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2008 36: 43Toxicol PatholElaine M. Merisko-Liversidge and Gary G. Liversidge

Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds  

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43

Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds

ELAINE M. MERISKO-LIVERSIDGE AND GARY G. LIVERSIDGE

From 1Elan Drug Technologies, King of Prussia, Pennsylvania, USA.

ABSTRACT

More than 40% of compounds identified through combinatorial screening programs are poorly soluble in water. These molecules are difficult toformulate using conventional approaches and are associated with innumerable formulation-related performance issues. Formulating these compoundsas pure drug nanoparticles is one of the newer drug-delivery strategies applied to this class of molecules. Nanoparticle dispersions are stable and havea mean diameter of less than 1 micron. The formulations consist of water, drug, and one or more generally regarded as safe excipients. These liquiddispersions exhibit an acceptable shelf-life and can be postprocessed into various types of solid dosage forms. Drug nanoparticles have been shownto improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routesof administration can be identified with milligram quantities of drug substance, providing the discovery scientist with an alternate avenue for screen-ing and identifying superior analogs. For the toxicologist, the approach provides a means for dose escalation using a formulation that is commerciallyviable. In the past few years, formulating poorly water-soluble compounds using a nanoparticulate approach has evolved from a conception to a real-ization whose versatility and applicability are just beginning to be realized.

Keywords. Nanoparticles; NanoCrystal Technology; poorly water-soluble compounds.

Rapamune®; Emend®, TriCor 145®, and MegaceES®. There arealso other products in late-stage development delivered by oral,injectable, and inhalation routes using NanoCrystal Technology.Commercial success has spurred renewed interest in the area ofnanoparticulate drug delivery, as evidenced by the establishmentof several nanoparticle-based companies (Table 1) and a flurry ofresearch activities in the past 10 years. This overview will focuson why this approach has gained such wide acceptance and theadvantages of using such an alternate approach to formulatepoorly water-soluble molecules for improving drug performanceand patient compliance.

THE SOLUBILITY CHALLENGE

It is estimated that ~40% of active substances identified throughcombinatorial screening programs are difficult to formulate as aresult of their lack of significant solubility in water (Lipper, 1999;Lipinski, 2000, 2002). In one sense, this is understandable. If a molecule must penetrate a biological membrane to be absorbed,the molecule generally must possess some hydrophobic orlipophilic characteristics. The classical approach to deal with thisissue is to generate various salts of a poorly water-soluble moleculeso as to improve solubility while retaining biological activity.Alternately, screening is continued to identify analogs or prodrugswith enhanced solubility. If successful, there would be little need topursue a formulation approach that involves nanoparticle produc-tion. The problem is that, frequently, these approaches are not suc-cessful, and the molecule is abandoned early on in its developmentprocess or the product is launched with suboptimal propertiesincluding poor bioavailability, lack of fed/fasted equivalence, lackof optimal dosing, presence of extra excipients that pose limitationswith respect to dose escalation, and ultimately, poor patient com-pliance (Table 2). When these types of situations arise, a nanopar-ticle formulation approach has proven to be very useful and

INTRODUCTION

The use of nanoparticles as a drug-delivery approach for vari-ous difficult-to-formulate reagents is not a new concept (Poste et al., 1976; Poste and Kirsh, 1983; Davis et al., 1987; Douglas et al., 1987; Papahadjopoulos, 1988). In pharmaceutics, nanopar-ticles are typically defined as a discrete internal phase consistingof an active pharmaceutical ingredient having physical dimen-sions, less than 1 micron in an external phase. Also, nanoparticlescan be designed to form de novo when exposed to the appropriatebiological fluid (Shott, 1995). The pharmaceutical industry duringthe past three decades has developed and marketed severalnanoparticlate pharmaceuticals with major emphasis on intra-venous products—for example, intravenous nutritional fat emul-sion (Intralipid®) and liposomal products (Doxil®, AmBisome®).The inability to achieve high drug loading, the cost of ingredientsand processing, and the restricted number of suitable excipientshave hitherto limited the broader use of these formulationapproaches. Elan’s NanoCrystal® Technology, which focuses onpoorly water-soluble drugs, has addressed many of these majorconcerns and has successfully expanded the scope and use ofnanoparticulates or nanosuspensions to include the oral, inhala-tion, intravenous, subcutaneous (SubQ) and intramuscular (IM),and ocular routes of delivery (Merisko-Liversidge, Liversidge,et al., 2004)

