interface.ing of the drug into the interface was quantifiedrfacial partition coefficient by Leodidis and Hatton

14 A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925

(Leodidis and Hatton, 1990a). Using phase equilibrium analyseson the solubilization of amino acids in AOT reverse micelles, theauthors shodepended won solute cstrongly onmoment oftrolyte typegeneral linand solute cusing noniand Zemb,

These stat the interand its solucurvature osolute itselsolute andtion at thealso drug pwhose soluwith the using to cosuto dramatictation.

1.5. Micro

Improvepeptides, lidiscussed ihave also sof hydrophal. tested thsolved in thLabrafil, ldiabetic maimprovemewith insulisub-cutanehand, Kraeavailabilityvenous insuto 6.4% whard gelatitinin and cand Ritschmicroemuland Flynn,

Improvesystem wasleuprolideacetylglucoAlso, intra-dermal groulcers in rgastric aqu

The beneficial effects of microemulsions in these applicationswere attributed to the prevention of degradation in the gastro-

nal eid coroem

e sta#5,

adisred tmed

e ens phtesMadanci, wa-lysicathotein

the rnmesyste

in tet al.all tissoels.dropmultions di

g lo

rmafor

es thThesistrats re

es ann asg pr

a con

lizatirug straticipihe syhat cfluenlityandlizatandationwed that interfacial partition coefficient of the soluteeakly on surfactant concentration and did not dependoncentration and aggregate geometry. It dependedthe factors that affect surface pressure or bending

the surface film, e.g., solvent type and external elec-and concentration. Also, Testard and Zemb showed a

ear relationship between induced curvature variationontent of the interfacial film for a hydrophobic solute

onic surfactant based o/w microemulsions (Testard1999).udies indicate that hydrophobic solute is solubilizedface of reverse micellar and microemulsion systemsbility is affected by system variables that affect thef the interfacial film. Moreover, the presence of thef affects the system, depending on the nature of thethe surfactant. The phenomenon of drug solubiliza-interface affects not only drug loading capacity butrecipitation upon dilution. For example, for a drugbilization capacity at the interface has been increasede of a cosurfactant, dilution with aqueous phase lead-rfactant migration away from the interface can leadreduction in drug loading capacity, causing precipi-

emulsions for protein and peptide delivery

ment in the oral bioavailability of hydrophobic cyclicke cyclosporine A, using SEDDS and SMEDDS isn Section 3.1 and Section 4.3. SMEDDS systemshown promise in improving the oral bioavailabilityilic linear peptides and proteins. For example, Cilek ete oral absorption of recombinant human insulin dis-e aqueous phase of w/o microemulsions composed ofecithin, ethanol, and water in streptozotocin-inducedle Wistar rats. The authors demonstrated significantnt in oral pharmacological availability comparedn solution, although it was 0.1% compared withous administration (Cilek et al., 2005). On the otherling and Ritschel found that the oral pharmacological

of insulin microemulsions as compared to intra-lin in beagle dogs was 2.1%, which further increasedith the encapsulation of gelled microemulsions inn capsules along with the protease inhibitor apro-oating of the capsules for colonic release (Kraelingel, 1992). Improved oral delivery of insulin fromsion system was also demonstrated by others (Cho1989).d oral bioavailability from the w/o microemulsionalso shown for the linear water-soluble nonapeptide

acetate (Zheng and Fulu, 2006) and dipeptide N-saminyl-N-acetylmuramic acid (Lyons et al., 2000).gastric administration of w/o microemulsion of epi-

wth factor was more effective in healing acute gastricats as compared to both intra-peritoneal and intra-eous solution administration (Celebi et al., 2002).

intestithe lip

MicstoragPatenthorse rcompabasedsolublaqueousubstra2001;of enhstratespoly(ldizedthe prowhileenviroin thisfurther(Vaze

Inwere dity levof hymicroeseparaaqueoution.

2. Dru

Phausuallymixtursions.adminsystemmicelldilutio

Drutem issolubihave dconcen

for preity in tdose ttors incapabiwatercrystalstableapplicnvironment and the permeability enhancing effect ofmponents.ulsion systems have also been claimed to improve

bility of proteins. For example, Owen and Yiv (US633,226) disclose improved chemical stability ofh peroxidase after storage in w/o microemulsions aso aqueous solution. In addition, w/o microemulsion-ia have been utilized for immobilization of waterzymes, such as lipase, in the internal, dispersedase for biocatalytic conversion of water-insoluble

in the outer non-aqueous layer (Schuleit and Luisi,amwar and Thakar, 2004). In a similar applicationng enzyme mediated catalysis of non-aqueous sub-ter soluble protein myoglobin was cross-linked tone), which was in turn covalently attached to oxi-de, in an o/w microemulsion environment such thatwas present in the water-rich external environment,eactant, styrene, was present in the internal oil-richnt. Catalysis of epoxidation of styrene by myoglobinm was higher than aqueous solution, which increasedhe presence of bicontinuous microemulsion system, 2004).hese applications hydrophilic peptides or proteinslved in the aqueous phase at or below their solubil-This review, however, will focus on solubilizationhobic molecules in SMEDDS and diluted o/wsions while preventing physical instability of drugby crystallization on storage or precipitation uponlution, with particular relevance to oral administra-

ading capacity in micelles and microemulsions

ceutical micellar and microemulsion systems aremulated as oil + surfactant cosurfactant/cosolventat exist as reverse micelles or w/o type microemul-e systems are diluted with water in vivo or beforeion. Solubilization or drug loading capacity in thesefers to the drug concentration achievable in reversed the ability of these systems to undergo aqueousmonophasic systems.ecipitation from a self-emulsifying drug delivery sys-sequence of concentration exceeding the equilibriumon capacity. Consequently, systems formulated toolubilization capacity much higher than the requiredon would be expected to show the least propensitytation in vivo. Drug loading or solubilization capac-stem also determines the minimum volume per unitan be formulated. Thus, an understanding of fac-cing drug loading capacity while maintaining the

of the system to undergo monophasic dilution withminimizing the tendency for drug precipitation orion in diluted systems is essential to the design ofappropriately low-volume systems for drug deliverys.

