Overview of preparation methods of polymeric and lipid-based … · This review article provides a...

INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS https://doi.org/10.1080/00914037.2017.1332623

5 Overview of preparation methods of polymeric and lipid-based (noisome, solid lipid, liposome) nanoparticles: A comprehensive review Fateme Haghiralsadata,b , Ghasem Amoabedinyb,c, Samira Naderinezhadc , Marco N. Helderd, Elham Akhoundi Kharanaghie and Behrouz Zandieh-Doulabid

aDepartment of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran, Tehran, Iran; bDepartment of Nano 10 Biotechnology, Research Center for New Technologies in Life Science Engineering, University of Tehran, Tehran, Iran; cDepartment of Biotechnology

and Pharmaceutical Engineering, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran; dDepartment of Oral & Maxillofacial Surgery, VU University Medical Center, MOVE Research Institute Amsterdam; eDepartment of Biotechnology, Faculty of Advanced Science and Technologies, University of Isfahan, Isfahan, Iran

ABSTRACT A wide number of drug nanocarriers have emerged to improve medical therapies, and in Q2particular to achieve controlled delivery of drugs, genes or gene expression-modifying compounds, or vaccine antigens to a specific target site. Of the nanocarriers, lipid-based and polymeric nanoparticles are the most widely used. Lipid-based systems like niosomes and liposomes are non-toxic self-assembly vesicles with an unilamellar or multilamellar structure, which can encapsulate hydrophobic/hydrophilic therapeutic agents. Polymeric nanoparticles, usually applied as micelles, are colloidal carriers composed of biodegradable polymers. Characteristics such as loading capacity, drug release rate, physical and chemical stability, and vesicle size are highly dependent on experimental conditions, and material and method choices at the time of preparation. To be able to develop effective methods for large scale production and to meet the regulatory requirements for eventual clinical implementation of nanocarriers, one needs to have in-depth knowledge of the principles of nanoparticle preparation. This review paper presents an overview of different preparation methods of polymeric and novel lipid-based (niosome and solid lipid) nanoparticles.

GRAPHICAL ABSTRACT

ARTICLE HISTORY Received &�Accepted &��

KEYWORDS Drug delivery; noisome; polymeric nanoparticles; preparation method; solid lipid nanoparticles

45

1. Introduction

Despite great success in the lead optimization program, highly lipophilic drug candidates are the major outcomes of such critical drug discovery drives [1]. Although many of these drug

50candidates have exceptional in vitro potency, lack of significant solubility in water often presents challenges such as [2]: .� Poor bioavailability. .� Variations in bioavailability when in fed or fasted state.

none defined

CONTACT Ghasem Amoabediny [email protected] Department of Nano Biotechnology, Research Center for New Technologies in Life Science Engineering, University of Tehran, Tehran, Iran. Q1Color versions of one or more of the figures in the article can be found online on at www.tandfonline.com/gpom. © 2017 Taylor & Francis

3b2 Version Number : 11.0.3184/W Unicode (Apr 10 2014) File path : P:/Santype(JATS)/Journals/TandF_Production/GPOM/v0n0/GPOM1332623/GPOM_A_1332623_J.3d Date and Time : 20/7/17 and 21:47

https://doi.org/10.1080/00914037.2017.1332623http://orcid.org/0000-0002-8655-2118http://orcid.org/0000-0002-0703-2334https://crossmark.crossref.org/dialog/?doi=10.1080/00914037.2017.1332623&domain=pdf&date_stamp=2017-07-20mailto:[email protected]://www.tandfonline.com/gpom

.� Use of excipients such as co-solvents to improve water 55 solubility may prove to be harsh.

.� Drug precipitation after dosing.

.� Patient noncompliance. In recent years, the proportion of such insoluble drug

candidates has been estimated to be roughly 70% of new drug 60 discoveries. In addition, about 40% of the currently marketed

immediate-release oral drugs are practically water-insoluble [3].

A novel and successful strategy to improve solubility is drug encapsulation in a colloidal nanocarrier system, which

65 overcomes some of the problems of conventional medical treatment. Nanocarriers improve solubility, bioavailability, and biodistribution of both lipophilic and hydrophilic drugs [4].

Features such as large surface-to-mass ratio which causes 70 large functional surface, simple preparation methods, easy

engineering of targeted nanoparticles, low degradation rate, preventing harmful side-effects, and large capacity of drug loading of nanocarriers have revolutionized drug delivery systems (DDS) [5].

75 Wide number of colloidal drug nanocarriers have been discovered to improve medical therapies. Based on the material used in their preparation, they are categorized as polymer-based or lipid-based systems.

Polymer-based nanoparticles are colloidal carriers 80 composed of biodegradable polymers. They effectively carry

drugs, proteins, and DNA to target cells and tissues. Storage stability and long in vivo half-life in the blood stream are positive aspects, however, their low polymer degradation rate which may cause toxicity is a negative feature [6].

85Lipid-based colloidal carriers have been introduced to over-come the toxicological issues exhibited by polymeric systems. Prominent research has been performed on lipidic systems including liposomes, niosomes, nanoemulsions, micelles, cubosomes, and lipid nanoparticles. Lipid nanoparticulate

90DDS applications and routes of administration depend on their architecture and particle size [7]. Figure 1 shows some of the available lipid particulate DDS. Liposomes represent the first-generation of drug carriers, which were already described in the early 20th century [6]. Niosomes comprise

95vesicular systems which are more stable than liposomes due to the nonionic surfactants instead of phospholipids used for preparing them. Niosomes have recently been shown to greatly increase transdermal drug delivery and can also be used in targeted drug delivery [8]. The other useful lipid-based

100nanoparticle type are solid lipid nanoparticles which are prepared by lipids that are solid at room temperature [7].

This review article provides a summary of properties of the polymeric, and lipid-based nanoparticles (niosome and solid lipid) and the manner of their preparation methods.

105Although each section of this article can be easily expanded into a separate complete review paper, we attempted to write a general review with a global presentation of the various preparation methods of these three novel and widely used nanoparticles.

1102. Polymeric nanoparticles

Since the 1980s, polymeric nanoparticles (PNPs) have been applied as micelles in drug delivery systems, and numerous polymers have been used to carry and deliver various drugs

Figure 1. Lipid particulate drug delivery systems.

2 F. HAGHIRALSADAT ET AL.

in last few years. These nanoparticles can deliver different 115 types of molecules including: low molecular weight drugs,

proteins, plasmid and antisense DNA, and short interfering RNA [9,10].

Polymeric nanoparticles have been extensively studied as drug carriers in the pharmaceutical field [11–14] and different

120 research teams have published reviews about the nanoparticle formation mechanisms [15,16].

Polymeric micelles, varying in size between 5 and 50 nm in aqueous solutions, are prepared by self-assembly of amphiphilic biodegradable, biocompatible, and FDAQ3 -approved

125 copolymers. The drugs can be entrapped or encapsulated in the polymeric micelles and transported to the tissues. The micelles can form hydrogen bonds by their hydrophilic blocks in aqueous solution around them. The drug trapped in the hydrophobic core will be well-protected against degradation

130 (Figure 2) [9,16–18]. Biosafety and biocompatibility of the used polymers are

important characteristics in the field of novel drug delivery systems. Researchers use both natural and synthetic polymers to make polymeric micelles.

135 Chitosan, gelatin, sodium alginate, and albumin are the natural polymers which are commonly used for the preparation of PNPs [17,19]. Synthetic polymers used for this approach include: polylactides (PLA), polyglycolides, poly(ε-caprolactone) (PCL), poly(lactide-co-glycolides)

140 (PLGA), polyanhydrides, polyorthoesters, polycyanoacrylates, polycaprolactone, polyglutamic acid, poly(maleic acid), poly (N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide, poly(ethylene glycol), and poly(methacrylic acid) [16–18].

145 The chemical structure and ability of functionalization of amphiphilic block copolymers is a feature that makes poly-meric micelles particularly interesting for drug delivery. Ligands and antigens could be conjugated to block copolymers to both increase the stability of micelles and control the release

150 of drug in body in DDS [18].

2.1. Advantages of polymeric drug delivery

Using polymeric nanoparticles can increase the stability of encapsulated drugs easily, carry and deliver higher amount of pharmaceutical agents to the desired tissue, protect the

155 contents against hydrolysis and enzymatic degradation, improve efficiency and effectiveness of treatments in compari-son to traditional oral and injection methods, and reduce irritation of tissue because of the polymeric shell [17,20].

2.2. Polymeric nanoparticles preparation methods

160The method of polymeric nanoparticles preparation is depend-ing on the intended application. Polymerization and drug dispersion in preformed polymers are the most common tech-niques for preparing PNPs in drug delivery approaches [17]. Polymerization techniques have drawbacks such as toxic and

165reactive residues, unreacted remaining monomers which may cause unwanted chemical reactions and/or increase the risk of formation of undesirable oligomers. Due to these drawbacks, the preformed polymers method is widely used in drug delivery systems [21].

170In general, parameters such as release-defining features, chemical nature, charge, hydrophilicity/hydrophobicity, swell-ing/de-swelling capacity, reactivation, and pH-dependency/ independency of the polymers may determine the polymer selection [22].

175The widely reported techniques for the preparation of polymeric nanoparticles from preformed polymers are: a) Solvent evaporation. b) Nanoprecipitation. c) Emulsification/solvent diffusion (ESD).

180d) High-pressure homogenization. e) Salting out. f) Dialysis. g) Spray drying. h) Supercritical fluid technology (SCF).

185Table 1 shows a summary of some nanosized polymeric micelles used in DDS.

2.2.1. Solvent evaporation In this method, the selected polymer is dissolved in an organic volatile solvent, such as dichloromethane and chloroform to

190create an emulsion. Recently, dichloromethane and chloro-form are being substituted by less toxic organic solvents like ethyl acetate. The emulsion is exposed to a high energy source, e.g., an ultrasonicator or homogenizer, to convert it into a nanoparticle suspension (Figure 3a). This stage is the key point

195of nanoparticle formation. After the fabrication of PNPs, the volatile solvent is removed by evaporation. Stirring speed, homogenizer type, and polymer concentration all influence nanoparticle characteristics. Then, for separating solid nano-particles, the residuals of the evaporation stage can be centri-

200fuged and washed with distilled water, and finally dried by lyophilization. The best nanoparticles will be formed using a high-speed homogenizer or ultrasonicator, followed by evap-oration under continuous stirring at room temperature and reduced pressure [10,17,21].