Four oral products incorporating the NanoCrystal technologyare currently marketed in the United States and other countries:

Address correspondence to: Elaine Merisko-Liversidge, PhD, Director,Elan Drug Technologies, 3500 Horizon Dr., King of Prussia, PA 19406; e-mail:Elaine.liversidge@elan.com.

The authors declare competing financial interest. Elan Drug Technologies is abusiness unit of Elan Pharma International Ltd., a division of Elan Corporation plc.

Abbreviations: IM, intramuscular; MPS, mononuclear phagocytic system;SubQ, subcutaneous.

Toxicologic Pathology, 36:43-48, 2008Copyright © 2008 by Society of Toxicologic PathologyISSN: 0192-6233 print / 1533-1601 onlineDOI: 10.1177/0192623307310946

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invaluable in all stages of the drug development and has openedopportunities for revitalizing marketed products with suboptimaldelivery.

NANOPARTICLE FORMULATIONS

There are various ways in which nanoparticles of poorlywater-soluble molecules are generated (Horn and Rieger, 2001;Muller et al., 2001; Rabinow, 2004; Merisko-Liversidge,Liversidge, et al., 2004). The approaches can be viewed asbeing a building-up approach through synthesis (Liu andFrechet, 1999), self-assembly (Letchford and Burt, 2007;Kawakami et al., 2002; Pouton, 2000), or precipitation of drugmolecules (Horn and Rieger, 2001). Alternatively, nanoparti-cles can be successfully generated using drug-fragmentationprocesses such as homogenization (Liedtke et al., 2000; Keckand Muller, 2006), microfluidation (Pace et al., 1999), ormilling (Liversidge and Cundy, 1995). Milling, which is theprocess used in generating Elan’s NanoCrystal colloidal dis-persions, is the recognized leader in the area of nanoparticulateresearch today.

No matter what approach is taken to generate drug nanopar-ticles, in comparison to particulates greater than 1 micron, sur-face area is increased (Figure 1). This increase in surface areaand surface interactions can be positively used to enhance the dissolution rate and provide a platform for controlling thepharmacokinetic properties of the dosage form. However,unless properly dampened, this tremendous increase in sur-face energy can cause the nanometer-sized drug particles to

spontaneously aggregate into a more thermodynamically stable state.

Critical to the generation of physically stable nanoparticlesis the use of various excipients that act to dampen or sensitizethe surface energy of the nanoparticles by way of steric and/orionic stabilization. An acceptable stabilizer should first be areagent that is generally recognized as safe for the intendedroute of administration. Secondly, a stabilizer must have prop-erties that allow it to properly wet the surface of poorly water-soluble compounds. Finally, a stabilizer should possessproperties so as to impart steric and/or ionic stabilization to thesurface of the nanoparticles. It should be emphasized that sur-face stabilization does not necessarily involve chemical graft-ing of the surface stabilizer to the molecule. Stabilization istypically driven by the mere adsorption of the stabilizer to thesurface of the poorly water-soluble compound.

Another consideration for obtaining a physically stablenanoparticle formulation is the ability to control the phenome-non referred to as Ostwald ripening. Ostwald ripening resultsfrom uncontrolled precipitation or crystallization of the active,leading to particle-size growth following stabilization(Ostwald, 1897; Boistelle and Astier, 1988; Ng et al., 1996).Ostwald ripening can be eliminated and/or reduced by control-ling a number of formulation parameters such as particle size,particle-size distribution, solids content, choice of stabilizer,and a fluid phase with minimal potential to solubilize thepoorly water-soluble compound. For instance, if a poorlywater-soluble compound is an acid or a base, the pH of thefluid phase can be adjusted so as to minimize ionization; thatis, acids would be processed under more acidic conditions, andfree bases would be processed at a higher pH.

