Review

Solid Lipid Nanoparticles and their potential for targeted brain drug

delivery.

Abstract-

Nanoparticles are solid colloidal particles ranging in size from 1 to 1000 nm (<1

μm) and composed of macromolecular material. Nanoparticles could be polymeric or

lipidic. Solid lipid nanoparticles (SLNs) are a class of lipidic nanoparticles. SLNs

combine the advantages of polymeric nanoparticles, fat emulsions and liposomes. This

review focuses on the techniques of SLN preparation, characterization of SLNs, their

stability issues and application. It also discuses the potential of SLNs in brain targeting.

Keywords- Nanoparticles, Solid lipid nanoparticles (SLNs), Targeted brain drug delivery,

Drug delivery systems.

Contents-

1. Introduction

2. SLN Production

2.1 Ingredients

2.1.1 Lipid

2.1.2 Emulsifier

2.1.3 Co-emulsifier

2.1.4 Other Excipients

2.2 Preparation Techniques

2.2.1 High shear homogenization and ultrasound

2.2.2 High pressure homogenization

2.2.3 Solvent emulsification/ evaporation

2.2.4 Microemulsion based preparation method

2.2.5 Homogenization followed by sonification

2.2.6 Solvent diffusion method

2.2.7 Solvent injection method

2.3 Secondary production steps

2.3.1 Sterilization

2.3.2 Lyophilization

2.3.3 Spray-Drying

3. Characterization of SLNs

3.1 Particle size and distribution

3.2 Surface charge

3.3 Entrapment efficiency

3.4 Cryatallinity and polymorphic behaviour

3.5 Gelation of SLNs

4. Stability of SLNs

4.1 Effect of light

4.2 Effect of temperature

2

4.3 Degree of crystallinity

5. Drug incorporation and drug release

6. Application of SLNs

6.1 Improved bioavailability

6.2 Controlled release

6.3 Cosmetic application

6.4 Adjuvant to vaccines

7. Techniques to target SLNs to brain

7.1 Particle size

7.2 Surface coating with hydrophilic polymers/surfactants

7.3 Use of ligands

8. Conclusion

Introduction

Solid Lipid nanoparticles (SLN) are

basically nanoparticles based on solid

lipids e.g., triglycerides. SLN are derived

from o/w emulsions by replacing the

liquid lipid (oil) by a solid lipid, i.e. a

lipid being solid at room and

simultaneously at body temperature.

These are in submicron size range (50–

1000 nm) and are made up of

biocompatible and biodegradable

materials capable of incorporating

lipophilic and hydrophilic drugs. SLN

join the advantages of colloidal lipid

emulsions with those of solid matrix

particles. The solid matrix particles help

modulate the drug release from SLN

which can further be exploited to

optimize the blood profile. Additional

advantages are good physical stability

and lack of leakage of drug from the

particles due to less mobility of the drug

molecule inside the particles. The

advantages of SLN over other colloidal

delivery systems can be enumerated as

below [1]:

Possibility of controlled drug

release and drug targeting

Increased drug stability

High drug payload

Incorporation of lipophilic and

hydrophilic drugs feasible

No biotoxicity of the carrier

Avoidance of organic solvents

No problems with respect to

large scale production and

sterilization

General structure of SLN

SLN Production

Ingredients

Lipid

Lipid matrices used for the production of

SLNs for i.v. administration should have

the following appropriate properties.

1. They should be capable of

producing small size particles (in

the nanometer size range) with

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low content of micro particles

(>5 µm).

2. They should possess sufficient

loading capacity for lipophilic

and possible also hydrophilic

drugs.

3. They should be suitable for

sterilization by autoclaving.

4. They should be stable in aqueous

dispersions, on long-term

storage, or alternatively they can

be lyophilized or spray dried.

5. They should be nontoxic.

6. They should be biodegradable.

The term includes triglycerides (e.g.

tristearin), partial glycerides (e.g.

Imwitor), fatty acids (e.g. stearic acid),

steroids (e.g. cholesterol) and waxes

(e.g. cetyl palmitate) [2].

