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Formulation of Nanosuspensions as a New

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 Current Nanoscience, 2009, 5, 417-427 417

Formulation of Nanosuspensions as a New Approach for the Delivery of Poorly

Soluble Drugs

Xiaohui Pu, Jin Sun*, Mo Li and Zhonggui He*

Department of Biopharmaceutics, School of Pharmacy, No. 103 Wenhua Road, Shenyang 110016, China

Abstract: Nanosuspensions have attracted much interest of many scientists as a new approach to deliver poorly soluble drugs because of
their process flexibility and special advantages such as improved oral bioavailability, high drug loading, targeting capabilities and so on.
Recently, the manufacture processes of nanosuspensions have developed quickly, and some new methods have emerged, for example,
controlled precipitation, emulsion method, microemulsion method and melt-emulsion method. Additionally, the post-process of nano-
suspension has also gained great progresses to expand the utility of nanosuspensions, including solidification technique and surface
modification technique. Moreover, the study on targeting delivery by nanosuspension following intravenous administration has become a
hot topic of many researches. In the article, we will highlight new developments in the production of nanosuspensions and summarize the
application of nanosuspensions via a variety of administration routes. In the end, we will overview the research and development
prospectives of nanosuspensions.

Keywords: Nanosuspension, poorly soluble drugs, bioavailability, layer-by-layer self-assembly, targeting.

1. INTRODUCTION
As shown in statistics, 1/3 of the drugs adopted by United
States Pharmacopoeia were classified as poorly soluble drugs.
Among the new chemical entities (NCE) discovered by pharmaceu-
tical chemist, 40% of NCE were poorly soluble compounds [1,2].
Also, 40% of the active pharmaceutical ingredients (API) obtained
by high-throughout screen were also poorly soluble molecules.
Lower bioavailability resulting from poor solubility and incomplete
dissolution in vivo, often holds back continuous development and
coming into the market of some promising NCE, or elicits insuffi-
cient therapeutic effects of certain drugs. The increasing number of
poorly soluble drugs requires innovative formulation approaches to
acquire a sufficient bioavailability after oral administration or at
least to make available intravenously injectable forms.
Poorly soluble compounds can be usually classified into two
types of molecules: “grease ball” and “brick dust” compounds [3].
Grease ball molecules represent highly lipophilic compounds with a
high logP, whereas brick dust molecules usually are compounds Fig. (1). The relationship between drug classification and the logP/melting
with a high melt point (m.p. >200) and a low logP. For example, point (modified after Wassvik, et. al. [4]).
78% of compounds with a ClogP of 6 and low melting point are
grease ball, whereas 52% of compounds with melting point of
potential drug expulsion during storage and complex manufacturing
250 and a ClogP of 2 belong to brick dust [4] (Fig. 1). The for-
method [21]. By contrast, brick dust molecules are poorly soluble
mer compounds can not form bonds with water molecules, so these
not only in water but also in oils, the above formulation strategies
compounds have poor aqueous solubility and their solubility is
do not work effectively due to low encapsulation efficiency and low
limited by solvation process. By contrast, the latter compounds
loading, and so the brick dust molecules are readily withdrawn
have high lattice energy and their solubility is limited by solid-state,
during the drug development stage.
in which the strong intermolecular bonds within the crystal struc-
ture restrict the solubility of the compound in water and in oils. For these reasons, Müller et al. [22, 23] firstly developed nano-
suspensions, a sub-micro colloidal dispersion system, to overcome
Grease ball molecules have easily passed through the drug de-
the above limitations in 1995. As for this system, pure drug parti-
velopment process pipeline to reach the market by adopting appro-
cles ranging in size from 10-1000 nm [24], were stabilized by sur-
priate formulation strategies, including incorporation of the proper
factants and polymeric materials. Drugs encapsulated within nano-
excipients (such as disintegrants, cosolvents, wetting agents, solubi-
suspensions exist in pharmaceutically acceptable crystalline or
lizers and cyclodextrins [5-11]) and application of micelles and
amorphous state. Nanosuspensions can successfully formulate the
lipid-based systems (emulsion [12,13], microemulsion [14], solid
brick dust molecules for improved dissolution and good absorption.
dispersion [15-17], liposome [18], solid lipid nanoparticle [19,20]
Apart from this, nanosuspensions have some following advantages:
and so on). But, there are still some deficiencies for the above for-
firstly, drugs no longer need to be in the soluble form. It is effective
mulations, such as low drug loading, high toxicity, poor stability,
for those molecules insoluble in oils [25]; secondly, the high drug
loading can be achieved as a drug exists in the form of pure solids,
and can significantly reduce the administration volume of high dose
*Address correspondence to these authors at the No. 59 Mailbox, Department of Bio- [25]; thirdly, nanosuspensions can increase the physical and chemi-
pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 cal stability of drugs as they are actually in the solid state [26, 27];
Wenhua Road, Shenyang 110016, China; Tel/Fax: +86-24-23986321;
E-mail: hezhonggui@gmail.com; sunjin66@21cn.com
finally, nanosuspensions can provide the passive targeting

