TEKNOLOGI FARMASEUTIK II

Nanodispersed
Systems
NANODISPERSED SYSTEMS
 Nanodispersed systems such as liposomes,
nanoemulsions and lipid nanoparticles, have become
increasingly important as potential vehicles for the
controlled delivery of cosmetics and for the optimized
disposition of active ingredients in particular skin
layers.
 Moreover, these systems develop their own vehicle
effects, which may enhance the desired effects.
NANODISPERSED SYSTEMS

 Liposome:Lipid bilayer enclosing an aqueous

core
NANODISPERSED SYSTEMS

 Nanoemulsion: Lipid monolayer enclosing a

liquid lipid core
NANODISPERSED SYSTEMS

 Lipid nanoparticle: Lipid monolayer

enclosing a solid lipid core
LIPOSOMES
 Liposomes are small, spherical vesicles which consist
of amphiphilic lipids, enclosing an aqueous core.
 The lipids are predominantly phospholipids which form
bilayers similar to those found in biomembranes
 In most cases the major component is phosphatidyl
choline.
 Depending on the processing conditions and the
chemical composition, liposomes are formed with one
or several concentric bilayers.
LIPOSOMES

Chemical structure and schematic

representation of a phospholipid
(lecithin)
LIPOSOMES
 Liposomes are often distinguished according to their number of
lamellae and size.
 Small unilamellar vesicles (SUV), large unilamellar vesicles
(LUV) and large multilamellar vesicles (MLV) or multivesicular
vesicles (MVV) are differentiated
 SUVs show a diameter of 20 to approximately 100 nm. LUVs,
MLVs, and MVVs range in size from a few hundred nanometers
to several microns.
 The thickness of the membrane (phospholipid bilayer)
measures approximately 5 to 6 nm.
Schematic illustration of liposomes of
different size and number of lamellae
SUV: Small unilamellar vesicles, LUV:
Large unilamellar vesicles,
MLV: Multilamellar vesicles, MVV:
Multivesicular vesicles

                                         
NANOEMULSIONS

 Nanoemulsions can be defined as oil-in-water

emulsions with mean droplet diameters ranging
from 50 to 1000 nm.
 Usually, the average droplet size is between
100 and 500 nm.
 The terms sub-micron emulsion (SME) and
mini-emulsion are used as synonyms.
NANOEMULSIONS

 Emulsions which match this definition have

been used in parenteral nutrition for a long
time.
 Usually, SMEs contain 10 to 20 per cent oil
stabilized with 0.5 to 2 per cent egg or soybean
lecithin
NANOEMULSIONS
 The preparation of SUVs starts usually with
MLVs, which then are transformed into small
vesicles using an appropriate manufacturing
technique, e.g. high-pressure homogenization.
 Niosomes and sphingosomes are vesicles with
a similar structure.
 In contrast to liposomes, nonionic surfactants,
e.g. polyglyceryl alkyl ethers, or sphingolipids
make up the bilayer of niosomes and
sphingosomes, respectively
Chemical structure of
lipids forming
sphingosomes and
niosomes
NANOEMULSIONS

 The preparation of nanoemulsions requires

high-pressure homogenization.
 The particles which are formed exhibit a liquid,
lipophilic core separated from the surrounding
aqueous phase by a monomolecular layer of
phospholipids.
 The structure of such lecithin stabilized oil
droplets can be compared to chylomicrons.
NANOEMULSIONS
 Nanoemulsions therefore differ clearly from the
liposomes, where a phospholipid bilayer separates an
aqueous core from a hydrophilic external phase
 If nanoemulsions are prepared with an excess of
phospholipids, liposomes may occur concurrently
NANOEMULSIONS

 Due to their lipophilic interior, nanoemulsions

are more suitable for the transport of lipophilic
compounds than liposomes.
 Similar to liposomes, they support the skin
penetration of active ingredients and thus
increase their concentration in the skin
NANOPARTICLES
 Frequently defined as solid colloidal particles ranging in size
from 10 nm to 1 μm.
 Nanoparticles are built from macromolecular and/or
molecular assemblies, in which the active principle is
dissolved, entrapped, encapsulated, or even adsorbed or
attached to the external interface.
 Advantage of nanoparticles with regard to other colloidal
drug delivery systems (liposomes, niosomes,
microemulsions etc.) and a fortiori to nanoemulsions, is their
great kinetic stability and rigid morphology.
NANOPARTICLES
 Nanoparticles can be divided into two main families:
– nanospheres, which have a homogeneous structure in the whole
particle,
– nanocapsules, which exhibit a typical core-shell structure.
 Main challenge of the formulation of nanoparticles is
adapting the choice of their own structure to the final aims of
drug delivery: Biocompatibility of the polymer,
physicochemical properties of the drug, and therapeutic
goals
Nanocapsules

 It consists of colloidal objects exhibiting a core-

shell structure.
 The core acts as a liquid reservoir for drugs, mainly
lipophilic solvent (and usually oil) but also aqueous
core NC
 The shell is generally made of polymers,
preferentially biodegradable, i.e. dense and rigid,
even if on the nanometric scale
Nanocapsules