205Bilati et al. studied the effect of sonication on PLGA nano-particles properties prepared using the solvent evaporation method. Varying intensity and duration of the sonication process will have impact on the final nanoparticle size [23].

2.2.2. Nanoprecipitation 210The other name of this method is solvent–displacement

method. This method is based on self-precipitation of polymers in the anti-solvent phase. Preformed polymer and drug are dissolved in an organic intermediate polar and water-miscible solvent. This phase is added to a stirred

Figure 2. Polymeric micelles prepared by self-assembly of block copolymers and drugs.

INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS 3

215aqueous solution which is a totally miscible solvent but is an anti-solvent for the polymers, and contains a stabilizer under ambient condition. At the interface of organic solvent and water, polymers will accumulate. Fast diffusion and surface tension of the solvents will stimulate the generation of a col-

220loidal suspension. The formed nanoparticles can be collected by solidification (Figure 3b). Concentration of polymer, stir-ring speed, and the amount and solubility of solvent and anti-solvent phases can affect the size of the nanoparticles. This technique is limited to water-miscible solvents, does

225not need the use of homogenizer or ultrasonicator, and can easily be scaled-up for industrial production. A disadvantage of the nanoprecipitation method is the complexity of selecting the appropriate solvent, anti-solvent, and polymer to produce spontaneous emulsification. Due to the water miscibility of

230both solvents, this method is not useful for encapsulating hydrophilic drugs and just appropriate for lipophilic ones [10,17,21]. Nanoprecipitation has been studied for several polymers such as PLGA, PLA, PCL, and poly(methyl vinyl ether-co-maleic anhydride) by different researchers [24–28].

2352.2.3. Emulsification/solvent diffusion In this method preformed polymer and drug are mixed with an organic solvent which is partially miscible with water. Water is added slowly to this solution to eventually reach the saturation and thermodynamic equilibrium point. By

240adding excess water, the solution becomes supersaturated, and consequently nanoparticles are formed due to the physico-chemical imbalance. The more water is added, the more nanoparticles are fabricated and incorporated in the water phase. Finally, PNPs can be separated by filtration or solvent

245evaporation (Figure 3c) [17,21]. The relative amounts of water and polymer concentration will influence particles size. The benefits of this technique are high efficiency of drug loading, no need for a homogenizer, simplicity of scalingup, and narrow size distribution. However, generating PNPs by the

250ESD method needs high volumes of water to formulate suspensions, and hydrophilic drugs encapsulation yield is low by this method [10]. Several drugs such as mesotetra (hydroxyphenyl)porphyrin, doxorubicin, coumarin, and plasmid DNA loaded in PLGA and PLA have been produced

255by the ESD technique by different researchers [29–32].

2.2.4. High-pressure homogenization High pressure milling is the main force to form nanosized particles in this technique. Preformed polymers and drugs are dispersed in medium, and passed through a high-pressure

260homogenizer (HPH) for several times. Usually the pressure is increased step by step, to eliminate clogging of the particles in the narrow homogenizer hole [33]. The common types of equipment used to produce nanoparticles in HPH method are the microfluidizer [34] and the piston-gap homogenizer

265[35]. In the microfluidizer the particle suspension, which is usually dispersed in an aqueous solvent, is pumped into a chamber where milling forces are applied to reduce particle size [36]. In the piston-gap homogenizer, dispersed particles in an aqueous or organic solvent are passed through a narrow

270gap with a diameter of 25 µm. The final size of nanoparticles Tabl

e 1.

A

sum

mar

y of

som

e po

lym

eric

nan

opar

ticle

s pr

epar

ed b

y se

vera

l tec

hniq

ues

to d

eliv

er A

PIs/

prot

eins

.

Tech

niqu

e AP

Is/pr

otei

ns

Cate

gory

Po

lym

er

Rout

e M

ean

size

or

size

rang

e (n

m)

Refe

renc

e

Solv

ent

evap

orat

ion

Mox

iflox

acin

An

tibio

tic

Poly

(lact

ic-c

o-gl

ycol

ic a

cid)

(PL

GA)

In v

itro

164–

490

[44]

Em

ulsif

icat

ion

solv

ent

evap

orat

ion

Ellip

ticin

e An

tican

cer

Poly

-(3-h

ydro

xybu

tyra

te-c

o-3-

hydr

oxyv

aler

ate)

In

vitr

o 26

5 [4

5]

Emul

sific

atio

n so

lven

t ev

apor

atio

n Ci

spla

tin

Antic

ance

r Po

ly(3

-hyd

roxy

vale

rate

-co-

4-hy

drox

ybut

yrat

e)

In v

itro

100–

200

[46]

Em

ulsif

icat

ion

solv

ent

evap

orat

ion

Etop

osid

e To

poiso

mer

ase

inhi

bito

r PL

GA

In v

itro

105

[47]

Em

ulsif

icat

ion

solv

ent

evap

orat

ion

Insu

lin

Horm

one

Dex

tran

O

ral

160–

250

[48]

Em

ulsif

icat

ion

solv

ent

evap

orat

ion

Acyc

lovi

r An

tivira

l M

etho

xy p

olye

thyl

ene

glyc

ol

In v

itro

141

[49]

17

2 Ch

itosa

n Em

ulsif

icat

ion

and

nano

prec

ipita

tion

Pacl

itaxe

l An

tican

cer

PEGy

late

d PL

GA

In v

itro

112

[50]

In

viv

o (IV

) 19

0 N

anop

reci

pita

tion

Spar

floxa

cin

Antib

iotic

PL

GA

Oph

thal

mic

18

0–19

0 [5

1]

Nan

opre

cipi

tatio

n 9-

Nitr

ocam

ptot

heci

n An

tican

cer

PLGA

In

vitr

o 20

7 [5

2]

Nan

opre

cipi

tatio

n Ci

spla

tin

Antic

ance

r PE

Gyla

ted

PLGA

In

vitr

o 14

0 [5

3]

Nan

opre

cipi

tatio

n–hi

gh-p

ress

ure

hom

ogen

izer

(HPH

) 10

-Hyd

roxy

cam

ptot

heci

n An

tican

cer

Polo

xam

er 1

88

Ora

l 13

1 [5

4]

HPH

Om

epra

zole

Pr

oton

pum

p in

hibi

tor

Polo

xam

er 1

88

Pare

nter

al

<1,

000

[55]

Sp

ray-

dryi

ng

Itrac

onaz

ole

Anti-

fuga

l Po

loxa

mer

188

—

45

0 [5

6]

Salti

ng o

ut

Savo

xepi

ne

Antip

sych

otic

Po

ly(D

,L-la

ctic

aci

d)

In v

itro

228

[57]

D

ialy

sis

VEGF

Q4

and

Bcl-2

tar

getin

g siR

NA

Gene

sile

ncin

g siR

NA

Glyc

ol c

hito

san

Intr

aven

ously

inje

ctio

n 24

3 [5

8]

Dia

lysis

D

oxor

ubic

in

Antic

ance

r Po

ly(D

,L-la

ctid

e-co

-gly

colid

e)

In v

itro

100–

200

[42]

Su

perc

ritic

al f

luid

tec

hnol

ogy

Ibup

rofe

n An

ti-in

flam

mat

ory

Poly

(N-v

inyl

-2-p

yrro

lidon

e)

—

40

[59]


will depend on the applied pressure, and few homogenization rounds [37].

2.2.5. Salting out This technique is a modified version of the ESD method and

275 based on the separation of a water soluble solvent from an aqueous solution by salting-out agents. In the first step, preformed polymer and drug are dissolved in a water miscible organic solvent. In the second step, this solution is added to an aqueous phase which contains colloidal stabilizer as well as

280 chemical electrolyte or nonelectrolyte agents such as calcium chloride, magnesium chloride, magnesium acetate, or sucrose, to induce the salting-out effect. Stirring rate should be constant in this process. Salting-out effect prevents the interspersing of organic solvent with water. By adding excess

285 water to the emulsion, the diffusion of the organic phase will be increased and nanoparticles will be formed (Figure 4a). Afterward, PNPs can be separated by filtration and removing the excess solvents and salting-out agents. The type of salting- out agent will affect the drug encapsulation efficiency of this

290 technique. High efficiency, easy scalingup, and no need for high temperatures are the advantages of salting-out method, in particular for heat-sensitive drugs. However, it needs high quantities of water for washing, and is not applicable for hydrophilic drugs [10,17,21,38]. This method is studied by

295 Galindo-Rodriguez et al. [39] and Mendoza-Muñoz et al. [40] for fabricating PNPs.

2.2.6. Dialysis Dialysis offers a method for the generation of surfactant-free, small, and narrow size-distributed nanoparticles with high

300 efficiency. Preformed polymer and drug are mixed in an organic solvent and positioned in the dialysis tube with proper molecular size cutoff. Dialysis membrane is a semi-permeable membrane which allows passive transport of solvents and

nonsolvents. Dialysis is performed against a nonsolvent 305miscible with the first solvent. The movement of nonsolvent

inside the membrane will cause polymer formation and aggre-gation because of reduction of solvent quantity (Figure 4b). Nanoparticle sizes are influenced by the type of polymer and solvents [17,21]. PNPs preparation with PLGA by dialysis

310method is assessed by different researchers [41,42].

2.2.7. Spray drying Spray drying is a single-step method which is used for generat-ing stable nanoparticles from a liquid phase. Preformed poly-mer and drug are dissolved in water and spray-dried after

315syringe filtering. Spray-drying will occur by atomization at tem-peratures between 30 and 55°C. Solvent will evaporates under these conditions, and PNPs will precipitate (Figure 4c) [43].

2.2.8. Supercritical fluid technology Supercritical fluid technology produces PNPs by an environ-

320ment-friendly method utilizing supercritical fluids. PNPs that have been generated by this technique are pure without any residual organic solvents. Preformed polymer and drug are mixed with a supercritical fluid under ambient conditions. Afterward, the solution is transferred to a pre-expansion tank,

325and heated to 40°C isobarically under the pressure of 27.6 Pa. The solution crosses a capillary nozzle or an orifice into air. Rapid decrease of pressure causes a high degree supersatura-tion which results in the generation of particles (Figure 5a).

The obtained products by this way are microscaled instead of 330nanoscaled, which is a drawback for this technique. To resolve

this problem, a combined SCF–ESD approach can be used, where the SCF solution is dispersed into aqueous environment and afterward passed through a nozzle the nozzle, which results in the fabrication of nanoparticles (Figure 5b). The concen-

335tration of polymer and the degree of saturation will influence the shape and size of particles [10,15,17].