1573-4137/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

418 Current Nanoscience, 2009, Vol. 5, No. 4
Fig. (2). Two differing manufacture processes of nanosuspensions.
‘bottom-up’ process,  ‘top-down’ process. I. The process includes dissolving drugs
in solvents or heating drug to fuse. II. The process is adding drug’s solution to surfactants’ solution. III. The technology used to this process can be microe-
mulsion, fusion-emulsion and supercritical fluid method. IV. The process is energy-addition step, which includes heat and/or mechanical energy. V. The drugs
are blended with surfactants and water by high speed dispersing homogenizer.VI. The process can be high-pressure homogenization and milling.
capabilities when injected intravenously, and represent a very
promising targeting carrier system for anti-cancer agents due to
enhanced permeability and retention effect [21, 28]. So the nano-
suspensions are considered as the most promising system for the
delivery of poorly soluble drug.
This review focuses on the different aspects of nanosuspensions,
including manufacturing process, characterization techniques,
post-production processes, in vitro and in vivo properties, and ap-
plication in drug delivery via various administration routes. In the
case of surface modification, we introduced the novel coating
strategy of layer-by-layer self-assembly technique for controlled
release and targeting capability.
2. MANUFACTURING PROCESSES
For the nanosuspensions manufacture, there are two converse
methods (Fig. 2): ‘bottom-up’ and the ‘top-down’ technologies [29].
The bottom-up technology is an assembling method from molecules
to nano-sized particles, including microprecipitation, microemul-
sion, melt emulsification method and so on. The top-down tech-
nology is a disintegration approach from large particles, microparti-
cles to nanoparticles, such as high-pressure homogenization and
media milling method. The processes and principles of these meth-
ods will be described in detail and Table 1 showed their advantages
and disadvantages.
2.1. High-Pressure Homogenization
The process can be summarized into three steps: firstly, drug
powders are dispersed in a stabilizer solution to form
pre-suspension; then pre-suspension was homogenized by the
high-pressure homogenizer at a low pressure for several times as a
kind of premilling, and finally was homogenized at a high pressure
for 10-25 cycles until the nanosuspensions with the desired size
were prepared. According to the liquids used to suspend drug pow-
ders, the method is classified into homogenization in water (Dis-
soCubes), homogenization in water-free media and water mixtures
(Nanopure).
During homogenization, drug particles are fractured by cavita-
tion, high-shear force and the collision of the particles against each
other. In the homogenization gap, the dynamic pressure of the fluid
Pu et al.
increases with the simultaneous decrease in static pressure below
the liquid boiling point at room temperature according to the Ber-
noulli’s equation. In consequence, the liquid starts boiling and
forms gas bubbles at room temperature, and the bubbles will im-
plode when the suspension leaves the gap and normal air pressure is
reached again (called cavitation). The implosion forces are suffi-
ciently high to break down the drug microparticles into nanoparti-
cles. As for this method, homogenization pressure and the number
of homogenization cycles were the most important parameters af-
fecting particles size and size distribution. Additionally, percentage
of solid content, types and combination of surfactants and the
hardness of drugs influence the resulting nanoparticles properties.
2.2. Milling Method
This patent-protected technology was developed by Liversidge
et al. and can be divided into three steps: firstly, drug and surfac-
tants were mixed to form a homogeneous mixture and inputted into
the milling chamber; secondly, the milling pearls or the milling ball
was put into, and certain amount of water was or not added into the
milling chamber; thirdly, the miller was turned on for about several
to dozens of hours to prepare the nanosuspensions. This method
was called as wet-milling method if the water and other liquid was
used, otherwise called dry-milling method. Alternatively, it can be
further divided into jet-milling, pearl-milling and ball-milling
method according to the types of the milling media used.
In this method, the high energy and shear forces generated by
the breach and the collision between the milling media and the drug,
are the input energy to break the micro-sized into nano-sized parti-
cles. Particle size here is determined by stress intensity and the
number of contact points. The milling media usually include glass,
zirconium oxide or highly cross-linked polystyrene resin. A general
problem of pearl mills is potential erosion from the milling pearls
leading to product contamination [33]. If glass and highly
cross-linked polystyrene resin are used as the pearl material, ero-
sion can be minimized.
2.3. Microprecipitation or Controlled Precipitation
Precipitation has been applied for years to prepare submicron
particles within the last decade [34-36], especially for the poorly
soluble drugs. Typically, the drug is firstly dissolved in a solvent.
Formulation of Nanosuspensions as a New Approach Current Nanoscience, 2009, Vol. 5, No. 4 419

Table 1. The Advantages and Disadvantages of Different Nanosuspensions Manufacturing Processes

The Methods Advantages Disadvantages

widely applying regions, ease of scale-up and little batch-to-batch variation

pretreatment of micronized drug particles and
[30], narrow size distribution in the final product [31], allowing aseptic pro-
High-pressure homogenization presuspending materials before subjecting it to
duction of nanosuspensions for parenteral administration and flexibility in
homogenizeation
handling the drug quantity [32]

potential erosion of material from the milling

Milling the same as those for high-pressure homogenization
pearls

narrowly applying space, wide size distribution

Microprecipitation low need of energy, stable products and simple process
and potential toxicity of non-aqueous solvents

low need of energy, stable products, simple process, small size of particles and high concentration undesired surfactants and
Emulsion and microemulsion
uniform particle distribution residual solvents

much smaller, more uniform and more stable compared to that by the micro-
Microprecipitation-high pressure ho-
precipitation; less mechanical force and energy compared with the The manufacturing process is complicated.
mogenization
high-pressure homogenization

