Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release

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Review

Drug nanocrystals In vivo performances

Lei Gao 1 Guiyang Liu 1 Jianli Ma Xiaoqing Wang Liang Zhou Xiang Li

Department of Pharmacy The First Af 1047297liated Hospital of General Hospital of PLA No 51 Fucheng Road Beijing 100048 China

a b s t r a c ta r t i c l e i n f o

Article history

Received 1 December 2011

Accepted 8 March 2012

Available online 20 March 2012

Keywords

Poorly soluble drugs

Drug nanocrystals

Bioavailability

Pharmacokinetics

Pharmacodynamics

Targeting drug delivery

Over the past few decades there has been a considerable research interest in drug nanocrystal system as a

pharmaceutical approach for poorly soluble drugs At the beginning lots of works have been done to study

various technologies associated with production of drug nanocrystals and their in vitro physical and chemical

properties such as morphology formulation composition stabilities crystalline structure and enhanced sol-ubility and dissolution velocity Recently in vivo behaviors of the nanocrystals have been generally studied in

animals (including human) and the results proved that drug nanocrystals could be used as a versatile formu-

lation to alter and improve the pharmacokinetic pharmacodynamic and targeting properties of poorly solu-

ble drugs In this paper in vivo performances of drug nanocrystals exhibited in animals in different

administration route were reviewed and the advantages of drug nanocrystals in the aspect ofsafety pharma-

codynamics pharmacokinetics and targeting delivery were discussed in detail

copy 2012 Elsevier BV All rights reserved

Contents

1 Introduction 419

2 In vivo performances of nanocrystals in different administration route 419

21 Safety and toxicity 419

211 Safety issues of poorly soluble drugs 419

212 Advantages of nanocrystal formulations in terms of safety 419

22 Effects on the pharmacokinetic properties 420

221 Oral administration route 420

222 Injection administration route 423

223 Ophthalmic administration route 424

224 Pulmonary administration route 424

23 Effects on the pharmacodynamic properties 425

24 Targeting delivery 425

241 Passive targeting 426

242 Speci1047297c organs targeting 426

243 Cell-based drug delivery of drug nanocrystals 427

3 Conclusions 427

Acknowledgment 427

References 427

Journal of Controlled Release 160 (2012) 418ndash430

Abbreviations AN aqueous nanosuspension Apo apolipoprotein AUC area under the blood concentrationndashtime curve BCS biopharmaceutics classi1047297cation system BMM

bone marrow-derived macrophage CL clearance rate Cmax maximum plasma concentration CNV choroidal neovascularization EPR enhanced permeability and retention GI

gastrointestinal GIT gastrointestinal tract ICS Inhaled corticosteroids iv intravenous IVIVC in vitrondashin vivo correlation MPS mononuclear phagocyte system MRT mean res-

idence time MTT methyl thiazolyl tetrazolium NSAIDs non-steroidal anti-in1047298ammatory drugs PEG polyethylene glycol RBCs red blood cells RES reticuloendothelial system

RITC rhodamine B isothiocyanate SDS sodium dodecyl sulfate Tmax time to maximum plasma concentration Vd volume of distribution

Corresponding author Telfax +86 10 66867405

Corresponding author Telfax +86 10 66867081

E-mail addresses business_gaoleiyahoocn (L Gao) liuguiygmailcom (G Liu)1 Contributed equally to this paper

0168-3659$ ndash see front matter copy 2012 Elsevier BV All rights reserved

doi101016jjconrel201203013

Contents lists available at SciVerse ScienceDirect

Journal of Controlled Release

j o u r n a l h o m e p a g e w w w e l s e v i e r c o m l o c a t e j c o n r e l



1 Introduction

At present about 40 of the drugs being in the development pipe-

lines are poorly soluble even up to 60 of compounds coming direct-

ly from synthesis are poorly soluble [1] The poor solubility makes

these drugs very dif 1047297cult to perform the pharmacological screening

of compounds for potential drug effects It was reported that 70 of

the potential drug candidates were discarded due to low bioavailabil-

ity related with poor solubility in water before they ever reached thepharmaceutics department [2] Many different techniques have been

developed to overcome the solubility problem of poorly soluble

drugs eg solubilization solvent mixtures inclusion compounds

complexation and so on A basic problem is that these formulation

techniques can only be used to a certain number of drugs exhibiting

special features required to employ the formulation principle ( eg

molecule 1047297ts into the cavity of the cyclodextrin ring being soluble

in certain organic agents) [3] When it comes to drugs which are in-

soluble in both aqueous and organic media (drugs so-called lsquobrick

dust drugsrsquo) these approaches are often ineffective

Over the past two decades drug nanocrystal technology has been

undoubtedly the highlight in pharmaceutical 1047297eld One of its major

contributions is the bene1047297ts that can be gained by formulating poorly

soluble drugs [4] This approach generally produces dispersions of

drug nanocrystals in a liquid medium (typically water) which are

called ldquonanosuspensionsrdquo Nanosuspensions consist essentially of

pure drug nanoparticles (100ndash1000 nm) and a minimum amount of

surface active agents required for stabilization At present ap-

proaches developed to produce drug nanosuspensions mainly include

the so called lsquobottom uprsquo (precipitation) and lsquotop downrsquo (media mill-

ing high pressure homogenization etc) The bottom up technology

dissolves the drug in solvent and then precipitates it by adding the

solvent to a non-solvent These techniques are not widely used be-

cause of some prerequisites such as usage of organic solvents and

the drug should be soluble at least in one solvent [5] The top down

technologies are disintegration methods and so can be employed

for all insoluble drugs including lsquobrick dust drugsrsquo Drug nanocrystals

exhibit many advantages including high ef 1047297ciency of drug loading

easy scale-up for manufacture relatively low cost for preparationand applicability to various administration routes such as oral [6]

parenteral [7] ocular [8] and pulmonary delivery [9] All these advan-

tages have so tremendous impacts on promoting drug nanocrystals

successfully from experimental researches to patients that several

products have been launched into market (Table 1)

During the last decade of the 20th century lots of experiments

have been done to study the manufacturing technologies of drug

nanocrystals and their in vitro physical and chemical properties

such as procedure parameters formulation composition physical

and chemical stability crystalline structure enhanced saturation sol-

ubility and dissolution rate bioadhesion and so on Some published

reviews have well summarized and discussed results of these re-

searches from different aspects [3ndash510ndash14] In the last ten years

more and more attentions were paid to the in vivo performances of

nanocrystals in animals (including human) and many exciting 1047297nd-

ings were obtained This review will speci1047297cally focus on these 1047297nd-

ings including safety pharmacokinetics pharmacodynamics and

targeting effects of drug nanocrystals Some expanded studies of

drug nanocrystals in recent years such as moieties-modi1047297ed polymer

layers and cell-based drug delivery system will also be discussed in

this review

2 In vivo

performances of nanocrystals in differentadministration route

21 Safety and toxicity

211 Safety issues of poorly soluble drugs

Safety is a primary issue for medicines thus the toxicity assessment

is the most important data for registration of a new medicine For the

poorly soluble drugs safety issue may be more troublesome Due to

their low solubility a large amount of organic cosolvents or solubilizers

should be added in most cases before they are formulated as injectable

solution which will result in unwanted side effects or even toxicities

[15ndash17] For examples the Cremophor-EL ndash a solubilizer used in

paclitaxel product Taxolreg ndash is associated with serious side-effects

such as hypersensitivity nephrotoxicity and neurotoxicity [18] Renal

injury occurring in the commercially available itraconazole injection

Sporanoxreg is concerned with the cyclodextrin-solubilizing agents

[19] In addition precipitation of the poorly soluble drugs from the

non-aqueous formulation once it is diluted withblood is another poten-

tial problem [20] Oral delivery as a non-invasive route is safe in most

cases However the high and prolonged local concentration may be

an issue involved in oral application of the poorly soluble drugs espe-

cially for the irritative drugs such as non-steroidal anti-in1047298ammatory

drugs (NSAIDs) Similar issue may restrict the mucosa delivery since

precipitation of drugs on the mucosa surface resulting from the very

limited dissolution will also cause local irritation [21]

212 Advantages of nanocrystal formulations in terms of safety

Drug nanocrystals are generallyreported as a safe and well tolerated

formulation in many administration route compared with the conven-tional products This is mainly attributed to following advantages

2121 Fine particle size As for the submicron delivery system particle

size is a crucial factor in determining whether or not it can be used in

parenteral route For iv injection the content of particles larger than

5 μ m should be controlled strictly because the smallest size of blood

capillaries is about 5 μ m Existenceof a high content of particles larger

than 5 μ m can lead to capillary blockade and embolism Drug nano-

suspensions as colloidal aqueous dispersions can be well tolerated

in iv route in many reports Fine particle size also helps improve

safety of oral poorly soluble drugs in some cases by increasing the

distribution uniformity in the gastrointestinal (GI) 1047298uid and avoiding

the high and prolonged local concentration [22] Nano-sized particles

are also bene1047297cial to a better toleration in the mucosa delivery such

Table 1

Key characteristics of available commercial drug products based on drug nanoparticle technology

ProductCompany Drug compound Indication Nano-sizing approach Administration route Date of FDA approval

Gris-PegregNovartis Griseofulvin Anti-fungal Bottom up coprecipitation Oral 1982

CesametregLilly Nabilone Anti-emetic Bottom up coprecipitation Oral 2005

RapamuneregWyeth a Sirolimus Immunosuppressant Topndashdown media milling Oral 2000

