European Journal of Pharmaceutical Sciences 18 (2003) 113–120
`
`www.elsevier.com / locate / ejps
`
`Review
`N anosizing: a formulation approach for poorly-water-soluble compounds
`*
`Elaine Merisko-Liversidge , Gary G. Liversidge, Eugene R. Cooper
`Elan Drug Delivery,3500 Horizon Dr., King of Prussia, PA 19406, USA
`
`Received 21 August 2002; received in revised form 15 November 2002; accepted 18 November 2002
`
`Abstract
`
`Poorly-water-soluble compounds are difficult to develop as drug products using conventional formulation techniques and are frequently
`abandoned early in discovery. The use of media milling technology to formulate poorly-water-soluble drugs as nanocrystalline particles
`
`offers the opportunity to address many of the deficiencies associated with this class of molecules. NanoCrystal Technology is an attrition
`process wherein large micron size drug crystals are media milled in a water-based stabilizer solution. The process generates physically
`stable dispersions consisting of nanometer-sized drug crystals. Nanocrystalline particles are a suitable delivery system for all commonly
`used routes of administration, i.e. oral, injectable (IV, SC, and IM) and topical applications. In addition, aqueous dispersions of
`nanoparticles can be post-processed into tablets, capsules, fast-melts and lyophilized for sterile product applications. The technology has
`been successfully incorporated into all phases of the drug development cycle from identification of new chemical entities to refurbishing
`marketed products for improving their performance and value.
` 2002 Elsevier Science B.V. All rights reserved.
`
`Keywords: Poorly-water-soluble compounds; Nanoparticles and drug delivery
`
`1 . Introduction
`
`It is estimated that 40% or more of active substances
`being identified through combinatorial screening programs
`are poorly soluble in water (Lipinski, 2001, 2002). When
`these molecules are formulated using conventional meth-
`ods, the performance of the drug in preclinical screens is
`oftentimes erratic and highly variable.
`In the clinic,
`conventional formulations of poorly-water-soluble drugs
`are frequently plagued with problems such as poor and
`highly variable bioavailability. The dosage form is often-
`times affected by the fed–fasted state of the patient and its
`onset of action is slower than anticipated. All of these
`issues lead to sub-optimal dosing and poor performance.
`Generally,
`it
`is more expeditious and cost effective to
`chemically re-design the molecule,
`than to move a
`blemished molecule through the development process
`(Lipinski et al., 1997; Lipper, 1999; Venkatesh and Lipper,
`2000; Veber et al., 2002).
`Currently, there are a limited number of formulation
`approaches available for compounds that are poorly solu-
`ble in water. The most direct approach for enhancing
`solubility is to generate a salt. If, however, the compound
`
`*Corresponding author. Tel.: 11-610-313-5130.
`E-mail address: elaine.liversidge@elan.com (E. Merisko-Liversidge).
`
`is non-ionizable, solubility concerns are generally ad-
`dressed by micronization and / or the development of oil-
`based solutions in gelatin capsules, i.e. soft-gel technology.
`In addition, co-solvents, surfactants or complexing agents
`such as cyclodextrins (Stella and Rajewski, 1997; Loftsson
`and Brewster, 1996; Akers, 2002) have been employed.
`Reasonable success has also been met
`in formulating
`water-insoluble drugs using emulsion (Nakano, 2000;
`Floyd, 1999), microemulsion (Lawrence and Rees, 2000)
`and solid dispersion technology (Leuner and Dressman,
`2000; Serajuddin, 1999; Breitenbach, 2002). Although
`some of these approaches have been successfully utilized,
`especially for highly potent compounds with low dose
`requirements, there is a growing need for more effective
`and versatile ways to handle formulation issues associated
`with poorly-water-soluble molecules. A broadly based
`technology applicable to this class of molecule could have
`a tremendous impact on discovery effectiveness and
`improve the performance of products suffering from
`formulation-related issues.