Few compliant objects, larger particles from it

Melt emulsification avoidance of organic solvents compared to the solvent diffusion
than solvent diffusion

Then this solution is mixed with a miscible antisolvent in the pres-
ence of surfactants. Rapid addition of a drug solution to the anti-
solvent (usually water) leads to sudden supersaturation of drug in
the mixed solution, and generation of ultrafine crystalline or amor-
phous drug solids. This process involves two phases: nuclei forma-
tion and crystal growth. When preparing a stable suspension with
the minimum particle size, a high nucleation rate but low growth
rate is necessary. Both rates are dependent on temperature: the op-
timum temperature for nucleation might lie below that for crystal
growth, which permits temperature optimization [37].
High-supersaturation conditions are needed for rapid nucleation by
adding drug in minimum volume of a water-miscible organic solu-
tion into the water under rapid mixing at low temperature. This
rapid dilution with water results in high- supersaturation conditions,
and causes spontaneous nucleation and a subsequent reduction of
the supersaturation condition in the vicinity of the nucleating crys-
tals, and reduction of crystal growth rates. In this process, the ratio
of mixing time (
mix) to precipitation time (
precip) is a very impor-
tant parameter influencing the resulting particle size. As
mix is re-
duced relative to
precip, the greater supersaturation (more rapid nu-
cleation) and longer time for precipitation (including condensation
and coagulation) may produce the minimum particle size until a
threshold value is reached. It is also pointed out that the stabilizers
should be added to aqueous phase, organic phase or both.
2.4. Emulsion and Microemulsion Method
There are three methods to fabricate drug nanosuspensions by
the emulsification method: particles precipitation by evaporating
low–medium boiling point solvents with negligible water solubility,
by a quenching technique using partially water-miscible solvents,
such as benzyl alcohol and butyl lactate, or by a extracting tech-
nique using supercritical CO2 (SC CO2) as extraction agent. Such
solvents are used as the dispersed phase of the emulsion to load the
solute.
In the first method, an organic solvent or mixture of solvents
loaded with drug is dispersed in the aqueous phase containing suit-
able surfactants to form an emulsion or microemulsion. The organic
phase is then evaporated under reduced pressure so that the drug
particles precipitate instantaneously to form a nanosuspensions
stabilized by surfactants. Since a particle is formed in an emulsion
droplet, it is flexible to control the nanoparticle size by controlling
the droplet size. Organic solvents usually included acetone, meth-
ylene chloride, chloroform [38, 39] and relatively safer ethyl acetate
and ethyl formate etc [40].
The second method uses partially water-miscible solvents such
as butyl lactate, benzyl alcohol, triacetin and ethyl acetate as the
dispersed phase [41-43]. The emulsion or microemulsion is formed
by the conventional dispersion method and the drug nanosuspen-
sions are obtained by diluting the emulsion or microemulsion with
relatively large amount of water. The dilution causes complete dif-
fusion of the internal phase into the external phase, and leads to
instantaneous formation of the nanosuspensions. The manner of
diluting the emulsion included high-pressure homogenization or
magnetic stirring, the former much more efficient than the latter
[43].
The third method employs some organic solvents such as ethyl
acetate (EA), toluene, or dichloromethane (DCM) to dissolve the
drug as the internal phase. This solution was then dispersed into
solvent-saturated aqueous solution containing surfactants to form a
crude emulsion and subjected to high-pressure homogenization to
form an ultrafine emulsion. The extraction of solvents and particle
precipitation was carried out in an electrically heated stainless-steel
extraction column. SC CO2 was conversed from the bottom of the
extraction column at a certain flow rate, and the emulsion was de-
livered from the top countercurrently using a semi-preparative
HPLC pump at a constant flow rate. The ratio of the flow rates of
the SC CO2 to the emulsion was maintained constant. During this
process, the organic solvent was extracted quickly by SC CO2 and
the aqueous drug nanosuspensions were formed at the bottom of the
column simultaneously [44].
2.5. Microprecipitation-High Pressure Homogenization
(NANOEDGE)
The NANOEDGE process (Baxter Healthcare Corporation)
consisted of the precipitation of friable materials and subsequent
fragmentation under high shear and/or thermal energy input, that is,
a combination of microprecipitation and high-pressure homogeni-
zation [45, 46].
The preparation process can be summarized into five steps [47].
Firstly, the drug was dissolved in a drug-soluble organic solvent to
form a solution. Secondly, the stabilizers were dissolved in the
second solvent in which drug was insoluble. Thirdly, the drug solu-
tion was added to the second solvent under high-speed agitation.
Then, drug precipitated as microparticles during the diffusion from
the miscible solvent to the second solvent. At the same time, the
surfactants in the solution were adsorbed into the surface of the
freshly formed microparticles rapidly to protect them from aggrega-
tion or growth and then pre-suspension was prepared. Finally,
420 Current Nanoscience, 2009, Vol. 5, No. 4
pre-suspension was homogenized under a suitable pressure for sev-
eral times. This is a process of adding energy, and can further re-
duce the size of particles and reinforce interactions between drug
nanoparticles and stabilizers.
2.6. Melt Emulsification Method
The melt emulsification method traditionally was used to pre-
pare solid lipid nanoparticles, but Kocbek et al. [43] firstly used it
to prepare ibuprofen nanosuspensions. There are four steps in the
production of nanosuspensions by melt emulsification method.
Firstly, drug was added to aqueous solution containing stabilizer.
Secondly, the suspension was heated above the melting point of the
drug and homogenized with high-speed homogenizer to form an
emulsion with melted liquid drug as the dispersed phase. Thirdly, it
was transferred to a high-pressure homogenizer for homogenization.
During this process, the temperature was maintained above the
melting point of the drug. Finally, the emulsion was then cooled at