Emulsifier

Emulsifier should be nontoxic,

compatible with other excipients,

capable of producing desired size with

minimum amount used, and also provide

adequate stability to the SLNs, by

covering their surface. Some of the

examples are Phosphatidyl choline 95%

(Epikuron 200), Soy lecithin (Lipoid S

75, Lipoid S 100)

Egg lecithin (Lipoid E 80), Poloxamer

188 (Pluronic F 68), Poloxamer 407,

Poloxamine 908, Polysorbate 80,

Cremophor EL, Solutol HS 15.

Co-emulsifier

Due to the low mobility of the

phospholipid molecules, sudden lack of

emulsifier on the surface of the particle

leads to particle aggregation and increase

in the particle size of SLNs. To avoid

this, co emulsifiers like glycocholate

(ionic), tyloxapol (nonionic polymer) are

employed. Other Co-emulsifiers used are

Taurocholate sodium salt,

Taurodeoxycholicacid sodium salt,

Sodium oleate, Cholesteryl

hemisuccinate, Butanol and Sodium

dodecyl sulphate.

Other excipients

Cryoprotectants : Trehalose, Glucose,

Mannose, Maltose, Lactose, Sorbitol,

Mannitol, Glycine, Polyvinyl pyrolidone

(PVP), Polyvinyl alcohol (PVA) and

Gelatin.

Charge modifiers: Stearylamine,

Dicetylphosphate, Dipalmitoyl

phosphatidyl choline (DPPC) and

Dimyristoyl phophatidyl glycerol

(DMPG).

Preservatives : Thiomersal.

Preparation techniques

High shear homogenization and

ultrasound

This was the older technique for the

production of Solid lipid

nanodispersions. Both methods are

widespread and easy to handle.

However, dispersion quality is often

compromised by the presence of

microparticles. Also ultrasound carries

the risk of metal contamination. Ahlin et

al. used a Lak Tek rotor–stator

homogenizer to produce SLN by melt–

emulsification [1]. They investigated the

influence of different process

parameters, including emulsification

time, stirring rate and cooling conditions

on the particle size and the zeta

potential. Lipids used in this study

included trimyristin (Dynasan114),

tripalmitin (Dynasan116), tristearin

(Dynasan118), a mixture of mono-, di-

and triglycerides (WitepsolW35,

WitepsolH35) and glycerol behenate

(Compritol888 ATO), poloxamer 188

was used as steric stabilizer (0.5 w%).

For WitepsolW35 dispersions the

4

following parameters were found to

produce the best SLN quality: stirring

for 8 min at 20 000 rpm, the optimum

cooling conditions: 10 min at 5000 rpm

at room temperature. In contrast, the best

conditions for Dynasan116 dispersions

were a 10-min emulsification at 25 000

rpm and 5 min of cooling at 5000 rpm in

cool water (T=16◦C). Higher stirring

rates did not significantly change the

particle size, but slightly improved the

polydispersity index. No general rule can

be derived from differences in the

established optimum emulsification and

cooling conditions. In most cases,

average particle sizes in the range of

100–200 nm were obtained in the study.

High pressure homogenization

High pressure homogenization has

emerged as a reliable and powerful

technique for the preparation of SLN. In

contrast to other techniques, scaling up

represents no problem. High pressure

homogenizers push a liquid with high

pressure (100–2000 bar) through a

narrow gap (in the range of a few

microns). The fluid accelerates on a very

short distance to very high velocity (over

1000 km/h). Very high shear stress and

cavitation forces disrupt the particles

down to the submicron range. Typical

lipid contents are in the range 5–10%

and represent no problem to the

homogenizer. Two general approaches

of the homogenization step, the hot and

the cold homogenization techniques, can

be used for the production of SLN. In

both cases, a preparatory step involves

the drug incorporation into the bulk lipid

by dissolving or dispersing the drug in

the lipid melt [1].

Hot homogenization

The lipid with the incorporated drug is

then dispersed in hot aqueous surfactant

mixture. This mixture is then premixed

using a stirrer to form a coarse pre-

emulsion. High pressure homogenization

is then done at a temperature above the

melting point of the lipid to obtain a hot

o/w nanoemulsion. Upon cooling

solidification results and solid lipid

nanoparticles are obtained.