EmendregMerck a Aprepitant Antiemetic Topndashdown media milling Oral 2003

TricorregAbbott a Feno1047297brate Hypercholesterolemia Topndashdown media milling Oral 2004

Megacereg ESPar Pharma a Megestr ol a cetat e A ppetite stimulant T opndashdown media milling Oral 2005

TridlidetradeSkye Pharmaa Feno1047297brate Hypercholesterolemia Topndashdown highndashpressure homogenization Oral 2005

Invega SustennaJohnson

amp Johnson

Paliperidone palmitate Antidepressant Topndashdown high- pressur e hom ogeniz ation I nj ect ion 20 09

a

Cited from Elan FDA Orange Book SkyePharma

419L Gao et al Journal of Controlled Release 160 (2012) 418ndash430



as ocular and pulmonary delivery by reducing the occurrence of the

local irritation or gritty feel (Table 2) In addition for pulmonary de-

livery nano-sized particles in nebulized droplets could reduce the

drug loss in the upper airway compared with the microparticle

forms which can deposit in the back of the mouth and throat This

is especially important for the inhaled corticosteroids (ICS) Deposit-

ing of the ICS in these regions could lead to localized immune sup-

pression and side effects such as oral yeast infections thrush and

dysphonia (Table 2)

2122 Safe composition Due to the aqueous property and safe com-

position of nanosuspensions the need for organic solvents or extreme

pH ranges for solubilization of poorly soluble drugs is excluded This

provides an opportunity to escalate dose and reduce solvent-related

adverse effects [23] For example paclitaxel nanosuspensions showed

LD50 of 100 mgkg in mice much higher than 35 mgkg of Taxolreg

[24] Safe composition also favors pulmonary delivery of nanosuspen-

sions because the usage of cosolvents which may cause irritation will

be avoided However one prerequisite should be met that is the sta-

bilizers used do not cause any allergic or immune response It is

reported that deoxycholate might stimulate adverse effects included

cough dyspnea bronchospasm nausea and vomiting with aerosol-

ized administration [25ndash27] In contrast Tween 80 and Poloxamer407 do not elicit any immune response or changes in pulmonary his-

tology and are considered as safe surfactants for pulmonary adminis-

tration [2829]

2123 Tolerance to various sterilizations Several sterilization ap-

proaches have been successfully applied to drug nanosuspensions

such as gamma irradiation 1047297ltration sterilization and thermal steril-

ization (in case the drug itself is not sensitive to temperature and the

stabilizers are suitable) [30] An aseptic production line for nanosus-

pension products has even been realized by Baxter Company [24] It

is very important for the injection application

2124 Attenuate side effects related to transient high systemic exposure

After injection drug nanocrystals could move in the circulation as

submicron particles for a certain time period Then they might be rec-

ognized as foreign matters and rapidly cleared by phagocytic cells of

mononuclear phagocyte system (MPS) which are abundant in special

tissues and organs such as liver and lung [31ndash33] In these cases

nanosuspensions formulations will reduce the risk of undesired ad-

verse effects related to the initial plasma peak [734ndash36]

22 Effects on the pharmacokinetic properties

It has been well known that many characteristics of drug nanoparti-

cle systems such as particle size surface properties and so on deter-

mine their release absorption distribution and targeting ability

which further in1047298uences the in vivo fates of nanoparticles [4950] Stud-

ieson drugnanocrystals have also disclosedthe similar1047297ndings Altered

pharmacokinetics resulted from different particle size distribution and

coated polymer chains have been reported in these studies

221 Oral administration route

Drug absorption in the GIT is considered to involve a dissolution

step of the drug from formulation into aqueous luminal 1047298uids fol-

lowed by transporting the drug across the GI epithelium The dissolu-

tion is considered as the rate determining process in the oral delivery

[5152] Poorly soluble compounds tend to be eliminated from the GITbefore they completely dissolve Therefore biopharmaceutically ac-

ceptable formulations for poorly soluble drugs mainly belong to the

biopharmaceutics classi1047297cation system (BCS) II and IV compounds

are a challenge Because slow and erratic dissolution prevent rapid

and complete absorption of these compounds especially for drugs

mainly absorbed in a narrow window in the GIT

Many reports verify that drug nanocrystals have many positive ef-

fects on the oral drug delivery of poorly soluble drugs Manifestations

on the blood pro1047297les are the changes of pharmacokinetic parameters

generally including increased maximum plasma concentration

(Cmax) reduced time to maximum plasma concentration (Tmax) en-

hanced area under the blood concentrationndashtime curve (AUC) and re-

duced fastedfed variability (Table 3) The mechanisms contributed

for the improved absorption could be majorly summarized as two

Table 2

Data related on safety of drug nanocrystal formulations in different administration routes

Administration route Drugs Technology Safety advantages Animals References

Injection delivery Itraconazole High pressure homogenization Being tolerated at signi1047297cantly higher doses and higher

survival compared with solution

Rats [19]

Paclitaxel High pressure homogenization LD50 increase by 3 times compared with Taxolreg and no

allergic reaction occurred

Rats [24]

Paclitaxel Media milling Not induce hemolysis at normal level Mice [37]

Paclitaxel Precipitation None of six mice died at dose of 60 mgkg six died at dose of 30 mgkg

as solution no hemolysis of nanosuspensions vs 100 hemolysis of Taxolreg

Mice [18]

Nimodipine High pressure homogenization Better tolerated compared with commercially available ethanol solution Rabbits [38]

AZ68 Media milling No adverse events Rats [35]

Oridonin High pressure homogenization Increase antitumor ef 1047297cacy while reducing systemic side effects Rats [31]

Curcumin High pressure homogenization Reduce the erythrocyte hemolysis dramatically compared with the

solution no local irritation for nanosuspension

Rabbits [39]

UG558 Media milling No adverse events Rats [36]

R MKP 23 High p ressur e hom ogeniz ation Well t oler at ed w ithout any signs of ac ut e toxicity Mice [40]

Melarsoprol High pressure homogenization 2-fold increase in LD50 compared with the solutionPains and necrosis

occurred in the solution group was suppressed

Rats [41]

Oral delivery Naproxen Media milling Reduction in the gastric irritation Rats [22]

SU5416 Media milling No adverse events Human [42]

UG558 Media milling No adverse events even at higher dose Rats [36]

Pulmonary delivery Budesonide NR a Well tolerated with no evidence of bronchospasm Human [43]

Itraconazole Spray freezing into liquid No evidence of bronchiolar peribronchiolar perivascular in1047298ammation

and epithelial ulceration

Mice [44]

Itraconazole Spray freezing into liquid Better tolerated than the oral solution mortality and morbidity

reduce vs the oral solution at the same dose Signi1047297

cantly prolongthe median survival times

Mice [45ndash47]

Budesonide NR a Reduce the dose and toxicity compared with the microsuspension

reduce the possibility of thrush due to the deposition in back

of the mouth and throat

Human [48]

a NR Not reported

420 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430



points i) improved solubility and dissolution rate and ii) bioadhe-

sion to the intestinal wall

When drugs are administered as nanocrystal formulations a high

drug concentration gradient between GIT and blood vessel will mark-

edly improve absorption and result in a high bioavailability (Fig 1) It

is attributed to the increased saturation solubility and dissolution ve-

locity of drug nanocrystals in digestive juice One classic example is

danazol a poorly soluble gonadotropin inhibitor [6] The absolute bio-

availability of marketed danazol conventional microsuspensions in

beagle dogs (200 mg 10 μ m) was only 52 When administered asan aqueous nanosuspensions (200 mg 169 nm) an absolute bioavail-

ability of 823 could be achieved meanwhile the Tmax was reduced

and the Cmax was increased by 15 times This study did not further in-

vestigate the possible differences of in vivo performances between the

two formulations However it is undoubtedly that for nanosuspen-

sions the same ef 1047297cacy equal to the conventional formulations can

be available at a much lower dose It should be bear in mind that crys-

talline state is another factor affecting the dissolution behavior of

drugs Drugs in the amorphous state possess higher solubility and fas-

ter dissolution rate due to the higher inner energy [5354] Therefore

when dosed through the oral route the drug nanosuspensions in

amorphous rate would show more signi1047297cant effects on enhancing

bioavailability than the crystalline nanosuspensions provided the

high energy state could be kept in the GIT [35]

Fig 1 Drug nanocrystals form a high drug concentration gradient between GIT and

blood vessel due to the increased saturation solubility and dissolution velocity in diges-

tive juice and lead to a signi1047297cant improvement on absorption

Table 3

Changes of pharmacokinetic properties of oral drug nanocrystal formulations compared with the conventional partners

Drugs Nanosizing

methods

Dosage form

(mean particle size)

Control


Comparison of the

pharmacokinetic parameters

Animals References

Danazol Media milling Aqueous

nano-suspensions

(AN) (169 nm)

Unmilled suspensions

(10 μ m)

15-fold increase in Cmax 16-fold

increase in bioavailability speeded

up the absorption

Beagle

dogs

[6]

Naproxen Media milling AN (270 nm) Unmilled suspensions

(20 μ m)

15-fold increase in Cmax 125-fold increase

in bioavailability speed up the absorption

Rats [22]

Feno1047297b rat e H igh pr essu rehomogenization

AN (356 nmand 194 nm)