Figure 3. (a) Schematic of the solvent-evaporation method, (b) schematic of the nanoprecipitation method, (c) schematic of the emulsification/solvent diffusion technique.


3. Solid lipid nanoparticles

Solid lipid nanoparticles (SLN) were developed in the 1990s as an alternative carrier in DDS [60–64]. SLNs are colloidal drug

340 carrier systems which are prepared from lipids that are solid at both room and body temperature, such as tricaprin,

tripalmitin, trilaurin, glycerol behenate, glycerol palmitostea-rate and waxes, such as cetylpalmitate [66]. Many emulsifiers have been used to stabilize them, including poloxamers,

345Tween 80, soya lecithin, and sodium dodecyl sulfate. Selection of stabilizer depends on the chosen lipid and administration

Figure 4. (a) Schematic of the salting out technique, (b) schematic of the dialysis technique, (c) schematic of the spray drying technique.

Figure 5. (a) Experimental setup for preparation of polymer nanoparticles by rapid expansion of supercritical fluid solution, (b) experimental setup for the rapid expansion of supercritical fluid solution into liquid solvent process, (c) schematic of the spray drying technique for SLNs. Note: SLN, solid lipid nanoparticle.


route [5]. SLNs are used to carry and deliver hydrophilic and hydrophobic drugs, macromolecules, such as proteins and peptides, genes or gene expression-modifying compounds,

350 antigens, and food molecules [66]. SLNs can carry drugs by either one of two models: solid solution model and core-shell model (Figure 6a). Drug is dispersed within the lipid matrix in the first model and in the second model drug is dispersed in the core (inside) or the shell (outside) of SLNs. In which

355 SLN made depends on the choice of the preparation method [67].Q5 SLNs provide some advantages. They (i) improve bioavailability of drugs; (ii) reduce drug mobility due to the solidness of lipid; (iii) reduce biodegradation of drugs; (iv) use biodegradable lipids; (v) can avoid the use of organic

360 solvents in preparation methods to decrease toxicity; (vi) can be functionalized for controlled drug delivery; (vii) can be easily produced in large quantities; and (viii) are more stable in in vivo application than other lipid nanocarriers. However, low drug loading capacity due to their crystalline structure,

365 change of release profiles, drug expulsion after storage- induced polymeric transition, and high water content of the dispersions are disadvantages of SLNs [7,66,68–71].

Solid lipid nanoparticles have been extensively studied as drug carriers in the pharmaceutical fields [6,72–76] and

370 different research teams have published reviews about the SLN formation mechanisms [6,71,77,78].

3.1. Solid lipid nanoparticles preparation methods

Solid lipid nanoparticles are made up of solid lipid, emulsifier, and water/solvent using different methods [79]. Selection of

375preparation method depends on solubility and stability of the drug, type of lipid, and route of administration [7]. The widely reported preparation techniques are: a) High pressure homogenization. b) Ultrasonication/high speed homogenization.

380c) Solvent evaporation method. d) Solvent emulsification–diffusion method. e) Supercritical fluid method. f) Microemulsion based method. g) Spray drying method.

385h) Double emulsion method [70,77–81]. Table 2 shows a summary of some SLNs used in DDS.

3.1.1. High-pressure homogenization High-pressure homogenization is a simple, reliable, and easy to scaleup technique for the preparation of SLNs [70,82]. This

390method was first used for SLN production by Muller and Luke [80] Q7. HPH involves high pressure (100–2,000 bar), which pushes the drug–lipid solution through a narrow gap (few micron sizes) rapidly. The particle size is decreased to submi-cron by the impact of shear stress, cavitation force, and turbu-

395lence [66,70,79,80]. HPH can be performed by two general approaches: hot or cold homogenization. In both techniques the lipid is melted at 5–10°C above its melting point, and the drug is dissolved in the molten lipid [77].

In the hot HPH method, the drug–lipid mixture is com-400bined with the aqueous surfactant solution by high speed

stirring and then passed through high pressure homogenizer at the same temperature. However, the particle sizes can be low due to the high temperature and decreased viscosity of

Figure 6. (a) Models of drug incorporation into SLN, (b) structure of niosome (Redrawn from Uchegbu and Vyas [119]), (c) classification of niosomes as a function of size and number of bilayers. MLV, multilayered vesicle; SUV, small unilamellar vesicle; LUV, large unilamellar vesicle, (d) a schematic diagram of the proniosome protocol. Note: SLN, solid lipid nanoparticle; MLV, multi-lamellar vesicles; SUV, small unilamellar vesicles; LUV, large unilamellar vesicles. Q6


the liquid. This technique can be used for lipophilic drugs 405 [7,80,81].

In the cold HPH method, the drug–lipid mixture is rapidly cooled by liquid nitrogen or dry ice. Then the solid mixture is ground by milling to microparticles and dispersed in cool surfactant solution. This presuspension is then passed through

410 a HPH at room or below room temperature to get desired SLNs. This method is suitable for processing heat-labile drugs or hydrophilic drugs [80,81]. It has been used by Silva et al. [83] to prepare risperidon-loaded SLNs.

3.1.2. Ultrasonication/high-speed homogenization 415 Solid lipid nanoparticles can also be prepared by ultrasonica-

tion or high-speed homogenization techniques. To accomplish smaller particle sizes, combination of both ultrasonication and high-speed homogenization can be applied. In this method, the drug is mixed with molten solid lipid and added to aque-

420 ous surfactant solution and mixed by a high speed homogeni-zer (8,000 rpm for 15 min) [66]. Afterward, the pre-emulsion solution is ultrasonicated at 0°C by a sonicator to reduce par-ticle sizes. The obtained nanoparticles are filtered and stored at 4°C [81]. This method reduces shear stress and uses com-

425 monly available equipment. However, metal contamination due to ultrasonication, and physical instability such as particle growth upon storage are likely to occur in this method [80,84].

3.1.3. Solvent evaporation Solid lipid nanoparticles can also prepared by solvent evapor-

430 ation method. The lipophilic drug is dissolved in an organic water-immiscible solvent like cyclohexane and dichloro-methane. The solution is emulsified in an aqueous solution using a high speed stirrer [7,77]. The solvent is evaporated at room temperature and reduced pressure, resulting in nano-

435 particles being formed in the aqueous phase by precipitation of the lipid. The particle sizes depend on the lipid concentration in the organic phase. This method is continuous and can be scaled up easily. However, biomolecules may be damaged and residual organic solvent may remain in this method

440 [80,81]. This technique has been studied by different research-ers for drug delivery approaches [85].

3.1.4. Solvent emulsification–diffusion In this method, a partially water-miscible solvent which dissolves the lipid, such as benzyl chloride, butyl acetate, ethyl

445acetate, etc., is used. Initially, at the temperature that lipid dissolves in solvent, water is added slowly to the solvent to arrive the saturation and thermodynamic equilibrium point. Thereafter, lipid and drug are dissolved in this saturated solvent. Subsequently, a saturated aqueous phase containing

450surfactant is added to the initial phase which contains lipid, by mixing with a stirrer to form an oil–water emulsion, followed by water addition to the system in a ratio of 1:5 to 1:10 to initiate solvent diffusion and lipid nanoparticle forma-tion. This step is performed at room temperature, or at initial

455lipid dissolving temperature. Finally, the solvent is removed by vacuum evaporation or lyophilization [81]. This method is used by researchers to prepare SLNs for different pharmaceu-tical aims [86–88].

3.1.5. Supercritical fluid method 460This is an alternative method for preparation of SLNs using a

supercritical fluid. Usually the dissolving power of fluids may be different under ambient and supercritical conditions. In this technique, lipid and drug are dissolved in a supercritical fluid and mixed under critical pressure and temperature in a

465homogenizer. Afterward, this mixture is passed through an atomizer in an expansion vessel. The fluid is allowed to evaporate and SLNs are formed [77]. Of the many candidate gases available, such as CO2, ammonia, ethane, methane, and propane, CO2 is the best choice as supercritical fluid in

470this method because (i) it is generally safe; (ii) has an easily accessible critical point; (iii) is not toxic; (iv) is not expensive; and (v) is environmentally acceptable [81]. In addition to the process describe above, nanoparticles can also be produced by other combinations: gas/supercritical anti-solvent, aerosol-

475solvent/extraction-solvent, and supercritical fluid extraction of emulsions [70]. In the latter method, the use of organic solvents is avoided, dry powder nanoparticles are obtained, and only mild pressure and temperature are needed [80]. This method is used for the preparation of SLNs in several studies

480[89–91].

Table 2. A summary of some solid lipid nanoparticles used in drug delivery systems.

Technique APIs/proteins Category Stabilizer Route Mean size or size

range (nm) Reference

HPH Risperidone Antipsychotic Imwitor1� 900K Oral 114 [83] Tagat1� S Sodium deoxycholate

HPH Clotrimazole Antifungal Dynasan1116 In vitro

3.1.6. Microemulsion-based method Microemulsions are clear solutions composed of a lipid phase in water (low melting fatty acid, drug, emulsifier, co-emulsi-fier, and water). Addition of a hot microemulsion to cold

485 water (2–3°C) while stirring leads to precipitation of lipids as fine particles. Finally, the prepared SLNs can be collected by ultracentrifugation. This method needs high volumes of water and efficiency of SLN production is low [66,80]. This method has been studied by different researchers [92,93].

490 3.1.7. Spray drying Spray drying is a cheaper alternative process to lyophilization [80]. In this method, the molten drug–lipid solution is atomized by centrifugal, pneumatic, ultrasonic, or electrostatic atomization techniques and then transferred to a spray dryer

495 which is heated by hot gas. Rapid evaporation of solvent generates dried SLNs. The obtained nanoparticles can be separated by a cyclone, an electrostatic precipitator, or a filter (Figure 5c) [84]. This method is recommended for lipids with melting points over 70°C [70].

500 3.1.8. Double emulsion This method is commonly used for hydrophilic drugs. The drug is dissolved in an aqueous solvent and is then added to the melted lipid. A stabilizer like gelatin or poloxamer-407 is added to the emulsion and then this solution is dispersed in an aque-

505 ous phase which contains hydrophilic emulsifier such as PVA. The nanodrops can be separated by evaporation or filtration of the double emulsion solution [81]. Double emulsion is used for preparing SLNs for various pharmaceutical uses [94,95].