Cold homogenization

The lipid with the incorporated drug is

solidified in liquid nitrogen or dry ice

and then grinded in a powder mill (50-

100 µm). The above obtained powder is

dispersed in an aqueous surfactant

dispersion medium. High pressure

homogenization is then done at room

temperature or below to obtain solid

lipid nanoparticles. In general larger

particle sizes and broader size

distribution is obtained in cold

homogenization process. This method

also minimises thermal exposure of the

sample.

Solvent emulsification / evaporation

One of the methods of preparation of

nanoparticles is by precipitation in o/w

emulsions. The lipophilic material is

dissolved in a water-immiscible organic

solvent (e.g. cyclohexane) that is

emulsified in an aqueous phase. Upon

evaporation of the solvent a nanoparticle

dispersion is formed by precipitation of

the lipid in the aqueous medium. The

mean particle size depends on the

concentration of the lipid in the organic

phase. Very small particles could only be

obtained with low fat loads (5 %) related

to the organic solvent. With increasing

lipid content the efficiency of the

homogenization declines due to the

higher viscosity of the dispersed phase.

The advantage of the process is

avoidance of thermal stress while use of

organic solvent is a clear disadvantage.

5

Microemulsion based preparation

method

Microemulsions stable composed of

lipophilic phase (lipid), a surfactant, co-

surfactant, and water. Addition of

microemulsions to water leads to

precipitation of the lipid phase forming

fine particles. Firstly lipid is melted and

drug is dispersed in molten lipid. A

mixture of water, surfactant, and co-

surfactant is heated to a temperature at

least equal to the melting temperature of

the lipid. This aqueous surfactant

solution is added to the lipid melt under

mild stirring to obtain transparent

microemulsion. This microemulsion is

then dispersed in water at 2◦C–10

◦C

under mild mechanical stirring. Rapid

recrystallization of oil droplet on

dispersion in cold aqueous medium

produces SLNs. Formation of SLNs is

due to precipitation process and not

stirring. The obtained lipid nanoparticles

dispersion can be washed with water by

diafiltration and lyophilized.

Homogenization followed by

sonication

It is a simple, sensitive and reproducible

method used to prepare SLNs. Drug,

lipid, and emulsifier are dissolved in a

common solvent and evaporated under

reduced temperature to obtain solvent

free drug dissolved or dispersed lipid

phase. Drug loaded lipid melt is then

homogenized with hot aqueous

surfactant in solution for three minutes

using homogenizer to get coarse

emulsion. The coarse emulsion so

obtained is ultrasonicated using

ultrasonicator to obtain nanoemulsion.

SLNs are formed upon cooling to room

temperature. SLNs of clozapine were

prepared by this method to obtain the

nanoparticles in the size range of 60-380

nm [3].

Solvent diffusion method

The first step in the production of lipid

nanoparticles by the solvent diffusion

technique is to prepare a solvent in water

emulsion with a partially water miscible

solvent containing the lipid. Upon

transferring a transient oil-in-water

emulsion into water and continuous

stirring, droplets of dispersed phase

solidifies as lipid nanoparticles due to

diffusion of the organic solvent. Further,

the suspension is purified by

ultrafiltration [2].

Solvent injection method

The basic principle for the formation of

SLNs is similar to the solvent diffusion

method. However, SLNs are prepared by

rapidly injecting a solution of solid lipids

in water miscible solvents into water.

Mixture of water miscible solvents can

be used to solubilize solid lipids.

Normally used solvents in this method

are acetone, ethanol, isopropanol, and

methanol [2].

Secondary production steps

Sterilization

Sterilization of SLNs is most important

especially if SLNs are to be administered

by parenteral and pulmonary routes.

Aseptic production, filtration, γ-

irradiation and heating are normally used

to achieve sterility. The high

temperatures reached during autoclaving

causes formation of a hot o/w

nanoemulsion. On subsequent slow

cooling of the system, SLNs are

reformed but some nanodroplets merge

to form a larger SLN than the initial.

