Conventional and Alternative Pharmaceutical Methods to Improve Oral Bio Availability of Lipophilic...

Asian Journal ofPharm aceut ics

CONVENTIONAL AND ALTERNATIVE PHARMACEUTICAL METHODS TO IM-PROVE ORAL BIOAVAILABILITY OF LIPOPHILIC DRUGS

BHUPENDRA G. PRAJAPATI AND MADHABHAI M. PATEL

S. K. Patel College Of Pharmaceutical Education & Research, Ganpat Vidyanagar, Ganpat University, Kherva.

Pin: 382711, Mehsana, Gujarat, India.

E-mail: [email protected] and [email protected].

ABSTRACT

Out of newly discovered drugs m ore then 40 % drugs are lipophilic and out of which up to 40 % of

pharmacologically active new molecules failed to reach to market only due to little or no water solubility;

a serious challenge for the successful development and commercialization of new drugs in the pharma-

ceutical industry. Therefore various formulation strategies have been investigated to improve the solu-

bilit y and the rate of dissolut ion to enhance the oral bioavailabilit y of lipophilic drugs. I n the present

review the different approaches discussed to overcome this problem, and successfully deliver the lipo-

philic drug for mankind.

Keywords: Lipophilic, bioavailability, dissolution, solubility

INTRODUCTIONIt is one of the major challenges to synthesize any newmolecule, which is pharmacologically active for the re-searchers and pharmaceutical companies. It not onlytakes a long time but also consumes a lot of money.Out of this research around 40% of lipophilic drug can-didates fail to reach market although exhibiting poten-tial pharmacodynamic activities.1, 2 No matter how ac-tive or potentially active a new molecular entity (NME)is against a particular molecular target, if the NME isnot available in solution at the site of action, it is not aviable development candidate. As a result, the devel-opment of many exciting NMEs is stopped before theirpotential is realized or confirmed because pharmaceu-tical companies cannot afford to conduct rigorous pre-clinical and clinical studies on a molecule that does nothave a sufficient pharmacokinetic profile due to poorwater solubility. Even some of the lipophilic drugs onthe market have to be administered at high doses. Morethan 90% of drugs approved since 1995 have poor solu-bility, poor permeability, or both 3. A marketed drug withpoor water solubility can still show performance limita-tions, such as incomplete or erratic absorption, poorbioavailability, and slow onset of action. Effectivenesscan vary from patient to patient, and there can be astrong effect of food on drug absorption. Finally, it maybe necessary to increase the dose of a poorly solubledrug to obtain the efficacy required.

Although pharmaceutical companies have been able toovercome difficulties with very slightly soluble drugs,those with aqueous solubility of less than 0.1 mg/mlpresent some unique challenges. These drugs are par-ticularly good candidates for advanced solubilizationtechnologies developed by companies specializing indrug delivery. These strategies include the solubiliza-tion and surfactants, the use of different polymorphic/amorphic drug forms, the reduction of drug particle size,the complexation (e.g., cyclodextrins) and the forma-tion of solid drug solutions/dispersions.4, 5

Solubilization and SurfactantsOne approach to increase the bioavailability of lipophilicdrugs is the solubilization of the drugs by means of pHadjustment, cosolvent, microemulsification, self-emulsi-fication, micelles, liposomes and emulsions.6 Each hasits advantages and limitations.

pH adjustmentpH adjustment is the simplest and most commonly usedmethod to increase water solubility of ionizable com-pounds. However, this salt formation is infeasible forunionized compounds. The formed salts may also con-verse to respective acid or base forms in gastrointesti-nal-tract (GIT).