4. Niosome

510 Niosomes are nanocarriers that have been considered by many researchers and pharmaceutical companies. Niosomes are colloidal particles formed from the self-assembly of nonionic surfactants in aqueous medium resulting in closed bilayer structures. They were introduced in the cosmetics industry

515 for the first time in the 1970s and were used as DDS from the 1980s on Nasir et al. [103]. They can accommodate light-weight molecules, proteins and genes during their bilayer membrane formation [104]. Hydrophilic molecules are embedded in the particle core, whereas hydrophobic ones will

520 localize within the bilayer shell (Figure 6b). Niosomes are single or multiple layered. They are classified in terms of size or few bilayer: (i) multi-lamellar vesicles (MLV), (ii) large unilamellar vesicles (LUV), and (iii) small unilamellar vesicles (SUV) (Figure 6c) [105]. Niosomes are fabricated from amphi-

525 philic, nonionic synthetic surfactants with or without choles-terol or other lipids [7]. Niosomes and liposomes are similar in structure and mode of drug entrapment. Biodegradability, biocompatibility, easy storage and handling, low toxicity, and the ability to functionalize for targeted drug delivery are

530 benefits of both liposomes and niosomes, but the synthetic surfactant which is used in niosome production causes lower cost and higher chemical stability than is the case for the phospholipid-containing liposomes [7,106]. In recent years, numerous researchers have studied different ways of preparing

535niosomes and their subsequent application in pharmaceutical settings [107–111].

4.1. Niosome preparation methods

The general method of preparing niosomes involves solvent evaporation to produce a lipid film, followed by hydration

540with hydration medium. However, there are variants of this method that influence few bilayers, drug entrapment efficiency, size, and size distribution of niosomes. Which prep-aration method should be selected depends on the intended niosome application [8].

545The widely reported preparation techniques are: a) Thin film hydration technique. b) Freeze-drying. c) Reverse phase evaporation. d) Ether injection.

550e) Sonication method. f) Microfluidization method. g) Proniosome application. h) Heating method. i) Freeze–Thaw method.

555j) Bubble method. Table 3 shows a summary of some niosomes used in DDS.

4.1.1. Thin film hydration technique In this technique, surfactants and cholesterol are dissolved in an organic solvent or a mixture of volatile organic solvents. Then

560the solvent is evaporated under reduced pressure. Subsequently, a great volume of aqueous buffer is added to the resulting thin layer on the inner surface of the vessel at temperature above the transition temperature of the used lipid. The hydration step in which the two phases interact, more than any other steps, will

565affect the properties of the niosomes (Figure 7a). Subsequently, the aqueous phase containing drug is added slowly to the flask at room temperature. It is possible to remove and retrieve the formed noisome particles by several techniques, such as centri-fugation, dialysis or filtration. The niosomes preparations can

570be lyophilized and packaged under aseptic conditions. This method of noisome production is currently not used,

because of deficiencies in particle size reduction, as well as ves-icle formation with many layers. The niosomes produced by this method are therefore primarily used as an intermediate product.

575Current efforts aim to resolve the mentioned deficiencies by testing alternative methods for particle size reduction such as using a HPH, or passing prepared MLVs by high pressure through appropriate size cutoff membranes [8]. Drugs which are loaded by this method include: minoxidil, nimesulide, insu-

580lin, glucocorticoid, methotrexate, antioxidants, etc [112–117].

4.1.2. Freeze-drying In this method, a surfactant, cholesterol, and other additives are dissolved in an organic solvent, after applying a thin film hydration procedure. The buffers to be used in this part of

585process must contain glucose or any other appropriate anti- freeze material (cryoprotectant). After hydration and MLV niosome formation, vesicles are chopped and converted into SUV vesicles. They are dried completely by freeze-dryer devices, after which drug enclosure inside the niosomes is


Figure 7. (a) Thin film hydration protocol (Redrawn from Moghassemi and Hadjizadeh [124]), (b) a schematic diagram of drug inducing to the freeze dried niosomes, (c) noisome preparation by reverse phase evaporation protocol (Redrawn from Moghassemi and Hadjizadeh [124]), (d) a schematic diagram of the ether injection protocol (Redrawn from Moghassemi and Hadjizadeh [124]).

Table 3. A summary of some niosomes used in drug delivery systems.

Technique APIs/protein Category Stabilizer Route Mean size or size

range (nm) Reference

Thin film hydration Minoxidil Antihypertensive vasodilator Brij 52, cholesterol Transdermal 976 [113] 1082 441 Brij 76, cholesterol 575 843 Span 20, Cholesterol

Span 40, Cholesterol Span 60, Cholesterol

Thin film hydration Dithranol Anti-psoriatic Span 60, cholesterol Transdermal 5,000 [133] Thin film hydration Gentamicin Antibiotic Tween 60, cholesterol Ophthalmic 1,200 [134]

1,040 Tween 80, cholesterol 760 Brij 35, cholesterol

Thin film hydration Meloxicam Anti-inflammatory Span 60, cholesterol Transdermal 187 [135] Thin film hydration Ketoconazole Antifungal Span 40, cholesterol In vitro 5,400 [136]

4,800 6,300 Span 60, cholesterol

Tween 60, cholesterol Freeze-drying Ginkgo biloba Herbal medicine Tween 80, Span 80, cholesterol Oral 661 [137] Reverse Phase

Evaporation 5-Aminolevulinic

acid Photodynamic therapy

(anticancer) Span 60, cholesterol Transdermal 611 [138]

Reverse phase evaporation

Ellagic acid Antioxidant Span 60 and Tween 60, cholesterol Transdermal 124–752 [122]

Ether injection Diclofenac sodium

Anti-inflammatory Span 60, Sorbitan monostearate, cholesterol

In vitro 3,700 [123]

Ether injection Fluconazole Antifungal Span 60, cholesterol Oral 70–78 [126] Ether injection Adriamycin Anticancer Dialkyl polyglycerol ether,

cholesterol Pulmonary — [128]

Sonication Cilexetil Antihypertensive Span 60, cholesterol Oral 242 [139] Sonication Dynorphin B Endogenous opioid peptide Span 60, cholesterol Intravenously

injection 220–250 [140]

Sonication Lornoxicam Anti-inflammatory Span 60, cholesterol Transdermal 1,125 [141]


590 accomplished by mixing of the dried nanoparticles with a drug-containing aqueous phase (Figure 7b) [118].

4.1.3. Reverse phase evaporation This method is designed to form large monolayer niosomes (LUV). These kinds of single-layered niosomes have several

595 advantages in comparison with multilayer niosomes such as: high encapsulation capacity of water soluble drugs and savings in the amount of lipid needed.

In the first preparation step, surfactant and necessary addi-tives are dissolved in an organic solvent. Then the aqueous

600 phase, containing the drug, is added to the organic phase, whereafter the two-phase system is converted to an emulsion by sonication or other mechanical devices. In this stage, water droplets are dispersed in the organic solvent and surfactant molecules surround them. The organic solvent is removed

605 by rotary evaporation under reduced pressure. During this evaporation process, LUVs are formed (Figure 7c) [119,120]. This method has been used for the preparation of niosomes entrapping naltrexone, ellagic acid (EA), diclofenacsodium (DCS), acetazolamide, etc [120–123].

610 4.1.4. Ether injection In this method, a small amount of lipid is dissolved in diethyl ether or a mixture of ether and ethanol, followed by slow injec-tion into an aqueous phase containing water-soluble drugs and surfactant (at the transition temperature of the surfactant).

615 Subsequently, the remaining ether is removed under vacuum. Ultimately, mono-layer vesicles are produced (Figure 7d) [124]. This method has been used for the preparation of niosomes with entrapped gadobenate, DCS, fluconazole, rifampicin, adriamycin, etc [123,125–128].

620 4.1.5. Sonication method In this procedure, drug solution is added to surfactant/ cholesterol, whereafter the mixture is exposed to a sonicator probe at the surfactant transition temperature for minutes [129]. The sonication procedure has been used for diallyldisul-

625 fide loading in niosomes [130].

4.1.6. Microfluidization method This procedure has several advantages such as: more uniform-ity, smaller size, direct formation of monolayer niosomes, and

higher repeatability. In this method, high velocity jets are used 630in micrometer scale. The lipid is dissolved in isopropyl alcohol

and passed through a central channel, whereas an aqueous solution is added from out of two adjacent channels. Lipid and adjacent aqueous flows are concentrated at the intersec-tion point. Inflow velocities will determine flow concentrations

635at the intersection point and the thus created interface [129]. Niosome formation using this method depends on

penetration of lipid nanoparticles by the aqueous phase, eventually leading to self-assembly of lipid nanoparticles and finally vesicle formation. Size and size distribution of

640nanoparticles can be controlled by varying lipid concentra-tions and flow conditions.

4.1.7. Proniosome application In this method, a water-soluble carrier is coated with surfac-tant. Then the carrier is resolved during the hydration process

645at a temperature above the surfactant transition temperature, whereby niosomes are formed. Some remarkable advantages of this process are: high velocity of the production process, and easy applicability of this method in industrial productions (Figure 6d) [118].

6504.1.8. Heating method In this method, the vesicle components are hydrated separately under nitrogen atmosphere at room temperature for 1 h. Then, heating at 120°C in containers stirred at a speed less than 1,000 rpm is performed for 15 min, to completely

655melt the vesicle components. Then, the temperature is reduced to transition temperature of the surfactant, the drug, surfactant and other additives are added to each other, and stirred for a certain period of time to trap the drug into the vesicles (Figure 8a) [131].

6604.1.9. Freeze–thaw method In this method, the first step is to create empty niosomes according to the thin film hydration procedure. After reducing the size of the niosomes, they are kept at � 196°C for 5 min with an appropriate concentration of drug, followed by rapid

665transfer into a water bath at surfactant transition temperature for 5 min. This cycle is repeated two to four times so that the drug becomes efficiently enclosed in the vesicles during the

Figure 8. (a) A schematic diagram of the heating protocol (Redrawn from Moghassemi and Hadjizadeh [124]), (b) schematic diagram of the freeze–thaw protocol.


cycles. This method is appropriate for protein trapping in the vesicles (Figure 8b) [132].

670 4.1.10. Bubble method This method allows preparation of niosomes without using organic solvents. Surfactants and additives are mixed in an aqueous phase under nitrogen atmosphere at 70°C. They are mixed for 15 s with high speed homogenizer. Finally, nitrogen

675 bubbles are blown through the mixture at 70°C [124].