Even though there is a slight increase in

the particle size, the particles are still in

the colloidal size range. Cavalli et al.

studied the influence of autoclaving on

6

sizes and stability of drug free and drug

loaded SLNs. SLNs dispersed in

different dispersion media were

autoclaved at 121◦C under 2 bar pressure

for 15 min. The high temperatures

reached during autoclaving causes

formation of a hot o/w nanoemulsion.

On subsequent slow cooling of the

system, SLNs are reformed but some

nanodroplets merge to form a larger

SLN than the initial. It was observed that

there was an increase in the average

diameter of SLNs, with slight change in

polydispersity index following

autoclaving but the particles still being

in the colloidal range. Thus, SLNs

sterilized by autoclaving can still

maintain their almost spherical shape

without any significant increase in size

or distribution, which was indeed

confirmed by transmission electron

microscopy (TEM) analysis [4].

Filtration sterilization of dispersed

systems requires high pressure and is not

applicable to particles >0.2 µm. The

sterilization should not change the

properties of the formulation with

respect to physical and chemical stability

and the drug release kinetics.

Lyophilization

Aqueous dispersions of SLNs may not

be stable physically for a long period of

time, also drug release properties may be

altered on storage. To avoid these

problems, it is necessary to convert such

aqueous dispersions into dry product by

lyophilization or spray drying. Change in

the particle size during lyophilization

can be minimized by optimizing the

lyophilization process parameters such

as freezing velocity and redispersion

method. Lyophilized SLNs have to be

reconstituted before use [2].

Spray-drying

This is an alternative method to

lyophilization to convert aqueous

dispersion of SLNs into dry product.

During spray-drying of SLNs, elevated

temperatures and shear forces increase

the kinetic energy, leading to frequent

particle collision. General drawback of

this method is risk of melting of SLNs

prepared with lipids of lower melting

point, during spray drying. This problem

can be avoided using higher melting

point lipids [2].

Characterization of SLNs

Particle size and distribution

Size of nanoparticles can be determined

by several methods such as photon-

correlation spectrometry (PCS), TEM,

scanning electron microscopy (SEM),

SEM combined with energy-dispersive

X-ray spectrometry, scanned probe

microscopy and Fraunhofer diffraction.

Among these methods, most widely used

methods are PCS and electron

microscopy methods.

PCS method determines the

hydrodynamic diameter of the

nanoparticles. This technique is based on

dynamic laser light scattering due to

Brownian movement of particles in

dispersion medium. PCS measures the

fluctuation of the intensity of scattered

light, which is caused by the particle

movement. This method is suitable for

the measurement of particles in the size

range of few nanometers to 3 µm.

Westesen et al. prepared various SLNs

using Witepsol W 35, tripalmitin and

glycerol monostearate. PCS results

showed that lipid dispersions consist of

particles of lower nanometer size range.

The particle size depends on the nature

of matrix as well as type and amount of

the emulsifying agent. Increasing the

amount of emulsifier generally

7

decreased the mean particle size. The

combination of phospholipids and

sodium glycocholate yielded smaller

particle sizes than the nonionic block co-

polymer Pluronic F 68 [5].

SEM and TEM are very useful in

determining shape and morphology of

lipid nanoparticles and allow

determination of particle size and

distribution. TEM determines the

particle size with or without staining.

SEM has high resolution and the sample

preparation is relatively easy. SLNs

whose particle size has to be determined

must be conductive; otherwise,

nanoparticles are coated with a

conductive metal (gold). SEM uses

electrons transmitted from the specimen

surface, while TEM uses electrons

transmitted through the specimen.

Alternative method for routine

measurement of particle size is laser

diffraction (LD). This method is based

on the dependency of the diffraction

angle on the particle radius. Advantage

of LD method is its ability to measure

nanoparticle of broad size range (from

nanometer to lower millimetre range).

Another advanced microscopic

technique used for characterization of

nanoparticles is atomic force microscopy

(AFM). This is a new tool to image the

original unaltered shape and surface

properties of the particles. In this

technique, the force acting between the

surface and probing tip results in a

spatial resolution up to 0.01 nm. Sample

preparation is simple and the samples

need not be conductive. Hence, it allows

the analysis of hydrated and solvent

containing samples.