ColsolventColsolvents are the mixtures of miscible solvents often

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used to solubilize lipophilic drugs. The solubilizing ex-cipients used in commercially available oral and inject-able formulations are listed in Table 1. Currently, thewater-soluble organic solvents are polyethylene glycol400 (PEG 400), ethanol, propylene glycol, and glycerin.For example, Procardia® (nifidipine) was developed byPfizer contains glycerin, peppermint oil, PEG 400 andsodium saccharin in soft gelatin capsules. The water-insoluble solvents include long-chain triglycerides (i.e.peanut oil, corn oil, soybean oil, sesame oil, olive oil,peppermint oil, hydrogenated vegetable oil and hydro-genated soybean oil), medium-chain triglycerides(Miglyol 812), beeswax, d-a- tocopherol (vitamin E) andoleic acid. Progesterone is a water-insoluble steroid andis solubilized in peanut oil (Prometrium®).

MicroemulsionMicroemulsion is a thermodynamically stable iso-tropi-cal dispersion composed of a polar solvent, oil, a sur-factant and a cosurfactant. The formation ofmicroemulsions is spontaneous and does not involvethe input of external energy. One theory considers nega-tive interfacial tension while another considers swollenmicelles. The surfactant and the cosurfactant alternateeach other forming a mixed film at the interface contrib-uting to the stabil ity of the microemulsion.Microemulsions are potential drug delivery systems forpoorly water-soluble drugs due to their ability to solu-bilize the drugs in the oil phase, thus increasing theirdissolution rate. 7 Even if the microemulsions are dilutedafter oral administration below the critical micelles con-centration (CMC), the resultant drug precipitates havea fine particle size allowing enhanced absorption.8

Self EmulsificationIn the absence of external phase (water), the mixtureof oil, surfactant, cosurfactant, one or more hydrophilicsolvents and cosolvent forms a transparent isotropicsolution that is known as the self-emulsifying drug de-livery system (SEDDS). This forms fine O/W emulsionsor microemulsions spontaneously upon dilution in theaqueous phase and is used for improving lipophilic drugdissolution and absorption 9, 10 The self-emulsificationprocess is specific to the nature of the oil/surfactantpair, surfactant concentration, oil/surfactant ratio andtemperature at which self-emulsification occurs. Theease of emulsification could be associated with the easeof water penetrating into the various liquids crystallineor gel phases formed on the surface of the droplet. A

few parameters have been proposed to characterizethe self-emulsifying performance including the rate ofemulsification, the emulsion size distribution and thecharge of resulting droplets. Among them, emulsiondroplet size is considered to be a decisive factor in self-emulsification/ dispersion performance, since it deter-mines the rate and extent of drug release and absorp-tion.11 In addition, positively charged emulsion dropletscould be obtained by incorporation of a small amount ofcationic lipid (oleylamine) into such system. 10, 12 The oralbioavailability of progesterone was significantly en-hanced in rats by forming positively charged emulsionin comparison to the corresponding negatively chargedformulation. 12

One of the advantages of SEDDS in relation to scale-upand manufacture is that they form spontaneously uponmixing their components under mild agitation and theyare thermodynamically stable. The drawbacks of thissystem include chemical instabilities of drugs and highsurfactant concentrations. The large quantity of surfac-tant in self-emulsifying formulations (30-60%) irritatesGIT. Consequently, the safety aspect of the surfactantvehicle had to be considered. Moreover, volatilecosolvents in the conventional self-emulsifying formu-lations are known to migrate into the shells of soft orhard gelatin capsules, resulting in the precipitation ofthe lipophilic drugs. As an example of self-emulsifica-tion, Neoral® is composed of ethanol, corn oil-mono-ditriglycerides, Cremophor RH 40 and propylene glycol.It exhibits less variability and better drug uptake com-pared to Sandimmune®. There is a long list of watersoluble, insoluble and surfactants, which can use assolubilizing excipients. 13

