Pharma Tips

Colloidal Dispersions

By: Pharma Tips | Views: 2455 | Date: 02-Jun-2011

MicellesSurfactant MicellesPolymeric Micelles

Colloidal Dispersions

 

Colloidal Dispersions

 

1 Micelles
Micelles are self-assembling colloidal systems with particle size normally ranging
from 5 to 100 nm (Kabanov et al. 1992; Torchilin 2007). They are classified as colloidal
dispersion because of their particle size. Micelles are spontaneously formed
when amphiphilic molecules are placed in water at a certain concentration and temperature.
Property of micellization is generally displayed by molecules that possess
two distinct regions with opposite affinities toward a particular solvent (Mittal and
Lindman 1991). At a low concentration, the molecules exist separately in a solution.
However, when the concentration is increased, the molecules quickly self-assemble to
form spherical micelles (Fig. 1.4). The hydrophobic portions of the molecules condense
to form the core, whereas the hydrophilic portions constitute the shell or corona
of the micelle (Lasic 1992). The concentration at which micellar association ensues is
called the critical micelle concentration (CMC) and the temperature below which
amphiphilic molecules exist separately is known as critical micellization temperature
(CMT). The core of the micelle can solubilize lipophilic substances, whereas the
hydrophilic outer portion serves as a stabilizing interface to protect the hydrophobic
core from external aqueous environment. The process of micellization leads to free
energy minimization of the system as the hydrophobic portions of the molecule are
concealed and hydrogen bonds are established between hydrophilic portions in water.

Micelles are attractive candidates as drug carriers for delivering poorly watersoluble
drugs. Micelles can solubilize a drug at concentrations much greater than its
intrinsic solubility, which results in an increased bioavailability and a reduced toxicity.
Incorporation of a drug into a micelle alters release kinetics and enhances the
stability of the drug by reducing the access of water and biomolecules. Micelles
generally have narrow size distribution and the size can be easily controlled by altering
the formulation conditions. Due to their size range, they can be conveniently
sterilized by filtration through a membrane with a 0.2 mm cutoff. Specific targeting
can be achieved by chemically conjugating a targeting molecule on the surface of a
micelle. Passive targeting to tumors can also be achieved due to enhanced permeability
and retention effect (EPR effect). Tumors have leaky vasculature and inefficient
lymphatic drainage system, which results in a greater accumulation of micelles in
tumors compared with normal tissues. Desirable properties of a pharmaceutical
micelle include small size, narrow size distribution, low CMC value (low millimolar
to micromolar), and high drug loading efficiency. Pharmaceutical micelles can be
used through various routes such as parenteral, nasal, oral, otic, and ocular.

1.1 Surfactant Micelles
Micelles made from surfactants (especially nonionic surfactants) have been commonly
used to deliver drugs and biomolecules. They can efficiently entrap hydrophobic
drugs and form uniform particles. The water is distributed anisotropically
within the micelle, i.e., concentration decreases from the shell to the core (Torchilin
2002). Thus, the position of a drug within the micelle depends on its polarity; more
hydrophobic drug tends to stay closer to the core, whereas drugs with slight polarity
are located closer to the micelle shell. A limitation of surfactant micelles is that they
are not very stable and break apart rapidly upon dilution, which may cause premature
release and precipitation of the drug. The stability of surfactant micelles is
severely compromised at concentrations lower than their CMC. Surfactant micelles
typically have a rather high CMC, which may lead to concerns about surfactantrelated
toxicity. Micelle destabilization also compromises drug stability as the drug
is exposed to blood components immediately upon systemic administration. Thus,
surfactant molecules with lower CMC values and greater stability need to be developed
to overcome these limitations.

1.2 Polymeric Micelles

Micelles prepared from block copolymers have attracted much attention lately
because of their better stability and biocompatibility (Gaucher et al. 2005). They
are made from amphiphilic block copolymers with a large difference in solubility
between hydrophobic and hydrophilic portions. Polymeric micelles generally have
CMC values that are several orders of magnitude lower than typical CMC values
for surfactants. As a result, polymeric micelles show enhanced stability and slower
dissociation at lower concentrations compared with surfactant micelles (Jones and
Leroux 1999). Surface functionalization of a polymeric micelle can be easily performed
by chemically attaching a targeting moiety. Their low CMC values and
lower rate of dissociation also allow for prolonged release of entrapped drug.
Copolymer for micellization can be synthesized by using two or more polymer
blocks with contrasting solubility profiles. Poly (ethylene glycol) (PEG) is the most
commonly used hydrophilic (shell forming) block (Torchilin 2002; Nishiyama and
Kataoka 2003). Various molecular weights of PEG have been used for micelle
preparation. PEG is highly biocompatible and forms a highly stable shell to sterically
protect the hydrophobic core. It has also been shown to be efficient at escaping
recognition by the reticuloendothelial systems (RES), thereby extending the circulation
time of micelles in the blood (Kwon et al. 1997). Moreover, PEG copolymers
usually have a low polydispersity (Mw/Mn ratio), which enables strict control of
micelle size. Surface functionalization of PEG micelles can be easily performed by
chemically linking a targeting moiety. Thus, PEG micelles can be used for active
targeting to cells and tissues. Copolymers prepared by conjugating PEG with poly
lactic acid (PLA) and poly (ethylene oxide) (PEO) have been extensively investigated
as micellar vehicles (Yasugi et al. 1999). Other commonly used hydrophilic
polymer blocks are poly (N-vinyl-2-pyrrolidone) (PVP), poly (vinyl alcohol) (PVA),
and poly (vinylalcohol-co-vinyloleate). Triblock pluronic copolymers with an
A-B-A structure (Ethylene oxide)x-(Propylene oxide)y-(Ethylene oxide)x have been
extensively characterized (Kabanov et al. 2005). A variety of molecular weights and
block lengths of Pluronic copolymers is available commercially. These copolymers
have shown promise for delivering drugs and genes in vitro and in vivo.

1.3 Polymer-Lipid Micelles
A variety of hybrid micelles with lipid core and hydrophilic polymer shell has
recently been investigated. Such micelles have shown good stability, longevity, and
capability to accumulate into tissues with damaged vasculature (EPR effect).
Micelles prepared by conjugation of PEG and phosphatidylethanolamine (PE) have
been studied for delivery of anticancer drug Camptothecin (Mu et al. 2005). Such
conjugation resulted in formation of very stable micelles having low toxicity and
high delivery efficiency. PEG-PE conjugate form micelles with CMC in micromolar
range, which is about 100-fold lower than conventional detergent micelles.
Polymer lipid micelles can be formed easily by spontaneous micellization in aqueous
media similar to surfactant and polymer micelles, and their size can be tailored
by varying the molecular weight of the conjugate.

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