Professional Documents
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Review
Abstract
Recent advances in nanoparticle systems for improved drug delivery display a great potential for the administration of active
molecules. Generally, the lipid systems presented the advantage of their low toxicity due to their composition of physiological lipids
compared to polymeric particles. The physico-chemical stability of the lipid carriers showed variations due to their numerous
compositions and structures. This review consequently focuses on the physico-chemical stability of dispersions in the nanometer
range where the lipids are the main or the only components. It highlights on the destabilization mechanisms, the techniques used to
detect this destabilization and the inductors of the destabilization. Finally, the methods used to optimize the stability of lipid
nanoparticle systems are described in the last part.
r 2003 Elsevier Ltd. All rights reserved.
Keywords: Review; Physico-chemical stability; Lipid; Drug delivery systems; Nanoparticles
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4284
2.
3.
Stability measurements . . . . . .
3.1. Physical stability . . . . . .
3.1.1. Crystallization . . .
3.1.2. Modication of size
3.1.3. Modication of zeta
3.2. Interfacial stability . . . . .
the
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of lipid colloidal
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Abbreviations: BSA, Bovine serum albumin; CETP, Plasma cholesteryl ester transfer protein; DMPG, Dimyristoylphosphatidylglycerol; DOPC,
Dioleoylphosphatidylcholine; DOPE, Dioleoylphosphatidylethanolamine; DPPC, Dipalmitoylphosphatidylcholine; DPPG, Dipalmitoylphosphatidylglycerol; DPPE, Dipalmitoylphosphatidylethanolamine; DSC, Differential scanning calorimetry; DSPC, Distearoylphosphatidylcholine; DSPG,
Distearoylphosphatidylglycerol; FFF, Field-ow fractionation; HDL, High-density lipoprotein; HPLC, High performance liquid chromatography;
LD, Laser diffraction; LDL, Low-density lipoprotein; NMR, Nuclear magnetic resonance; NTU, Nephelometric Turbidity Units; PCS, Photon
correlation spectroscopy; PEG, Polyethyleneglycol; PLs, Phospholipids; PLA 50, poly(d,l-lactic acid) containing 50% l-repeating units; SAXS, Xray scattering; SLN, Solid lipid nanoparticle; TL, Trilaurin; USP, United States Pharmacopeia
*Corresponding author. Tel.: +33-241-735-855; fax: +33-241-7358-53.
E-mail address: jean-pierre.benoit@univ-angers.fr (J.-P. Benoit).
0142-9612/03/$ - see front matter r 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0142-9612(03)00331-4
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4.
Destabilization inductors . . . . . . . . . . .
4.1. Process parameters . . . . . . . . . . .
4.1.1. Formulation method . . . . . .
4.1.2. Sterilization . . . . . . . . . .
4.2. Composition . . . . . . . . . . . . . .
4.2.1. Particle composition . . . . . .
4.2.2. Continuous phase composition:
4.2.3. Encapsulation of drugs . . . .
4.3. Storage parameters . . . . . . . . . . .
4.3.1. Inuence of light . . . . . . . .
4.3.2. Inuence of temperature . . . .
4.3.3. Inuence of packing material .
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electrolyte concentration and pH
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5.
Stability optimization . . . . . . . . . . . . . . .
5.1. Chemical stability . . . . . . . . . . . . .
5.1.1. Addition of anti-oxidants . . . . .
5.1.2. Water elimination . . . . . . . . .
5.2. Physical stability . . . . . . . . . . . . . .
5.2.1. Steric stabilization . . . . . . . . .
5.2.2. Electrostatic stabilization/repulsion
5.2.3. Lipid composition . . . . . . . . .
5.2.4. Cream or hydrogel incorporation .
5.2.5. Optimization of storage parameters
6.