Polymeric Modification (Polymorphs)Polymorphs are different crystalline forms of a drug that

may have different physicochemical properties and bio-

logical activities, such as shelf-life, melting point, vapor

pressure, solubil ity, morphology, density and

bioavailability. 14, 15 Metastable forms are associated with

higher energy with increased surface area, subsequently

solubility, bioavailability and efficacy. 15, 16 With regard to

bioavailability, it is preferable to change drug from crys-

tal forms into metastable or amorphous forms. How-

ever, the possibility of a conversion of the high energy

amorphous or metastable polymorph into a low energy

crystal form having low solubility cannot be ruled out

2 Volume 1, Issue 1, April - June, 2007

Asian Journal ofPharm aceut ics Review Art icles

during manufacture and storage. It is preferable to de-

velop the most thermodynamically stable polymorph of

the drug to assure reproducible bioavailability of the

product over its shelf-life under a variety of real-world

storage conditions. For instance, ritonavir is the active

ingredient in Norvir®, a protease inhibitor used to treat

HIV/AIDS. It was launched by Abbott Laboratories in

1996 as an amorphous semisolid dispersion consisting

of medium chain triglycerides, polyoxyl 35 castor oil, cit-

ric acid, ethanol, polyglycolyzed glycerides, polysorbate

80, propylene glycol and 100 mg of ritonavir. The disso-

lution and the oral bioavailability were decreased due

to crystallization of amorphous ritonavir into an insoluble

crystal form during storage. This polymorph (form II)

was 50% less soluble than the original form in the mar-

ket, and caused the drug to fail its regulatory dissolu-

tion specifications. Finally, the drug was relaunched with

the form II polymorph in a soft gelatin formulation that

required refrigeration. Therefore, it is important to note

that the selection of a polymorph of a drug should bal-

ance between solubility and stability to maintain its

potency over the shelf-life period.

Particle Size ReductionMicronization or nanonization is one of the most prom-ising approaches to improve the bioavailability of lipo-philic drugs by an increase in surface area and satura-tion solubility via reduction of the particle size to lessthan 1µ .10 Such size reduction cannot be achieved bythe conventional milling techniques. Patented engineer-ing processes have come up based on the principles ofpearl milling (NanoCrystals®), high-pressure homogeni-zation (DissoCubes®), solution enhanced dispersion bysupercritical fluids (SEDS), rapid expansion fromsupercritical to aqueous solution (RESAS), spray freez-ing into liquid (SFL) and evaporative precipitation intoaqueous solution (EPAS). 17

Pearl millingBased on pearl milling the drug microparticles are groundto nanoparticles (< 400 nm) in between the moving mill-ing pearls. The milling efficiency is dependent on theproperties of the drug, the medium and the stabilizer.Rapamune®, an immune suppressant agent, is the firstFDA approved nanoparticle drug using NanoCrystals®technology developed by Elan Drug Delivery. Emend®is another product containing 80 or 125 mg aprepitantformulated by this technique.

Overall in general the limitation of the pearl milling pro-cess is the introduction of contamination to the productfrom the grinding material, batch-to-batch variations andthe risk of microbiological problems after milling in anaqueous environment.

High-pressure homogenizationDissoCubes® manufacture involves dispersing a drugpowder in an aqueous surfactant solution and passingthrough a high-pressure homogenizer, subsequentlynanosuspensions are obtained. The cavitation forceexperienced is sufficient to disintegrate drug frommicroparticles to nanoparticles. The particle size is de-pendent on the hardness of the drug substance, theprocessing pressure and the number of cycles applied.The possible interesting features of nanosuspensionsare, 18:

Increase in saturation solubility and dissolution

rate of drug

Increase in adhesive nature, thus resulting in

enhanced bioavailability

Increase the amorphous fraction in the particles,

leading to a potential change in the crystallinestructure and higher solubility

Possibil i ty of surface modification of

nanosuspensions for site-specific delivery

Possibility of large-scale production, the prereq-

uisite for the introduction of a delivery systemto the market

However, only brittle drug candidates might be brokenup into nanoparticles by this technique. A few pointshas to be considered, such as chemical instability of frag-ile drugs under the harsh production conditions, Ostwaldripening in long-term storage, toxicity of surfactants,redispersibility of the dried powder, batch-to-batch varia-tion in crystallinity level and finally the difficulty of qual-ity control and the stability of the partially amorphousnanosuspensions.