A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925 15

2.1. Solubilization capacity in reverse micelles

Micellar and microemulsion systems are often able to solubi-lize higher amount of drug than its individual components. Forexample, Spernath et al. reported that the solubility of lycopene,a hydrophobic carotenoid obtained from tomatoes, in the reversemicelles of (R)-(+)-limonene (limonene) and polysorbate 60(Tween 60) (4:6) was 2500 ppm, about three times higher thanin either individual component (700 ppm in (R)-(+)-limoneneand 800 ppm in Tween 60) (Spernath et al., 2002). Highersolubilization capacity in reverse micellar systems was alsonoted for phytosterol, whose solubility was 150,000 ppm in thereverse micelles of limonene and Tween 60 (4:6), about sixtimes higher than in either individual component (25,000 ppmin each) (Spernath et al., 2003). This higher capacity for sol-ubilization was attributable to the interfacial locus of drugsolubilization, which has higher solubilization capacity than thecore. Higher solubilization capacity at the interface is a functionof drugsurfactant interactions leading to drug association atthe interface. These interactions depend on the hydrophobicity,functional groups, and shape of both the drug and the surfac-tant/cosurfactant. The shape influences sub-molecular proximityor fit of interacting molecules to maximize interactions. Thus,different excipients and different grades of similar excipientscan show markedly different solubilization capacity for a givendrug.

The solubilization capacity progressively decreases uponaqueous dilution, as the micellar system passes through swollenw/o reverse micelles, to bicontinuous phase, to o/w microemul-sion system

to be caused by the change in the locus of drug solubilizationassociated with microstructural transitions during aqueous dilu-tion (Spernath et al., 2003). In addition, migration of watermiscible cosurfactant away from the interface upon aqueousdilution could lead to reduced drug solubilization capacity at theinterface. Evaluation of drug solubilization capacity at differentdilution levels allows the formulator to define the appropriatedilution range for a given formulation with minimum likelihoodof drug precipitation.

2.2. Dilutability as monophasic systems

An approach to improve the dilutability of drug containingsurfactant/oil reverse micelles with aqueous phase is to expandthe monophasic/isotropic region through a wide range of com-positions. When the expanded isotropic region covers aqueousdilutability through a range of compositions with different watercontent, called dilution line, the systems so formed have beencalled dilutable U-type microemulsions. An example of the roleof surfactant in determining the monophasic region and dilutionline are represented in Fig. 2 (Spernath et al., 2006). The dilu-tion line N73 in Fig. 2A represents 7:3 composition of the ethyllaurate/acetic acid (1:3) and phosphatidyl choline (PC)/Tween80/propylene glycol (PG) (1:3:10) axis in reverse micelles (inthe absence of water). Upon progressive addition of water, thesystem progresses to the third axis of the phase diagram alongthe dilution line N73 through the monophasic region (Fig. 2A).Therefore, both the composition of the formulation and the areaof the monophasic region are important to ensuring successful

s di

Fig. 2. Phase (A) dacid (1:3) sys s diluaxis. AT repre ce ofmonophasic r regioet al., 2006).. This reduction in solubilization capacity is thought aqueou

diagram of a 6-component system and factors influencing monophasic region.tem stabilized with mixed surfactants PC/HECO40/PG (1:3:10) and an aqueousents the percentage of monophasic region. (B) and (C) represent the influen

egion. (D) represents the variation in the percentage of isotropic or monophasiclution without breaking the microemulsions.

emonstrates 1-phase and 2-phase regions of a ethyl laurate/acetiction line N73 from the non-aqueous reverse micelles to the waterusing Tween 60 (B) versus triglycerol monooleaste (C) on then with the use of different chain length acid surfactants (Spernath

16 A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925

The role of HLB of the surfactant in determining the area ofmonophasic region is illustrated in an extreme case in Fig. 2Band C. Thsystem comcol, and Twhydrophilicwith a hydr(Fig. 2C) (micelles ofof the micr

Certainmonophasipropylene gacids, e.g.,o/w microas cosolvenphase, and/promoting

Aqueousion systemfrom w/o tinvolves ching water stheir breakHou and Sw/o microein the dispwithout coradius of ctions amonwhere soluture of theby modificresult in inction capaciattractive ftion capaciprovide uslization ofmicroemulthe spontanactions canmaintainin

By partacids alterthe spontancapacity fosystem is rture has a tlevel at theform a larga tendencyform mixedthe isotropifilm.

Use of ocant increa

depending on the type of acid used. As shown in Fig. 2D, pro-pionic acid was the most efficient in increasing the area of the

ic reroge

inssivec aciservr me

olub

g sopondvalu% o

t poldrop

theAsmul

tribuayer.

typmul

onolasurfutesolarurfathoreaseh theon tholub

ole(Mi

lizatirol

sitiomul

n oftantsandtionne swhicts, e.ath eacta

couldubilis pheen

s ofn linncree isotropic or single phase region of 5-componentposed of limonene, water, ethanol, propylene gly-een 60 (Fig. 2B) reduced significantly when thesurfactant, Tween 60 (HLB 14.9), was replaced

ophobic surfactant, triglycerol monooleate (HLB 6.2)Spernath et al., 2006). Aqueous dilution of reversethe latter system would invariably result in breakingoemulsion system into two phases.formulation approaches can lead to increase in thec region. Addition of polyols, e.g., glycerin andlycol; short-chain alcohols, e.g., ethanol; and organicpropionic acid, increase the monophasic region of

emulsions (Garti et al., 2001). These additives actts, by promoting solubility of the drug in the bulk