Surface charge

Surface charge is measured by

measuring the zeta potential. The

measurement of the zetapotential allows

predictions about the storage stability of

colloidal dispersions. At higher

zetapotential, particle aggregation is less

likely to occur, due to electrical

repulsions. Zetapotential measurement

also helps in designing dosage form with

reduced RES uptake.

Entrapment efficiency

The entrapment efficiency of the system

can be determined by measuring the

concentration of free drug in the

dispersion medium. Ultrafiltration is

generally employed to separate

dispersion medium. This consists of

filter membrane (molecular weight cut-

off 20 000 Dalton) at the base of the

sample recovery chamber. The sample is

placed in the outer chamber and

subjected for centrifugation so that

aqueous phase moves into the sample

recovery chamber through filter

membrane. Analyzing drug

concentration in an aqueous phase gives

entrapment efficiency.

Entrapment efficiency= (wt. of the drug

in system - wt. of drug in aqueous phase) wt. of the drug in system

* 100

Other parameter to be considered in the

selection of a suitable lipid is loading

capacity. Loading capacity is generally

expressed in percent related to lipid

matrix. Tetracaine, etomidate and

prednisolone have been used as model

drugs to assess the drug loading capacity

and entrapment efficiency of SLNs.

Drugs were incorporated in

concentrations of 1%, 5% and 10%

based on the lipid mass. The entrapment

efficiency achieved with tetracaine and

etomidate varied between 80% and 98%

depending upon SLNs composition.

With prednisolone, greater than 70%

8

loading in tribehenin SLNs was achieved

[2].

Crystallinity and polymorphic

behaviour

Crystallinity and polymorphic behavior

of SLNs strongly influence drug

incorporation and release rates.

Triglycerides (matrix constituents) used

in the SLNs preparations have the ability

to crystallize as more than one distinct

crystalline species and are said to be

polymorphic. The main polymorphic

forms are α, β′ and β. These different

polymorphs have different melting

points, X-ray diffraction (XRD) patterns,

and solubilities, even though they are

chemically identical. Dispersed

triglyceride particles recrystallize on

rapid cooling in the metastable form (α)

and transform rapidly via β′ form into

the thermodynamically stable form (β)

upon storage. These transitions are slow

in the bulk triglycerides.

Thermodynamic stability and lipid

packing density increases and drug

incorporation rates decreases in the

following order, super cooled melt <α-

modification < β′-modification < β –

modification.

Gelation of SLNs

Gelation phenomena describe the

transformation of low-viscosity SLN

dispersion into a viscous gel. This

process may occur very rapidly and

unpredictably. In most cases, gel

formation is an irreversible process

which involves the loss of the colloidal

particle size. It can be stimulated by

intense contact of the SLN dispersion

with other surfaces and shear forces. If

gelation occurs in vitro during

preparatory steps of SLN

characterization, results will be

influenced by artefact generation. The

lipoid S 75 (phosphatidylcholine rich

soylecithin product as an emulsifier)

stabilized tripalmitate dispersions

exhibited fast and considerable particle

growth on cooling of the colloidally

dispersed tripalmitate [2].

Stability of SLNs Aqueous dispersions of SLNs are stable

up to 3 years. Destabilizing factors such

as light, temperature and degree of

crystallinity of lipid matrix influence the

long term stability of SLNs.

Effect of light

Increase in intensity of light radiation

leads to accelerated particle growth and

gelation. Brown glass absorbs the light

at short wavelengths (300–600 nm) and

prevents high energetic radiation from

falling on SLN dispersion, and thus,

stability of SLNs is increased when

stored in brown glass. The zeta potential

of the dispersions in brown glass is

found to be higher due to less light

exposure. Thus reductions in zeta

potential due to light exposure of the

SLNs affect the physical stability of the

SLNs [6].

Effect of temperature

Increase in temperature causes a

decrease in microviscosity (less rigidity

of emulsifier film), leading to

destabilization. The effects of the

temperature on compritol SLNs were

analyzed by storing them at 8◦C, 20

◦C,

and 50◦C under exclusion of light.

Storage at 50◦C induced rapid particle

growth within 3 days. Dispersions stored

at 20◦C showed improved stability,

however, became solid within 3 months.