a suitable temperature and the drug particles precipitated and even-
tually formed the nanosuspensions. The particle size can be finely
adjusted by the process parameters, such as drug concentration,
type and concentration of stabilizers, cooling conditions, and ho-
mogenization procedure.
3. CHARACTERIZATION TECHNIQUES
The characteristics of nanoparticles exert an essential role in
some in vitro and in vivo properties of nano-drug delivery system
(Nano-DDS). For example, safety, efficacy and stability of
Nano-DDS are affected by the particle size, particle size distribu-
tion and zeta potential; solid state of nanoparticles influences the
dissolution performance by impact forces that shatter the lattice
along dislocation boundaries. So the nanoparticles characterization
is of a great importance to predict in vitro and in vivo Nano-DDS
performance. Compared to the particle/microparticle, the in vivo
pharmacokinetic performance and biological function of nanoparti-
cles strongly depends on its surface characteristics and solid state,
including mean particle size and distribution, particle charge (zeta
potential), crystalline state and particle morphology.
3.1. Mean Particle Size and Particle Size Distribution
The mean particle size and the span of particle size distribution
(polydispersity index, PI) are two important characteristic parame-
ters because they affect the saturation solubility, dissolution rate,
physical stability, even in-vivo behavior of nanosuspensions. The
Noyes–Whitney equation [48, 49], Ostwald–Freundlich equation
[50, 51], Kelvin equation [52-54] and the Prandtl equation [55]
could be used to explain the relationships among particle size, satu-
ration solubility and dissolution rate of nano-preparations. Gao et al.
[56] had studied the effect of particle size on in-vivo pharmacoki-
netic behavior of oridonin (ORI) nanosuspensions following intra-
venous administration in rats. ORI nanosuspensions with a mean
particle size 103.3
15 nm was quickly removed from the circulat-
ing system. On the contrary, ORI nanosuspension with a mean par-
ticle size 897.2
14.2 nm exhibited a markedly delayed blood
clearance and a high uptake in RES organs.
At present, the mean particle size and PI could be measured by
several techniques such as laser diffractometry (LD), photon corre-
lation spectroscopy (PCS), microscope and coulter-counter. LD can
detect and quantify the drug microparticles during the production
process. LD yields a volume size distribution and can be used to
measure particles ranging from 0.05 Gm up to 2000 m [57]. PCS
usually is used to determine the mean particle diameter and PI of
nanosuspensions. Measuring range of PCS is from 3 nm to 3 m
[58]. The coulter-counter gives the absolute number of particles per
volume unit for the different size classes, and it is a more efficient
and appropriate technique than LD for quantifying the contamina-
tion of nanosuspensions by microparticulate drugs. On-line moni-
Pu et al.
toring of particle size by near-infrared spectrum [59] is also a good
choice.
3.2. Surface Charge (Zeta Potential)
Zeta potential gives certain information about the surface
charge properties and further the long-term physical stability of the
nanosuspensions. The value of particle surface charge indicates the
strength of the interactive force between particle and particle at the
nano-surfaces, which is the basis to nanosuspensions stability at the
macroscopic level. In order to obtain an electrostatically stabilized
nanosuspension, a minimum zeta potential of ± 30 mV is required
[60, 61]. In the case of a combination of electrostatic and steric
stabilization, a minimum zeta potential of ±20 mV is desirable [62].
The zeta potentials values were commonly assessed by determining
the particle electrophoretic mobility using the Zetasizer (Malvern
Instruments Ltd., UK) and converting the electrophoretic mobility
to the zeta potential via the Helmholtz-Smoluchowski equation [63].
In the field of materials science, an electroacoustic technique
(AcoustoSizer, Matec Applied Sciences, USA) can also be used in
the determination of the zeta potential [64].
3.3. Crystalline State and Particle Morphology
The assessment of the crystalline state and particle morphology
together helps in understanding the polymorphic or morphological
changes that a drug might undergo when subjected to nanosizing.
Additionally, during nanosuspensions preparation, drug crystalline
state is likely to be partially converted to an amorphous form.
Hence, it is essential to measure the extent of amorphous drug gen-
erated during the nanosuspensions production. The changes in the
solid state of the drug particles as well as the extent of the amor-
phous fraction can be determined by X-ray diffraction analysis [65,
66] and supplemented by differential scanning calorimetry [29, 67].
In order to get an actual understanding of particle morphology, the
techniques such as scanning electron microscopy (SEM) [29, 68,
69], atomic force microscope [69, 70] or transmission electron mi-
croscopy (TEM) [70, 71] are preferred.
4. IN VITRO AND IN VIVO PROPERTIES
4.1. Saturation Solubility and Dissolution Rate
Dissolution rate is an important factor to assess the benefits
from nanosuspensions in relation to the traditional meso- or mi-
cro-formulations (e.g. coarse powder, micronized product), espe-
cially when designing the rapid-release dosage forms for poorly
soluble drugs. Paddle and basket methods (USP30) and
film-dialysis can be used to determine the dissolution rate. In addi-
tion to the adhesive properties [72, 73] of nanosuspensions, in-
creased dissolution rate and supersaturation solubility are the main
advantages of nanosuspensions compared to traditional dosage
forms. For example, the dissolution rate of ibuprofen nanosuspen-
sions was increased by more than three times compared to the mi-
cronized ibuprofen [43].
4.2. In-Vivo Pharmacokinetic Performance
The establishment of relationship between in-vitro release and
in-vivo absorption and the monitoring of the in-vivo performance of
the nanosuspensions are essential to a successful preparation, irre-
spective of the administration route and the delivery systems. For
oral nanosuspensions, the drug dissolution rate can influence
in-vivo biological performance of formulations to a larger extent.
For instance, albendazole nanosuspensions enhanced the C max to
1.5-2 times than that of microsuspension, and increased the AUC0-