Solution enhanced dispersion by thesupercritical fluids (SEDS)

The SEDS process was developed and patented by the



Review Art icles

University of Bradford.19 The use of a coaxial nozzleprovides a means whereby the drug in the organic sol-vent solution mixes with the compressed fluid CO2(antisolvent) in the mixing chamber of the nozzle priorto dispersion, and flows into a particle-formation vesselvia a restricted orifice. Such nozzle achieves solutionbreakup through the impaction of the solution by ahigher velocity fluid. The high velocity fluid creates highfrictional surface forces, causing the solution to disinte-grate into droplets. A wide range of materials has beenprepared as carriers of microparticles and nanoparticlesusing the SEDS process 19. A key step in the formationof nanoparticles is to enhance the mass transfer ratebetween the droplets and the antisolvent before thedroplets coalesce to form bigger droplets. In anotherstudy, a significant decrease in the particle size isachieved by using the ultrasonic nozzle-basedsupercritical antisolvent process.20, 21

Rapid expansion from supercritical to aqueoussolution (RESAS)This process induces rapid nucleation of the supercriticalfluid dissolved drugs and surfactants resulting in par-ticle formation with a desirable size distribution in a veryshort time. The surfactants in the supercritical fluid sta-bilize the newly formed small particles and suppressany tendency of particle agglomeration or particle growthwhen spraying this solution (drug + surfactant + CO2)into an aqueous solution containing a second surfacemodifier.22, 23 The low solubility of poorly water solubledrugs and surfactants in supercritical CO2 and the highpressure required for these processes restrict the util-ity of this technology in pharmaceutical industry.

Spray freezing into liquid (SFL)The SFL technology was developed and patented bythe University of Texas at Austin in 2003 and commer-cialized by the Dow Chemical Company. This techniqueinvolves atomizing an aqueous, organic, aqueous-or-ganic cosolvent solution, aqueous-organic emulsion orsuspension containing a drug and pharmaceutical ex-cipients directly into a compressed gas (i.e. CO2, he-lium, propane, ethane), or the cryogenic liquids (i.e. ni-trogen, argon, or hydrofluoroethers). The frozen par-ticles are then lyophilized to obtain dry and free-flow-ing micronized powders 24. Using of acetonitrile as thesolvent increased the drug loading and decreased thedrying time for lyophilization. The dissolution rate wasremarkably enhanced from the SFL powder contained

amorphous nanostructured aggregates with high sur-face area and excellent wettability.25

Evaporative precipitation into aqueous solution(EPAS)The EPAS process utilizes rapid phase separation tonucleate and grow nanoparticles and microparticles oflipophilic drugs. The drug is first dissolved in a low boil-ing point organic solvent. This solution is pumpedthrough a tube where it is heated under pressure to atemperature above the solvent's boiling point and thensprayed through a fine atomizing nozzle into a heatedaqueous solution. Surfactants are added to the organicsolution and the aqueous solution to optimize particleformation and stabilization. In EPAS, the surfactant mi-grates to the drug-water interface during particle for-mation, and the hydrophilic segment is oriented towardsthe aqueous continuous phase.4 The hydrophilic stabi-lizer on the surface inhibits crystallization of the grow-ing particles and therefore facilitates dissolution rates.