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4296
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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4297
1. Introduction
Recent advances in nanoparticle systems for improved drug delivery display a great potential for the
administration of active molecules [1]. These drug
carriers allow the properties of the drug being carried
to be hidden and then to control and target its
release. It allows drug protection against chemical and
biological degradation related to the administration route. Therefore, the physico-chemical characteristics of the carriers themselves govern the types of
application.
Inside the numerous nanoparticle systems, lipid
structures were largely developed for various administration routes [2]. Liposomes, micelles, nanoemulsions,
microemulsions, and solid lipid nanoparticles (SLNs)
were the main lipid colloidal structures studied due to
their low toxicity, their ability to carry hydrophilic or
lipophilic drugs, their ability to control and localize the
release of the active drug, and their small size. All of
them were potential drug carriers for oral, topical, and
parenteral administrations.
Generally, the lipid systems presented the advantage
of their low toxicity due to their composition of
physiological lipids compared to polymeric particles.
However, a chemical transformation of these lipids
might change the structure of the system, the load and/
or release capacity, the interfacial properties, and their
in vivo fate. Physical modications can also occur. The
ARTICLE IN PRESS
B. Heurtault et al. / Biomaterials 24 (2003) 42834300
Ionizing radiation
Sonication
Surfactants
Electrolytes
pH
Drug
Temperature
Light
Packing material
Lipid matrix
Surfactants
Drug
Temperature
Light
Formulation process
Temperature
EFFECTS
Hydrolysis
Oxidation
Zeta potential
4285
Creaming
Gelling
Size increase
Drug release
Crystallisation
Polymorphism
Drug release
Crystalline drug structure
Size increase
Membrane permeability
Drug release
Particle aggregation
Phase inversion
Structure modification
Interfacial stability
Drug location
Mobility
Destruction
Drug release
PHYSICO-CHEMICAL
INSTABILITY
Surfactant
Temperature
Packing material
Drug
Fig. 1. Destabilization mechanisms and consequences on lipid particles. Bold, normal or underlined scripts were used for the composition, the
storage and the formulation process inductors, respectively.
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4288
isolation of the cell membrane which required considerable care to maintain structure and biochemical
activity [48].
IntralipidTM is composed of emulsion droplets with a
mean diameter of 360 nm containing a triacylglycerol
core emulsied by a PL monolayer, and of PL
unilamellar liposomes with a diameter of 85 nm. The
interfacial destabilization of both emulsion and liposomal particles leads to a rapid spreading of triacylglycerol
molecules from the core of the emulsion and to the
formation of a true monomolecular lm. The observed
higher global rate constant of spreading of IntralipidTM
in comparison with liposomes was attributed to the
higher spreading capacity of the core of the emulsion
particles [49] (Table 1).
HDL lipoproteins consist of a core of neutral lipids
encapsulated by a monolayer of polar lipids and
apolipoproteins. Surface balance and monolayer techniques have also been used to investigate the surface
properties of human lipoproteins at air/liquid interfaces
[56,57]. A rst study compared LDL and HDL3 surface
pressure/area isotherms (HDL3 has a density between
1.125 and 1.21 g/ml). Considering the molecular area
obtained for lipids, it indicated that LDL phospholipids
form more condensed monolayers than HDL3 phospholipids. The closer packing in the LDL phospholipids
monolayer has been attributed to the greater content of
saturated phosphatidylcholines and sphingomyelin with
respect to HDL3 content. Furthermore, the inuence of
lipid molecular packing on the afnity of human
apolipoprotein A1 for HDL3 and LDL surface lipids
was evaluated by monitoring the adsorption of apo A1
to monolayers of these lipids spread at various initial
surface pressures.
The spreading of HDL3 at the air/water interface led
to a breaking of these particles and to the liberation of
their core content. A schematic model describing the
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4289
Table 1
Lipid structures studied at the interfaces
Ref.