and the relative bioavailability (Fr) by 1-2 times than those of mi-
crosuspension (Fig. 3) [74]. For intravenously injected nanosuspen-
sions, the organ distribution in part depends on the nanoparticle size
and surface property. Surface hydrophilicity/hydrophobicity and
Formulation of Nanosuspensions as a New Approach
Fig. (3). Mean plasma concentration of albendazole sulfoxide-time curves after oral administration of albendazole formulations to rats at a dose of 50 mg/kg (n
= 6). ABZ-Sup: microsuspension including polysorbate 80 (0.5%); ABZ-T: nanosuspension stabilized by polysorbate 80 (0.5%); ABZ-P: nanosuspension
stabilized by poloxamer 188 (0.5%); ABZ-HT: nanosuspension stabilized by HPMC K4MCR P (0.5%) & Polysorbate 80 (0.5%) (Reprinted from Mittapalli, et
al. [74]).
interactions with plasma proteins are considered as important fac-
tors affecting the in-vivo organ distribution behavior after i.v. injec-
tion of nanosuspensions [75-78]. With the quick development of
physical chemistry and biochemistry, many techniques to evaluate
the surface properties and protein interactions have emerged re-
cently. For example, hydrophobic interaction chromatography,
previously employed to determine the surface hydrophobicity of
bacteria [79], can be used to determine surface hydrophobicity [80].
2-D PAGE [75] can be employed for the quantitative measurement
of protein adsorption to nanoparticle surface after i.v. injection of
drug nanosuspensions to animals.
Although establishment of an in-vitro/in-vivo relationship is
extremely important to nanosuspensions, the biorelevant studies
have not been reported by far. Especially, the correlation of phar-
macokinetics and pharmacodynamics will be a further research
topic.
5. POST-PRODUCTION PROCESSING
5.1. Solidification Techniques
Nanoparticles are usually produced in the liquid media, that is,
nanosuspensions. The nanosuspensions usually have the stability
issues involved in the physical (e.g. Ostwald ripening and agglom-
eration) and chemical (e.g. hydrolysis) processes. In this case, solid
dosage forms are considered more attractive, due to their patient
convenience (marketing aspects) and good stability. Therefore,
transformation of nanosuspensions into the solid dosage form is
desirable. Solidification methods of the nanosuspensions include
some unit-operations such as pelletization, granulation, spray dry-
ing or lyophilization [81]. As the primary objective of the nanopar-
ticulate system is rapid dissolution, disintegration of the solid form
and redispersion of the individual nanoparticles should be rather
rapid, so that it does not impose a barrier on the integrated dissolu-
tion process. Drying of nanoparticles can create stress on the parti-
cles that can cause aggregation. For example, drying may lead to
crystallization of the polymers such as poloxamers, thereby com-
promising their ability to prevent aggregation. Drying can also cre-
ate additional thermal stresses (due to heat for spray drying or
Current Nanoscience, 2009, Vol. 5, No. 4 421
freezing for lyophilization) that may destabilize the particles. Due
to the above considerations, adding matrix-formers to the suspen-
sion prior to solidification is necessary. At present, except for tradi-
tional lyoprotectants (such as glucose, sucrose, trehalose, lactose,
mannitol, sorbitol, maltose and dextran) [82-86]
some new ma-
trix-formers have received significant interest. Van Eerdenbrugh et
al. had successfully used microcrystalline cellulose to displace su-
crose as a matrix former during freeze-drying of itraconazole
nanosuspensions [87], and had again evaluated four alternative
matrix formers [Avicel®PH101, Fujicalin® (CaHPO4), Aerosil®200
(SiO2) and Inutec®SP1] for their capability in preserving rapid
dissolution after spray-drying of nanosuspensions [88]. In addition,
the effect of surface hydrophobicity on drug dissolution behavior
upon redispersion had been investigated, indicating the more in-
tense hydrophobicity, the more aggregation of the nanoparticles and
the slower the drug’s dissolution after solidification [89].
5.2. Surface Modification Techniques
Nanosuspensions have the particular characteristics to increase
the saturation solubility and dissolution rate for the poorly soluble
drugs. But in some cases, the rapid or burst release of nanosuspen-
sions may result in the side effect and toxicity. As a colloid
nanoparticle system, nanosuspensions usually can target the mono-
cyte phagocytic system (MPS), which can aid in the treatment of
lymphatic-mediated diseases [90], like Mycobacterium tuberculosis,
Listeria monogyna, Leishmania sp. The action is called as ‘passive
targeting’. However, the passive targeting process could pose an
obstacle when either macrophages are not the desired targets or
accumulated drug is toxic to MPS cells. Hence, in order to bypass
the phagocytic uptake of the drug, its surface properties need to be
tuned, just like stealth liposomes [91, 92] and nanoparticles [93,
94].
Faced with the above problems, the surface modification of
nanosuspensions will be very necessary. In the case of burst release
and passive targeting, the controlled release and long residence at
site of action may be effective. For example, Tan et al. had pre-
pared layer-by-layer self-assembly coated procaine hydrochloride
422 Current Nanoscience, 2009, Vol. 5, No. 4 Pu et al.