Micronized suspensions(5ndash10 μ m) and coarse

suspensions

18ndash125-fold increase in Cmax 17ndash17-foldincrease in bioavailability 13ndash23-fold

reduction in Tmax

Rats [55]

Feno1047297b rat e H igh pr essu re

homogenization

AN (340 nm) Micronized feno1047297brate

(5 μ m)


in bioavailability 49-fold reduction in Tmax

Rats [56]

Ketopr ofen Media millin g Pellets con taining

dried nanocrystals

powder (265 nm)

Pellets containing

microcrystalline powder

(65 μ m)



Dogs [57]

AZ68 Media milling

(crystalline)

AN (125 nm) Solution Amorphous suspensions possessed

higher Cmax and smaller Tmax compared

with the crystalline nanosuspensions

the bioavailability was similar

for the two formulations

Rats [35]

Precipitation

(amorphous)

AN (200 nm)

UG558 Media milling AN(190 nm) Microsuspensions

(12 μ m)

35ndash37-fold increase in

Cmax 36ndash45-fold increase in

bioavailability

Rats [36]

13- Dicyclohexylurea Media milling AN (950 nm) Unmilled dispersions (385 μ m) Peak

plasmaexposure

increased

over anorder of

magnitude

Rats [58]

Spironolactone High pressure

homogenization

AN (400 nm) Microsized dispersions

(1ndash5 μ m)

35ndash45-fold increase in Cmax 33ndash51-fold

increase in bioavailability

Rats [59]

BMS-488043 Media millin g AN (120 nm) Microsized tablets

(95 b 7 μ m)



Dogs [60]

A BCS II

substance

Media millin g AN (280 nm) Microsized dispers ions

(4 μ m)



Rats [61]

Cilo stazol Media millin g AN (220 nm) Microsized dispers ions

(13 and 24 μ m)

Fastedfed ratios of the Cmax AUC Tmax

and MRT were signi1047297cantly reduced

Beagle

dogs

[62]

Aprepi tan t Media millin g AN (120 nm) Microsized dispers ions

5 μ m

No food effect at a dose of 2 mgkg 80

mgkg and 125 mgkg

Beagle

dogs

[63]

Cyclosporine High pressure

homogenization

AN (962 nm) Solid lipid nanoparticles

(157 nm) and commercial

microemulsion Sandimmunreg

A very disappointing results blood

concentrations were in the range

between 30 and 70 ngml over a

period of 14 h

Pigs [64]

It rac onaz ole Precipitat ion AN (2 67 nm) Spora nox pellets c ontainingmicroparticles

12ndash18-fold increase in Cmax 15ndash18-foldincrease in bioavailability the fastedfed

ratio of AUC was markedly reduced

Rats [84]

MRT mean retention time AUC area under the concentrationndashtime curve Cmax maximum plasma concentration Tmax time to maximum plasma concentration




It is generally known that nanoparticles possess general mucoadhe-

sion to biological mucosa including GI mucosa [65] This mucoadhesion

effect also plays an important role in the enhancement of oral bioavail-ability There are fourgeneral theories of mucoadhesion mechanisms of

nanoparticles the electronic theory (electrostatic attraction forces be-

tween the surfaces of particles and mucus) the adsorption theory (sec-

ondary forces such as hydrogen and van der Waals bonds between the

surfaces of particles and mucus) the diffusion theory (interpenetration

and physical entanglement of the protein of the mucus and polymer

chains) and the trapping theory (retention of nanoparticles by the un-

even mucosa surface) The profound reasons for these theories exceed

the scope of this paper some other reviews could be referred to

[65ndash68] Because of mucoadhesion to GI mucosa drugs can be released

exactly at the absorption sites This leads to a higher concentration gra-

dient and also a prolonged retention time [55] To strengthen the

mucoadhesion further processing or surface modi1047297cation could be

done Incorporation of drug nanocrystals into a mucoadhesive polymer

or modifying the surface with cationic polymers can facilitate stronger

adhesiveness to the negative mucin on the mucosa surface [69ndash71]

Some researchers believe that transcellular uptake of polymeric

nanoparticulates through epithelial cells is another reason for the en-

hancement of oral bioavailability [7072ndash74] However there has been

no research on the evidence of direct uptake of drug nanocrystals

Moreover even for polymeric nanoparticulate the reported data are

con1047298icting and confusing mainly due to two reasons Firstly the factors

controlling intestinal absorptionof particles are too complicatedmdash

sizenature of the polymer zeta potential vehicle coating materials or other

adhesion factors presence of nutrients havebeen determined as critical

factors in1047298uencing particle uptake Secondly a major source of confu-

sion may lie in the large variety of analytical methods and models that

have been employed to investigate particle uptake [72] Transcellular

uptake of nanoparticles majorly occurred through two types of intesti-

nal cells enterocytes and M cells of Peyers patches However because

of the limited transcytotic capability of enterocytes and small propor-

tion (~ 1) of M cells in total intestinal surface the level of uptake and

to what extent it helps the oral absorptionare still suspected [75] Stud-

ies by Ponchel et al found that the body distribution of 14C-labeled PLA

nanoparticles 1 h after administration showed that 97 of radioactivity

was localized in the GIT Only 3 was recovered in other organs sup-

porting the particle translocation through the mucosa is a limited pro-

cess [65] For drug nanocrystals lots of works should be done to

investigate the evidences of direct uptake pathway and some potential

in1047298uencing factors such as surface properties and particle size

Some authors speculated that the ability of drug nanocrystals to en-

hance bioavailability should partly attributed to the inhibition effects of

coated surfactants on the ef 1047298ux function of the P-glycoprotein (P-gp)

which is located in the apical membranes of intestinal absorptive cells

[5676] Indeed many studies have demonstratedthat some surfactants

such as Tween 20 Tween 80 Pluronic L61 Vitamin E TPGS and so on

can enhance the membrane transport by modulating the intestinal P-

gp function [77ndash79] However all of the results are obtained from ex-

perimental data in models of Caco-2 cells everted gut sac in situ perfu-

sion and rats and so on There are still no related reports in humans For

nanosuspensions we think two points should be questioned before dis-

cussing the action of added surfactants First is the poorly soluble drugindeed a P-gp substrate Second are the amounts of surfactants added

for stabilization suf 1047297cient to inhibit the P-gps function

Poorly soluble drugs often exhibit increased or accelerated ab-

sorption when they are administered with food This can be attrib-

uted to the enhancement of the dissolution rate in the GIT caused

by many factors such as delayed gastric emptying increased bile

secretion larger volume of the gastric 1047298uid increased gastric pH

(for acidic drugs) and increased splanchnic blood 1047298ow [62] For ex-

ample it was reported that a standard high fat breakfast increased

both the rate and extent of cilostazol absorption in human after

oral administration of 100 mg tablet [80] suggesting that the oral

bioavailability of cilostazol could be enhanced by food effects The

fastedfed variation will be dangerous for drugs with a narrow ther-

apeutic window When poorly soluble drugs are formulated as uni-form nanosuspensions this variation may be minimized The reason

is that the dissolution rate of nanocrystals is fast enough even

under the fasted condition Then the absorptions both in fasted

and fed state might be a permeability-limited progress and the ab-

sorption difference resulting from variable dissolution between the

two conditions will be eliminated (Fig 2) Studies by Jinno et al

showed that the fastedfed variation in Cmax AUC tmax and MRT

were almost eliminated when cilostazol nanocrystals dispersions

(220 nm) were given in dogs [62] Feno1047297brate is another drug vul-

nerable to food effect The extent of absorption varies from 30 to

50 when the traditional feno1047297brate tablets in the fasting state to

60ndash90 when it is given after a meal [56] When tablet formulation

containing feno1047297brate nanoparticles were given the food effect is

absent in human [81]

Fig 2 Oral absorption of microcrystals of poorly soluble drugs generally is a

dissolution-limited process in both fastedfed state (A) Absorption of drug nanocrys-

tals generally is a permeation-limited process (B) Therefore the variation between

fasted and fed state may be eliminated




It should be bear in mind that most drug nanocrystal formulations

used in the in vivo experiments are aqueous dispersions (Table 3)

however when it comes to the clinical application solid dosage

forms are usually more acceptable by patients [82] It can be seen

that most of the marketed nanoparticles formulations are solid

forms (Table 1) In order to solidi1047297cation 1047297rst the aqueous nanosus-

pensions should be transformed into dry powders suitable to gener-

ate tablets capsules pellets etc This transformation can be

achieved using different methods including lyophilization spray dry-ing granulation and pelletization [83ndash86] The drying process should

be well designed to avoid particle aggregation If aggregation occurs

the bene1047297ts that can be gained from large surface of the original

nanometer-sized particles would be greatly compromised In general

protectants (usually sugars) are often added to nanosuspensions to

minimize the particle size growth during a drying process

The redispersion progress of a solid formulation containing drug

nanocrystals in the GIT is more complex Physiological factors (in-

cluding pH variation compositions of the digestive juice and GI peri-

stalsis etc) affecting dispersion of nanocrystals are complicated [87]