`A newer drug delivery approach for poorly-water-solu-
`ble compounds has come about in the last few years. In
`this approach, poorly-water-soluble compounds are formu-
`lated as nanometer-sized drug particles. There are various
`methodologies for generating drug nanoparticle formula-
`tions (Tom and Debenedetti, 1991; Pace et al., 1999;
`
`0928-0987 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved.
`doi:10.1016 / S0928-0987(02)00251-8
`
`0001
`
`PSG2011
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
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`

`114
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`
`Muller et al., 2001; Rogers et al., 2001). This review,
`
`however, will focus on NanoCrystal Technology whereby
`poorly-water-soluble drugs are formulated as nanometer-
`sized drug crystals using high-shear media mills. Since this
`approach has been adapted to handle milligram quantities
`of drug substance, for the research scientist this technology
`provides an avenue to improve screening efforts without
`having to deal with solubility-related performance issues.
`For the pharmaceutical scientist, this approach provides a
`universal process suitable for formulation development and
`commercialization of various dosage forms. The first
`
`product to incorporate this technology is Rapamune , an
`immune suppressant agent, marketed by Wyeth Research
`Laboratories.
`
`2 . Nanocrystalline particles
`
`Nanocrystalline particles are nanometer-sized drug par-
`ticles of a poorly-water-soluble compound. Fig. 1 shows an
`electron micrograph and a diagrammatic representation of
`drug particles formulated as a colloidal dispersion. The
`electron-dense nanometer-sized particles exhibit a defined
`geometrical shape which is dictated by the morphology of
`the unprocessed crystalline powder, fracture plane of the
`crystals and drug / stabilizer interactions. The effects of
`shape on the properties and biological performance of the
`formulations have not been fully evaluated.
`Nanocrystalline dispersions consist of water, drug and
`stabilizer. If required, other excipients such as buffer, salts
`
`Fig. 1. Nanocrystalline drug particles. The transmission electron micro-
`
`graph of a NanoCrystal Colloidal dispersion magnified 35,0003. The
`insert provides a visual description of
`the crystalline nanoparticles
`generated using wet milling technology. The nanoparticles are typically
`less than 400 nm and are physically stabilized with a polymeric excipient.
`
`and sugars can be added to the dispersion. For most
`nanocrystalline formulations, drug concentration is 400
`mg / ml or less. The choice and concentration of stabilizer
`are selected to promote the particle size reduction process
`and generate physically stable formulations. To be effec-
`tive, the stabilizer must be capable of wetting the surface
`of the drug crystals and providing a steric or ionic barrier.
`In the absence of the appropriate stabilizer,
`the high
`surface energy of nanometer-sized particles would tend to
`agglomerate or aggregate the drug crystals. Physically
`stable nanocrystalline formulations are obtained when the
`weight ratio of drug to stabilizer is 20:1 to 2:1. Too little
`stabilizer induces agglomeration or aggregation and too
`much stabilizer promotes Ostwald ripening. The process of
`identifying an appropriate stabilizer(s) for a drug candidate
`is empirical and can be accomplished using milligram
`quantities of drug. Many commonly used pharmaceutical
`excipients such as the cellulosics, pluronics, polysorbates
`and povidones are acceptable stabilizers for generating
`physically stable nanoparticle dispersions (Liversidge et
`al., 1992; Kibbe, 2000; Schott, 1955). Oftentimes, stabili-
`zation is achieved using a combination on a non-ionic plus
`ionic stabilizer.
`Nanocrystalline dispersions are prepared using media
`milling processes (Liversidge et al., 1992). The milling
`chamber is charged with milling media, water, drug and
`stabilizer as depicted in Fig. 2. Drug concentration general-
`ly ranges from 1 to 400 mg / ml. High-energy-generated
`shear forces and / or the forces generated during impaction
`of the milling media with the drug provide the energy
`input to fracture drug crystals into nanometer-sized par-
`ticles. The process can be performed in either a batch or
`re-circulation mode. In batch mode, the time required to
`obtain dispersions with unimodal distribution profiles and
`mean diameters ,200 nm is 30–60 min. A comparison of
`the size of naproxen crystals before and after media
`milling is shown in Fig. 3. The media milling process
`readily fractures micron-sized drug crystals into a homoge-
`neous nanoparticle dispersion. The media milling process
`can successfully process micronized and non-micronized
`drug crystals. Once the formulation and process are
`optimized,
`there is very little batch-to-batch variation
`detected in the quality of the dispersion and processing
`time. A concern raised regarding the media milling pro-
`cesses for pharmaceutical applications is the quality and
`durability of the milling media used in manufacturing.