Table 2. The New Drug Application Based on Nanosuspensions Technique Reported and Marketed by Now

Drugs Indication Author or Company Route Status

Paclitaxel Anticancer American Bioscience Intravenous Marketed

Danazol Hormone Rogers T.L. Oral Reported [34]

Naproxen Anti-inflammatory Anchalee Ain-Ai Oral/parenteral Reported [104]

Probucol Lipid lowering Jyutaro Shudo Oral Reported [105]

Rapamune Immunosuppressant Elan Nanosystems Oral Marketed

Emend Anti-emetic Elan Nanosystems Oral Marketed

Cytokine inhibitor Crohn’s disease Elan Nanosystems Oral Phase II

Fenofibrate Lipid lowering SkyePharma Oral Marketed

Megestrol acetate Steroid hormone Par Pharmaceuticals Oral Marketed

paliperidone palmitate Anti-schizophrenia Johnson and Johnson Oral Phase III

Loviride Antivirotic B. Van Eerdenbrugh Intravenous Reported [28]

Busulfan Anticancer SkyePharma Intrathecal Undisclosed

Budesonide Asthma Jerry Z. Yang Pulmonary Reported [63]

Fluticasone Asthma Jerry Z. Yang Pulmonary Reported [63]

Insulin Diabetes BioSante Oral Undisclosed

Clofazimine Antimycobacterials K. Peters Intravenous Reported [106]

Buparvaquone Antibiotic Müller R. H. Oral Reported [91]

Oridonin Anticancer Lei Gao Intravenous Reported [55]

AZ68 Anticancer Kalle S. Oral/Intravenous Reported [107]

Ascorbyl palmitate Antioxidant Veerawat T. Intravenous Reported [68]

Hydrocortisone Glucocorticoid M.A. Kassem Ophthalmic Reported [108]

Prednisolone Glucocorticoid M.A. Kassem Ophthalmic Reported [108]

Hexadecadrol Glucocorticoid M.A. Kassem Ophthalmic Reported [108]

Aphidicolin Antileishmanial O. Kayser Oral Reported [109]

Dihydroartemisinin Antimalarial Jiraporn C. Intravenous Reported [69]

Cilostazol Antiplatelet agent Jun-ichi Jinno Oral Reported [110]

Spironolactone Diuretics P. Langguth Intravenous Reported [111]

Carbamazepine Psychotolytic D. Douroumis Oral Reported [112]

Omeprazole Proton pump inhibitor Jan Möschwitzer Intravenous Reported [26]

Thymectacin Anticancer Elan Nanosystems Intravenous Undisclosed

Silver Eczema NUCRYST Topical Phase 

Mitotane Adrenal Cortex Hormones Michele Trotta Oral Reported [40]

Griseofulvin Antifungal Boris Y. Shekunov Oral Reported [41]

Tarazepide Selective CCKa-antagonist C. Jacobs Oral Reported [113]

Albendazole Anthelmintic drug Mittapalli P. K. Oral Reported [74]

Azithromycin Antimicrobial Dianrui Zhang Oral Reported [114]

Ketoprofen Analgesic Remon J.P. Oral Reported [115]