Nanocrystals of basic drugs are more easily affected by pH variation in

the GIT For weak bases a nanometer-sized drug formulation will dis-

solve fast and more ef 1047297ciently in the low stomach pH environment

During transit from stomach to duodenum the rise in pH may illicit

uncontrolled precipitation of drug substance [88] In addition stabi-

lizer type should be screened by monitoring the change of particle

size after reconstitution in different pH media [89] After rehydration

in GI 1047298uid the nanocomplex disperses into separated nanocrystals

following the dissolution of 1047297llers Stabilizer molecules attached on

the surface of nanocrystals will offer ionic or steric repulsion among

nanocrystals given that they are not affected by the GIT environment

[690] In general ionic stabilizers are effective in aqueous environ-

ment but during the drying they may become less effective because

the ionized state is not maintained in dry material In addition ionic

stabilizers are also sensitive to changes in pH and ionic strength

when the dried powders redisperse in the GI 1047298uid [90] On the con-

trary in most cases the polymer and non-ionic surfactant stabilizers

can be effective to support suf 1047297cient steric repulsion in GI 1047298uid

given that the amount of stabilizers is enough [91]

The establishment of an in vitrondash

in vivo correlation (IVIVC) is anessential part for the study of oral formulations For the Class II

drugs dissolution is a rate-limiting step in the GIT so in general

they have a good IVIVC result [92] When they are processed into

nanocrystal formulations an IVIVC should be reevaluated again

since their dissolution velocity has been markedly enhanced In the

other hand the IVIVC data also help modulate the process and the

amount of matrix in the progress of drying nanosuspensions Howev-

er research on the IVIVC of nanocrystal formulations has not been

reported but we believe it will be the next focus in this 1047297eld

222 Injection administration route

For many cases intravenous injection is requested to meet some

treatment purpose such as immediate effects overcoming the 1047297rst

pass effect targeting effect and so on Due to its suf 1047297ciently small

size and safe aqueous composition nanosuspensions can be injected

intravenously and achieve 100 bioavailability [86] Compared with

other carrier-based solid nanoparticles such as solid lipid nanoparti-

cles polymer-based nanoparticles and liposomes carrier-free nano-

crystals would experience a much faster particle size reduction

during the process of dissolution This may lead to a distinct pharma-

cokinetic progress after iv administration because particle size is an

Table 4

Changes of pharmacokinetic properties of intravenous nanosuspensions compared with the conventional partners

Drug Methods Dosage form


Control


Comparison of the


Animals References

Asulac rine High p ressur e hom ogeniz at ion AN ( 13 3 nm) Organic solut ion 15- fold r edu ction in Cmax23-fold increase in t12 62-fold

increase in Vd 27-fold increase in

CL 27-fold increase in MRT

25-fold reduction in AUC

Rats [34]

Melar sopr ol High p ressur e hom ogeniz at ion AN ( 29 5 nm) Organic solut ion 22- fold inc rease in t12 14-fold

increase in Vd 14-fold reduction

in CL 2-fold reduction in AUC

Rats [41]

AN (409 nm) 3-fold increase in t12 13-fold reduction

in Vd 45-fold reduction in CL 42-fold

reduction in AUC

13-Dicyclohexylurea Media milling AN (NR)a Organic solution All parameters were similar to

those of solution

Rats [94]

Oridonin High p ressur e hom ogeniz at ion AN ( 10 33 nm) Organic solut ion All p ara meters w ere sim ilar to

those of solution 17-fold reduction

in Cmax 7-fold increase in t12 51-fold

increase in Vd 19-fold reduction in CL

62-fold increase in MRT 18-foldincrease in AUC

Rabbits [32]

AN (8972 nm)

It rac onaz ole High p ressur e hom ogeniz at ion AN ( 58 1 nm) Organic solut ion 17- fold inc rease in Cmax 31-fold

increase in t12 18 reduction in AUC 18

increase in CL 28 increase in MRT 79

increase in Vd

Rats [19]

AZ68 Precipitation AN (125 nm) Organic solution No signi1047297cant differences with

solution by means of plasma pro1047297les

Rats [35]

Media milling AN (200 nm)

Cyclosporine Precipitation AN (NR) Organic solution All parameters were similar to

those of solution

Rats [93]

Cu rc um in High p ressur e hom ogeniz at ion AN ( 21 02 nm) Organic solut ion 31- fold inc rease in Cmax

112-fold increase in MRT

48-fold increase in AUC

Rabbits [95]

Flu rb ip rofen High p ressur e hom ogeniz at ion AN ( NR ) Organic solut ion All p ara meters w ere sim ilar

to those of solution

Rats [96]

Vd volume of distribution CL clearance rate MRT mean retention time AUC area under the concentration ndashtime curve Cmax maximum plasma concentration Tmax time to max-

imum plasma concentration t12 plasma half lifea

NR Not reported




important factor affecting the in vivo fate of the colloidal drug system

[32] Apart from this other natures also play important roles such as

the intrinsic drug solubility and the properties of the nanocrystal

coatings [423] The pharmacokinetic performances of nanosuspen-

sions after injection can be summarized as follows

i) Pharmacokinetic properties similar to solution

In some cases drug nanocrystals with small particle size (general-

ly b200 nm) or relatively high intrinsic solubility dissolve imme-

diately in the blood circulation after injection due to the highdissolution rate and the rapid dilution and stirring of theblood cir-

culation [35] which leads to pharmacokinetic properties similar

to drug solution (Table 4) [43288]

ii) Carrier nanoparticulate-like pharmacokinetic properties

Drug nanocrystals with relatively large particle size or very poor

solubility dissolve slowly in circulation In this case drug nano-

crystals would circulate in blood circulation as submicron particles

for a certain time period In this progress they could be recognized

as foreign matters and rapidly cleared by phagocytic cells of MPS

which is abounded in liver lung and spleen and so on [32] It

was reported the uptake of nanoparticles by the reticuloendothe-

lial system (RES) organs following iv injection might taken from

a few minutes to hours depending on their particle size and com-

position [94] In phagocytic cells nanoparticles dissolve slowly inthe phagolysosomes The free lipophilic drug might pass through

the phagolysosomal membrane and enter into the cytoplasm

and then exit the cell by diffusing down the drug concentration

gradient which lead to a sustained release progress [433] Com-

pared with drug solution pharmacokinetic parameters are mark-

edly different Generally the Cmax and AUC would be reduced V dwould be increased and MRT and t12 would be much prolonged

(Table 4) Distribution among tissues and organs is also changed

the fraction distribute to the RES organs would increase

It can be discerned that particle size is an important factors

in1047298uencing the pharmacokinetics properties of injected nanosuspen-

sions Studies by our group showed that intravenously injected

897 nm oridonin nanosuspensions accumulated in the liver whereas

103 nm nanosuspensions exhibited a pharmacokinetics similar to asolution [32] This gives nanosuspensions a good 1047298exibility when fac-

ing different treatment needs Therefore in vivo fate of nanosuspen-

sions following injection could be modulated by conveniently

adjusting several parameters such as particle size When a rapid dis-

solution and action onset are desired a relatively small particle size

is necessary On the contrary when looking forward to treating

macrophages-related diseases such as macrophage infections auto-

immune blood disorders diabetes as well as rheumatoid arthritis a

larger particle size is more advantageous

223 Ophthalmic administration route

Most of ophthalmic diseases are treated with topical application of

eye drops (solution or microsuspensions) In conventional eye drops

ocular bioavailability is low due to the rapid and extensive drug losscaused by drainage through the nasolacrimal duct and blinking [97]

Frequent instillations are necessary in order to maintain therapeutic

effect which in turn leads to poor patient compliance or undesirable

side effects from unwanted systemic drug absorption [98] For ocular

delivery of poorly soluble drugs because the organic solvents and ex-

treme pH should be avoid when considering the high sensitivity of the

eye tissue preparations such as microsuspensions and ointments have

been developed to meet the therapeutic requires [99] These prepara-

tions are often accompanied by several issues such as irritation blurred

vision and de1047297cient concentration due to the limited drug solubility in

lachrymal 1047298

uids and various anatomical barriers [100]Many studies have shown that ophthalmic drug delivery can ben-

e1047297t to a large extent from nanoparticle drug delivery system [101]

Among them carrier-free nanocrystals exhibit more advantages Con-

taining only pure drug particles in nano-size range nanosuspensions

minimize the irritation to eyes consequently decrease tearing and

drainage of instilled dose [100] Higher solubility and dissolution

rate due to the huge surface area can promote or facilitate transfer

of drug molecules from the tear phase into the eye tissue [102] In ad-

dition the bioadhesion of dug nanocrystals will signi1047297cantly prolong

the contact time with the eye surface [103104] These advantages

lead to an increased AUC and MRT (Table 5) In addition to enhance

the viscosity of the nanoparticles and strengthen the bioadhesion to

the eye surface nanoparticles can be incorporated into a suitable

mucoadhesive base or ocular inserts to further prolong retention

time and achieve a sustained release of the drug for a stipulated

time period [8105] Nanosuspensions of different viscosity were pre-

pared by Kassem et al by incorporating the nanoparticles into differ-

ent concentrations of hydroxyethyl cellulose The results found that

the AUC and MRT were markedly enhanced with the increase of the

viscosity [105] Studies by Pignatello et al also found that after sur-

face modi1047297cation by bioadhesive hydrophilic polymer 1047298urbiprofen

and ibuprofen nanosuspensions demonstrated a good effect of

sustained-release following ocular administration [102]