Nanoparticle dispersions generated using NanoCrystal tech-nology consist of drug and stabilizer, and most commonly, thefluid phase is water. These dispersions are processed using ahigh-energy media mill with highly cross-linked polystyrene,

44 LIVERSIDGE AND LIVERSIDGE TOXICOLOGIC PATHOLOGY

TABLE 1.—Current industrial leaders in nanoparticle technology.

Formulation Approaches for Poorly Water-Soluble Drugs

Media milling nanoization Elan Drug TechnologiesMicrofluidization/homogenization Baxter

SkyePharmaSupercritical fluid technology Nektar

LavipharmRxKineticsEurandFerro

Alternative approaches DENAMany academic interests

TABLE 2.—Major issues associated with poorly water-soluble compounds.

• Poor bioavailability• Inability to optimize lead compound selection based on efficacy and safety• Fed/fasted variation in bioavailability• Lack of dose-response proportionality• Suboptimal dosing• Use of harsh excipients, i.e., excessive use of cosolvents and other excipients• Use of extreme basic or acidic conditions to enhance solubilization• Uncontrollable precipitation after dosing• Noncompliance by the patient, i.e., inconvenience of the dosage platform

FIGURE 1.—The plot demonstrates the increase in surface area obtainedwhen solids are fractured from the micron-size range (microparticles) tothe nanometer-size particles used in the various nanoparticle formulationsto improve the performance of poorly water-soluble compounds.

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which provides a highly durable milling media resulting inefficient processing of crude drug crystals to a homogenousnanoparticle–nanocrystalline dispersion with a particle sizeapproximately 1 micron or less. The key characteristics ofNanoCrystal formulations for poorly water-soluble molecules are

• the versatility of the approach: suitable for many dif-ferent classes of compounds, provided the aqueoussolubility is less than 10 mg/ml.

• the potential to achieve formulations with high drugloading: 300 mg/g or (30% w/w).

• a drug-to-stabilizer ratio on a weight basis typically10:1 or lower: 30% drug to 3% or lower stabilizerconcentration.

• usefulness for all routes of administration: oral, pul-monary, intravenous, SubQ, IM, and ophthalmic.

• the ability to be readily postprocessed into most com-monly used dosage forms: tablets, capsules and ster-ile products.

• proven technology: four marketed products in theUnited States, Europe, and Canada.

NANOPARTICLES: THE BIOLOGICAL BENEFITS

As previously discussed, the property of nanoparticle for-mulations that make this approach highly beneficial is relatedto the surface properties imparted on nanometer-sized entities.Although in recent years, tremendous emphasis and focus havebeen placed on nanotechnology research, as early as 1906,Ostwald published “The World of the Neglected Dimensions,”wherein colloidal nanoparticles exhibited special propertiesthat resided between the molecular and the material sciences(Shott, 1995). In practice, applying NanoCrystal Technology orone of the alternate nanoparticle formulation approaches to themany formulation and performance issues associated withpoorly water-soluble compounds in the pharmaceutical indus-try provide many benefits. These benefits can be categorizedinto three major areas: formulation-performance improvementsrelated to enhanced dissolution, safer and more patient-compliantdosage forms, and the potential for dose escalation for improve-ments in efficacy.

