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
 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  Incorporation of lipophilic and

hydrophilic drugs feasible
Solid Lipid nanoparticles (SLN) are  No biotoxicity of the carrier
basically nanoparticles based on solid  Avoidance of organic solvents
lipids e.g., triglycerides. SLN are derived  No problems with respect to
from o/w emulsions by replacing the large scale production and
liquid lipid (oil) by a solid lipid, i.e. a sterilization
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 General structure of SLN
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 SLN Production
molecule inside the particles. The
advantages of SLN over other colloidal Ingredients
delivery systems can be enumerated as Lipid
below [1]: Lipid matrices used for the production of
SLNs for i.v. administration should have
 Possibility of controlled drug the following appropriate properties.
release and drug targeting 1. They should be capable of
 Increased drug stability producing small size particles (in
 High drug payload the nanometer size range) with

2
 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,
3
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
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
4
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.
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].
5
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
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
6
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
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
7
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%
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
8
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
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
9
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
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
10
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,
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
11
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.
References
1) Wolfgang Mehnert, Karsten Mader,; Solid lipid nanoparticles: Production,
characterization and applications; Advanced Drug Delivery Reviews 47, (2001),
165–196.
2) Manjunath, K., Suresh Reddy, J., and Venkateswarlu, V,; Solid Lipid
Nanoparticles as Drug Delivery Systems; Methods Find Exp Clinical
Pharmacology 27(2), (2005), 1–20.
3) Venkateswarlu, V., Manjunath, K.; Preparation, characterization and in vitro
release kinetics of clozapine solid lipid nanoparticles; Journal of Controlled
Release 95, (2004), 627-638.
4) Cavalli, R., Caputo, O., Carlotti, M.E., Trotta, M., Scarnechia, C., Gasco, M.R.;
Sterilization and freeze-drying of drug-free and drug-loaded solid lipid
nanoparticles; International Journal of Pharmaceutics 148, (1997), 47-54.
5) Westesen, K., Siekmann, B., Koch, M.H.J.; Investigation on the physical state of
lipid nanoparticles by synchrotron X-ray diffraction; International Journal of
Pharmaceutics 93, (1993), 189-99.
6) Freitas, C., Muller, R.H.; Effect of light and temperature on zetapotential and
physical stability in solid lipid nanoparticle (SLN) dispersions; International
Journal of Pharmaceutics 168, (1998), 221-9.
7) Demirel, M., Yazan, Y., Muller, R.H., Kilic, F., Bozan, B.; Formulation and in
vitro–in vivo evaluation of piribidil solid lipid micro and nanoparticles; Journal of
Microencapsulation 18(3), (2001), 359-71.
8) Wissing, S.A., Muller, R.H.; Solid lipid nanoparticles as carrier for sunscreens:
In vitro release
and in vivo skin penetration; Journal of Controlled Release 81, (2002), 225-33.
9) Kaur. I. P., Bhandari. R., Bhandari. S., Kakkar. V.,; Potential of solid lipid
nanoparticles in brain targeting; Journal of Controlled Release 127, (2008), 97–
109.
10) Kreuter, J.; Nanoparticles system for brain delivery of drugs; Advanced Drug
Delivery Reviews 47, (2001), 65–81.
11) Blasi, P, Giovagnoli, S, Schoubben, A, Ricci, M, Rossi, C,; Solid lipid
nanoparticles for targeted brain drug delivery; Advanced Drug Delivery Reviews
59, (2007), 454–477.

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