4.1.11. Liposome Liposome is a common biliary-spherical carrier composed of phospholipid for biocompatibility, cholesterol for stability and charging agent as an anti-agglomerative or for specific

680 application, e.g., gene delivery [142]. There are several advan-tages in applying liposome including the ease of synthesis, high biocompatibility and similarity with biological mem-brane, biodegradable, nonstimulating agent for the immune system, producible on a large scale, and applicable to drugs

685 with different nature [143]. However, there are a challenge in using liposome due to in

vivo and in vitro instability but it could be solving by modifi-cation of liposome (e.g., PEGylation) and still proposed as a low risk vehicle [144]. The experimental synthesis method is

690 similar to niosomal preparing. Thanks to sustained-release properties of liposomal drugs,

the toxicity activity (for cytotoxic agent) could be improving, leads to pharmaceutical benefits increase and also damage to normal tissue. Delivery of drugs to nonspecified site leads to

695 loss of drugs followed by high-dose drug [145]. To address this issue, sensitizing liposome with the unique features of target cells is a developing technique including functionalizing liposome with peptide and antibody known as active targeting, and incorporation with lipid or specific agent as passive target-

700 ing to create thermos, pH, light sensitive and liposome reduction [146–150].

The permeability of membrane containing glucose and glycerol is dependent on saturation of membrane phospholi-pids and permeability increase with increasing saturation

705 within membrane [151]. Liponiosome, combination of niosome and liposome, is

new developed particles benefits from noisome and liposome both. It could deliver high amount of hydrophilic/hydrophobic drugs and therapeutic gene. Their diameter size is less than

710 150 nm, stable and biocompatible [152]. Increasing the phase change temperature (Tc) of surfactant

will increase the entrapment efficacy and decrease the permeability [153]. Increasing the acyl chain leads to increase in hydrophobic drug encapsulation.

715 Polysorbate PEGylated with sorbitan fatty acid esters (Tween surfactant) play an important role in improving drug entrapment due to PEG agent in comparison to other surfactant [104]. Polyethylene glycol (PEG) is the hydrophilic, biocompatible and biodegradable polymer. In thin film

720 hydration technique, PEG should be added in the final step of liposome preparation, in hydration step [154,155]. By PEGylation, the cellular uptake of nanoparticles might decrease, however the blood circulation of nanoparticles is

prolonged. PEGylation enhances the steric hindrance which 725leads to agglomeration decrease of particles [156,157].

Considering the investigation result on the effect of cholesterol content, we found 30–40% cholesterol content in liposomal formulation that plays a critical role in controlling drug release and improving entrapment efficiency [145]. The

730presence of cholesterol in bilayer space in vesicle compete with drug loading, and high amount of cholesterol may decrease drug entrapment efficacy. As described by El-Laithy et al. [158], the entrapment efficiency enhanced by increasing choles-terol content due to filling the empty space between surfactant

735(phospholipid) by cholesterol, as vesicular cement, leads to strength increase and the permeability decrease of membrane.

Most important parameters involved in drug loading are solubility of drug in melted lipid, polymorphic states of lipid and physio chemical structure of solid lipid matrix [159]. Rise

740in drug release occurs by increasing effective area of particles [160].

Nowadays, nanocarriers are extensively used in food, phar-maceutical, sanitary, and cosmetic industry. Thus, improving large-scale manufacturing can be a response to growing

745indeed. There are several introduced methods for synthesis liposome in pilot or industrial scale. Liposome Producer (Ilya Co., Iran) is a developed instrument for liposome controlling and sterile producing [161].

Industrial method for nanoparticles preparation includes 750aerosol flow reactor method (dissolving drug in volatile organic

solvents followed by spraying with inert gas at 40–400°C) [162], supercritical fluid-based technologies (dissolving drug in super-critical fluid such as CO2 followed by sudden expansion and supersaturation and the deposition of the nano/microdrug)

755[163], HPH (nanodrugs were formed under the strong shear stress, and most affected parameters in size of particles are pressure of homogenizer and few homogenization cycles) [164], continuous precipitation method (by solving drug in water-soluble solvent followed by adding to water contained

760stabilizer) [165] and milling media techniques (size reduction of soluble and insoluble drugs in water with water or buffer using mill made by glass, zirconium oxide and polystyrene resins under the influence of shear force for 45 min) [166].

4.1.12. Gene delivery and liposome 765Gene therapy mainly performed by targeting delivery of thera-

peutic gene within targeted cell or tissue using viral or nonviral vehicles. Applying nonviral vehicles is preferred more because of the problem associated with the viral vehicles, such as (i) immunogenicity (stimulation of the host immune system),

770(ii) toxicity, (iii) mutagenesis, due to the arrival of the gene fragment in a misplaced position, (iv) limitation in transfec-tion of high amount of gene, and (v) costly and arduous production [166].

Applying nanoparticles instead of viral vehicle benefits 775from additional advantages, such as incorporation molecular

imaging agent. Cationic liposomes are in use as gene transfec-tion vector in drug/gene delivery system coping with the limitations of viral vector [168].

There are various methods for encapsulation/incorporation 780of nucleic acids in liposome, e.g., passive encapsulation, etha-

nol drop, reverse phase evaporation, spontaneously formed


vesicles by ethanol injection, and encapsulation in destabilized liposome [169].

4.1.13. In vitro characterization of nanoparticles 785 Loading efficiency. The high drug/gene loading in low

amount of lipid is a positive point in delivery system. There are various methods for determination of drug loading efficacy: (i) digesting lipid membranes with alcohol (ethanol, methanol, and propanol) and Triton X-100 with the volume

790 ratio of 1:20 (suspension:solvent) followed by reading UV–vis spectrophotometer at λmax of drug and calculation the entrap-ment efficiency using the calibration curve of drug in solvent [142,145]. (ii) Centrifuging the suspension using refrigerated centrifuge (17,000g, 60 min and 4°C) followed by reading the

795 absorbance of drug in supernatant regarding to unloaded drug. The loading efficacy was then calculated by difference of initial drug and unloaded drug [142,158].

To determine the successful gene loading efficiency, various amount of liposomes was loaded with gene followed by expos-

800 ing to electrophoresis at 30 kV, unloaded gene then was migrated throughout the gel and loaded gene was entrapped in electrophoresis well. In another method, determination of entrapment efficiency is performed by spectrophotometry at 260 nm [144].

805 Drug release pattern. To study drug release pattern, the semi in vivo medium should be simulated to achieve an approximate drug release pattern close to cells and modified nanoparticle formulation to achieve a controlled release formulation. Drug release is performed by (i) dialysis tube,

810 (ii) reverse dialysis, and (iii) Franz diffusion cell [170]. The medium is contained PBS or FBSQ8 at 37°C (or 42°C for cancer-ous cells), pH 7.4 (or 4, 5.4, and 6.5 for lysosome, endosomal cells, and tumor tissue, respectively) and under gentle vibration. Drug release is calculated by online/offline reading

815 at λmax using spectrophotometer.

Chemical interaction. Therapeutic drug/gene should be entrappedQ9 into/loaded on nanoparticles physically without any chemical interaction between drugs/gene or nanoparticles composition. This means the therapeutic activity may not

820 change during encapsulation. FTIR/IR and MALDI–TOF mass spectroscopy analysis [145,171].

Size diameter, surface charge and shape. The size diameter, zeta potential, and polydispersity index (dispersion index) is monitored using dynamic light scattering technique. Vesicles

825 larger than 1 µm are instable. Decrease in the amount of surfac-tant, low temperature and high drug dose will increase the size. Increasing the ratio of surfactant to lipid and using nonionic surfactant will cause to size reduction of particles [172]. The type and density of electric charge on the surface of liposome

830 effects the interaction of cells–liposome. Neutral electric charge of liposome has low physical stability and also no interaction with cells. Negative charged liposome interacts with cells by endocytosis, and liposomes are exited from plasma and transfer to cells quickly. Positively charged liposome have high interac-

835 tion with negatively charged cytoplasm and interact with cellu-lar membrane by fusion [173]. High zeta potential leads to agglomeration reduction [145]. Surface appearance, internal

bilayers, homogeneity, approximate size diameter is obtained by microscopic imaging using cryo-transmission electron

840microscope and scanning electron microscope [145].

Stability evaluation. The stability of drug/gene delivery system is assayed in two aspects: (i) storage stability (physical stability): the nanoformulation is monitored during 6-month in terms of size diameter, zeta potential, drug/gene loading

845efficiency and PDI by determination in predetermined time intervals [174], (ii) stability of gene delivery system in plasma (biological stability): since free gene is instable serum, gene- loaded liposome is exposed to human serum and the cellular uptake images after and before exposer is compared together

850[175].

4.1.14. Therapeutic efficiency of formulation Therapeutic nanodrugs may cause toxicity on body organs. Small particles are more simply transfected to cell and cause toxicity. The surface charge of nanoparticles leads to increase

855in reactivity with cells and protein. Free oxygen radical is so reactive which leads to oxidative stress. As drug/gene is loaded on nanoparticles, the therapeutic activity should be determined and compared with free drug to specify the effect of encapsula-tion. Cytotoxicity assay (e.g., XTT, MTT, CyQUANT, Alamar

860blue) is performed to compare the cytotoxicity of blank liposome, free drug and drug-loaded liposome. By encapsula-tion of chemotherapy drug, cytotoxicity of drug may be enhanced due to sustained release feature comes by encapsula-tion. CyQUANT assay is based on DNA replication samples,

865cells are seeded in 96 well plate and treated with the following groups under study (blank liposome, free drug, and drug- loaded liposome) followed by washing with PBS and replacing PBS by CyQUANT1� lysis buffer. Then samples passed three freeze and thaw cycle and DNA of duplicate samples was deter-

870mined by fluorescence exposure [142]. Alamar blue assay is a method to measure proliferation of cells based on metabolic mitochondrial activity of cells. Cells (104 per well) were treated with samples diluted in medium. After 24, 48 or 72 h, cells were washed by PBS and Alamar blue solution was added, followed

875by 3 h incubation and cell viability reading by microplate spectrophotometer at 570 nm (excitation)/600 nm (emission) wavelength [145]. The MTT Q10assay is a colorimetric assay for evaluation of cell metabolic activity. For MTT assay, after treatment cell with samples, MTT solution (3-(4,5-

880dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) is added. After 3 h incubation, DMSO is added to dissolve crystals. Cell viability is determined by fluorescence exposure. IC50 doses is an index to determine the concentrations of inhibiting the cell growth by 50% [145].