224 Pulmonary administration route

Directpulmonarydeliveryin humans can be achieved using an aero-

sol generated by either an inhaler or nebulizer This administration

route has been generally considered as an attractive way for non-

invasive drug delivery in both systemic and local applications [106]Formulations containing nanoparticulates have demonstrated many

advantages in pulmonary route among them drug nanocrystals show

a great potential for pulmonary delivery of poorly soluble drugs

[107108] Two kinds of pulmonary formulations containing drug nano-

crystals have been reported (Table 6) One is aqueous nanosuspensions

packaged and administered by a nebulizer Drug nanocrystals can be

collected and transported into the lung by the small aerosol droplets

generated by the nebulizer [48] The other one is inhaled powders con-

taining dried nanocrystals dispersed in some inhalable carriers (eg

inhalable lactose) [120] These powders can be inhaled by commercial

dry powder inhalers Compared to the conventional microparticles for

pulmonary use nanoparticles offer a more homogenous distribution

of drugs in the nebulized droplet or among the inhalable carriers

(Fig 3) This is bene1047297cial for a more precise dosageAerodynamic diameter of droplets should be in range from 1 to

5 μ m to be retained in smaller airways and respiratory bronchioles

Table 5

Changes of pharmacokinetic properties of ophthalmic nanosuspensions compared with the conventional partners

Drug Metho ds Dose form (mean particle size) C ontro l Compari son of the pharmacokinetic paramete rs Animals R eferences

Hydroco rtison e Precipitati on AN (300 nm) So lution 1 8-fold incre ase in AUC 13-fold increase in MRT Rabbits [99]

Media milling AN (300 nm) 20-fold increase in AUC 13-fold increase in MRT

Hydrocortisone High pressure homogenization AN (539 nm) Solution 18-fold increase in IOPmax 24-fold increase in AUC


Rabbits [104]

Prednisolone High pr essu re homogeniza tion AN ( 21 1 nm) Solut ion 23-f old inc rease in IOPmax 30-fold increase in AUC


Rabbits [104]

Dexamethasone High pressure homogenization AN (930 nm) Solution 18-fold increase in IOPmax 22-fold increase in AUC


Rabbits [104]




[107] When drug nanocrystals in aerosol droplets deposit in the lung

they can spread more evenly on the lung surface especially when

coated stabilizers have a good spreadability Then drug nanocrystals

dissolve rapidly in the lung lining 1047298uid leading to a high concentra-

tion due to their nano-range size This is very helpful for localized

treatment or prophylaxis of respiratory diseases Many studies have

demonstrated that pulmonary delivery of nanosuspensions favor

higher lung tissue concentrations and markedly raise the lung to

serum ratio of drugs compared with other administration route

[109ndash112] Beside this this is also conducive to a rapid onset of sys-

temic effect [113ndash115] Because high drug concentration in the alveoli

would raise the driving force for permeation through the alveolar

membrane and result in higher Cmax and earlier Tmax [43] When

nanosuspensions contain particles in amorphous form characterized

by higher inner energy this effect is more obvious [116]

However in spite of these advantages there are also some notable

issues in pulmonary delivery of drug nanosuspensions Nebulization

is a complex process affected by the characteristics of the nebulizer

and compressor droplet size properties of the formulation breathing

pattern of the patient and respiratory tree anatomy [43] In additiontypes of surface coatings of nanocrystals may also in1047298uence the safety

of pulmonary application (see Section 21)

23 Effects on the pharmacodynamic properties

For poorly soluble drugs (mainly belong to BCS II andor IV) in-

vestigations on pharmacological effects are usually not easy Some-

times these drugs can exhibit visible in vitro pharmacological effects

after dissolving in non-aqueous solvents But in vivo experiments

are dif 1047297cult to obtain the similar results mainly due to the drug

recrystalization caused by the very limited solubility in physical liq-

uids Meanwhile the interference of organic solvents used on the

pharmacological effects to the body cannot be ignored The advent

of drug nanocrystal technology is signi1047297cant for new drug discovery

With this approach in vivo data can be obtained early in the discovery

process by utilizing non-ideal prototype compounds prior to making

a major investment in the search for ef 1047297cacious drug-like compounds

[58] In addition many in vivo studies have proved that drug nano-

crystals can effectively improve the local or systemic therapeutic ef-

fects compared with conventional formulations

Due to the bioadhesion properties drug nanocrystals can bring

marked improvement on local pharmacological effects for suf 1047297cient

local drug concentration gradient on mucosa surfaces For example re-

garding the pathophysiological situation of Cryptosporidium the local-

ization of the pathogen in the epithelial membrane of the GIT will be of

advantage for applying mucoadhesive nanosuspensions which directly

interact with the pathogen coating of the entire infected GIT [69]

Drug nanocrystals can also be effective on improving systemic ef-

fects It is majorly credited to their altered pharmacokinetic properties

compared to the conventional formulations In most cases an equilib-rium constant of drug distribution exists between diseased tissues and

systemic circulation So drug concentration in diseased tissues would

increase or reduce in proportion to the systemic exposure Since

drug nanocrystals can improve the systemic absorption and lead to

an increase in AUC more drug molecules will distribute into diseased

tissues resulting in improved therapeutic ef 1047297cacy [118119] It is very

common in most extravascular administration routes such as oral ad-

ministration route mucosal administration route etc For example

Kayser et al found that when administered as nanosuspensions oral

absorption of amphotericin B was signi1047297cantly improved compared

to conventional commercial formulations such as Fungizonereg AmBi-

somereg and micronized amphotericin B Accordingly oral amphoteri-

cin B nanosuspensions signi1047297cantly reduced parasite numbers in the

liver of infected female Balbc mice by 286 whereas other formula-tions did not show any curative effect at all upon oral administration

[120] Another studies by Ghosh et al also demonstrated that oral

13-dicyclohexylurea nanosuspensions could raise antihypertensive

ef 1047297cacy due to an increased bioavailability [58]

In some other cases the improvements of pharmacological effects

for drug nanocrystals are mainly resulted from their targeting ability

to deliver drugs to the diseased tissues such as infected macrophages

tumors brain and so on This will be discussed at length in the next

section

24 Targeting delivery

A major problem associated with drug therapy is the inability to

deliver drugs to a speci1047297c site of the body without causing nonspeci1047297c

Table 6

Changes of pharmacokinetic properties of pulmonary nanocrystal formulations compared with the conventional partners

Drug Methods Dose form (mean particle s ize) Con trol Comparison of the ph armacokinetic parameters Animals Referen ces

Budesonide NR AN given by Pari LC jet nebulizer

(75ndash300 nm)

Pulmicort

Respulesreg

(44 μ m)

18-fold increase in Cmax 17-fold reduction in Tmax no

signi1047297cant different in AUC 13-fold increase in t12

Human [43]

Budesonide NR AN given by a jet nebulizer

(less than 1 μ m)

Pulmicort

Respulesreg

(44 μ m)

15-fold increase in Cmax 30-fold reduction in Tmax little

reduction in the AUC no markedly differents in t12

Human [48]

Itraconazole Media-milled VSultra-rapid freezing

process

AN given by Aeronebreg nebulizer(190 nm and 150 nm)

ndash Cmax and AUC of amorphous nanoparticles were morethan 3 times than those of crystalline nanoparticles

Rats [116]

Itraconazole Precipitation AN given by Aeronebreg nebulizer

(less than 1 μ m)

Organic

solution

Signi1047297cantly enhance the lung concentration and the

Lungserum ratio while reduce the serum

Rats [45ndash47113]

Atropine

sulfate

Precipitation Inhaled powder using lactose as

carriers given by a dry powder

inhaler (300 nm)

Micro-

powder

(30 μ m)

The nano powder reached therapeutic concentration

within 10 min and Tmax within 15 min There was no

comparison data

Human [117]

NR Not reported

Fig 3 Compared with microparticles (A) nanoparticles (B) have a more homogenous

distribution of drugs in the nebulized droplet or among the inhalable carriers




toxicity [121] By developing colloidal drug delivery systems a new

frontier has be opened for improving targeting drug delivery [122]

Many kinds of molecules (including small molecules peptides siR-

NAs antibodies genes etc) can be targeted to certain diseased sites

through incorporation of them in nanocarriers such as liposomes mi-

celles and polymeric nanoparticles [123124] However a basic prob-

lem of these nanocarriers is that the loading capacity for drugs is

relatively low in most cases When the aim is to target only a small

fraction of the totally administered drugs reaches the target siteswhich might not be enough to reach a therapeutic level [125] Nano-

crystals can be used for targeting delivery as their surface properties

and in vivo behavior can easily be altered In addition with a loading

capability of 100 they can also ensure a high drug concentration to

the target sites [1837] Recently increasing studies have manifested

that targeting to different sites can be achieved by using drug nano-

crystal approach

241 Passive targeting

At the beginning iv nanosuspensions were developed with the

aim to replace toxicologically problematic excipients in existing iv

formulations on the market (examples are Taxolreg and Sporanoxreg

mentioned above) However after iv administration of nanosuspen-

sions in animals the pharmacokinetic was completely different to

the solution in some cases If the drug nanocrystals do not dissolve

rapidly they will be opsonized in the circulation and recognized as

foreign matters and rapidly cleared by the phagocytic cells of MPS

which are abounded in special tissues and organs such as liver lung

and spleen [3234] This is one of the mechanisms of passive targeting

progress of nanoparticles [126127] Studies by Rabinow et al [19]

found that following iv administration of itraconazole nanosuspen-

sions in rats crystalline material was clearly evident in the macro-

phages of a transmission electron micrographic section of the

spleen and splenic cytoplasmic enlargement and vacuolation of mac-

rophages were also observed Gao et al [104] found that curcumin

nanosuspensions with an average size of 2102 nm could be trans-

ported into the reticuloendothelial system such as liver spleen and

lung via phagocytosis effect with the high concentration which

were many times (from 5 to 96 times) higher than that of the curcu-min solution However the clearance of the MPS is not desirable

when a comparatively enduring and high drug concentration in the

circulation is requested Then to bypass the phagocytic uptake of

the drug its surface properties need to be altered to avoid opsoniza-

tion as in the case of stealth liposomes [128ndash130] For example poly-

ethylene glycol (PEG) is generally regarded as an effective surface

modi1047297er It can block and delay the opsonization process by providing

hydrophilic protective layer which can repel the absorption of opso-

nin proteins Shegokar et al reported that PEGylated nevirapine

nanocrystals showed signi1047297cantly decreased macrophage uptake

compared with unmodi1047297ed nanocrystals After iv injection the MRT

of PEGylated nevirapine nanosuspensions in rats was two times of

that of unmodi1047297ed nanosuspensions [131]