However, compritol SLNs stored at 8◦C

in the dark were stable over the storage

period of 3 years [2]. Storing the

dispersions at higher temperature leads

9

to a reduction of the zeta potential faster

than storing at lower temperature. Thus,

if SLN dispersions are not exposed to

light and stored at lower temperatures,

the zeta potential remains practically

unchanged and the dispersions are

stable. The energy input in the form of

light and temperature changes the

crystalline structure of the lipid. This

crystal orientation can result in change in

Nernst potential and simultaneously zeta

potential.

Degree of crystallinity

Dispersions with high recrystallized lipid

phase show an increased particle growth.

Depending upon the nature of lipid,

recrystallization of the lipid (after SLNs

formation) takes place very quickly

within minutes. However, it can be

retarded up to weeks or months.

Stabilization of SLNs dispersions can be

achieved by inhibition of the

transformation of the lipid to the stable

modification by addition of inhibitors to

the lipid matrix [2].

Drug incorporation and drug

release

A wide variety of drugs with different

lipophilicity can be incorporated in

SLNs. Eg. diazepam, cortisone,

prednisolone, retinol, timolol,

pilocarpine, idarubicin, camptothecin,

cyclosporine, vitamin E palmitate,

etomidate, tetracaine [1].

In most cases, burst release is observed

from SLN. For example, both hot and

cold homogenization produced SLN

released tetracaine and etomidate

immediately [1]. In contrast, it was

possible to retard the release of

prednisolone by the cold

homogenization technique [1]. An

appropriate selection of the

homogenization temperature permitted

the modification of the release profile.

The release kinetics depends on the

release conditions (sink or non-sink

conditions, release medium etc).

Applications of SLNs

Improved bioavailability

Peroral bioavailability of various poorly

soluble drugs was improved by

incorporating them in SLNs.

Bioavailability of piribidil was improved

more than two-folds compared with pure

piribidil, when administered in SLNs

[7]. Intraduodenal administration also

showed enhanced bioavailability in same

cases.

Controlled release

SLNs provide controlled release too. Eg.

Prednisolone could be incorporated up to

3.6% and 1.67% in cholesterol SLNs and

compritol SLNs respectively, and

showed prolonged release of drug over 5

weeks [2]. By modifying the chemical

nature of the lipid matrix, controlled

release of drugs can be tailored.

Cosmetic application SLNs are the new generation carriers for

cosmetics, especially for UV blockers.

The crystalline cetylpalmitate SLNs

have the ability of reflecting and

scattering UV radiation on their own

thus leading to photo protection without

the need for molecular sunscreens.

Introduction of sunscreens into SLNs

leads to a synergistic photo protection.

Photo protection effect was increased

three- fold, after incorporation of the

molecular sunscreen 2- hydroxy-4-

methoxy benzophenonoe into the SLNs

dispersion. Physical sunscreens (e.g.

titanium dioxide) can be added to SLNs

formulation as well. SLNs show superior

reflection of UV radiation compared to

10

traditional emulsions. It has been shown

that incorporation of molecular

sunscreen oxybenzone in SLNs

decreased the rate of release compared

with equally sized emulsions, by up to

50% [8]. They are also able to provide

sustained release carrier system;

therefore, sunscreen remains longer on

the surface of the skin where it is

intended to act.

Adjuvant to vaccines

Adjuvants are used in vaccine

preparation to enhance the immune

response. In SLNs, lipid components

being in the solid state degrade more

slowly providing a longer lasting

exposure to the immune system.

Advantages of use of SLNs compared to

traditional adjuvants are their

biodegradation and their good

tolerability by the body [2].

Techniques to target SLNs to

brain The amazing growth in recent years of

CNS drugs on the market has generated

enormous research efforts in an attempt

to develop new drugs and new delivery

systems for brain diseases. Lipid

nanoparticles like solid lipid

nanoparticles (SLNs) may represent, in

fact, promising carriers due to their

prevalence over other formulations in

terms of toxicity, production feasibility,

and scalability.