`
`Currently, the milling media used for the NanoCrystal
`Technology is a proprietary highly cross-linked poly-
`styrene resin. In addition, during process development and
`validation potential in-process impurities are monitored.
`Residual monomers are typically ,50 ppb and insolubles
`generated during processing are no more than 0.005%
`w / w based on the drug concentration of the dispersion or
`resulting solid dosage form.
`It is well documented that various processes can ad-
`versely induce polymorphic transitions (Byrn et al., 1995).
`
`0002
`
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`

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`
`115
`
`Fig. 2. The Media Milling Process is shown in a schematic representation. The milling chamber charged with polymeric media is the active component of
`the mill. The mill can be operated in a batch or re-circulation mode. A crude slurry consisting of drug, water and stabilizer is fed into the milling chamber
`and processed into a nanocrystalline dispersion. The typical residence time required to generate a nanometer-sized dispersion with a mean diameter ,200
`nm is 30–60 min.
`
`Fig. 3. The particle size distribution profile of naproxen crystals before (m) and after milling (d). Before milling, the drug crystals had a mean particle
`size of 24.2 microns. After being processed for 30 min in a media mill, the mean particle size of the nanocrystalline dispersion was 0.147 microns with
`D 5 0.205 microns. The particle size measurements were generated using laser light diffraction in a Horiba LA-910 using polystyrene nanospheres
`90
`ranging in size from 0.1 to 10 microns as standards.
`
`0003
`
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`

`116
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`
`For nanoparticles prepared by wet milling technology, this
`has not been an issue (Liversidge and Cundy, 1995). The
`milling process is performed under controlled temperature
`conditions and the aqueous phase effectively dissipates the
`heat generated during processing. In addition, basic testing
`methods performed before and after milling can be readily
`implemented to ensure the chemical
`integrity of
`the
`compound.
`Finally, a few comments should be made regarding the
`physical stability of the colloidal dispersions resulting from
`media milling processes. In the liquid state, the dispersions
`are very stable, especially if the solubility of the drug is
`less than 1 mg / ml and the drug, using wet-milling
`technology, can be formulated at concentrations greater
`than 100 mg / ml. For drug candidates that are slightly
`soluble, with time and under accelerated temperatures,
`evidence of Ostwald ripening may be observed (Schott,
`1955). However, dispersions of nanoparticles can be post-
`processed as a dry powder for solid dosage development or
`lyophilized for injectable products. These dried powders
`are designed to re-disperse into nanometer-sized particles
`when placed in water or an alternate water-based environ-
`ment. The ability of the dried powder to re-disperse into a
`non-aggregated / non-agglomerated nanoparticulate disper-
`sion is critical to the development of a solid dosage form
`that maintains the benefits of this enabling drug delivery
`technology.
`
`3 . Applications for oral delivery
`
`Dissolution kinetics is the primary driving force behind
`the improved pharmacokinetic properties of nanoparticle
`formulations of poorly-water-soluble compounds (Liver-
`sidge and Cundy, 1995). The dissolution rate of a drug is a
`function of its intrinsic solubility and particle size. For
`poorly-water-soluble drugs, surface area of the drug par-
`ticles drives dissolution. As described by the Nernst–
`Brunner and Levich modification of the Noyes–Whitney
`model of dissolution (Dressman et al., 1998; Horter and
`Dressman, 2001), surface area of the drug is directly
`proportional to its rate of dissolution:
`
`dX / dt 5 (A 3 D/d) 3 (C 2 X /V )
`
`where X is the amount of drug in solution, t is time, A is
`the effective surface area, D is the diffusion coefficient of
`the drug, d is the effective diffusion boundary layer, C is
`the saturation solubility of the drug, and V is the volume of
`the dissolution medium.