Lipid structures
Experimental eld
Interface
[37]
[50]
[36]
[51]
[39]
Spreading theory
Spreading process
Spreading process
Spreading kinetics
Spreading kinetics
Adsorption/spreading comparison
Spreading kinetics
Spreading kinetics
Air/water
Air/liquid
Air/water
Air/water
Air/water
[44]
[52]
[42]
[53]
[46]
[45]
[47]
[54]
Liposomes DOPC
Liposomes DMPC
Liposomes
Liposomes DOPC
Liposomes DPPC
DPPC:DSPC:SL
Liposomes (proteo-glycolipidic)
Liposomes
Emulsion
Liposomes DMPC
Liposomes DMPC
Liposomes
Liposomes
Liposomes (proteo-glycolipidic)
Liposomes (proteo-glycolipidic)
Liposomes PC
Liposomes DOPC
[55]
[56]
[57]
DMPC
DPPC
Liposomes
HDL3 and LDL
HDL3
[58]
[59]
HDL3
Oil-in-water emulsion
[40]
[49]
Spreading kinetics
Spreading kinetics
Surface pressure hysteresis lms
PL/drug interactions
Biological membrane modelization
Biological membrane modelization
Biological membrane modelization
Spreading process with enzymatic action (phospholipase A2)
on liposomes
Air/aqueous buffer
Air/water
Air/water
Air/water
Air/water
Air/aqueous solution of drug
Air/aqueous buffer
Air/aqueous buffer
Air/water
Air/water
Air/water
Air/water
Air/water
Air/water
Note: PLA 50, poly(d,l-lactic acid) containing 50% l-repeating units; BSA, bovine serum albumin; HDL, high-density lipoprotein; CETP, plasma
cholesteryl ester transfer protein.
Fig. 3. Schematic model describing the two processes involved in the formation of the surface lm from a spread HDL3 suspension: diffusion of
intact structures (1) or adsorption of partially open HDL3 (1a) and lm formation (1b). From [57], with permission from Elsevier.
ARTICLE IN PRESS
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3. Stability measurements
At the end of the destabilization phenomena, most of
the previously described processes can be directly
observed (creaming, coalescence, gelling). The nal
product becomes a non-homogeneous system and can
change in viscosity properties. However, the beginning
of the destabilization process could be detected earlier
using appropriate tools as described herewith. Chemical
instability can be observed by classical methods. HPLC
or thin layer chromatography is the main technique used
to measure the production of new chemical entities due
to the peroxidation or hydrolysis of PL. However,
physical instability can be detected directly by the
mechanism implied (crystallization) or by the consequences on the dispersion. The method to detect
interfacial instability is developed at the end of this
chapter.
3.1. Physical stability
3.1.1. Crystallization
3.1.1.1. Differential scanning calorimetry. Thermoanalysis of the SLNs provides information about crystallization behavior, the timing of polymorphic transitions,
fusion temperature, enthalpy, and the degree of crystallinity of melt-homogenized glyceride nanoparticle dispersions [60,61].
3.1.1.2. X-rays. Crystals diffract X-rays in the same
way that visible light is dispersed into a color spectrum
by a ruled grating (i.e., a piece of glass with ne parallel
lines of equal width drawn on it). This is due to the fact
that X-rays have wavelengths of about the same
magnitude as the distance between the atoms or
molecules of crystals. The X-ray diffraction pattern is
photographed on a sensitive plate arranged behind the
crystal, and by such a method the structure of a crystal
may be investigated. It has become possible to determine
the distances of the various planes of the crystal lattice.
The structure of various compounds can be determined
in this way [14]. X-ray scattering (SAXS) often
completes the study. These techniques were used to
investigate crystallization tendency and polymorphic
transitions of triglyceride nanoparticles [25,26,62].
Crystallization directly concerned the lipids constituting the structure. The two next paragraphs describe
the consequences of the destabilization process on the
complete structures with modications according to
their size or zeta potential.