The body distribution of SLNs is

strongly dependent on their surface

characteristics, surface hydrophobicity,

surface mobility etc. The SLNs have

been proposed as suitable system to

deliver hydrophilic drugs like

diminazine and also for other BCS class

IV drugs like paclitaxel, vinblastine,

camptothecin, etoposide, cyclosporine

etc. These carriers can gain access to the

blood compartment easily (because of

their small size and lipophilic nature) but

the detection of these particles by the

cells of the reticuloendothelial system

(RES) i.e. the mononuclear phagocytic

system; MPS cells of the liver (Kupffer)

and that of spleen macrophages is a

major limitation for their use. Uptake of

nanoparticles by RES could result in

therapeutic failure due to insufficient

pharmacological drug concentration

build up in the plasma and hence at the

BBB [9]. The following methods have

been tried to increase the plasma half-

life of SLNs.

Particle size

SLNs of size below 200 nm have an

increased blood circulation and thus an

increase in the time for which the drug

remains in contact with BBB and for the

drug to be taken up by the brain.

Surface coating with hydrophilic

polymers/surfactants

The high rates of RES mediated

detection and clearance of colloidal

carriers by liver, significantly reduce the

half-life of the drug. This RES

recognition can be prevented by coating

the particles with a hydrophilic or a

flexible polymer and/or a surfactant.

Hydrophobic surfaces promote protein

adsorption and that negative surfaces

activate the complement system and

coagulation factors. Hydrophilic

character stabilizes the nanoparticles by

reducing opsonization and phagocytosis

as well as uptake by neutrophilic

granulocytes, thus increasing the blood

circulation time and hence the

bioavailability. Coating with

polyethylene glycol (PEG), a polymer of

hydrophilic nature shows promising

results. The chemical nature of the

overcoating surfactant is of importance,

11

as only polysorbate-coated particles

were found to show results in CNS

pharmacological effect while a coating

with poloxamers, poloxamine 908,

Cremophors (EZ or RH40) or

polyoxyethylene(23)-laurylether was not

effective [9]. The reported mechanism of

action was the transport of polysorbate-

coated nanoparticles across the BBB via

endocytosis by the brain capillary

endothelial cells. This endocytosis would

be triggered by a serum protein,

apolipoprotein E, reported to adsorb on

polysorbate 20, 40, 60, or 80- coated

nanoparticles after a 5-min incubation in

citrate-stabilized plasma at 37 °C, but

nanoparticles coated with poloxamers

338, 407, Cremophor EL, or RH 40

could not cross the BBB [10].

Use of ligands

Ligands that specifically bind to surface

epitopes or receptors on the target sites

can be coupled to the surface of the

long-circulating carriers. Certain cancer

cells over express certain receptors, like

folic

acid (over-expressed in cells of cancers

with epithelial origin), LDL (B16

melanoma cell line shows higher

expression of LDL receptors) and

peptide receptors (such as somatostatin

analogs, vasoactive intestinal peptide,

gastrin related peptides, cholecystokinin,

leutanising hormone releasing hormone).

Attaching suitable ligands for these

particular receptors on to the

nanoparticles would result in their

increased selectivity. The presence of

specific ligands on the surface of

nanoparticles could lead to their

increased retention at the BBB and a

consequent increase in nanoparticle

concentration at the surface of BBB.

Two new SLN formulations made with

biocompatible materials, such as

emulsifying wax and Brij® 72, and

stabilized by P80 and Brij® 78 were

proposed for brain drug targeting. The

aforementioned particles showed a

significant brain uptake, measured

during a short term in situ rat brain

perfusion experiment [11].

Conclusion SLNs can be successfully used as an

alternative colloidal drug delivery

system. Clear advantages of SLN

include the composition (physiological

compounds), the rapid and effective

production process including the

possibility of large scale production, the

avoidance of organic solvents and the

possibility to produce high concentrated

lipid suspensions. High-pressure

homogenization is a suitable method for

the production of SLNs, and this method

could be easily scaled up for large scale

industrial production. Both lipophilic

and hydrophilic drugs can be

incorporated into SLNs, with help of

high pressure homogenization methods.

Also targeting to specific sites like brain

and tumor cells can be achieved by

coupling SLNs with suitable ligands.

12

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