`The ability to formulate poorly-water-soluble molecules
`as nanometer-sized crystals can have a dramatic effect on
`bioavailability. If the drug particles are near spherical in
`shape, nanoparticles reduced in size from 10 microns to
`200 nm generate a 50-fold increase in surface area to
`volume ratio. This increase in surface area can have a
`
`major impact on drug absorption, provided the formulation
`retains or disperses into discrete particles after dosing. If
`bioavailability is truly dissolution rate limited, particle size
`reduction can significantly improve the performance of the
`drug (Liversidge and Cundy, 1995). The effects of particle
`size on the bioavailability of a poorly-water-soluble drug
`are demonstrated in Fig. 4 (Loper, 1999). In this study, the
`bioavailability of a poorly-water-soluble drug candidate
`was improved as the particle size of the preparation was
`reduced from 5 to 0.1 micron using wet media milling
`technology. This pattern of results is routinely observed,
`provided the primary factor effecting the bioavailability of
`the drug is rate and extent of dissolution. As currently
`practiced, formulating compounds as nanocrystalline dis-
`persions will not be of value when bioavailability is
`affected by metabolic- and / or permeation-related issues. In
`the future, it should be possible to combine this technology
`with agents that enhance permeation (Aungst, 2000) and /
`or minimize gut-related metabolic issues (Benet et al.,
`1999; Kusuhara et al., 1998). This combination of ap-
`proaches would lend itself to molecules referred to in the
`biopharmaceutics classification system as class four mole-
`cules. These molecules are poorly water soluble and have
`limited membrane permeability.
`For poorly-water-soluble molecules, there are benefits to
`be gained when dissolution is no longer a limiting factor.
`As shown in Fig. 5, a nanocrystalline formulation of
`danazol, whether administered as a liquid or a capsule,
`effectively reduced the variable performance observed with
`
`the marketed product, Danocrine . For poorly-water-solu-
`ble compounds, food plus the physiological environment
`induced by the fed state oftentimes is conducive for
`improving the bioavailability of the drug. In contrast, there
`
`Fig. 4. For poorly-water-soluble compounds, the particle size of the drug
`crystals can effect bioavailability. The graph shows the plasma con-
`centration time curve of a poorly-water-soluble discovery compound. The
`compound was administered orally at an identical dose to fasted dogs as
`nanoparticles or as cruder dispersions. The only variable was the mean
`particle size of each dispersion: 100 nm (o); 500 nm (d); 2 microns (j);
`and 5 microns (,).
`
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`

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`
`117
`
`fold increase in the AUCs during the first hour of the
`study. In addition to this need for improving the rate of
`absorption, for various therapeutic classes there is also the
`need for the medication to be effective over a prolonged
`period of time. For poorly-water-soluble drugs, this need is
`being met by using nanoparticles in combination with
`well-established controlled release, delayed release and
`pulsatile release technology. In addition, since the surface
`properties of the nanoparticles can be readily altered,
`particles can be generated with bioadhesive properties that
`provide an opportunity to impact the biological perform-
`ance of a drug (Lee et al., 2000). Finally, it should be
`stressed that, if properly formulated, the dispersions can be
`processed, using standard equipment, into tablets, capsules
`and fast melts. Nanocrystalline particles provide a phar-
`maceutics approach that is highly versatile while eliminat-
`ing or minimizing the development issues associated with
`this class of molecule.