NANOPARTICLES: IMPROVED PERFORMANCE

The activity of a compound depends on its ability to dissolveand interact with the relevant biological target, either throughdissolution and absorption or dissolution and receptor interac-tion. The poor bioavailability of poorly water-soluble moleculesthat are not permeation-rate limited can be attributed to dissolu-tion-rate kinetics. The dissolution rate is directly proportional tothe surface area of the drug, according to the Noyes-Whitneymodel for dissolution kinetics (Noyes and Whitney, 1897). Drugcrystals reduced in size from 10 microns to 100-nm particlesgenerate a 100-fold increase in surface-area-to-volume ratio.This increase in surface area has a profound impact on thebioavailability of the molecule (Figure 1). For oral drug deliv-ery, drug crystals must dissolve to be absorbed. Although thereare some reports that uptake of nanoparticulate materials can be

mediated by various cellular or paracellular processes (Jani et al., 1992; Hillery and Florence, 1996), improving absorptionremains the primary means for increasing the bioavailability ofa poorly water-soluble compound (Horter and Dressman, 2001).If the bioavailability of a poorly water-soluble compound is dis-solution-rate limited, approaches that afford delivery usingnanometer-sized particles of drug improve bioavailability byenhancing dissolution rate (Liversidge and Cundy, 1995; Petersand Muller, 1996; Horn and Rieger, 2001; Wu et al., 2004;Langguth et al., 2005; Jinno et al., 2006; Kocbek et al., 2006).This maximizes the amount of soluble drug that is free to beabsorbed. This is especially true for poorly water-soluble com-pounds absorbed at a defined region of the gastrointestinal tract(Figure 2). For instance, a large percentage of compounds areabsorbed maximally at the duodenal–jejunal area (Wilding,2000). If dissolution is not complete when the dosage form tran-sits this area, bioavailability will be seriously compromised(Figure 3a). Similarly, if bioavailability depends on the nutri-tional state of the subject or is not dose proportional, nanoparti-cle formulations have been shown to reduce or eliminate sucheffects (Figure 3b and 3c).

For parenteral applications, one of the first questions thatshould be addressed is when a nanoparticle approach should beconsidered for a poorly water-soluble drug candidate. If the drugcandidate requires an excessive amount of cosolvents or extremepH conditions or is a low-potency molecule requiring a high-dose, the nanoparticle approach would be of value. To reiterate,nanoparticle formulations basically consist of the drug, an externalphase (which is typically water and a minimal amount of stabi-lizer), and a reagent that has a proven history of safe use for theintended application. Buffering and/or isotonicity agents can beadded, provided they are compatible with the formulation and do

Vol. 36, No. 1, 2008 POORLY WATER-SOLUBLE COMPOUNDS 45

FIGURE 2.—The diagram demonstrates one of the primary issuesassociated with poorly water-soluble molecules whose bioavailabil-ity is dissolution-rate limited. On the left, large drug particles cannotadequately dissolve, which results in the inability to be absorbed. On theright, nanometer drug particles are rapidly dissolved during transit throughthe gut, thus maximizing absorption and improving bioavailability.

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not disrupt the colloidal stability of the nanoparticulate formula-tion. For sterility assurance, all current methods available havebeen applied (i.e., terminal heat, gamma irradiation, filtration, andaseptic production). The method of choice is dictated by the prop-erties of the compound and properties of the colloidal dispersionso that the end product meets the appropriate specification for itsintended purpose. In essence, the drug-particle formulationapproach provides an opportunity to have safer, less toxic par-enteral medications that lend themselves to opportunities for doseescalation, enhanced efficacy, and improved patient tolerability. Afew examples demonstrating the benefits of using a nanoparticletechnology such as NanoCrystal Technology for parenteral prod-ucts in clinical studies have been published for intravenous(Mouton et al., 2006) and pulmonary applications (Kraft et al.,2004). Preclinical studies have been published for SubQ (Wisneret al., 1996; Wolf et al., 1994; Merisko-Liversidge, McGurk,et al., 2004) and IM (Shah et al., 2007) applications ofNanoCrystal formulations. In all cases, the formulations haveproven to be well tolerated and provide alternate formulationapproaches for poorly water-soluble therapeutics, thus broad-ening their applications and use.