or cosurfactants, by affecting interfacial structure anddrug solubility at the interface.s dilutability of w/o reverse micellar or microemul-s proceeds through a series of structural changes

o bicontinuous to o/w system, which concurrentlyanges in drug solubilization capacity. Factors affect-olubilization capacity of w/o microemulsions beforedown into bicontinuous structures were reported byhah (Hou and Shah, 1987). Addition of water to amulsion system could result in water incorporation

ersed phase. The growth of microemulsion dropletsalescence during this process is limited by either theurvature of the interface or the attractive interac-g droplets (Hou and Shah, 1987). For the systemsbilization capacity for water is limited by the curva-interfacial layer, reduction in spontaneous curvatureation of the interface or the continuous phase canreased solubilization. For systems where solubiliza-

ty is limited by the critical droplet radius, reduction inorces among droplets would increase the solubiliza-ty of water (Hou and Shah, 1987). These principleseful insights to the analogous scenario of solubi-hydrophobic solute in the dispersed phase of o/w

sions. Thus, incorporating components that increaseeous curvature and/or increase soluteinterface inter-

be useful in increasing drug solubilization whileg monophasic characteristics of the system.itioning into the interface, short-chain alcohols andthe molecular structure of the interface and decreaseeous curvature, thus leading to higher solubilizationr the dispersed phase. In reverse micelles, when theich in oil and poor in surfactants, the surfactant mix-endency to partition mainly into the oil phase and itsinterface is below the concentration that is needed toe area of w/o microemulsions. Ethanol, however, hasto penetrate the interface at low surfactant content tofilms (Spernath et al., 2006). Thus, ethanol enlarges

c region by increasing the flexibility of the surfactant

rganic acids as a cosurfactant also leads to signifi-se in the isotropic region of microemulsion formation

isotrop40-hydand PGprogreorganithat obsimila

2.3. S

Drucorres

was e

used 2factanthe hystudiedsions.microewas atmonol

Themicroetant mof thecontribume, pof the sThe auto incron botof oildrug slarge meridessolubi

Thecompomicroelizatiosurfac1:1:8)a funclycope14.9),factan(Spernof surfrange

Solaqueouand Twin termdilutioupon igion in systems stabilized with PC, polyoxyethylene-nated castor oil (HECO40 or Cremophor RH40),1:3:10 weight ratio. The area of isotropic regionly decreased with increasing carbon chain length ofd (Spernath et al., 2006). This behavior is similar toed with alcohols and is postulated to proceed throughchanisms (Garti et al., 2001; Hou and Shah, 1987).

ilization capacity in diluted microemulsions

lubilization capacity in microemulsions vis-a`-vising micelles and the oil used for solubilizationated by Malcolmson et al. (1998). The authors/w microemulsions and micelles of nonionic sur-yoxyethylene-10-oleyl ether (Brij 96) to solubilizehobic drug testosterone propionate (log P 4.78) androle of the type of oil on drug solubility in microemul-shown in Table 2, drug solubility was higher insions than corresponding micelles and the oil, whichted to drug solubilization in the interfacial surfactant

e of oil significantly influenced drug solubility insions. This was due to oil penetration in the surfac-yer, causing a dilution of the polyoxyethylene region

actant that lies close to the hydrophobic region andto drug solubility. Variations in the oil molecular vol-

ity, size, and shape led to variations in its penetrationctant monolayer and influence on drug solubilization.s concluded that the ability of an o/w microemulsiondrug solubility over the equivalent micelle dependssolubility of drug in the dispersed phase, influencee nature of microemulsion droplet, and the site of

ilization within the surfactant aggregate. The use ofcular volume polar oils, e.g., caprylic acid triglyc-glyol 812), was recommended to maximize drugon in microemulsions.e of surfactant type and percent aqueous phasen on the solubilization capacity in diluted o/wsions was reported by Spernath et al. (2002). Solubi-lycopene in microemulsions stabilized by differentin 25% limonene/ethanol/Tween 60 (1:1:3 and75% water containing o/w microemulsions wasof the HLB of surfactants (Fig. 3A). Maximum

olubilization was observed using Tween 60 (HLBh reduced dramatically when more hydrophilic sur-

g., Tween 40 and Tween 20 (HLB 16.7) were usedt al., 2002). This indicated a suitable range of HLB

nt or system to maximize drug solubilization. Thisbe drug specific, but is usually 1016.

zation capacity of lycopene was also dependent on thease dilution of a 1:1:3 mixture of limonene, ethanol60 (Fig. 3B). Four different regions were identifiedlycopene solubilization capacity along the aqueous

e. The solubilization capacity decreases dramaticallyasing aqueous phase content of the system from 0

A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925 17

Table 2Solubility of testosterone propionate in micelles, various oils, and corresponding microemulsions at two different surfactant (Brij 96) concentrationsOil type Solubility in oil (%w/w) Drug contribution from oil content to

the solubility in microemulsionsSolubility in micelles/microemulsions (%w/v) at surfactant level of15% 20%

Micelles 0.000 0.365 0.430Tributyrin 8.78 0.176 0.553 0.641Miglyol 812 6.20 0.124 1.150 1.300Soybean oil 3.42 0.068 0.531 0.656Ethyl butyrate 18.64 0.373 0.471 0.486Ethyl caprylate 12.17 0.243 0.489 0.599Ethyl oleate 5.79 0.116 0.497 0.641Heptane 0.92 0.018 0.354 0.4861-Heptene 4.28 0.086 0.402 0.424Hexadecane 1.70 0.034 0.431 0.5201-Hexadecene 1.74 0.035 0.389 0.573

Abbreviations: DMTG: dimethoxytetraethylene glycol. Note: Table modified from Malcomson et al. to report only mean values. Solubility in water 0.009% (w/w).