nanogels, which can effectively reduce and minimize the high burst
release of drug compared to uncoated nanogels [95]. Mucoadhesive
bupravaquone nanosuspensions can increase the adhesion to the gut
wall and prolong residence at gastrointestinal tract, and the results
of pharmacodynamic experiments revealed a 10-fold reduction in
the infective score of cryptosporidium parvum as compared to the
bupravaquone nanosuspensions without mucoadhesive polymers
after oral administration [96, 97]. In the case of the passive target,
the engineering of stealth nanosuspensions (analogous to stealth
liposomes) by using various surface coatings to the desired site is
the future direction of targeted drug delivery systems. For instance,
modification of the surface of nanoparticles with phosphol-
ipid-polyethylenegylcol (PEG) chains [98] could delay protein ad-
sorption binding and opsonization of the nanoparticles, thereby
reducing macrophage uptake. This would increase circulation time,
and give the particles the opportunity to find, and leak out of dis-
continuities of vasculature in neoplasms, infections and inflamma-
tions [99, 100]. Zahr et al. [101] modified surface of dexametha-
sone nanoparticles via layer by layer assembly with PEGlyted
polyelectrolytes to get long-circulating preparations. Turning to the
Formulation of Nanosuspensions as a New Approach
Fig. (4). Concentration of radioactivity in tissues post-dosing with IV
itraconazole nanosuspensions as a single dose of 10 mg/kg (Reprinted from
Rabinow, et al. [122]).
special properties of the functional excipient coating on the surface
of nanoparticles, it can be realized to actively target the desired
disease sites. For example, Kreuter had successfully targeted the
peptide dalargin to the brain by employing surface modified poly-
isobutyl cyanoacrylate nanoparticles [102]. Albumin-bound pacli-
taxel nanosuspension (nab-paclitaxel) successfully accumulated
tumor tissue by binding of albumin to a cell surface, 60-kDa glyco-
protein (gp60) receptor (albondin) as well as via caveolar transport
and binding of albumin to SPARC (secreted protein acid and rich in
cysteine) [103].
6. APPLICATIONS
Nanosuspensions have been used to prepare diverse dosage
forms by post-production processing. The smaller particle size and
larger surface area lead to increased dissolution rate and oral ab-
sorption. Additionally, the nanoparticulate nature might dictate
naturally targeting of the monocyte phagocytic system (MPS), and
result in unusual pharmacokinetic consequences. At present, there
are many drugs in the form of nanosuspensions to be reported and
marketed (Table 2) via the various administration routes, including
oral, parenteral, ophthalmic and pulmonary routes.
6.1. Oral Drug Delivery
In general, oral administration is first choice for various drugs
due to good patient compliance, readily transportation, simple
manufacture process. The major problem associated with oral ad-
ministration is low bioavailability and finally its inadequate effi-
cacy due to poor solubility and incomplete dissolution. Oral nano-
suspensions have been specifically used to increase the absorption
rate and bioavailability of drugs [116] due to much larger surface to
volume ratio. For example, when formulating azithromycin as
Current Nanoscience, 2009, Vol. 5, No. 4 423
nanosuspensions, the dissolution rate was significantly enhanced in
the nanometer-sized system, more than 65% dissolved in 5 h, as
opposed to only 20% of the micronized drugs [114].
Apart from improved oral absorption, nanosuspensions offer the
following advantages: dose proportionality, low inter-subject vari-
ability. Drug nanosuspensions can be easily incorporated into vari-
ous dosage forms such as tablets, capsules and fast melts by means
of standard manufacturing techniques. Ketoprofen nanosuspensions
have been successfully incorporated into pellets for the sustained
release the drug over a period of 24 h [115].
6.2. Parenteral Drug Delivery
Injections provide fast onset of action, accurate dose, reliable
efficacy and avoidance of first-pass metabolism. Previously, injec-
tions of poorly water-soluble drugs were usually approached by
formulating drugs with excessive amounts of co-solvents, solubi-
lizers, surfactants and carrier materials, which may induce serious
toxicity. For instance, marketed paclitaxel injection containing
Cremophor EL often result in anaphylactoid reactions. To establish
a more acceptable formulation, an injectable nanosuspensions for-
mulation of poorly water-soluble drugs has emerged. Successful
formulation has been reported as applied to antineoplastic agents
[117], anaesthetic agents [118], antifungals and antibacterials [119],
as well as for agents for malignant hyperthermia [120] and cancer
pain [121].
Nanosuspensions can be administered via different parenteral
routes, such as intraarticular, intraperitoneal and intravenous injec-
tions. In some cases, their nanoparticulate nature dictates MPS tar-
geting. If intravenously administered nanoparticles do not dissolve
immediately, they will initially distribute to MPS organs [109], in
particular the Kupffer cells in the spleen and liver [122] (Fig. 4).
Subsequent drug dissolution in MPS provides a depot effect of
these organs. The finding of initial sequestration by the MPS, fol-
lowed by slow release is generally found for intravenously admin-
istered itraconazole nanoparticulate dosage forms [123].
6.3. Ophthalmic Drug Delivery
Most of ocular diseases are treated with topical application of
drug solutions administered as eye drops. The present therapy with
conventional eye drops (solution or microsuspensions) requires
frequent instillation due to the rapid and extensive pre-corneal loss
caused by drainage through the naso-lacrimal duct and the
non-productive absorption after corneal permeation and blinking.
Frequent instillation leads to poor patient compliance, and admini-
stration of a large dose induces glaucoma, cataract formation and
damage of optic nerve.
Ophthalmic drug delivery, more than any other route of ad-
ministration, may benefit to a large extent from the characteristics
of nano-sized drug particles. The nanometer size represents a state
of matter characterized by higher solubility, higher surface area
available for high dissolution, better bioadhesion and corneal pene-
tration, and less frequent instillation. Therefore nanosuspensions
can increase the local availability and biological activity of the drug
compared with that of drugs administered in classical aqueous eye-
drops. Nanosuspensions manufactured by Kassem et al. [107] as an
ophthalmic delivery system for certain glucocorticoid drugs can
illustrate this findings (Table 3).
Besides the natural bioadhesion of the nanoparticulate, surface
charge and modified surface by suitable gel matrix and bioadhesive
matrix allow prolonged residence in the cul-de-sac and sustained
release of the drug. If nanoparticles have a positive charge, signifi-
cant improvement in drug performance can be achieved. The posi-
tive charge present in these nanoparticles could account for a strong
interaction with the negatively charged mucosa of the conjunctiva,
thus allowing for a sufficient residence time to permit an efficient
424 Current Nanoscience, 2009, Vol. 5, No. 4 Pu et al.