`
`4 . Applications for injectable products
`
`Nanocrystalline formulations are a suitable dosage form
`for poorly-water-soluble injectable products (Merisko-
`Liversidge et al., 1996; Cooper, 2000; Bittner and Mount-
`field, 2002). The question that is oftentimes raised is why
`and when would it be advantageous to use nanoparticles as
`opposed to a more traditional formulation approach. One
`of the major advantages is that drug nanoparticles provide
`an opportunity for dosing at significantly higher levels than
`what can be accomplished using a more traditional ap-
`proach. Harsh solvents or co-solvents present in a tradi-
`tional formulation for this class of molecules are, often-
`times, dose limiting as a result of the toxicity of the
`excipients. Nanocrystalline formulations do not contain
`solvents and the stabilizers present in the formulation are
`chosen based on their safe use in injectable products. The
`ability to safely dose at higher levels provides an oppor-
`tunity for dose escalation that can impact performance. For
`instance, Fig. 6 compares the performance of paclitaxel, a
`poorly-water-soluble anticancer agent, formulated as the
`
`marketed product (Taxol ) using Cremophor EL / ethanol
`mixture to solubilize the drug and prepared as a nanoparti-
`
`Fig. 5. Nanocrystalline particles can reduce absorption variability re-
`sulting from the presence or absence of food. The data compare the
`performance of various dosage forms of danazol administered to vol-
`unteers in the fed and fasted state at a 200 mg dose. The variability
`observed in the commercial product was significantly lowered when
`danazol was formulated using nanoparticles and administered as a liquid
`dispersion or a dry-filled capsule.
`
`is often a loss in bioavailability in the fasted state, due to
`the absence of solubility enhancing agents present in food
`and bile. However, when poorly-water-soluble drugs are
`formulated as a uniform dispersion of nanometer-sized
`particles, variation in bioavailability, resulting from the fed
`vs. fasted state, can be minimized.
`Improving the dissolution rate of a poorly-water-soluble
`compound generally correlates with faster absorption rates
`(Liversidge and Conzentino, 1995). This can be a par-
`ticularly desirable feature for therapeutics, such as naprox-
`en and other poorly-water-soluble compounds, targeting
`pain control. For naproxen, it would be highly beneficial to
`have a dosage form with a fast onset of action. Table 1
`shows the results of a human pharmacokinetic study. The
`bioavailability of nanocrystalline naproxen is compared to
`
`that of the marketed products: Naprosyn (suspension) and
`
`Anaprox
`(tablet). Though many of the pharmacokinetic
`parameters remain unchanged, the time to reach maximal
`drug concentrations is approximately 50% less for the
`nanocrystalline dispersion, while maintaining a 2.5–4.5-
`
`Table 1
`Human pharmacokinetics of naproxen following oral administration of a nanocrystalline naproxen suspension, a Naprosyn
`tablets in the fed state. Dose: 500 mg / volunteer and N523
`
`
`
`suspension and Anaprox
`
`
`
`PK parameter
`
`T
`max
`AUC
`
`(h)
`
`(0 – 1 h)
`
`(mg h / l)
`
`(mg / l)
`(mg h / l)
`
`C
`max
`AUC
`(0 – a)
`(h)
`t
`
`1 / 2
`
`Formulation
`
`Nanocrystalline
`naproxen
`
`1.6961.05
`33.4969.12
`(27.3% CV)
`50.8966.03
`810.246166.858
`16.1864.42
`
`Naprosyn
`
`
`
`3.3361.32
`13.3868.1
`(61.1% CV)
`49.0966.44
`49.656188.12
`16.1662.81
`
`Anaprox
`
`
`
`3.2061.68
`7.4168.94
`(120.7% CV)
`53.4567.16
`863.976231.28
`14.8263.55
`
`0005
`
`

`

`118
`
`E. Merisko-Liversidge et al. / European Journal of Pharmaceutical Sciences 18 (2003) 113–120
`
`cles is determined by a multitude of factors, including the
`physical properties of the particles, the dose, infusion time
`and the dissolution of the drug particles in the hemo-
`dynamic pool of blood. For drug candidates that have
`solubility in the mg / ml range or are ionizable, following
`intravenous administration the nanoparticles will dissolve.