885Cellular uptake assay is performed to determine the track of the cellular transfection in liposomal drug. Cells is seeded in -well plates (density of 2 � 105 cells/well) and treated with samples (intrinsically fluorescence or dyed with fluorescent agent) for 3 h at 37°C in humidified incubator. Then cells

890are washed three times with PBS and fixed with 4%, parafor-maldehyde solution. Before fluorescence imaging, cell’s nucleus is stained with DAPI (4′,6-diamidino-2-phenylindole) for 15 min [174]. For adherent cells in all method, cells should be transferred to well up to 24 h before starting experiment.


895 The antioxidant activity of encapsulated drug in liposome is determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as a simple, reversible and inexpensive test. DPPH is stable radical with purple color that changed to yellow after receiving electron from anti-oxidant sample. The absorbance

900 at 517 nm is related to anti-oxidant activity of sample. Samples are mixed with DPPH and methanol. Then, placed in a dark place for 1 h and the anti-oxidant activity is read by spectro-photometer [176].

4. Conclusion

905 Polymer-based nanocarriers (PNPs) are prepared by self- assembly of amphiphilic biodegradable copolymers in aqueous solution. Ligands and antigens can be conjugated to block copolymers for controlled DDS. The most important features of PNPs are increased stability of encapsulated drugs, ability

910 to carry, and deliver higher amounts of pharmaceutical agents to the desired tissue, and protection of its contents against hydrolysis and enzymatic degradation.

Niosomes are bilayer vesicles like liposomes which are formed by self-assembly of nonionic surfactants in the aque-

915 ous phase. These nanoparticles can encapsulate a wide range of hydrophilic, lipophilic, and amphiphilic drugs. Some of the major advantages of the niosomes compared to liposomes include their low price, high stability, and lack of necessity for special storage conditions. These advantages have led to

920 increased interest in producing and using niosomal nanopar-ticles as compared to liposomal nanoparticles.

Solid lipids nanoparticles are colloidal drug carrier systems which are prepared from lipids that are solid at room and body temperature, and utilized to carry and deliver hydrophilic and

925 hydrophobic drugs. They can be functionalized for targeted DDS, and are more stable than other lipid nanocarriers. Improving bioavailability and reducing biodegradation of drugs are the most important characteristics of SLNs.

Acknowledgments 930

The authors express their appreciation to Mohadeseh Hashemi, researcher from Department of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran, Tehran, Iran assist-ance during the project.

935 Conflict of interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There is no conflict of interest.

ORCID 940

Fateme Haghiralsadat http://orcid.org/0000-0002-8655-2118 Samira Naderinezhad http://orcid.org/0000-0002-0703-2334

References

[1] Porter, C. J.; Trevaskis, N. L.; W. N. C. Lipids; and lipid-based 945 formulations: Optimizing the oral delivery of lipophilic drugs.

Nat. Rev. Drug. Discov. 2007, 6, 231–248.Q11

[2] Merisko-Liversidge, E. M.; G. G. L. Drug nanoparticles: Formulating poorly water-soluble compounds. Toxicol. Pathol. 2008, 36, 43–8.

[3] Kawabata, Y.; Wada, K.; Nakatani, M.; Yamada, S.; Onoue, S. 950Formulation design for poorly water-soluble drugs based on bio-

pharmaceutics classification system: Basic approaches and practical applications. Int. J. Pharmaceut. 2011, 420, 1–10.

[4] Sawant, R. R.; Torchilin, V. P. Multifunctional nanocarriers and intracellular drug delivery. Curr. Opin. Solid State Mater. Sci.

9552012, 16, 269–275. [5] Buse, J.; El-Aneed, A. Properties, engineering and applications of

lipid-based nanoparticle drug-delivery systems: current research and advances. Nanomedicine 2010, 5, 1237–1260.

[6] Shah, R.; Eldridge, D.; Palombo, E.; Harding, I. Introduction. Lipid 960Nanoparticles: Production, Characterization and Stability, Springer,

2015, pp. 1–7. [7] Attama, A. A.; Momoh, M. A.; Builders, P. F. Q12Lipid nanoparticulate

drug delivery systems: a revolution in dosage form design and development. In: Recent Advances in Novel Drug Carrier Systems;

965InTech, 2012. pp. 107–140. [8] Yadav, J. D.; Kulkarni, P. R.; Vaidya, K. A.; Shelke, T. G. Niosomes:

A review. J. Pharm. Res. 2011, 4(3), 632–636. [9] Miyata, K.; Christie, R. J.; Kataoka, K. Polymeric micelles for nano-

scale drug delivery. React. Funct. Polym. 2011, 71, 227–234. 970[10] Nasir, A.; Kausar, A.; Younus, A. A review on preparation, proper-

ties; and applications of polymeric nanoparticle-based materials. Polym.-Plast. Technol. Eng. 2015, 54, 325–341.

[11] Sawdon, A. J.; Peng, C-A. Polymeric micelles for acyclovir drug delivery. Colloids Surf. B Biointerfaces 2014, 122, 738–745.

975[12] Kreuter, J. Drug delivery to the central nervous system by polymeric nanoparticles: What do we know? Adv. Drug Deliv. Rev. 2014, 71, 2–14.

[13] Yang, Y.; Pan, D.; Luo, K.; Li, L.; Gu, Z. Biodegradable and amphiphilic block copolymer–doxorubicin conjugate as polymeric

980nanoscale drug delivery vehicle for breast cancer therapy. Biomaterials 2013, 34, 8430–8443.

[14] Kumari, A.; Yadav, S. K.; Yadav, S. C. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf. B Biointerfaces 2010, 75, 1–18.

985[15] Rao, J. P.; Geckeler, K. E. Polymer nanoparticles: Preparation techniques and size-control parameters. Progr. Polym. Sci. 2011, 36, 887–913.

[16] Zhang, S. Y.; Wu, Y.; Gu, Z. W.; He, B.; Luo, K. Biodegradable polymeric nanoparticles based on amphiphilic principle: Construc-

990tion and application in drug delivery. Sci. China Chem. 2014, 57, 461–475.

[17] Nagavarma, B. V. N.; Yadav, H. K. S.; Ayaz, A.; Vasudha, L. S.; Shivakumar, H. G. Different techniques for preparation of polymeric nanoparticles: A review. Asian J. Pharm. Clin. Res.

9952012, 5, 16–23. [18] Pallerla, S.; Prabhakar, B. Review on polymers in drug delivery.

Am. J. PharmTech Res. 2013, 3, 900–917. [19] Raizada, A.; Bandari, A.; Kumar, B. Polymers in drug delivery: A

review. Int. J. Pharma Res. Dev. Online 2010, 2, 9–20. 1000[20] Mora-Huertas, C. E.; Fessi, H.; Elaissari, A. Polymer-based nano-

capsules for drug delivery. Int. J. Pharmaceut. 2010, 385, 113–142. [21] Devasier, B.; Sanghyo, K. Application of Nanotechnology in Drug

Delivery; InTech, 2014. Q13[22] Khandare, J.; Haag, R. Pharmaceutically used polymers: principles,

1005structures; and applications of pharmaceutical delivery systems. In: Scha¨fer-Korting, M., ed. Handbook of Experimental Pharmacology. 197, Springer: Germany, 2010, pp. 221–250.

[23] Bilati, U.; Allemann, E.; Doelker, E. Sonication parameters for the preparation of biodegradable nanocapsules of controlled size by the

1010double emulsion method. Pharm. Dev. Technol. 2003, 8, 1–9. [24] Barichello, J. M.; Morishita, M.; Takayama, K., Nagai, T. Encapsu-

lation of hydrophilic and lipophilic drugs in PLGA nanoparticles by the nanoprecipitation method. Drug Dev. Ind. Pharm. 1999, 25, 471–476.

1015[25] Nemati, F.; Dubernet, C.; Fessi, H.; Verdiere, A. C.; Poupon, M. F.; Puisieux, F.; Convreur, P. Reversion of multidrug resistance using


http://orcid.org/0000-0002-8655-2118http://orcid.org/0000-0002-0703-2334

nanoparticles in vitro: Influence of the nature of the polymer. Int. J. Pharm. 1996, 138, 237–246.

[26] Molpeceres, J.; Guzman, M.; Aberturas, M. R.; Chacon, M. L. B. 1020 Application of central composite designs to the preparation of

polycaprolactone nanoparticles by solvent displacement. J. Pharm. Sci. 1996, 85, 206–213.

[27] Irache, J. M.; Huici, M.; Konecny, M.; Espuelas, S.; Campanero, M. A.; P. A. Bioadhesive properties of gantrez nanoparticles. Molecules

1025 2005, 10, 126–145. [28] Arbos, P.; Wirth, M.; Arangoa, M. A.; Gabor, F.; Irache, J. M.

Gantrez AN as a new polymer for the preparation of ligand nano-particle conjugates. J. Control. Release 2002, 83, 321–330.

[29] Vargas, A.; Pegaz, B.; Debefve, E.; Konan-Kouakou, Y.; Lange, N.; 1030 Ballini, J.-P. Improved photodynamic activity of porphyrin loaded

into nanoparticles: An in vivo evaluation using chick embryos. Int. J. Pharm. 2004, 286, 131–145.

[30] Konan, Y. N.; Gurny, R.; Allémann, E. State of the art in the deliv-ery of photosensibilizers for photodynamic therapy. Photochem.

1035 Photobiol. B 2002, 66, 89–106. [31] Yoo, H. S.; Oh, J. E.; Lee, K. H.; Park, T. G. Biodegradable nano-

particles containing PLGA conjugate for sustained release. Pharm. Res. 1999, 16, 1114–1118.

[32] Lu, W.; Zhang, Y.; Tan, Y.-Z.; Hu, K.-L.; Jiang, X.-G.; Fu, S.-K. 1040 Cationic albumin conjugated pegylated nanoparticles as novel drug

carrier for brain delivery. J. Control. Release 2005, 107, 428–448. [33] Kipp, J. The role of solid nanoparticle technology in the parenteral

delivery of poorly water-soluble drugs. Int. J. Pharmaceut. 2004, 284, 109–122.

1045 [34] Parikh, I.; Selvaraj, U. Composition and method of preparing microparticles of water-insoluble substances. Google Patents; 1999.

[35] Muller, R. H.; Becker, R.; Kruss, B.; Peters, K. Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution. Google Patents;

1050 1999. [36] Jafari, S. M.; He, Y.; Bhandari, B. Optimization of nano-emulsions

production by microfluidization. Eur. Food Res. Technol. 2007, 225 (5–6), 733–741.

[37] Kaialy, W.; Al Shafiee, M. Recent advances in the engineering 1055 of nanosized active pharmaceutical ingredients: Promises; and

challenges. Adv. Colloid Interface Sci. 2015.Q14[38] Sovan, L. P.; Utpal, J.; Manna, P. K.; Mohanta, G. P.; Manavalan, R.