 The advantages of such a structure are:

– Firstly, the high drug encapsulation efficiency due to the
optimized drug solubility in the nanoparticle core and
low polymer content compared to polymeric
nanospheres.
– Secondly, since the drug is ‘protected’ within the NC
core, tissue irritation at the administration site as well as
the burst effect are lowered, and the drug itself remains
protected against degradation.
LIPID NANOPARTICLES
 Lipid nanoparticles have a similar structure as
nanoemulsions.
 Their size ranges typically from 50 to 1000 nm.
 The difference is that the lipid core is in the
solid state
 The matrix consists of solid lipids or mixtures of
lipids.
LIPID NANOPARTICLES
 To stabilize the solid lipid particle against
aggregation, surfactants or polymers are
added
 Unlike, natural lecithins are preferred as is the
case with nanoemulsions.
 If lipid nanoparticles are intended to be used as
a carrier, the active ingredients are dissolved
or finely dispersed in the lipid matrix.
Scheme for the production of lipid nanoparticles by the hot or cold homogenization technique

1 Melt lipid; dissolve or solubilize active ingredient in the lipid

. Hot homogenization technique Cold homogenization technique

2 Disperse melted lipid in hot aqueous surfactant Cooling and recrystallization of active lipid mixture
solution using liquid nitrogen or dry ice

3 Preparation of a pre-emulsion by means of a Milling of the active lipid mixture by means of a ball
rotor-stator homogenizer mill or a jet mill

4 High-pressure homogenization above the Disperse lipid microparticles in cold aqueous

melting point of the lipid surfactant solution

5 Cooling and recrystallization High-pressur homogenization at or below room

temperature
SOLID LIPID NANOPARTICLES
 Solid lipid nanoparticles are commonly defined as nanoscaled
lipid matrices, solid at physiological temperatures and
stabilized by surfactants
 Developed at the beginning of the 1990s as an alternative
carrier system to emulsions, liposomes and polymeric
nanoparticles
 Research activities in SLN previously focused almost
exclusively on pharmaceutical applications, and within
these pharmaceutical applications mainly on non-dermal
administration routes, such as oral administration and
parenteral injection
SLN
 SLN is an attractive carrier for topical cosmetics
and pharmaceutical products
 Lipid nanoparticles, due to the safety of the
component materials and the controlled release
abilities, possess a great potential and have
generated a large interest in the industrial and
academic worlds
 SLN provides occlusive properties which helps
with the hydration of the skin
SLN : Advantages
– Possibility of controlled drug release and drug
targeting.
– Increased drug stability.
– High drug payload.
– Incorporation of lipophilic and hydrophilic drugs
fesibility.
– No biotoxicity of the carrier.
– Avoidance of organic solvents.
– No problems with respect to large scale production
and sterilization
Mechanism of action:
Nanoparticles

 Attributed to their association with the skin surface.

 The small particle size ensures close contact with
the stratum corneum >>> the amount of
encapsulated agent penetrating into the viable skin
facilitates drug transport by changing the
vehicle/stratum corneum partition coefficient
Mechanism of action: Lipid
Nanoparticles

 Lipid nanoparticles with a continuous matrix of

non-polar lipids seem to act more passively by
an adhesion onto the skin surface rather than
to deliver their drug load actively into or
through the skin.
 A potential advantage of this nanoparticle
adhesion onto the skin is that there would be a
possible depot formation mechanism
SLN
 Three diiferent models for incorporation of active
ingredients into SLN
Homogeneous matrix model
Drug-enriched shell model
Drug-enriched core model
SLN

 A homogeneous matrix with molecularly dispersed

drug or drug being present in amorphous clusters is
thought to be mainly obtained when applying the
cold homogenisation method and when
incorporating very lipophilic drugs
 An outer shell enriched with active compound can
be obtained when phase separation occurs during
cooling process from the liquid oil droplet to the
formation of a solid lipid nanoparticle
SLN

 A core enriched with active compound can be

when the opposite occurs, which means the active
compound starts precipitating first and the the shell
will have distinctly less drug
 This leads to a membrane controlled release
governed by the Fick law of diffusion.
NANOSTRUCTURED LIPID
CARRIER (NLC)

 For the production of NLC, spacially very different

lipid molecules are mixed, i.e. blending solid lipids
with liquid lipids (oils)
 The resulting matrix of the lipid particles shows a
melting point depression compared to the original
solid lipid but the matrix is still solid at body
temperature
NLC

 Depending on the blend, different types of NLC are

obtained.
 The basic idea is that by giving the lipid matrix a
certain nanostructure, the pay-load for active
compounds is increased
 There are three different types of NLC compared to
the more or less highly ordered matrix of SLN.
NLC

 The three types of

NLC :
– The imperfect type
– The amorphous
type
– The multiple type
NLC

 A potential problem in SLN is the formation of a

perfect crystal, which can be compared to a dense
‘brick wall’.
 Using different molecules, i.e. different ‘stones’ to
build the matrix or ‘wall’, leaves enough
imperfections to accommodate the drug
NLC