Table 3. Mean Values of Pharmacodynamic Parameters for Three Drugs Solution and Corresponding Nanosuspensions (Mean ± S.E.)

Preparations %IOPmax Tmax (h) AUC0–8 h HVD(h) HVDR (h) MRT (h)

(% increase in IOP. h)
Hydrocortisone 9.77 ± 0.37*** 1.35±0.11† 23.27 ± 1.08*** 2.36±0.28* 2.36±0.28*** 2.40±0.08***

solution

Hydrocortisone 17.22 ± 1.32 1.60±0.10 56.89 ± 4.60 3.13± 0.29 4.69 ± 0.26 3.47 ± 0.15

nanosuspension

Prednisolone 11.49±0.83*** 1.80± 0.08† 34.60 ± 2.64*** 3.11±0.31* 3.11±0.31*** 2.88±0.08***

solution

Prednisolone 25.70 ± 1.24 1.85 ± 0.07 103.18 ± 7.21 3.87 ± 0.28 5.82 ± 0.27 3.71 ± 0.07

nanosuspension

Dexamethasone 13.87±1.05*** 1.55± 0.09† 66.02 ± 5.85*** 4.82±0.33* 4.82±0.33*** 4.33 ± 0.11*

solution

Dexamethasone 24.97 ± 1.27 1.75 ± 0.08 148.05 ± 7.69 6.10 ± 0.29 8.39 ± 0.17 4.95 ± 0.30

nanosuspension

Statistical differences between the nanosuspensions of each drug and corresponding solution. % IOPmax: the maximum percentage increase in intraocular pressure (IOP); Tmax: the
time of maximum response; AUC0–8: the area under percentage increase in IOP versus time curve; HVD: half peak IOP response intensity prevails; HVDR: half value duration
relative to reference; MRT: the mean residence time. * p = 0.05 significant; ** p = 0.01 highly significant; *** p = 0.001 very highly significant; † Insignificant.

drug release [124,125]. Wrapping nanosuspensions in appropriate
gel matrix or bioadhesive matrix is another technique to prolong
retention time. After surface modification by biodegradable hydro-
philic polymer, flurbiprofen nanosuspensions demonstrated good
effect of sustained-release following ocular administration [125].
6.4. Pulmonary Drug Delivery
Pulmonary delivery is the preferred route of drug administration
in the treatment of many respiratory diseases, such as asthma and
chronic obstructive pulmonary disease [126,127].
Over years, solution, microsuspension, and dry powder as con-
ventional formulations were used in the preclinical studies
[127,128]. The utility of these formulations, however, has some
limitations in the preparation and delivery. For example, vehicle
tolerability of solution formulations [129], limited diffusion and
dissolution of the drug, rapid clearance of the drug from the lungs
[130], less residence time, highly variable lung deposition and ex-
posure of microsuspensions [60,131-134] are formidable problems
associated with pulmonary drug delivery.
Nanosuspensions with a tailored particle size may overcome
many challenges in the pulmonary drug delivery. Compared to the
conventional formulations, nanosuspensions have several advan-
tages: firstly, easy to dose with a syringe-type delivery device in
animal studies, and more consistent drug distribution in the lung
than dry powder formulations; secondly, the increased adhesiveness
of the drug in nanosuspensions to mucosal surfaces [135] offers a
prolonged residence time for the drug at the absorption site. For
example, the plasma exposures for fluticasone and budesonide
nanosuspensions after the intratracheal administration were similar
to solutions and showed rapid absorption with first-order clearance
kinetic as a result of the deep lung deposition and fast onset [105].
Additionally, fluticasone concentrations in the lung decreased
gradually over 4 h after intratracheal administration [105].
7. CONCLUSIONS AND PROSPECTIVES
Nanosuspensions are considered as the most promising delivery
system for poorly soluble drugs, due to high bioavailability and less
inter- and intra-subjects variances. It is proved suitable to formulate
various poorly soluble drugs, in particular for the brick-dust mole-
cules poorly soluble in both water and oils, and can reduce the so-
cial investment and enhance the success rate in insoluble drug de-
velopment.
Altered pharmacokinetic profiles of drugs caused by nanosus-
pensions have become appreciable insofar as they improve safety
and efficacy. So the study on in-vivo biological performance is
extremely important, and the establishment of an in-vitro/in-vivo
relationship will become a hot research field in the further study of
nanosuspensions.
The combination of nanosuspension solidification technique
with traditional dosage forms, e.g. incorporating drug nanoparticles
into pellets, tablets or gels, will readily widen application of nano-
suspensions. Additionally their applications in buccal, nasal and
topical delivery will represent a more beautiful prospective.
Surface modification of the drug nanosuspensions can further
increase the benefits, e.g. stabilizing blood level of drugs by con-
trolling drug release and targeting specific organ by using special
surface ligands in the production process or layer-by-layer
self-assembly technology. Controlled drug release and functional-
ized surface coatings capable of eliciting passive or active targeting,
will be regarded as the future promising step in the nanosuspen-
sions research.
ACKNOWLEDGEMENT
We are grateful for financial support from the National Basic
Research Program of China (973 Program), No. 2009CB930300.
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Accepted: June 03, 2009