Nanoparticle: An overview of preparation and characterization. J. Appl. Pharm. Sci. 2011, 6, 228–234.

1060 [39] Galindo-Rodriguez, S.; Allémann, E.; Fessi, H.; Doelker, E. Physicochemical parameters associated with nanoparticle forma-tion in the salting-out, emulsification-diffusion, and nanoprecipita-tion methods. Pharm Res. 2004, 21, 1421–1439.

[40] Mendoza-Muñoz, N.; Quintanar-Guerrero, D.; Allémann, E. The 1065 impact of the salting-out technique on the preparation of colloidal

particulate systems for pharmaceutical applications. Recent Pat. Drug Deliv. Formul. 2012, 6, 236–249.

[41] Jeong, Y.-I.; Cho, C.-S.; Kim, S.-H.; Ko, K.-S.; Kim, S.-I.; Shim, Y.-H.; Nah, J.-W. Preparation of poly(DL-lactide-co-glycolide) nanoparti-

1070 cles without surfactant. J. Appl. Polym. Sci. 2001, 80, 2228–2236. [42] Vu, M.-T.; Jeong, Y.-I.; Choi, C.; Nam, J.-P.; Son, D.-H.; Park, J.-K.;

Kim, W.-S.; Kim, M.-Y.; Jang, M.-K.; Nah, J.-W.; Kim, K.-J. Surfactant-free nanoparticles of doxorubicin-conjugated poly(DL- lactide-co-glycolide). Macromol. Res. 2010, 18, 1115–1120.

1075 [43] Mahalingam, M., Krishnamoorthy, K. Selection of a suitable method for the preparation of polymeric nanoparticles: Multi-criteria decision making approach. Adv. Pharm. Bull. 2015, 5, 57–67.

[44] Mudgil, M.; Pawar, P. K. Preparation and in vitro/ex vivo evaluation of moxifloxacin-loaded PLGA nanosuspensions for

1080 ophthalmic application. Sci. Pharm. 2013, 81, 591. [45] Masood, F.; Chen, P.; Yasin, T.; Fatima, N.; Hasan, F.; Hameed, A.

Encapsulation of ellipticine in poly-(3-hydroxybutyrate-co-3- hydroxyvalerate) based nanoparticles and its in vitro application. Mater. Sci. Eng. C 2013, 33, 1054–1060.

1085 [46] Shah, M.; Ullah, N.; Choi, M. H.; Kim, M. O.; Yoon, S. C. Amorphous amphiphilic P (3HV-co-4HB)-b-mPEG block copolymer synthesized

from bacterial copolyester via melt transesterification: nanoparticle preparation, cisplatin-loading for cancer therapy and in vitro evaluation. Eur. J. Pharm. Biopharm. 2012, 80, 518–527.

1090[47] Yadav, K. S.; Sawant, K. K. Formulation optimization of etoposide loaded PLGA nanoparticles by double factorial design and their evaluation. Curr. Drug Deliv. 2010, 7, 51–64.

[48] Chalasani, K. B.; Russell-Jones, G. J.; Yandrapu, S. K.; Diwan, P. V.; Jain, S. K. A novel vitamin B12-nanosphere conjugate carrier

1095system for peroral delivery of insulin. J. Control. Release 2007, 117, 421–429.

[49] Sawdon, A. J.; Peng, C.-A. Polymeric micelles for acyclovir drug delivery. Colloids Surf. B Biointerfaces 2014, 122, 738–745.

[50] Danhier, F.; Lecouturier, N.; Vroman, B.; Jérôme, C.; Marchand- 1100Brynaert, J.; Feron, O.; Préat, V. Paclitaxel-loaded PEGylated

PLGA-based nanoparticles: In vitro and in vivo evaluation. J. Con-trol. Release 2009, 133, 11–17.

[51] Gupta, H.; Aqil, M.; Khar, R. K.; Ali, A.; Bhatnagar, A.; Mittal, G. Sparfloxacin-loaded PLGA nanoparticles for sustained ocular drug

1105delivery. Nanomedicine 2010, 6, 324–33. [52] Derakhshandeh, K.; Erfan, M.; Dadashzadeh, S. Encapsulation of

9-nitrocamptothecin, a novel anticancer drug, in biodegradable nanoparticles: Factorial design, characterization and release kinetics. Eur. J. Pharm. Biopharm. 2007, 66, 34–41.

1110[53] Dhar, S.; Gu, F. X.; Langer, R.; Farokhzad, O. C.; Lippard, S. J. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt (IV) prodrug-PLGA–PEG nanoparticles. Proc. Natl. Acad. Sci. 2008, 105, 17356–17361.

[54] Pu, X.; Sun, J.; Wang, Y.; Wang, Y.; Liu, X.; Zhang, P.; et al. 1115Development of a chemically stable 10-hydroxycamptothecin

nanosuspensions. Int. J. Pharm. 2009, 379, 167–173. [55] Möschwitzer, J.; Achleitner, G.; Pomper, H.; Müller, R. H.

Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension tech-

1120nology. Eur. J. Pharm. Biopharm. 2004, 58, 615–619. [56] Chaubal, M. V.; Popescu, C. Conversion of nanosuspensions into

dry powders by spray drying: a case study. Pharm. Res. 2008, 25, 2302–2308.

[57] Allémann, E.; Leroux, J.-C.; Gurny, R.; Doelker, E. In vitro 1125extended-release properties of drug-loaded poly (DL-lactic acid)

nanoparticles produced by a salting-out procedure. Pharm. Res. 1993, 10, 1732–1737.

[58] Lee, S. J.; Yook, S.; Yhee, J. Y.; Yoon, H. Y.; Kim, M.-G.; Ku, S. H.; et al. Co-delivery of VEGF and Bcl-2 dual-targeted siRNA polymer

1130using a single nanoparticle for synergistic anti-cancer effects in vivo. J. Control. Release 2015, 220, 631–641.

[59] Pathak, P.; Meziani, M. J.; Desai, T.; Sun, Y.-P. Formation and stabilization of ibuprofen nanoparticles in supercritical fluid processing. J. Supercrit. Fluids 2006, 37, 279–286.

1135[60] Schwarz, C.; Mehnert, W.; Lucks, J. S.; Müller, R. H. Solid lipid nanoparticles (SLN) for controlled drug delivery. I. Production, characterization and sterilization. J. Control. Release 1994, 30, 83–96.

[61] Morel, S.; Ugazio, E.; Cavalli, R.; Gasco, M. R. Thymopentin in solid lipid nanoparticles. Int. J. Pharm. 1996, 132, 259–261.

1140[62] Cavalli, R.; Caputo, O.; Carlotti, M. E.; Trotta, M.; Scarnecchia, C.; Gasco, M. R. Sterilization and freeze-drying of drug-free and drug- loaded solid lipid nanoparticles. Int. J. Pharm. 1997, 148, 47–54.

[63] Siekmann, B.; Westesen, K. P234 solid lipid nanoparticles stabilized by tyloxapol. Eur. J. Pharm. Sci. 1994, 2, 177.

1145[64] Bunjes, H.; Westesen, K.; Koch, M. H. J. Crystallization tendency and polymorphic transitions in triglyceride nanoparticles. Int. J. Pharm. 1996, 129, 159–173.

[65] Solid lipid nanoparticles. In: Mozafari, M. R., Q15ed. Nanocarrier Technologies: Frontiers of Nanotherapy; Springer: Netherland,

11502006, pp. 41–51. [66] Mishra, D.; Dhote, V.; Pradyumna, M. Solid lipid nanoparticles: A

promising colloidal carrier. Nano Carriers for Drug Delivery, pp. 278–301.

[67] Üner, M.; Yener, G. Importance of solid lipid nanoparticles (SLN) 1155in various administration routes and future perspectives. Int. J.

Nanomed. 2007, 2, 289–300.


[68] Weber, S.; Zimmer, A.; Pardeike, J. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for pulmonary application: A review of the state of the art. Eur. J. Pharm.

1160 Biopharm. 2014, 86, 7–22. [69] Das, S.; Chaudhury, A. Recent advances in lipid nanoparticle

formulations with solid matrix for oral drug delivery. AAPS PharmSciTech 2011, 12, 62–76.

[70] Garud, A.; Singh, D.; N. G. Solid lipid nanoparticles (SLN): 1165 Method, characterization and applications. Int. Curr. Pharm. J.

2012, 1, 384–393. [71] Singhal, G. B.; Patel, R. P.; Prajapati, G. B.; N. A. P. Solid lipid

nanoparticles and nanolipid carriers: As novel solid lipid-based drug carrier. Int. Res. J. Pharm. 2011, 2, 40–52.

1170 [72] Khurana, S.; Bedi, P. M. S.; Jain, N. K. Preparation; and evaluation of solid lipid nanoparticles based nanogel for dermal delivery of meloxicam. Chem. Phys. Lipids 2013, 175–176, 65–72.

[73] Weyenberg, W.; Filev, P.; van den Plas, D.; Vandervoort, J.; de Smet, K.; Sollie, P.; Ludwig, A. Cytotoxicity of submicron

1175 emulsions and solid lipid nanoparticles for dermal application. Int. J. Pharm. 2007, 337, 291–298.

[74] Liu, J.; Gong, T.; Fu, H.; Wang, C.; Wang, X.; Chen, Q.; Zhang, Q.; He, Q.; Zhang, Z. Solid lipid nanoparticles for pulmonary delivery of insulin. Int. J. Pharm. 2008, 356, 333–344.

1180 [75] Schäfer-Korting, M.; Mehnert, W.; Korting, H.-C. Lipid nanoparti-cles for improved topical application of drugs for skin diseases. Adv. Drug Deliv. Rev. 2007, 59, 427–443.

[76] Attama, A. A.; Reichl, S.; Müller-Goymann, C. C. Diclofenac sodium delivery to the eye: In vitro evaluation of novel solid lipid

1185 nanoparticle formulation using human cornea construct. Int. J. Pharm. 2008, 355, 307–313.

[77] Patil, J.; Gurav, P.; Kulkarni, R.; Jadhav, S.; Mandave, S.; Shete, M.; Chipade, V. Applications of solid lipid nanoparticle in novel drug delivery system. Br. Biomed. Bull. 2013, 1, 103–118.

1190 [78] Mukherjee, S.; Ray, S.; S. T. R. Solid lipid nanoparticles: A modern formulation approach in drug delivery system. Indian J. Pharm. Sci. 2009, 71, 349–358.