to 20% (re(region II),reduces up

Solubilitural transireverse micstudied by sto calculatsystems widilution. ThI was relatand water mleaving lesRegion IIsystem intocial area rechanged frwas strengresults indiences solutmicelles tostate of theof 50 mLat this dilutendency fo

g p

g pra SE

es so

ty fond fo

in tg inize afulontricroegedaturcrys. Asitycy oervecon

ng mThep rea

Fig. 3. Solubmicroemulsio60 (1:1:8) antransition regigion I), remains almost unchanged from 20 to 50%increases again from 50 to 67% (region III), and thenon further dilution (region IV).zation capacity of lycopene was related to the struc-tions taking place during aqueous dilution of theelle system. Structural transitions in the system wereelf-diffusion nuclear magnetic resonance (SD NMR)e diffusion coefficients of water and limonene inth and without lycopene, as a function of aqueouse decrease in drug solubilization capacity in region

ed to increasing interactions between the surfactantolecules, with a gradual swelling of reverse micelles,

s surfactant available for interaction with the solute.was associated with gradual transformation of the

a biocontinuous phase structure, while the interfa-mains almost unchanged. Over region III, the systemom a bicontinuous to an o/w microstructure, whichthened in region IV (Spernath et al., 2002). Thesecate that the amount of aqueous phase dilution influ-e solubilization capacity upon dilution of the reverseo/w microemulsions, which is related to the structuralsystem. Assuming fasted state gastric fluid volume

, SMEDDS that show highest solubilization capacitytion would, therefore, be expected to have the least

3. Dru

Drution ofinvolvcapacidrug aditionscominminimbe help

In cand mprolontempererningsystempropentendenbe obseratedby usi2003).develor drug precipitation in vivo. forms of dr

ilization capacity in microemulsions as a function of surfactant type and aqueous dns of composition (1, solid bars) (R)-(+)-limonene/ethanol/Tween 60 (1:1:3) and 7d 75% aqueous phase. (B) represents lycopene solubilization as a function of aqueouons of the microemulsion (Spernath et al., 2002).recipitation and solute crystallization

ecipitation upon oral administration and in vivo dilu-DDS or SMEDDS formulation is a rapid process thatlute exclusion from the solution whose solubilizationr the drug has suddenly reduced. In addition to thermulation variables, this process is affected by con-he gastrointestinal tract and the fate of lipids uponcontact with gastrointestinal fluids. Approaches tond models to mimic in vivo drug precipitation couldin improving bioavailability from these systems.ast, in vitro drug crystallization from diluted micellesmulsions involves formation of solute crystals overundisturbed storage. This process is usually slow,e dependent, and influenced by such factors gov-tallization as saturation solubility of the drug in thesystem with lower drug solubility will show higherfor crystallization, and vice versa. A comparison off several formulations to crystallize over time cand upon undisturbed storage of samples under refrig-ditions, which accelerates solute crystallization, orodified in vitro tests (Gao et al., 2004; Gao et al.,

refore, modeling in vitro drug crystallization can helpdy-to-use oral and parenteral microemulsion dosage

ugs.

ilution. (A) represents the solubilization capacity of lycopene in5% aqueous phase and (2, hatched bars) limonene/ethanol/Tweens weight percent in the microemulsions in relation to the structural

18 A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925

3.1. In vivo drug precipitation

Lipid socorrespondand Zhongpermeabilication systeof bioavailsolution orprecipitatesavoidance ogoverningcles than thand micellThe disperinduced emthan that ofof a lipid-sbioavailabiVitamin E (and halofanothers, e.g.2004), and

For examlent bioavafor atovaqu4.53) (Port(Hauss et alations wasThese studing oral biothe animal

Presentaimproves oor suspensiall cases, laimprovingassessmentof drugs, bdosage fororal bioava

3.2. Predic

Developpound preset al., 2004(Dahan andpared within vivo byand the rate

The tenis often alsexample, Dperform insolubilizedity (Dahan

model (Sek et al., 2002) incorporates the use of temperature,enzymes, and pH control to simulate in vivo conditions, fol-

by uree pandsiderdigening. 4Athe a(LC

lationlatione of dvitrovivo

void

reasitly odrugin viundeaspethersuphilic

cipitentusystto c

ystementshydPMCnylp2001elli eprovug,mulchesof H

4-follationlation

DDeaseao e

echa

effietedof t

tionlutions often achieve higher oral absorption thaning solid dosage forms of hydrophobic drugs (Shen, 2006), particularly class II (low solubility, highty) compounds as per the biopharmaceutics classifi-m (Lindenberg et al., 2004). However, improvementability upon presenting a hydrophobic drug in the

emulsion form can be compromised if the drugfrom the dosage form in vivo. In several cases,

f drug precipitation could be the predominant factorimprovement of oral bioavailability from lipid vehi-e size of the dispersed phase. The SEDDS, SMEDDS,ar systems have different levels of drug dispersion.sion size, upon in vivo dilution and bile-surfactantsulsification, of SMEDDS is expected to be smallerSEDDS, which, in turn, would be smaller than that

olution of drug. The influence of dispersion size onlity has been observed for several molecules, e.g.,Julianto et al., 2000), cyclosporine (Trull et al., 1995),trine (Khoo et al., 1998); while it is limited for some

, atovaquone (Sek et al., 2006), danazol (Porter et al.,ontazolast (Hauss et al., 1998) (Table 3).ple, the self-emulsifying formulations had equiva-

ilability to corresponding lipid-solution formulationsone (log P 5.31) (Sek et al., 2006) and danazol (log Per et al., 2004) in dogs, and for ontazolast (log P 4.00)l., 1998) in rats. The bioavailability of all these formu-higher than the corresponding aqueous suspensions.