ComplexationCyclodextrins and their derivatives have been employedas complexing agents to increase water solubility, dis-solution rate and bioavailability of lipophilic drugs fororal or parenteral delivery.26 The solubility enhancementfactors of pancratistatin, hydrocortisone, and paclitaxelare 7.5, 72.7 and 99000 by forming complexes withcyclodextrin derivatives.27 The lower the aqueous solu-bility of the pure drug, the greater the relative solubilityenhancement obtained through cyclodextrin complex-ation. Pharmaceutical applications of cyclodextins in drugsolubilization and stabilization 27, in vivo drug delivery28, toxicological issues and safety evaluation and mecha-nisms of cyclodextrins modifying drug release from poly-meric drug delivery systems have been previously re-viewed. Commercially available cyclodextrin based phar-maceutical products enumerated in Table 1 and manyare waiting for approval.29 Cyclodextrins are a group ofcyclic oligosaccharides obtained from enzymatic degra-dation of starch. The three major cylcodextins -, ß-,

and - (CD) are composed of six, seven, and eight D-

(+)-glucopyranose units. These agents have a torusstructure with primary and secondary hydroxyl groupsorientated outwards. Consequently, cyclodextrins havea hydrophilic exterior and a hydrophobic internal cavity.This cavity enables cyclodextrins to complex guest drugmolecules and hence alters the properties of the drugssuch as solubility, stability, bioavailability and toxicity



profiles.30 The forces driving complexation were attrib-uted to (i) the exclusion of high energy water from thecavity, (ii) the release of ring strain particularly in thecase of -CD, (iii) Vanderwall s interactions, and (iv) hy-drogen and hydrophobic bindings (Ross and Rekharsky,1996). ß-CD, the most widely used native cyclodextrins,is limited in its pharmaceutical application by its lowaqueous solubility (1.85 g/100 ml, 25°C), toxicity profileand low aqueous solubility of the formed complexes.Accordingly, derivatives such as hydroxypropyl-ß-CD (HP-ß- CD; Enapsin®) and sulphobutylether-ß-CD (SE-ß-CD;Captisol®) have been developed to produce more wa-ter-soluble and less toxic entities.

Solid solutions/dispersionsSolid dispersion was firstly introduced to overcome thelow bioavailability of lipophilic drugs by forming of eu-tectic mixtures of drugs with water-soluble carriers. Itwas defined as the dispersion of one or more activeingredients in an inert carrier matrix in solid-state pre-pared by melting (fusion), solvent or melting-solventmethod More than 500 papers have been published onthe subject and various materials are employed as drugcarriers. Despite an active research interest, the num-ber of marketed products arising from this approach isdisappointing mainly caused by the physical and chemi-cal instability and scale-up problems.31 Only two com-mercial products, a griseofulvin in polyethylene glycol8000 solid dispersion (Gris-PEG, Novartis) and a nabilonein povidone solid dispersion (Cesamet, Lilly) were mar-keted during the last four decades following the initialwork of Sekiguchi and Obi.32

CarriersMany water-soluble excipients were employed as carri-ers of solid solutions/dispersions. Among them, poly-ethylene glycols (PEG, Mw 1500-20000) were the mostcommonly used due to their good solubility in water andin many organic solvents, low melting points (under65°C), ability to solubilize some compounds and im-provement of compound wettability. The marketed Gris-PEG is the solid dispersion of griseofulvin in PEG 8000.The others carriers include polyvinyl pyrrolidone (PVP),polyvinylalcohol (PVA), polyvinylpyrrolidonepolyvinylacetate copolymer (PVP-PVA), hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC),urea, Poloxamer 407, sugars, emulsifiers (SDS, Tween80) and organic acids (succinic acid and citric acid). Be-cause of the rapid dissolution of the water-soluble car-

riers than the drugs, drug-rich layers were formed overthe surfaces of dissolving plugs, which prevented fur-ther dissolution of drug from solid dispersions. There-fore, surface-active or self-emulsifying agents includingbile salts, lecithin, lipid mixtures, Gelucire 44/14 33 andVitamin E TPGS NF 34 were used as additional additives,acting as dispersing or emulsifying carriers for the liber-ated drug to prevent the formation of any water-in-soluble surface layer. In addition, the release behav-iors of many drugs are also improved by using water-insoluble polymers such as crospovidone 35, 36 and en-teric polymers such as hydroxypropyl methylcellulosephthalate (HPMCP), cellulose acetate phthalate (CAP),Eudragit® L100 and S100 (Takada et al., 1989) andEudragit® E. 37