Another pathway of passive targeting effects of drug nanocrystals isaccumulation of drugs in solid tumors This can be attributed to the en-

hanced permeability and retention (EPR) effect caused by defective

tumor vasculature with disorganized endothelium at the tumor site

and a poorlymphatic drainage system [132133] Our group had proved

that the oridonin nanosuspensions possessed a stronger antitumor ac-

tivity in sarcoma-180 and H22 tumor bearing mice dueto the EPReffect

compared with the solution formulation with a highertumor to normal

tissues ratio of drugs [134135] These results indicate that drug nano-

suspension formulation might be a promising approach for the treat-

ment of tumors Similarly choroidal neovascularization (CNV) in eyes

aresupposed to have an environment similar to solid tumorsTherefore

some researchers believed that the similar EPR effect also worked in

these ocular diseases with character of angiogenesis which can

explained the retention of microparticles or large molecules in the

CNV lesion [136137] Studies by Yasukawa et al showed that retention

of rhodamine B isothiocyanate (RITC)-binding polyvinyl alcohol (mo-

lecular weight 220000) in the CNV lesion at 24 h after iv administra-

tion while free RITC administered intravenously largely disappeared

from the CNV lesion [138] However there have been no related studies

of drug nanosuspensions in this 1047297eld

242 Speci 1047297c organs targeting

It has been well known that the in vivo fate of the nanoparticulatescould be altered by changing the type of coated polymers which pro-

vides drug particles with protection (stabilization) release control and

other functions such as drug-targeting ability [37] Surface properties

of nanocrystals which can be adjusted by choosing different stabilizer

molecules determine the qualitative and quantitative composition of

proteins around the particles in circulation It is bene1047297cial in tissue-

speci1047297c drug delivery because ex vivo determination of protein adsorp-

tion by two-dimensional polyacrylamide gel electrophoresis allows

some prediction of tissue targeting [139] At present studies in this

1047297eld mainly focus on the brain-targeting Due to their too large sizes

(gt50 nm) nanoparticulates are known to be unable to transport

through the bloodndashbrain barrier (BBB) [140] Nevertheless in 1995

Kreuter et al found that Tween 80-coated polyisobutylcyanoacrylate

nanoparticles could be successfully used for in vivo administration of

drugs to the brain [141142] It was 1047297rst hypothesized that the Tween

80-coated nanoparticles were transported across the BBB via endocyto-

sis by the brain capillary endothelial cells [143] Recently it is generally

recognized that Tween 80-coated particles preferentially adsorb apoli-

poprotein E (Apo E) on their surface and then concentrate into the

brain induced by the Apo E receptors which is rich on the endothelial

cells of the BBB [93140144] Similarly it has been reported that nano-

crystals coated with some surfactants such as Tween 80 Poloxamer

188 serum albumin and sodium dodecyl sulfate (SDS) are bene1047297cial

for the brain uptake and the treatment of cerebral diseases

[8993131139] However results derived from these researches are

not always consistent for example Ben Zirar et al [41] found that the

poloxamers (including Poloxamers 184 188 388 407 and 908) did

not facilitate the passage through the BBB but the Tween 80 did The

reasons for the differences among different studies have still not beenunderstood Sometimes the proteins absorbed on the surface of nano-

particles also mean the rejection against certain organ For example

Lemke et al [139] found that the presence of Apo A-I and Apo A-IV on

the nanoparticle surface and low IgG γ and 1047297brinogen loading seems

to prevent them from hepatic uptake

To realize exactaf 1047297nity with speci1047297c organs some targeting moieties

such as folate transferrin and so on can be attached to the polymer

chains on nanocrystal surface [145146] However the question is that

polymer chains are not chemically anchored on nanocrystal surface So

they can be reversibly adsorbed onto and desorbed from nanocrystals

surfaces Although targeting moieties can be attached to the polymer

chains on nanoparticlesurface but polymer chains having targeting moi-

eties canthenbe detachedfrom the surface Therefore strongsurfaceab-

sorption at full coverage and possessing long-timescalefor desorption isnecessary for the successful preparation of targeting nanocrystals To re-

alize it a method of chemical cross-linking of the polymers and subse-

quent functionalization has been employed by some researchers

through which 1047297rm-conjugated polymer layers linked with special moi-

eties can be obtained Kim et al [37] successfully prepared stable

naproxen and paclitaxel nanosuspensions by using chitosans as steric

stabilizers which were thencross-linked by tripolyphosphateandconju-

gated with folic acid in turn The chemical reactions were performed

without destroying the stabilities of nanosuspensions and the release

pro1047297les of drug nanoparticles were signi1047297cantly modi1047297ed Another

study by Liu et al [18] prepared paclitaxel nanosuspensions with amor-

phous precipitate methods and further conjugated a folate ligand to the

stabilizer molecule Pluronic F127 for targeting delivery Methyl thiazolyl

tetrazolium (MTT) assay indicated that the new ligand-linked




nanocrystals show clear potential for clinical development compared

with both the solution and the non-targeting nanocrystals formulations

243 Cell-based drug delivery of drug nanocrystals

The signi1047297cantly increased dissolution velocity which is a distinct

advantage of nanocrystals simultaneously implies the problem that

drug nanocrystals might dissolve before reaching the target Cell-

based drug delivery approach canbe employed to deal with this prob-

lem Cell based delivery systems are identi1047297

ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or

therapeutics The systems can release the drug content in circulation

or at selected sites or could target the drug to other relevant cells in

the body [147] Among the animal cells of special relevance are mac-

rophages and red blood cells (RBCs) Macrophages are differentiated

cells of the immune system able to phagocytize microorganisms as

well as nanoparticulate materials So nanoparticulate systems are

particularly useful for the delivery of therapeutic agents to macro-

phages [148149] When macrophages are used as drug delivery sys-

tems they should be 1047297rst loaded with the nanoparticulate drug ex

vivo and then re-infused into the host where their content is distrib-

uted to tissues that favor homing of macrophages such as parasites

bacteria and viruses [150151] RBCs constitute potential biocompati-

ble carriers for different bioactive substances including protein drugs

as well as nanoparticulates They have unique properties such as bio-

degradability biocompatibility and long-term drug releasing and thus

are well suited for drug encapsulation [152] They can be easily han-

dled ex vivo by means of several techniques for the encapsulation of

different molecules and nanoparticulates [153]

For drug nanocrystals few studies related on cell based drug deliv-

ery have been reported but the existing results proved the feasibility

Dou et al designed a novel bone marrow-derived macrophage (BMM)

indinavir nanocrystals delivery system for antiretroviral treatment

[154] Light microscopic examination proved that indinavir nanocrys-

tals were successfully loaded into BMMs after culture in the presence

of indinavir nanosuspensions for 12 h Following iv administration

into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-

jan horsesrdquo for transport of drug into tissues which were known to be

targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-

vir in tissue and sera for up to 10 days in comparison with 6 h for the

non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded

RBCs systems were developed by Staedtke et al in order to improvean-

tifungal treatment [155] Amphotericin B nanocrystals encapsulation in

RBCs wasachieved by using hypotonichemolysis methodleading to in-

tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-

trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B

nanocrystal-RBCs leukocytes show a slow amphotericin B release

over 10 days and no alteration in cell viability

3 Conclusions

The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique

advantage and pharmaeconomical value drug nanocrystals are paid

increasing attentions as a promising approach Drug nanocrystals

can be applied to all the poorly soluble drugs to overcome the solubil-

ity and bioavailability problems because all the poorly soluble drugs

can be comminuted into drug nanocrystals Researches on drug nano-

crystals within recent years fully exhibit their excellent in vivo perfor-

mances in different administration routes Among these the most

exciting information is that properties of drug nanocrystals can be

conveniently altered to meet various treatment demands of different

diseases With the number of insoluble drug compounds in develop-

ment increasing it is anticipated that nanocrystals technology will at-

tract increasing attentions as a viable formulation option However

though drug nanocrystals demonstrate superiority over the carrier

colloid drug delivery systems such as easier production safer compo-

sition and higher drug loading correspondingly they also confront

some problems For example how to obtain a more controllable

drug dissolution rate in order to meet the treatment requirements

of different diseases or reduce the drug release in the progress of de-

livering the drugs into target sites How can we get a more 1047297rm con-

junction between ligand-linked stabilizers and nanocrystal surfaces

without the loss of their properties We believe that many studies

will focus on handling these problems in the future

Acknowledgment

This work was partially supported by the Scienti1047297c Foundation of

the First Af 1047297liated Hospital of General Hospital of PLA the project

number is QN201105

References

[1] C Lipinski Poor aqueous solubility mdash an industry wide problem in drug discov-ery Am Pharm Rev 5 (2002) 82ndash85