ies suggest that the role of dispersion size in improv-availability could be limited depending on the drug,species, or other overriding factors.tion of a hydrophobic drug in a dissolved formral absorption as compared to a corresponding solidon dosage form by avoiding the dissolution step. Inck of in vivo precipitation plays a predominant role inoral bioavailability of hydrophobic compounds. Theand minimization of the tendency for precipitationoth in vivo and in vitro, upon aqueous dilution of

ms is important to their utilization in improving theilability of hydrophobic drugs.

tion of in vivo drug precipitation

ment of a lipid formulation of a hydrophobic com-ents overabundance of choices of vehicles (de Smidt) and the development strategies are mostly empirical

Hoffman, 2006). Formulation choices can be com-respect to their tendency towards drug precipitationsuch empirical tests as dilutability in water in vitro

of drug crystallization.dency for in vivo drug precipitation in a formulationo evident in absorption simulation experiments. Forahan and Hoffman used an in vitro lipolysis model tovitro in vivo correlation (IVIVC) between lipolysis oflipophilic solute, vitamin D3, and oral bioavailabil-and Hoffman, 2006). The dynamic in vitro lipolysis

lowedinto thacids,is coning uncontai

Figacross

eridesformuformucentagthat inthe in

3.3. A

Incnificanin vivowaterstableThese

Anotion ofhydropas prewill evof thein vivothese sexcipi(MC),late (Hpolyviet al.,Simonthe imbic drthe forapproarationwas >formuformuto SMEto incrrats (G

3.4. M

Theinterprperiodnuclealtracentrifugation, and separation of the formulationhases: an aqueous phase containing bile salts, fattymonoglycerides along with dissolved drug (whiched available for absorption), a lipid phase contain-sted diglycerides and triglycerides, and a sedimentundissolved fatty acids (Dahan and Hoffman, 2006).represents the distribution of vitamin D3 moleculesqueous and sediment phase using long-chain triglyc-T) and medium chain triglycerides (MCT) in the. Upon 5-fold reduction of the amount of lipid in the, drug precipitation was evident with increasing per-rug in the sediment (Fig. 4B). This experiment showssimulation studies could be extrapolated to evaluate

drug precipitation tendency of the formulation.

ing in vivo drug precipitation

ng the solubilization capacity of the formulation sig-ver the desired drug concentration could help avoidprecipitation. Formulations that can be diluted with

tro without drug precipitation are likely to be morer in vivo conditions than those that are not dilutable.cts are discussed in Section 2.approach in this direction is to promote the forma-

ersaturated drug solution in vivo by incorporation ofpolymeric ingredients in the formulation that act

ation inhibitors. The supersaturated drug solutionsally precipitate due to the thermodynamic instabilityem, but if the precipitation is delayed long enoughover the drug absorption time, bioavailability froms can be improved. Several common pharmaceutical

act as precipitation inhibitors, e.g., methyl celluloseroxypropyle methylcellulse (HPMC), HPMC phtha-

P), sodium carboxymethyl cellulose (Na CMC), andyrrolidone (PVP) (Hasegawa et al., 1988; Raghavana; Raghavan et al., 2000; Raghavan et al., 2001b;t al., 1970). For example, Gao et al. demonstrated

ed oral bioavailability of an experimental hydropho-PNU-91325, with the use of 20 mg/g HPMC ination using both cosolvent and SEDDS formulation. The bioavailability improvement with the incorpo-PMC in a PEG 400 cosolvent-based formulation

d, while it was 2-fold for supersaturable SEDDSusing Cremophor EL compared with a micelleusing Tween 80 (Gao et al., 2004). In application

S formulation, inclusion of HPMC was demonstratedthe bioavailability of paclitaxel more than 9-fold int al., 2003).

nism of solute crystallization

ciency of a system to solubilize drug is commonlyin terms of the amount of drug dissolved over a shortime with reasonable degree of agitation. Whetherand crystallization would subsequently occur in such

A.S.Narang

etal./InternationalJo

urn

alofPharm

aceutics345(2007)92519

Table 3Relative bioavailability of lipid-based formulations of hydrophobic drugs

Drug name (log P value) Species tested Test product Reference product Increase in AUCFormulation AUC (Mean S.D.) Formulation AUC (Mean S.D.)

Vitamin E (log P 9.96) Humans Tween 80, Span 80, andVitamin E dissolved in palmoil in the proportion 4:2:4 toform SEDDS

AUC0 = 210.7 63.0 hg/mL Natopherol softgelatin capsules(solution in soybean oil)

AUC0 = 94.6 80.0 hg/mL 2-fold

Cyclosporine (log P 4.29) Humans SMEDDS, Neoral softgelatin capsules

SEDDS, Sandimmunesoft gelatin capsules

6.5-fold

Halofantrine (log P 9.20) Dogs SEDDS, MCT AUC0 = 5313 1956 h ng/mL SMEDDS, MCT AUC0 = 5426 2481 h ng/mL NoneSMEDDS, LCT AUC0 = 6973 2388 h ng/mL 1.3 fold

Atovaquone (log P 5.31) Dogs Solution in lipids + ethanol AUC073h = 31.8 9.3 hg/mL Aqueous suspension AUC073h = 9.4 1.0 hg/mL 3.4-foldSMEDDS,lipids + CremophorEL + ethanol

AUC073h = 31.8 8.4 hg/mL 3.4-fold

SMEDDS, lipids + Pluronic121 + ethanol

AUC073h = 33.7 13.0 hg/mL 3.4-fold

Danazol (log P 4.53) Dogs SMEDDS, LCT AUC010h = 270.5 38.5 h ng/mL Micronized powder AUC010h = 35.3 5.2 h ng/mL 7-foldSMEDDS, MCT AUC010h = 47.7 29.5 h ng/Ml 1.3-foldLipid solution, LCT AUC010h = 340.2 64.4 h ng/mL 9-fold