`In this situation, the biodistribution profile of the drug in a
`conventional formulation and a nanoparticle formulation
`will be equivalent. However, if the drug candidate has an
`intrinsic solubility in the mg / ml range, depending on the
`dose, the particles may not dissolve. Comparing the plasma
`profiles of paclitaxel and other poorly-water-soluble drugs
`formulated in solution, nanoparticles can generally be
`administered intravenously at higher doses (Table 2). In
`addition, the differences observed in the pharmacokinetic
`properties are in line with the differences that are antici-
`pated when comparing the distributional properties follow-
`ing IV injection of a drug in solution versus in a nanopar-
`ticulate platform. The decrease in clearance rate and
`limited volume distribution are currently explained by the
`sequestration of the nanoparticles primarily by the Kupffer
`cells of the liver. The interesting observation that has been
`repeatedly demonstrated is that entrapment of nanoparti-
`cles by the Kupffer cells does not adversely effect the
`safety profile of the drug. In actuality, for intravenous
`delivery, maximum tolerated dose can be increased by
`five- to 10-fold in comparison to solutions formulated with
`the aid of solvents, surfactants or cyclodextrins. In addi-
`tion, as shown in Table 3, sequestration by the phagocytic
`cells of the liver does not adversely effect efficacy. This
`can be explained by either of two working hypotheses. The
`first scenario is that the population of particles that avoids
`sequestration by the mononuclear phagocytic system
`(MPS) delivers a sufficiency of drug to the diseased site
`(Nouchi et al., 1998; Jain, 1996; Kong et al., 2000; Hobbs
`et al., 1998). Alternatively, once sequestered by the
`Kupffer cells, the cells act as a controlled release vehicle
`for the drug (Martin et al., 1982; Adachi et al., 1992; Soma
`
`Fig. 6. The efficacy of nanoparticle paclitaxel in the MV-522 human lung
`xenograft murine tumor model. The efficacy of the marketed product
`
`(Taxol ) and nanocrystalline paclitaxel was compared following in-
`travenous administration. Both formulations were administered at
`the
`maximum tolerated dose, i.e. the marketed product was administered at
`30 mg / kg (qd31). At this dose, a 22% death rate was observed for the
`marketed product. In comparison, nanocrystalline paclitaxel was well
`tolerated at 90 mg / kg (qd31). In this study, N59 for each experimental
`group. Data show the change in tumor weight for Controls (no treatment),
`Marketed Product (30 mg / kg) and Nanocrystalline Paclitaxel (90 mg /
`kg).
`
`the
`cle dispersion. The maximum tolerated dose of
`nanoparticle paclitaxel formulation is greater than that of
`the commercial product. This translates into an improved
`efficacy profile for the drug.
`In using a nanometer-sized particle formulation as an
`injectable, the particle nature of the formulation can effect
`its pharmacokinetic properties. Following intravenous in-
`jection, particles are sequestered by MPS-enriched organs,
`such as the liver and spleen (Illum et al., 1982; Juliano,
`1988; Toster et al., 1990; Stolnik et al., 1995; Neal et al.,
`1998; Liu et al., 2000; Moghimi et al., 2001). The
`biodistribution profile of intravenously injected nanoparti-
`
`Table 2
`Comparison of the maximum tolerated dose of IV administered anticancer agents formulated as nanocrystalline particles or using a marketed product, if
`available, or a more conventional formulation approach
`
`Compound and
`formulations tested
`
`Camptothecin
`(a) Nanocrystalline formulation
`(b) Solubilized (ethanol / Tween 80)
`
`Etoposide
`(a) Nanocrystalline formulation
`(b) Marketed product
`
`Paclitaxel
`(a) Nanocrystalline formulation
`
`(b) Marketed product
`
`Murine
`tumor
`model
`
`Panc03
`Panc03
`
`Panc03
`Panc03
`
`MV-522
`
`MV-522
`
`Injection
`schedule
`
`Bolus
`Bolus
`
`d3,5,7
`d3,5,7
`
`d35
`d31
`d35
`d31
`
`Total
`dose
`(mg / kg)
`
`48.6
`18.0
`
`69
`69
`
`100
`90
`100
`30
`
`No.
