Low solubility in drugs is a major problem for delivery and bioavailability, with 40% of new drugs failing in the development stage due to
undesirable physical properties, including low aqueous solubility.
One of the most commonly used technologies to circumvent this
problem is to formulate micelles from low molecular weight
surfactants. However, a major problem with micellar systems is
their breakdown in vivo as a result of dilution within the plasma,
resulting in their concentration dropping below their critical
micelle concentration (CMC).
As an alternative to surfactants,
amphiphilic polymers, which are polymers containing both
hydrophilic and hydrophobic fragments within the same
macromolecule, can be used. When these polymers are brought
into solution, their hydrophobic regions associate to form a
hydrophobic core that is surrounded by a highly hydrated coat.
Unlike low molecular weight surfactants, these polymers can be
formed with diverse architectures, including graft and block
copolymers.
Work from the research group is looking at the
development of novel graft polymers based on water-soluble
polymers such as polyallylamine (PAA). These novel PAA
polymers form nano-sized self-assemblies in an aqueous
environment, in the size range of 100 to 400 nm. Manipulation
of the polymeric structure allows the properties of these systems
to be controlled, including their CMC, drug solubilisation
properties, and protein complexation efficacy. For example,
grafting of cholesteryl groups to the PAA was shown to reduce
the critical aggregation concentration, and addition of quaternary
ammonium groups increased the overall solubility and stability
of these complexes in an aqueous solution. Using two model
hydrophobic drugs, griseofulvin and propofol, the authors were
able to show a linear relationship between polymer concentration
and drug loading, and using these systems, they were able to
improve solubility by 17- and 25-fold for griseofulvin and
propofol, respectively, when PAA was grafted with 5% of
cholesteryl groups and 45% of quaternary ammonium groups.
The group also looked at the application of these polymers to
improve the delivery of proteins. Unlike conventional small drug
molecules, proteins have poor penetration of the intestinal
membrane and easily undergo enzymatic degradation in the
gastro-intestinal fluid. Using their PAA systems, polymer–insulin
nanocomplexes were formed that were shown by negativestaining
scanning electron microscopy to be dense spherical
particles with the insulin incorporated within the structure. It
was proposed that this insulin complexation by their quaternised
polymers is through electrostatic as well as hydrophobic
interactions, since most proteins are negatively charged in nature
at neutral pH. These nanocomplexes were able to protect the
insulin for up to 4 hr in a trypsin-degradation study, with only
5–7% degradation occurring compared with complete
degradation of insulin from solution over the same time.
It was concluded that these novel PAA-based polymers
offer considerable potential for the future development of nanosized
delivery systems applicable to hydrophobic drugs, proteins,
and peptides.