[79] Mehnert, W.; Mäder, K. Solid lipid nanoparticles: Production, characterization and applications. Adv. Drug Deliv. Rev. 2012, 64,

1195 83–101. [80] Ekambaram, P.; Abdul Hasan Sathali, A.; K. P. Solid lipid nanopar-

ticles: A review. Sci. Rev. Chem. Commun. 2012, 2, 80–102. [81] Ramteke, K. H.; Joshi, S. A.; S. N. D. Solid lipid nanoparticle: A

review. IOSR J. Pharm. 2012, 1, 34–44. 1200 [82] Corrias, F.; Lai, F. New methods for lipid nanoparticles prep-

aration. Recent Pat. Drug Deliv. Formul. 2011, 5, 201–213. [83] Silva, A. C.; González-Mira, E.; García, M. L.; Egea, M. A.; Fonseca,

J.; Silva, R.; et al. Preparation, characterization and biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN):

1205 High pressure homogenization versus ultrasound. Colloids Surf. B Biointerfaces 2011, 86, 158–165.

[84] Battaglia, L.; Gallarate, M.; Panciani, P. P.; Ugazio, E.; Sapino, S.; Peira, E.; et al. Techniques for the preparation of solid lipid nano and microparticles. Application of Nanotechnology in Drug

1210 Delivery: InTech, 2014, pp. 51–75. [85] Kelidari, H. R.; Saeedi, M.; Akbari, J.; Morteza-Semnani, K.; Gill, P.;

Valizadeh, H.; et al. Formulation optimization and in vitro skin penetration of spironolactone loaded solid lipid nanoparticles. Colloids Surf. B Biointerfaces 2015, 128, 473–479.

1215 [86] Subedi, R. K.; Kang, K. W.; Choi, H.-K. Preparation and character-ization of solid lipid nanoparticles loaded with doxorubicin. Eur. J. Pharm. Sci. 2009, 37, 508–513.

[87] Yasir, M.; Sara, U. V. S. Solid lipid nanoparticles for nose to brain delivery of haloperidol: In vitro drug release and pharmacokinetics

1220 evaluation. Acta Pharm. Sin. B 2014, 4, 454–463. [88] Yasir, M.; Sara, U. V. S. Preparation and optimization of

haloperidol loaded solid lipid nanoparticles by Box–Behnken design. J. Pharm. Res. 2013, 7, 551–558.

[89] Campardelli, R.; Baldino, L.; Reverchon, E. Supercritical 1225 fluids applications in nanomedicine. J. Supercrit. Fluids 2015,

101, 193–214.

[90] Byrappa, K.; Ohara, S.; Adschiri, T. Nanoparticles synthesis using supercritical fluid technology—Towards biomedical applications. Adv. Drug Deliv. Rev. 2008, 60, 299–327.

1230[91] Almeida, A. J.; Souto, E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv. Drug Deliv. Rev. 2007, 59, 478–490.

[92] Shah, R. M.; Malherbe, F.; Eldridge, D.; Palombo, E. A.; Harding, I. H. Physicochemical characterization of solid lipid nanoparticles

1235(SLNs) prepared by a novel microemulsion technique. J. Colloid Interface Sci. 2014, 428, 286–294.

[93] Tiyaboonchai, W.; Tungpradit, W.; Plianbangchang, P. Formu-lation and characterization of curcuminoids loaded solid lipid nanoparticles. Int. J. Pharm. 2007, 337, 299–306.

1240[94] Nabi-Meibodi, M.; Navidi, B.; Navidi, N.; Vatanara, A.; Reza Rouini, M.; Ramezani, V. Optimized double emulsion–solvent evaporation process for production of solid lipid nanoparticles containing baclofene as a lipid insoluble drug. J. Drug Deliv. Sci. Technol. 2013, 23, 225–230.

1245[95] Miladi, K.; Sfar, S.; Fessi, H.; Elaissari, A. Encapsulation of alendro-nate sodium by nanoprecipitation; and double emulsion: From preparation to in vitro studies. Ind. Crops Prod. 2015. Q16

[96] Souto, E. B.; Wissing, S. A.; Barbosa, C. M.; Müller, R. H. Develop-ment of a controlled release formulation based on SLN and NLC

1250for topical clotrimazole delivery. Int. J. Pharm. 2004, 278, 71–77. [97] Liu, J.; Hu, W.; Chen, H.; Ni, Q.; Xu, H.; Yang, X. Isotretinoin-

loaded solid lipid nanoparticles with skin targeting for topical delivery. Int. J. Pharm. 2007, 328, 191–195.

[98] Silpa, N.; Naveen Chakravarthi, R.; Chandramouli, Y.; Jayaraj 1255Kumar, K.; Shanmugam, V. Moxifloxacin loaded solid lipid nano-

particles (SLNs): Preparation and characterization. Asian J. Pharm. Res. 2012, 2, 105–112.

[99] Verma, V. K.; Alpana, R. Development of piroxicam loaded SLN- based hydrogel for transdermal delivery. Q17

1260[100] Hu, J.; Ng, W. K.; Dong, Y.; Shen, S.; Tan, R. B. Continuous and scalable process for water-redispersible nanoformulation of poorly aqueous soluble APIs by antisolvent precipitation and spray-dry-ing. Int. J. Pharm. 2011, 404, 198–204.

[101] Chen, Y.; Jin, R.; Zhou, Y.; Zeng, J.; Zhang, H.; Feng, Q. [Prep-1265aration of solid lipid nanoparticles loaded with Xionggui powder-

supercritical carbon dioxide fluid extraction and their evaluation in vitro release]. Zhongguo Zhong yao za zhi¼ Zhongguo zhon-gyao zazhi¼ China J. Chin. Mater. Med. 2006, 31, 376–379.

[102] Li, Y.-Z.; Sun, X.; Gong, T.; Liu, J.; Zuo, J.; Zhang, Z.-R. Inhalable 1270microparticles as carriers for pulmonary delivery of thymopentin-

loaded solid lipid nanoparticles. Pharm. Res. 2010, 27, 1977-1986. [103] Nasir, A.; Harikumar, S. L., Amanpreet, K. Niosomes: An excellent

tool for drug delivery. Int J Res Pharm Chem. 2012, 2, 479–487. [104] Pardakhty, A.; Moshafi, M. H.; Moteshafi, H. Preparation of

1275niosomes containing chloramphenicol sodium succinate; and evaluation of their physicochemical; and antimicrobial properties. Pharm. Sci. 2007 1. Q18

[105] Makeshwar, K. B.; Wasankar, S. R. Niosome: A novel drug delivery system. Asian J. Pharm. Res. 2013, 3, 16–20.

1280[106] Bagheri, A.; Chu, B. S.; Yaakob, H. Niosomal drug delivery systems: Formulation, preparation and applications. World Appl. Sci. J. 2014, 32, 1671–1685.

[107] Khazaeli, P.; Sharifi, I.; Talebian, E.; Heravi, G.; Moazeni, E.; Mostafavi, M. Anti-leishmanial effect of itraconazole niosome on

1285in vitro susceptibility of Leishmania tropica. Environ. Toxicol. Pharmacol. 2014, 38, 205–211.

[108] Kong, M.; Park, H.; Feng, C.; Hou, L.; Cheng, X.; Chen, X. Construc-tion of hyaluronic acid noisome as functional transdermal nanocar-rier for tumor therapy. Carbohydr. Polym. 2013, 94, 634–641.

1290[109] Masotti, A. Niosomes as candidate bioconjugates for imaging and pH-sensitive drug delivery nanocarriers for rare pediatric tumors. J. Drug Deliv. Sci. Technol. 2013, 23, 22–24.

[110] Mahale, N. B.; Thakkar, P. D.; Mali, R. G.; Walunj, D. R.; Chaudhari, S. R. Niosomes: Novel sustained release nonionic stable

1295vesicular systems—An overview. Adv. Colloid Interface Sci. 2012, 183–184, 46–54.


[111] Marianecci, C.; di Marzio, L.; Rinaldi, F.; Celia, C.; Paolino, D.; Alhaique, F.; Esposito, S.; Carafa, M. Niosomes from 80 s to present: The state of the art. Adv. Colloid Interface Sci. 2014, 205,

1300 187–206. [112] Balakrishnan, P.; Shanmugam, S.; Lee, W. S.; Lee, W. M.; Kim,

J. O.; Oh, D. H.; et al. Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery. Int. J. Pharm. 2009, 377, 1–8.

1305 [113] Shahiwala, A.; Misra, A. Studies in topical application of niosomally entrapped nimesulide. J. Pharm. Pharm. Sci. 2002, 5, 220–225.

[114] Pardakhty, A.; Varshosaz, J.; Rouholamini, A. In vitro study of polyoxyethylene alkyl ether niosomes for delivery of insulin. Int.

1310 J. Pharm. 2007, 328, 130–141. [115] Marianecci, C.; Paolino, D.; Celia, C.; Fresta, M.; Carafa, M.; Alhai-

que, F. Non-ionic surfactant vesicles in pulmonary glucocorticoid delivery: Characterization and interaction with human lung fibro-blasts. J. Control. Release 2010, 147, 127–135.

1315 [116] Muzzalupo, R.; Tavano, L.; La Mesa, C. Alkyl glucopyranoside- based niosomes containing methotrexate for pharmaceutical appli-cations: Evaluation of physico-chemical and biological properties. Int. J. Pharm. 2013, 458, 224–229.

[117] Tavano, L.; Muzzalupo, R.; Picci, N.; de Cindio, B. Co-encapsula-1320 tion of antioxidants into niosomal carriers: Gastrointestinal release

studies for nutraceutical applications. Colloids Surf. B Biointerfaces 2014, 114, 82–88.

[118] Sankar, V.; Ruckmani, K.; Durga, S.; Jailani, S. Proniosomes as drug carriers. Pak. J. Pharm. Sci. 2010, 23, 103–107.

1325 [119] Uchegbu, I. F.; Vyas, S. P. Non-ionic surfactant based vesicles (niosomes) in drug delivery. Int. J. Pharm. 1998, 172, 33–70.

[120] Guinedi, A. S.; Mortada, N. D.; Mansour, S.; Hathout, R. M. Preparation and evaluation of reverse-phase evaporation and multilamellar niosomes as ophthalmic carrie

Overview of preparation methods of polymeric and lipid-based … · This review article provides a...

Documents

Transcript of Overview of preparation methods of polymeric and lipid-based … · This review article provides a...