Controlled PrecipitationControlled precipitation is a particle engineering tech-

nology that creates crystalline nanostructured drug

particles with rapid dissolution rates. With this technol-

ogy, the drug is dissolved in a suitable solvent then

precipitated into an aqueous solution in the presence

of crystal growth inhibitors to form drug nanoparticles.

Particles prepared by controlled precipitation have the

advantage of a narrower particle size distribution as

compared to particle size reduction technologies, such

as wet milling. The process is fast, continuous, and scal-

able with conventional process equipment. Levels of

residual solvents are low, and the excipients used are

pharmaceutically acceptable. The danazol powder pre-

pared by controlled precipitation shows substantially

improved bioavailability compared to the drug as-re-

ceived (micronized danazol). Tablets prepared on a

Carver press from precipitated danazol (equivalent to

200 mg danazol) formulated with microcrystalline cellu-

lose and carboxymethylcellulose (47.5:47.5:5) show

further enhancement in bioavailability. The increased

bioavailability observed with the control is due to an

excipient effect that enhances wettability of the pow-

der.38

Ultra-Rapid FreezingUltra-rapid freezing is a novel, cryogenic technology that

creates nanostructured drug particles with greatly en-

hanced surface area. The technology has the flexibility

to produce particles of varying particle morphologies,

based on control of the solvent system and process

conditions.



Review Art icles

The technology involves dissolving a drug in a water-miscible or anhydrous solvent along with a stabilizeracting as a crystal growth inhibitor. The drug/stabilizersolution is then applied to a cryogenic substrate. Thesolvent is removed by lyophilization or atmosphericfreeze-drying, resulting in highly porous, agglomerated

particles. As with controlled precipitation, this processuses pharmaceutically acceptable solvents, excipientsand conventional process equipment making it fast andscalable. An additional feature is that polymer absorp-tion on the crystal surface upon freezing aids reductionof Ostwald ripenin, e.g. Ketoconazole.38


Table 1: Cyclodextrin based commercially available products

Cyclodextrin/Drug

SE7 - ß- CD ( CAPTI SOL) /

ZipradidoneVoriconazole

- CD

PG1, Alprostadil

OP-1206Cefotiam hexetil HCl

ß-CD

PiroxicamPGE2BenexateIodineDexamethasone GlyteerNitroglycerin NimesulideTiaprofenic acid OmeprazoleME 1207 Cephalosporin

- CD

HP-ß-CD (Encapsin) ItraconazoleCisapride Mitomycin

Route

IMIV

IV

OralOral

Oral, RectalBuccalOralTopicalDermalBuccalOralOralOralOral

Oral, IVRectal IV

Market

Europe, USAEurope, USA

Europe, Japan,USA

JapanJapan

EuropeJapanJapanJapanJapanJapanEuropeEuropeEuropeJapan

Europe, USAEurope USA

Trade names

Zeldox, GeodonVfend

Prostanding,Prostavasin,EdexOpalmonPansporin T

Brexin, Cycladol,Brexidol Prostarmon EUlgut, LonmielMena-GalgleGlymesason Nitropen

Nimedex, Mesulid FastSurgamylOmbetaMeiact

SporanoxPrepusidMitozytrex

CONCLUSIONBy using one of the above techniques many lipophilicdrug were utilized successfully and will going to be manymore in future. The success ratio may depend on manyfactors from pilotization of techniques to uniformity ofthe product, as well as characterization. However, in fu-ture it may be possible to utilize all the NMEs, no matterwhat their properties are, if they are pharmacologicallyactive.

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articles.cgi?idArticle=262

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