[2] ER Cooper Nanoparticles a personal experience for formulating poorly watersoluble drugs J Control Release 141 (2010) 300ndash302

[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by

high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash

16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796

[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862

[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97

[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83

[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61

[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194

[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-

tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19

[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75

[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120

[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245

[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310

[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397

[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117

[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474

[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551

[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260

[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644

[21] SM Agnihotri PR Vavia Diclofenac-loaded biopolymeric nanosuspensions forophthalmic application Nanomedicine 5 (2009) 90ndash95

[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)

309ndash

313




[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440

[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339

[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237

[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753

[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548

[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144

[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502

[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574

[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186

[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327

[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381

[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic

evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186

[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547

[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486

[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138

[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343

[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142

[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237

[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656

[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304

[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72

[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224

[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102

[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP

Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554

[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74

[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17

[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31

[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651

[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80

[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99

[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237

[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31

[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833

[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-

pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA

Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84

[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458

[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329

[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174

[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-

tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192

[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64

[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146

[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89

[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31

[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23

[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16

[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568

[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85

[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27

[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680

[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233

[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245

[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845

[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27

[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556

[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31

[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353

[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102




[80] SLBramer WPForbesRelative bioavailabilityand effectsof a highfat mealon singledose cilostazol pharmacokinetics Clin Pharmacokinet 37 (Suppl 2) (1999) 13ndash23

[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70

[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308

[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558

[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for

oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-

lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288

[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808

[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501

[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122

[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash

brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical

process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579

[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132

[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80

[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170

[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296

[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234

[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211

[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13

[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333

[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181

[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151

[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5

[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255

[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-

cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash

B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence

of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218

[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133

[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261

[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247

[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455

[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319

[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599

[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74

[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107

[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188

[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119

[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new

nebulized corticosteroid J Allergy Clin Immunol 104 (1999) S175ndash

S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41

[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63

[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186

[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142

[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75

[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162

[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162

[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119

[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596

[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87

[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279

[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330

[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148

[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585

[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114

[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352

[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392

[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300

[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325

[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid

nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash

186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for

the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug

delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura

Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696

[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603

[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007

[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277

[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174




[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81

[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187

[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065

[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146

[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug

Deliv Rev 60 (2008) 286ndash

295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275

[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754

[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and

SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174

[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166

[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322

[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101

[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S

Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835

[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103




1 Introduction

At present about 40 of the drugs being in the development pipe-

lines are poorly soluble even up to 60 of compounds coming direct-

ly from synthesis are poorly soluble [1] The poor solubility makes

these drugs very dif 1047297cult to perform the pharmacological screening

of compounds for potential drug effects It was reported that 70 of

the potential drug candidates were discarded due to low bioavailabil-

ity related with poor solubility in water before they ever reached thepharmaceutics department [2] Many different techniques have been

developed to overcome the solubility problem of poorly soluble

drugs eg solubilization solvent mixtures inclusion compounds

complexation and so on A basic problem is that these formulation

techniques can only be used to a certain number of drugs exhibiting

special features required to employ the formulation principle ( eg

molecule 1047297ts into the cavity of the cyclodextrin ring being soluble

in certain organic agents) [3] When it comes to drugs which are in-

soluble in both aqueous and organic media (drugs so-called lsquobrick

dust drugsrsquo) these approaches are often ineffective

Over the past two decades drug nanocrystal technology has been

undoubtedly the highlight in pharmaceutical 1047297eld One of its major

contributions is the bene1047297ts that can be gained by formulating poorly

soluble drugs [4] This approach generally produces dispersions of

drug nanocrystals in a liquid medium (typically water) which are

called ldquonanosuspensionsrdquo Nanosuspensions consist essentially of

pure drug nanoparticles (100ndash1000 nm) and a minimum amount of

surface active agents required for stabilization At present ap-

proaches developed to produce drug nanosuspensions mainly include

the so called lsquobottom uprsquo (precipitation) and lsquotop downrsquo (media mill-

ing high pressure homogenization etc) The bottom up technology

dissolves the drug in solvent and then precipitates it by adding the

solvent to a non-solvent These techniques are not widely used be-

cause of some prerequisites such as usage of organic solvents and

the drug should be soluble at least in one solvent [5] The top down

technologies are disintegration methods and so can be employed

for all insoluble drugs including lsquobrick dust drugsrsquo Drug nanocrystals

exhibit many advantages including high ef 1047297ciency of drug loading

easy scale-up for manufacture relatively low cost for preparationand applicability to various administration routes such as oral [6]

parenteral [7] ocular [8] and pulmonary delivery [9] All these advan-

tages have so tremendous impacts on promoting drug nanocrystals

successfully from experimental researches to patients that several

products have been launched into market (Table 1)

During the last decade of the 20th century lots of experiments

have been done to study the manufacturing technologies of drug

nanocrystals and their in vitro physical and chemical properties

such as procedure parameters formulation composition physical

and chemical stability crystalline structure enhanced saturation sol-

ubility and dissolution rate bioadhesion and so on Some published

reviews have well summarized and discussed results of these re-

searches from different aspects [3ndash510ndash14] In the last ten years

more and more attentions were paid to the in vivo performances of

nanocrystals in animals (including human) and many exciting 1047297nd-

ings were obtained This review will speci1047297cally focus on these 1047297nd-

ings including safety pharmacokinetics pharmacodynamics and

targeting effects of drug nanocrystals Some expanded studies of

drug nanocrystals in recent years such as moieties-modi1047297ed polymer

layers and cell-based drug delivery system will also be discussed in

this review

2 In vivo

performances of nanocrystals in differentadministration route

21 Safety and toxicity

211 Safety issues of poorly soluble drugs

Safety is a primary issue for medicines thus the toxicity assessment

is the most important data for registration of a new medicine For the

poorly soluble drugs safety issue may be more troublesome Due to

their low solubility a large amount of organic cosolvents or solubilizers

should be added in most cases before they are formulated as injectable

solution which will result in unwanted side effects or even toxicities

[15ndash17] For examples the Cremophor-EL ndash a solubilizer used in

paclitaxel product Taxolreg ndash is associated with serious side-effects

such as hypersensitivity nephrotoxicity and neurotoxicity [18] Renal

injury occurring in the commercially available itraconazole injection

Sporanoxreg is concerned with the cyclodextrin-solubilizing agents

[19] In addition precipitation of the poorly soluble drugs from the

non-aqueous formulation once it is diluted withblood is another poten-

tial problem [20] Oral delivery as a non-invasive route is safe in most

cases However the high and prolonged local concentration may be

an issue involved in oral application of the poorly soluble drugs espe-

cially for the irritative drugs such as non-steroidal anti-in1047298ammatory

drugs (NSAIDs) Similar issue may restrict the mucosa delivery since

precipitation of drugs on the mucosa surface resulting from the very

limited dissolution will also cause local irritation [21]

212 Advantages of nanocrystal formulations in terms of safety

Drug nanocrystals are generallyreported as a safe and well tolerated

formulation in many administration route compared with the conven-tional products This is mainly attributed to following advantages

2121 Fine particle size As for the submicron delivery system particle

size is a crucial factor in determining whether or not it can be used in

parenteral route For iv injection the content of particles larger than

5 μ m should be controlled strictly because the smallest size of blood

capillaries is about 5 μ m Existenceof a high content of particles larger

than 5 μ m can lead to capillary blockade and embolism Drug nano-

suspensions as colloidal aqueous dispersions can be well tolerated

in iv route in many reports Fine particle size also helps improve

safety of oral poorly soluble drugs in some cases by increasing the

distribution uniformity in the gastrointestinal (GI) 1047298uid and avoiding

the high and prolonged local concentration [22] Nano-sized particles

are also bene1047297cial to a better toleration in the mucosa delivery such

Table 1

Key characteristics of available commercial drug products based on drug nanoparticle technology

ProductCompany Drug compound Indication Nano-sizing approach Administration route Date of FDA approval

Gris-PegregNovartis Griseofulvin Anti-fungal Bottom up coprecipitation Oral 1982

CesametregLilly Nabilone Anti-emetic Bottom up coprecipitation Oral 2005

RapamuneregWyeth a Sirolimus Immunosuppressant Topndashdown media milling Oral 2000

EmendregMerck a Aprepitant Antiemetic Topndashdown media milling Oral 2003

TricorregAbbott a Feno1047297brate Hypercholesterolemia Topndashdown media milling Oral 2004

Megacereg ESPar Pharma a Megestr ol a cetat e A ppetite stimulant T opndashdown media milling Oral 2005

TridlidetradeSkye Pharmaa Feno1047297brate Hypercholesterolemia Topndashdown highndashpressure homogenization Oral 2005

Invega SustennaJohnson

amp Johnson

Paliperidone palmitate Antidepressant Topndashdown high- pressur e hom ogeniz ation I nj ect ion 20 09

a

Cited from Elan FDA Orange Book SkyePharma












dysphonia (Table 2)















tration [2829]











































Table 2





Rats [19]



Rats [24]




Mice [18]






Rabbits [39]





Rats [41]