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Computer
Electrobalance
Fixed
Barrier
Force transducter
Wilhelmy
plate
Movable barrier
Substrate
Subphase
Trough
4.2. Composition
4. Destabilization inductors
During the development of nanoparticulate structures, the formulation process is the rst step which
might play a role on stability. The composition has to be
critically controlled for optimal stability without forgetting that the drug might also be a possible destabilizing
inductor. Finally, external parameters such as temperature and light appear to be of primary importance for
long-term stability.
4.1. Process parameters
4.1.1. Formulation method
The formulation process is an important parameter
acting on the initial polymorphic form of the lipid
nanoparticles. In the case of spray-drying, unstable
polymorphic forms were obtained due to rapid solvent
evaporation. The same consequence was observed with
the spray-congealing process of micropellets [23,61].
In the same way sonication has been described as an
inductor of PL oxidation [12].
4.1.2. Sterilization
Gamma-irradiation is a current sterilization technique
for pharmaceutical products. However, chemical degradation of the PL took place during irradiation [96].
Peroxidation of unsaturated PL has been observed as
well as hydrolysis and degradation processes such as
dehydrogenation, chain rupture and dimerization [97]. It
might lead to more negative zeta potentials, changes in
phase transition behavior, or smaller liposomes as
described by Stensrud [96], on distearoylphosphatidylcholine (DSPC) and distearoylphosphatidylglycerol
(DSPG) liposomes. Ionizing radiation has consequently
been excluded or at least, before it will be accepted as a
4.2.1.2. Surfactant. As previously described, the surfactant used in the formulations can be a lipid molecule like
PL; however, amphiphilic polymers or bile salts are also
used.
The paper of Ahlin et al. [99] showed the effect of PL
on zeta potential of glyceryl tripalmitate SLN dispersions at various concentrations of between 0.25% and
5%. At a pH value of around 7, the particles carried
negative charges due to the ionization of various minor
components in PL: phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol. The zeta potential decreased as the emulsier concentration
increased up to 2% (w/w). These results showed that
an increase in the amount of negatively charged PL
brought about a decrease in the zeta potential, which
reached a plateau region when the surface of SLN was
completely covered with PL molecules. The increased
negative surface charges might be a consequence of the
increased surface curvature of smaller particles, resulting in higher package density of PL molecules on the
particle surface [99].
In the case of Lipo.ds S75, the major component
(phosphatidylcholine) could not explain the stabilization induced. In fact, the impurities in the surfactant
sample acted as stabilizers and could be considered
as co-surfactants. As a consequence, the less tendency
of the Lipo.ds S75 stabilized systems to gell compared
to those stabilized by pure Lipo.ds S100 or E80
might be explained by the participation of minor
components (such as glycolipids) in the steric or
electrostatic stabilization as described by Westesen and
Siekmann [29].
Schwarz and Mehnert [100] compared the effect
of soybean lecithin (Lipoids) and Poloxamers 188 on
zeta potential. The charge of the Lipoids stabilized Witepsols (glyceride mixture) and Dynasans
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4.2.1.3. Co-surfactant. The inuence of the co-surfactant composition of lipospheres on the polymorphism of
lipid matrices has been also demonstrated by Aquilano
et al. [101] on stearic acid particles. Lipospheres were
obtained from a warm microemulsion process. Stearic
acid was crystallized in three polymorphic forms named
A, B, and C depending on their melting points: 46 C,
54 C, and 74 C, respectively. It appeared that the
polymorph B is favored by the presence of small
amounts of butanol [101]. The solvent mainly acted as
a single molecule placed sideways to the crystallizing
chains, forming perpendicular bonds to the chain
development axis. During the formulation processes,
butanol acted as an impurity, promoting both the
lowering of the surface tension of polymorph B and its
nucleation frequency [101].
The presence of n-butanol in the formulation of lipid
particles led to smaller particles (of stearic acid) due to
the stabilizing effect on the microemulsion interface.
And probably as a consequence of its effect on steric
crystallization, growth over time was minimal [102].