Ontazolast (log P 4.00) Rats SEDDS, 1:1 mix of Gelucire44/14 and Peceol

AUC08h = 752 236 h ng/mL Aqueous suspension,Tween 80 + HPMC

AUC08h = 65 15 h ng/mL 11-fold

SEDDS, 8:2 mix of Gelucire44/14 and Peceol

AUC08h = 877 104 h ng/mL 13-fold

SEDDS, Peceol AUC08h = 528 68 h ng/mL 8-foldEmulsion, soybeanoil + Tween 80

AUC08h = 1003 270 h ng/mL 15-fold

Atorvastatin (log P 6.26) Dogs SMEDDS, Labrafil,Cremophor RH40,propylene glycol

AUC024h = 2613.0 367.6 h ng/mL Lipitor Tablets 10 mg AUC024h = 1738.0 207.9 h ng/mL 1.5-fold

SMEDDS, Estol,Cremophor RH40,propylene glycol

AUC024h = 2568.3 408.0 h ng/mL Lipitor Tablets 10 mg AUC024h = 1738.0 207.9 h. ng/mL 1.5-fold

SMEDDS, Labrafac,Cremophor RH40,propylene glycol

AUC024h = 2520.81 308.4 h ng/mL Lipitor Tablets 10 mg AUC024h = 1738.0 207.9 h ng/mL 1.5-fold

Abbreviations: LCT, long-chain triglycerides; MCT, medium chain triglycerides.

20 A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925

Fig. 4. Distribution of Vitamin D3 molecules across the aqueous phase and the sediment of the dynamic in vitro lipolysis medium using high (A) or 5-times lower(B) lipid load of its long-chain triglyceride (LCT) or medium-chain triglyceride (MCT) solution. Modified from Dahan and Hoffman (Dahan and Hoffman, 2006).

a system depends on relative levels of drug solubilized vis-a`-visits saturation concentration in the system. Above saturation con-centration, the rate of nucleation would depend on actual soluteconcentration in the system and other factors, e.g., seed crystals,leading to e

Principlincreasingand Dinegloids (LaMdiagram, stion beyondfor nucleatheterogenecrystal grotion of soluis reachedimpurity ceation. The(Beattie, 19

This prinario of dsystems ascentration (with waterdrug conce(Garti et al

Fig. 5. LaMerequired for mof drug solubto immediate(LaMer and D

Assuming the saturation concentration of drug in the systemwith dilution follow the double lines as marked, reduction indrug concentration with dilution in the formulation would lead totendency for precipitation along either of lines 1, 2, or 3 depend-

on the starting drug concentration in the system. Based onount by which drug concentration in the system exceedsuratiit exfasalo

solubmulaonce

in addru

l roletions

reve

h soimitedilutule frither immediate or delayed drug precipitation.es governing solute precipitation with progressivelyconcentration in solution were elaborated by LaMerar in the study of formation of monodisperse col-

er and Dinegar, 1950). In the classical LaMerolute concentration progressively increases in solu-

saturation concentration until it reaches a thresholdion (the concentration that would lead to immediate,ous nucleation and solute precipitation). Thereafter,wth occurs on the formed nuclei leading to reduc-tion concentration until the saturation concentration(Fig. 5). Nucleation can occur heterogeneously onnters or homogeneously through spontaneous nucle-former leads to fewer, larger crystals than the latter89).

nciple could be extrapolated to the hypothetical sce-rug concentration in micellar and microemulsionillustrated in Fig. 6. This figure represents drug con-y-axis) in a reverse micelle upon progressive dilution(x-axis) to form an o/w microemulsion. Saturationntration in the system upon dilution is non-linear., 2006; Spernath et al., 2002; Spernath et al., 2003).

ing upthe amthe satwhichlead todilutedin the

Fordrug cThus,inhibitcruciacentra

3.5. P

Higis of lphasemolecr diagram representing the time dependence of concentrationonodispersity. This figure illustrates the supersaturation region

ility between the saturation and the concentration that would lead, heterogeneous nucleation in the case of monodisperse colloidsinegar, 1950).

Fig. 6. A hypsystems depicdilution. Withthe system ovlead to differeon concentration and the length of dilution line alongceeds, dilution along line 1 would be expected toter drug precipitation than line 2, while a systemng line 3 would be expected to maintain the drugilized state throughout.tion modifications tend to influence the saturationntration in the SMEDDS as well as upon dilution.dition to formulation approaches to minimize and

g precipitation, starting drug concentration plays ain determining the window of permissible drug con-upon dilution that do not lead to precipitation.

nting drug crystallization

lubilization capacity of reverse micelles, however,d use in improving oral bioavailability if aqueousion were to cause migration of the solubilized drugom interface to the outer aqueous phase, followed byothetical set of scenarios for SEDDS, SMEDDS, and micellarting different possibilities for drug supersaturation upon aqueousthe defined saturation drug concentrations at each composition of

er the dilution curve, different starting drug concentrations wouldnt outcomes in drug precipitation upon dilution.

A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925 21

drug precipitation, and uncontrolled absorption (Spernath et al.,2006). It is important, therefore, to develop systems that main-tain high dmicelles.

The proous dilutiomicroemuldocumentsDrug crysthydrophobple physicaupon additproposed tcomplete dtallizationaqueous enthe observasolubilizerslene glycolglycol help

Anothercipitation ovalue of sursoluble sursurfactantsthan 10. Ch2004/0052the greatestain a hydrovalues greasolubilize himprovemedrug uponsmall quanand the esssolvent for

The tendin studiestal forms oFuredi-Milby crystalli1999). Theof the artifinate as a suthe primarycould be swater/oil inof aspartamsion to 5 Cnucleationor at the inlocation offace leads tinitiated in