One final point that should be addressed is the potential alter-ation in biodistributional properties that can potentially resultwhen a compound is dosed using a nanoparticulate platform. It iswell established that various physical properties of a particulatecarrier can affect tissue distribution (Bittner and Mountfield,2002; Illum et al., 1982; Juliano, 1988). The tissue distributionfollowing intravenous injection of nanoparticulate carriers thatinvolve encasement or encapsulation technology such as lipo-somes and various polymeric carriers have been extensively stud-ied (Moghimi et al., 2001; Gabizon et al., 2003; Singh et al.,2006). Size, surface, and shape are important if the intention is totarget or avoid rapid uptake of the particulates by the mononu-clear phagocytic system (MPS) of the lung, liver, spleen, andbone marrow.

For drug nanoparticles that do not involve encapsulation tech-nology, tissue distribution is also dictated by the solubility of thecompound. If a compound is soluble in the blood pool, the drugnanoparticle, on dosing, will exhibit a pharmacokinetic and tis-sue-distribution profile very similar to the compound dosed as asolution (Pace et al., 1999; Mouton et al., 2006). Alternatively, ifthe compound is practically insoluble in the blood pool, whendosed, drug nanoparticles will behave very similarly to the othernanoparticulate platforms described above; that is, size and coat-ing can be used to target or avoid the MPS system (Merisko-Liversidge, Liversidge, et al., 2004; Rabinow, 2004). This abilityto use a particulate carrier to control tissue distribution of a com-pound can be beneficially used to direct high concentrations ofdrug to diseased sites while limiting exposure to healthy tissue.

WHAT THE FUTURE HOLDS

Nanoparticle-formulation technologies have provided thepharmaceutical industry with new strategies for resolvingissues associated with poorly soluble molecules. For newchemical entities, the technology has been of value when usedas a screening tool during preclinical efficacy and/or safety

46 LIVERSIDGE AND LIVERSIDGE TOXICOLOGIC PATHOLOGY

FIGURE 3.—Depicted are a few of the primary benefits observed when apoorly water-soluble compound is formulated using a nanoparticleapproach. (a) The bioavailability of a poorly water-soluble model com-pound formulated as a nanoparticle dispersion (red) or as a conventionalcrude suspension (yellow). (b) The bar graphs show the comparison in thefed/fasted variation in bioavailability of a model compound when formu-lated as a nanoparticle dispersion (red) or as a crude suspension (yellow).Many poorly water-soluble molecules whose bioavailability is dissolution-rate limited are not dose proportional. (c) A dose-escalation study is showndemonstrating dose proportionality for a nanoparticle formulation of apoorly water-soluble compound.

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studies. “Go/no go” decisions can be made rapidly with a for-mulation approach that is scaleable and marketable. Duringdevelopment, robust nanoparticle formulations can be post-processed into various types of patient-friendly dosage formsthat provide maximal drug exposure. For marketed productsrequiring life-cycle management opportunities, nanoparticleformulation strategies provide a means to incorporate an olddrug into a new drug-delivery platform, thus opening newavenues for addressing unmet medical needs (Figure 4). For thefuture, it is most likely that the drug-nanoparticle approachesthat have been developed in the past decade would be comple-mented with the many new approaches for drug targeting andpermeation enhancement that have, until now, been primarilyacademic and a research curiosity. It is also foreseeable thatcompound-selection strategies will change. Screening effortsto improve the water solubility of a compound will be a thingof the past, and more emphasis will be placed on efficacy andsafety that will shorten development times and bring new ther-apies and diagnostic agents for challenging diseases that haveyet to be controlled or eradicated. Since the inception of thearea of science devoted to nanotechnology by R. Feynman inthe late 1950s (Feynman, 1959), much has happened and manyaspects of our material world and well-being have been andwill most likely continue to be affected by new developments.The era of nanotechnology in the pharmaceutical industry hasbegun. During the next decade, it will be interesting to see if allthe promises envisioned become a reality.

ACKNOWLEDGMENTS

A special thank you to Veronique Brossette for the graphicsand Fidelma Callanan for assistance in preparation of the manu-script. Also, many thanks to the members of the Elan DrugDelivery Team who, throughout the years, have provided invalu-able insight and support.

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