`toxic
`deaths
`
`0 / 4
`1 / 4
`
`0 / 5
`2 / 5
`
`0 / 9
`0 / 9
`2 / 9
`2 / 9
`
`0006
`
`

`

`E. Merisko-Liversidge et al. / European Journal of Pharmaceutical Sciences 18 (2003) 113–120
`
`119
`
`Table 3
`Comparison of the efficacy of nanocrystalline paclitaxel with the conventional formulation using the mammary 16C murine tumor model (N55 for each
`experimental group)
`
`Treatment
`
`No treatment
`Nanopaclitaxel
`
`
`Taxol conventional
`formulation,
`cremophor / ethanol
`
`Total
`a
`dose
`(mg / kg)
`
`d
`NA
`87.5
`44
`87.5
`44
`
`Median tumor
`burden on
`day 11 (mg)
`
`2550 (763–3924)
`0 (0–0)
`0 (0–64)
`76 (0–256)
`417 (196–661)
`
`b
`
`T / C
`(%)
`
`NA
`0
`0
`3
`16
`
`Log
`10
`tumor
`cell kill
`
`c
`
`NA
`5.9
`2.8
`2.2
`1.2
`
`Cures
`tumor free
`day 162
`
`0 / 5
`3 / 5
`0 / 5
`0 / 5
`0 / 5
`
`a Dose administered intravenously on a daily 35 dosing schedule.
`b T / C (%): tumor wt. in Treated animals / tumor wt. in untreated Controls3100.
`]
`]
`c Log
`cell kill5tumor growth delay / 3.323tumor volume doubling time.
`10
`d NA, not applicable.
`
`et al., 2000). Currently, both scenarios are being further
`explored. In addition, studies are in progress to identify
`how best to manipulate the surface properties, size and
`shape of the nanoparticles to eliminate, when desirable,
`uptake by the phagocytic cells of MPS-enriched organs.
`This is the approach that has been successfully im-
`plemented in the work that has produced the ‘‘stealth’’
`liposome (Woodle, 1998; Gregoriades, 1995; Allen, 1997;
`Papisov, 1998) and has been utilized to demonstrate the
`passive targeting capability of other types of microcarriers
`(Couvreur et al., 1990; Gref et al., 1994; Stolnik et al.,
`1995; Moghimi et al., 2001). Future studies will focus on
`the second generation of nanocrystalline particles to be
`laced with functionalized surface coatings that are capable
`of eliciting passive or active targeting.
`
`5 . Conclusions
`
`The use of wet milling technology to formulate poorly-
`water-soluble compounds is a viable approach capable of
`resolving many of
`the current
`issues associated with
`developing
`and
`commercializing
`poorly-water-soluble
`molecules. The successful implementation of nanocrystal
`technology to a chemical entity is primarily driven by
`solubility properties of the drug and hence can be readily
`applied to various classes of compounds. Nanocrystalline
`formulations can be dried and post-processed into capsules
`and tablets. However, care must be taken to identify a
`process and formulation that yields a re-dispersible sold
`dosage form. For
`injectables,
`the dispersions can be
`sterilized by terminal heat (Na et al., 1999), filtration
`(Zheng and Bosch, 1997) or gamma irradiation and stored
`as a liquid or lyophilized and re-dispersed at the time of
`injection. Though this review is focused on oral and
`injectable applications of nanocrystalline formulations, the
`approach is a very versatile drug delivery platform and is
`suitable for other commonly used routes of administration
`such as nasal and pulmonary delivery (Wiedmann et al.,
`1997). In the last 10 years, nanoparticle technology has
`
`evolved from a conception to a viable commercializable
`drug delivery platform whose versatility and applicability
`are just beginning to be realized. The percentage of poorly-
`water-soluble molecules being identified as actives is
`increasing. New approaches for bringing these molecules
`to the market place in a timely fashion are a necessity for
`the success of the pharmaceutical industry and for addres-
`sing the unmet medical needs these therapeutics may
`provide.
`
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