For phation is thereflected in

lization at a given temperature. In the o/w microemulsionssolubilizing a hydrophobic solute, the primary location of drug

ysteher

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uencpolylismavairug solubilization upon aqueous dilution of reverse

blem of drug crystallizing out of solution upon aque-n of systems that form micelles, emulsions, andsions has been widely discussed in several patent, which also discuss ways to address this issue.allization of aqueous oil/surfactant solutions of theic drug fenofibrate (log P 5.58) was assessed by sim-l observation of appearance of crystals immediatelyion of water (US 2004/0005339 A1). The authorshe use of a water-miscible solubilizer that allowsrug dissolution and prevents or minimizes drug crys-in the formulation upon coming in contact with anvironment. Liang et al. (US 7,022,337 B2) extendedtion for possible crystallization up to 24 h. The use ofsuch as N-alkyl derivatives of 2-pyrrolidone, ethy-monoether, C812 fatty acid esters of polyethylene

ed maintain drug in solution upon dilution with water.approach that has been proposed to prevent the pre-f drug upon aqueous dilution is to balance the HLBfactants used in the formulation. Preferentially water-factants have an HLB value of greater than 10, whilethat have higher solubility in oil have a value of lessacra-Vernet et al. describe in US patent application

824 A1 that the risk of recrystallization of drug ist when using hydrophilic SEDDS, i.e., which con-philic surfactant and co-surfactant with having HLBter than 12. Although these formulations do help toydrophobic drugs, they may not lead to the desirednt in bioavailability. To prevent crystallization of theaqueous dilution, these authors proposed the use oftities of lipophilic phase with very low HLB values,ential presence of a cosurfactant which is also a goodthe drug.ency for solute crystallization is amply demonstrated

that have deliberately sought to achieve new crys-f molecules by using microemulsions. For example,hofer et al. prepared new polymorphs of aspartamezation from microemulsions (Furedi-Milhofer et al.,authors produced water/isooctane microemulsions

cial sweetener aspartame using diisooctyl sulfosucci-rfactant. Amount of surfactant and temperature werefactors determining the amount of aspartame which

olubilized. Aspartame was primarily located at theterface and acted as a cosurfactant. Crystallizatione was achieved by slow cooling of the microemul-. For drugs solubilized in the w/o microemulsions,could occur in either the dispersed water dropletsterface. The type of crystals formed depends on thethe drug in the system. Crystallization at the inter-

o the formation of long crystals, while crystallizationthe dispersed phase results in short crystals.rmaceutical applications, preventing the crystalliza-

desired goal. The tendency for crystallization isthe crystallization temperature or time to crystal-

in the scases w

(and sing aninterfaation.emulsiimity aand thchoiceresembthe rat

3.6. C

A ction, cincreasment opH andbution(Li etcombibate 20flavopan app(Li et athe incincreaspropordol solacidicsion fosolubil

Aquboth tsolutiothe precentrat2000).dent othe sosalts asurfactTheseof ioni

4. Oth

Intract, dis infle.g., limetabothe biom would influence the preferred site of nucleation. Ine drug resides at the interface along with surfactantimes also cosurfactant) molecules, molecular pack-ucture of the amphiphilic surfactant and drug at theould play a role in facilitating or inhibiting nucle-

example, resemblance of molecular structure of theo that of the crystallizing solute, which affects prox-acking of solute molecules, could increase nucleatione of crystallization (Davey et al., 1996). Therefore,surfactant with reference to its molecular structuree to that of the hydrophobic solute could influencedrug crystallization from a microemulsion.

ined use of solubilization approaches

ination of pH control with the use of micelliza-ency, or complexation is the first choice approach to

e solubility of hydrophobic drugs. Theoretical treat-increase in solubility observed with a combination ofer approaches has involved segregation of the contri-e ionized and the unionized species to solubilization1999a). The increase in solubility achieved with an of cosolvent (ethanol) or micellization (polysor-th pH modulation was demonstrated by Li et al. usingl as a model compound, which is weakly basic witht pKa of 5.68 and intrinsic solubility of 0.025 mg/mL999b). Flavopiridol solubility increased linearly withe in surfactant content of solution, with a slope thatith the reduction in pH. In contrast, increasing the

of cosolvent led to logarithmic increase in flavopiri-ity at all pH conditions, with the greatest increase at

hese approaches may be incorporated in microemul-lation to increase the saturation concentration andon capacity of the system.s solubility of a nonelectrolyte is also influenced bype and concentration of the electrolyte present inhe reduction in solubility of a hydrophobic drug ine of a salt or electrolyte is a function of salt con-as described by the Setschenow equation (Ni et al.,s salting-out effect of electrolytes is also depen-molar volume, aqueous solubility, and the log P of

(Shukla et al., 2003). Presence of electrolytes andffects the critical micellar concentration (CMC) ofand the structure of micelles and microemulsions.iderations should be taken into account with the usepharmaceutical excipients in these formulations.

actors inuencing bioavailability

tion to drug precipitation in the gastrointestinalbioavailability from self-emulsifying formulationsed by biopharmaceutical properties of the lipid,sis; and the drug, e.g., lymphatic transport, enteric, and efflux. Lipid-based formulations can influence

lability of hydrophobic drugs through several mech-

22 A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925

anisms, e.g., stimulation of pancreatic and biliary secretions,prolongation of gastrointestinal residence time, stimulation oflymphaticreduced me

4.1. Lymph

Lipid dsion of thrate of mlong-chainence the bidosage fortion cansurfactantspolyoxyle-and polyso6,096,338)tion. Ratebe compartransport, hof lipolysis

Dahan atriacetin),tex 355)),MCT, andtion as a fuand lipolysThey selec9.1) as hydicant lympthe formulstrongly colations, whdid not corThese resuin enterocyport pathwlymphatic tthat have siability of achoice of emaceutical

4.2. Inhibi

Absorbeexposed to(CYP3A4)lumen bycyte membbiopharmainhibitiondients. Forpolyethylenbeen showninclusion i

increase the bioavailability for drugs which are known substratesof P-gp efflux pumps.