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5. Stability optimization
5.1. Chemical stability
5.1.1. Addition of anti-oxidants
Oxidation can be prevented by excluding oxygen from
the vial, by the addition of an anti-oxidant such as atocopherol and butyl hydroxy toluene, or by the
selection of saturated acyl-chains in the PL. Peroxidation of PL in liposomes can be minimized by the use of
high-quality raw materials which are puried from
hydroperoxides and transition metal ions. Storage at
low temperatures reduced the rate of oxidation as well.
Furthermore, the use of partially saturated PL could be
a better choice than the PL carrying polyunsaturated
fatty acyl chains (natural egg phosphatidylcholine) [9].
Minimizing hydrolysis was possible by selecting an
environmental pH of 6.5, where PL have their maximum
stability, and low temperatures [112].
5.1.2. Water elimination
Another way to decrease the hydrolysis phenomenon
was the elimination of water in the sample by
lyophilization or spray-drying. Afterwards, the
powders should be reconstituted with the same particle
size distribution as the original dispersion. It gave
successful results on liposomes and SLN formulations [64].
4295
5.1.2.1. Lyophilization. Changes in particle size distribution during lyophilization were observed but were
minimized by optimizing the parameters of the lyophilization process, i.e. freezing velocity and redispersion
method (redispersion medium, for example). A longer
drying treatment on SLN suspensions gave no better
results [68]. In some cases, slower freezing proved to be
the best method [68], in contrast to other studies [64].
The thermal treatment should be adjusted for each
formulation [68]. Furthermore, the cryoprotector favored the redispersion of the freeze-dried SLNs [73].
Trehalose proved to be most effective cryoprotectant in
preventing particle growth during the freeze-drying
process [64,68]. Dextrose was suitable if high concentrations were used. Mannitol and lactose were not efcient
in protecting SLN dispersions [95]. Furthermore, the
presence of electrolytes in water reduced the zeta
potential with increasing concentration, i.e. with the
progression of the freezing process. The reduction in
zeta potential was considered to be one cause of
aggregation. Taking these factors into consideration, it
might be advantageous to remove the protonated
molecules which were present in the continuous phase
before lyophilization. Schwarz and Mehnert [64], thus
optimized the SLN freeze-drying by removing the
charged non-encapsulated drug in water, etomidate
and tetracaine, before lyophilization.
5.1.2.2. Spray-drying. Spray-drying was an alternative
method of lyophilization, to convert a liquid dispersion
into a dry product with the same goal: long-term stability.
Due to shear forces and temperature during the process,
destabilization of the systems can occur. Furthermore,
the redispersion properties have to be optimized. Freitas
and Muller
.
studied these parameters on three exemplary
SLN formulations composed of cetylpalmitate, Compritols 888 ATO (glyceryl behenate) or Synchrowaxs
HRSC (glyceroltribehenate and calcium behenate). Various parameters showed their ability to minimize the
temperature effect as well as the shear forces effect. By
addition of carbohydrates, the sugar layer around the
particles prevented the coalescence of molten lipid
droplets. A reduction of temperature effects can be
achieved by spraying alcoholic instead of aqueous SLN
dispersions, due to lower necessary inlet temperatures.
The inuence of shear forces could also be reduced by the
addition of carbohydrates. The sugar layer around the
particles protected the emulsier lm against shearing off
from the particle surface. Furthermore, a lower lipid
particle content reduced the probability of particle
contact and subsequent aggregation [77].
5.2. Physical stability
In the 1940s, two groups of scientists developed a
theory of colloidal stability now known as the
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6. Conclusion
5.2.2. Electrostatic stabilization/repulsion
Ionic surfactants like sodium dodecyl sulfate were
usually used to stabilize the emulsions. The polar group
was negative in water and a counter-ion was released.
The interface was consequently charged. An ion layer
was consequently formed preventing the coalescence of
the drops. However, the modication of the charge has
multiple consequences on biological applications (membrane interactions, protein interaction) and has to be
taken into account.
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[21]
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