Mice [44]




Mice [45ndash47]




Human [48]

a NR Not reported






























Table 3


Drugs Nanosizing

methods

Dosage form


Control


Comparison of the


Animals References


nano-suspensions

(AN) (169 nm)


(10 μ m)



up the absorption

Beagle

dogs

[6]


(20 μ m)



Rats [22]




suspensions


reduction in Tmax

Rats [55]


homogenization


(5 μ m)



Rats [56]


dried nanocrystals

powder (265 nm)

Pellets containing


(65 μ m)



Dogs [57]

AZ68 Media milling

(crystalline)






Rats [35]

Precipitation

(amorphous)

AN (200 nm)


(12 μ m)



bioavailability

Rats [36]


plasmaexposure

increased

over anorder of

magnitude

Rats [58]


homogenization


(1ndash5 μ m)



Rats [59]


(95 b 7 μ m)



Dogs [60]

A BCS II

substance


(4 μ m)



Rats [61]


(13 and 24 μ m)



Beagle

dogs

[62]


5 μ m


mgkg and 125 mgkg

Beagle

dogs

[63]


homogenization







period of 14 h

Pigs [64]




Rats [84]






















































































































































Table 4




Control


Comparison of the


Animals References





Rats [34]




Rats [41]



reduction in AUC


those of solution

Rats [94]






Rabbits [32]

AN (8972 nm)




increase in Vd

Rats [19]



Rats [35]



those of solution

Rats [93]




Rabbits [95]



Rats [96]



NR Not reported



























































lachrymal 1047298











































Table 5







Rabbits [104]



Rabbits [104]



Rabbits [104]







































































section




Table 6




(75ndash300 nm)

Pulmicort

Respulesreg

(44 μ m)



Human [43]


(less than 1 μ m)

Pulmicort

Respulesreg

(44 μ m)



Human [48]


process



Rats [116]


(less than 1 μ m)

Organic

solution



Rats [45ndash47113]

Atropine

sulfate



inhaler (300 nm)

Micro-

powder

(30 μ m)



comparison data

Human [117]

NR Not reported




















crystal approach































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313








































































































































































dysphonia (Table 2)















tration [2829]











































Table 2





Rats [19]



Rats [24]




Mice [18]






Rabbits [39]





Rats [41]







Mice [44]




Mice [45ndash47]




Human [48]

a NR Not reported






























Table 3


Drugs Nanosizing

methods

Dosage form


Control


Comparison of the


Animals References


nano-suspensions

(AN) (169 nm)


(10 μ m)



up the absorption

Beagle

dogs

[6]


(20 μ m)



Rats [22]




suspensions


reduction in Tmax

Rats [55]


homogenization


(5 μ m)



Rats [56]


dried nanocrystals

powder (265 nm)

Pellets containing


(65 μ m)



Dogs [57]

AZ68 Media milling

(crystalline)






Rats [35]

Precipitation

(amorphous)

AN (200 nm)


(12 μ m)



bioavailability

Rats [36]


plasmaexposure

increased

over anorder of

magnitude

Rats [58]


homogenization


(1ndash5 μ m)



Rats [59]


(95 b 7 μ m)



Dogs [60]

A BCS II

substance


(4 μ m)



Rats [61]


(13 and 24 μ m)



Beagle

dogs

[62]


5 μ m


mgkg and 125 mgkg

Beagle

dogs

[63]


homogenization







period of 14 h

Pigs [64]




Rats [84]






















































































































































Table 4




Control


Comparison of the


Animals References





Rats [34]




Rats [41]



reduction in AUC


those of solution

Rats [94]






Rabbits [32]

AN (8972 nm)




increase in Vd

Rats [19]



Rats [35]



those of solution

Rats [93]




Rabbits [95]



Rats [96]



NR Not reported



























































lachrymal 1047298











































Table 5







Rabbits [104]



Rabbits [104]



Rabbits [104]







































































section




Table 6




(75ndash300 nm)

Pulmicort

Respulesreg

(44 μ m)



Human [43]


(less than 1 μ m)

Pulmicort

Respulesreg

(44 μ m)



Human [48]


process



Rats [116]


(less than 1 μ m)

Organic

solution



Rats [45ndash47113]

Atropine

sulfate



inhaler (300 nm)

Micro-

powder

(30 μ m)



comparison data

Human [117]

NR Not reported




















crystal approach































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313


























































































































































































Table 3


Drugs Nanosizing

methods

Dosage form


Control


Comparison of the


Animals References


nano-suspensions

(AN) (169 nm)


(10 μ m)



up the absorption

Beagle

dogs

[6]


(20 μ m)



Rats [22]




suspensions


reduction in Tmax

Rats [55]


homogenization


(5 μ m)



Rats [56]


dried nanocrystals

powder (265 nm)

Pellets containing


(65 μ m)



Dogs [57]

AZ68 Media milling

(crystalline)






Rats [35]

Precipitation

(amorphous)

AN (200 nm)


(12 μ m)



bioavailability

Rats [36]


plasmaexposure

increased

over anorder of

magnitude

Rats [58]


homogenization


(1ndash5 μ m)



Rats [59]


(95 b 7 μ m)



Dogs [60]

A BCS II

substance


(4 μ m)



Rats [61]


(13 and 24 μ m)



Beagle

dogs

[62]


5 μ m


mgkg and 125 mgkg

Beagle

dogs

[63]


homogenization







period of 14 h

Pigs [64]




Rats [84]






















































































































































Table 4




Control


Comparison of the


Animals References





Rats [34]




Rats [41]



reduction in AUC


those of solution

Rats [94]






Rabbits [32]

AN (8972 nm)




increase in Vd

Rats [19]



Rats [35]



those of solution

Rats [93]




Rabbits [95]



Rats [96]



NR Not reported



























































lachrymal 1047298











































Table 5







Rabbits [104]



Rabbits [104]



Rabbits [104]







































































section




Table 6




(75ndash300 nm)

Pulmicort

Respulesreg

(44 μ m)



Human [43]


(less than 1 μ m)

Pulmicort

Respulesreg

(44 μ m)



Human [48]


process



Rats [116]


(less than 1 μ m)

Organic

solution



Rats [45ndash47113]

Atropine

sulfate



inhaler (300 nm)

Micro-

powder

(30 μ m)



comparison data

Human [117]

NR Not reported




















crystal approach































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313

















































































































































































































































































































Table 4




Control


Comparison of the


Animals References





Rats [34]




Rats [41]



reduction in AUC


those of solution

Rats [94]






Rabbits [32]

AN (8972 nm)




increase in Vd

Rats [19]



Rats [35]



those of solution

Rats [93]




Rabbits [95]



Rats [96]



NR Not reported



























































lachrymal 1047298











































Table 5







Rabbits [104]



Rabbits [104]



Rabbits [104]







































































section




Table 6




(75ndash300 nm)

Pulmicort

Respulesreg

(44 μ m)



Human [43]


(less than 1 μ m)

Pulmicort

Respulesreg

(44 μ m)



Human [48]


process



Rats [116]


(less than 1 μ m)

Organic

solution



Rats [45ndash47113]

Atropine

sulfate



inhaler (300 nm)

Micro-

powder

(30 μ m)



comparison data

Human [117]

NR Not reported




















crystal approach































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313


























































































































































































































Table 4




Control


Comparison of the


Animals References





Rats [34]




Rats [41]



reduction in AUC


those of solution

Rats [94]






Rabbits [32]

AN (8972 nm)




increase in Vd

Rats [19]



Rats [35]



those of solution

Rats [93]




Rabbits [95]



Rats [96]



NR Not reported



























































lachrymal 1047298











































Table 5







Rabbits [104]



Rabbits [104]



Rabbits [104]







































































section




Table 6




(75ndash300 nm)

Pulmicort

Respulesreg

(44 μ m)



Human [43]


(less than 1 μ m)

Pulmicort

Respulesreg

(44 μ m)



Human [48]


process



Rats [116]


(less than 1 μ m)

Organic

solution



Rats [45ndash47113]

Atropine

sulfate



inhaler (300 nm)

Micro-

powder

(30 μ m)



comparison data

Human [117]

NR Not reported




















crystal approach































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313























































































































































































































lachrymal 1047298











































Table 5







Rabbits [104]



Rabbits [104]



Rabbits [104]







































































section




Table 6




(75ndash300 nm)

Pulmicort

Respulesreg

(44 μ m)



Human [43]


(less than 1 μ m)

Pulmicort

Respulesreg

(44 μ m)



Human [48]


process



Rats [116]


(less than 1 μ m)

Organic

solution



Rats [45ndash47113]

Atropine

sulfate



inhaler (300 nm)

Micro-

powder

(30 μ m)



comparison data

Human [117]

NR Not reported




















crystal approach































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313



































































































































































































































section




Table 6




(75ndash300 nm)

Pulmicort

Respulesreg

(44 μ m)



Human [43]


(less than 1 μ m)

Pulmicort

Respulesreg

(44 μ m)



Human [48]


process



Rats [116]


(less than 1 μ m)

Organic

solution



Rats [45ndash47113]

Atropine

sulfate



inhaler (300 nm)

Micro-

powder

(30 μ m)



comparison data

Human [117]

NR Not reported




















crystal approach































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313














































































































































































crystal approach































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313














































































































































































































3 Conclusions
























Acknowledgment



number is QN201105

References

























309ndash

313









































































































































































































































































































































































































































Documents

Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release