ispe

sentilationcom

agepersze omu

availilarlfyinextehero

ted oin Eindisorpn wahowtaminbeinbioa

dispe

nclu

id-bahydn, ear symine ofher ihobin v

stitumictheuse

popuular eed thphaysteed innpre

ug-reingdru

l HLand

ort oDS,transport, increased intestinal wall permeability, andtabolism and efflux pump activity.

atic transport and lipolysis

igestion in the formulation increases the disper-e drug, which promotes its absorption. Lipolysisedium chain triglycerides (MCT) is higher thantriglycerides (LCT), which has been shown to influ-oavailability of hydrophobic drugs from lipid-basedms. Bioavailability from a lipid-based formula-be reduced by the use of lipolysis inhibiting, e.g., polyoxyethylene-10-oleoyl ether (Brij 96),35-castor oil (Cremophor EL), Cremophor RH40,rbate 80 (Crillet 4) (US patents 5,645,856 andin cases where lipolysis is important to drug absorp-of lipolysis of various lipids and formulations caned in vitro. The effect of lipids on lymphatic drugowever, can overwhelm the difference in their rate.nd Hoffman evaluated the impact of using short (C2,medium (C810, glyceryl tricaprylate/caprate (Cap-and long-chain (C18, peanut oil) triglycerides (SCT,LCT, respectively) on hydrophobic drug absorp-nction of lymphatic transport of the drug moleculeis of the formulation (Dahan and Hoffman, 2006).ted progesterone (log P 4.0) and vitamin D3 (log Prophobic drugs, of which only the latter has signif-hatic transport. Bioavailability of progesterone fromations followed the trend MCT > LCT > SCT whichrrelated with in vitro lipolysis data of these formu-ile that of vitamin D3 was LCT > MCT > SCT andrelate with the lipolysis data (MCT > LCT > SCT).lts were explained as a stimulation of lipid turnovertes by LCT, which led to increased lymphatic trans-ay capacity (Dahan and Hoffman, 2006). Increasedransport can also reduce hepatic metabolism of drugsgnificant first pass effect. Thus, to maximize bioavail-hydrophobic drug from the lipidic formulation, the

xcipients should also take into consideration biophar-properties of the drug.

tion of drug efux

d drug molecules entering the enterocyte aremetabolizing enzymes, e.g., cytochrome P-450 3A4, or can be secreted back into the gastrointestinalP-glycoprotein (P-gp) efflux pumps on the entero-rane. The impact of formulation ingredients on theceutical properties of drugs is also illustrated by theof drug efflux pumps by certain formulation ingre-

example, common pharmaceutical excipients likee glycol, Tween 80, and Cremophor EL, haveto inhibit P-gp activity (Hugger et al., 2002). Their

n the formulation, therefore, can be expected to

4.3. D

Preformution asadvantthe dission siSandimits bio

Simemulsihigher(NatopconsisVitamresultsand abficatiowere s

the Vithingshigherlower

5. Co

Lipery ofsolutiomicelloral adthe sizand othydroption ofof conlar andappear

Theinglymolecreviewtion onthese sobservoften uand drgoverntion ofoveralpumpstranspSMEDrsion size of emulsions

ng the drug in the dissolved form using lipid-baseds provides significant improvement of oral absorp-

pared to an oral solid or suspension dosage form. Thiscan be further improved in several cases by reducingion size of the dosage form. The reduction in disper-f cyclosporine A (log P 4.29) SEDDS formulation,ne, to its SMEDDS formulation, Neoral, improvedability by 6.5-fold (Trull et al., 1995) (Table 1).y, Julianto et al. (2000) observed that the self-g formulation of Vitamin E (log P 9.96) had 3-foldnt of absorption than its solution in soybean oill soft gelatin capsules). The SEDDS formulationf Tween 80, sorbitan monooleate (Span 80), anddissolved in palm oil in the proportion 4:2:4. Thesecated that, in addition to bile mediated emulsificationtion mechanism, formulation-induced in vivo emulsi-s useful in enhancing drug absorption. Similar resultsn by Yap and Yuen for tocotrienols, which belong to

E family (Yap and Yuen, 2004). Thus, given otherg equal, SMEDDS formulation is expected to havevailability than the SEDDS formulation because ofrsed phase size.

sions

sed systems are a promising choice for the deliv-rophobic molecules. These systems could be lipidmulsions, microemulsions, SEDDS, SMEDDS, orstems. These systems avoid the dissolution step uponistration and differ from one another with respect tothe dispersed phase and the content of surfactant

ngredients. They help improve the bioavailability ofic drugs through several mechanisms, e.g., facilita-ivo dispersion through the added surfactant, lipolysisent lipids, increased lymphatic transport, etc. Micel-roemulsion systems, being the most dispersed of all,most promising.of lipid-based delivery systems has become increas-lar for pre-clinical studies since most of the newntities are highly hydrophobic. Several studies havee formation of these systems, the role of composi-

se diagram, and drug release and bioavailability fromms. While improved drug entrapment and release is

almost all cases, improvement in bioavailability isdictable. Several studies have focused on formulationlated biopharmaceutical aspects that are important inoral bioavailability. These factors include precipita-g in vivo, digestability of lipids in the formulation,B of surfactant mix in the system, intestinal effluxmetabolizing enzymes, contribution of lymphatic

f drug to its absorption, etc. The design of SEDDS,and micellar systems presents a plethora of choices

A.S. Narang et al. / International Journal of Pharmaceutics 345 (2007) 925 23

that appear equivalent on surface and are usually selected empir-ically. Incorporation of these formulation and biopharmaceuticalconsideratitheir in viv

Amongthese systeplays the pneed to beand micellabove, duesystems forthis aspectrationale fofrom the syhave predithis risk.

Some keing these nsystem cantration, soconcentratiThe aspectconcentratimicroemulhave beento predict tprecipitatioin the formby the form

These smodels to pcipitation moutcome ofability of h

Acknowled

We thanmanuscript

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