The engineering and materials science considerations of dosage form design
in the development of novel therapeutic
strategies was addressed during the materials science sessions of the Conference
on September 12 and 13
Professor SANDY Florence (School of Pharmacy, University of London) outlined
the applications of self-assembly systems, where molecules formed ordered arrays
with the resulting structure having properties distinct from the constituent
components. Such systems were commonly found in nature, examples ranging from
phospholipid bilayers to more complex assemblies such as the tobacco mosaic
virus.
Both natural and synthetic supramolecular structures had been used pharmaceutically,
the classic example being micellar systems with more recent developments including
teroidal and polyhedral vesicles.
Recent developments included the synthesis of molecules which had been tailor-made
to form specific structures, this approach being considerably aided by our constantly
improving understanding of the relationship between molecular structure and
self-assembly behaviour. Such examples included lipid-peptide conjugates and
dendrimers, the latter involving the repeated attachment of branched units to
form an extensive unimolecular network into which a range of drugs might be
incorporated. Recent studies had indicated that these molecules themselves formed
ordered aggregates, presenting a further range of opportunities for the development
of delivery systems.
Professor Florence speculated on some of the possible future advances, including
the use of vesicles to form ordered templates within silicate matrices and the
use of “exploding” geodesic vesicles whereby individual vesicles might
become detached from the central body under controlled conditions, allowing
a packaged dose of drug to be delivered from a central reservoir.
Tissue engineering
An overview of recent work in the field of tissue engineering was given by Dr
Robin Quirk (working with Dr Kevin Shenk-
sheff, both of the Institute of Pharmaceutical Science, University of Nottingham).
Four main considerations in working towards the preparation of regenerated tissue
were needed. Firstly, a biodegradable polymer scaffold had to be selected and
designed to allow cell adhesion and the development of a functional tissue construct.
Polylactic acid (PLA) had been modified with adhesion peptides in order to promote
receptor-mediated cell adhesion and spreading, with non-specific interactions
being prevented by the incorporation of polyethylene glycol onto the polymer
surface.
Secondly, the cells had to be exposed to growth factors in a controlled and
reliable manner. This aspect had been addressed by incorporating the growth
factors into the polymer via the formation of a plasticised PLA foam in supercritical
carbon dioxide. On pressure release, the polymer returned to the vitreous state,
allowing slow release of the peptides via diffusion through the glassy matrix.
Thirdly, in generating tissues with highly organised architectures, the spatial
organisation of the scaffold had to be controlled. This might be achieved via
a microfluidic flow technique where channels of growth factor-rich polymer were
used to pattern the scaffold surface between PEG rich regions, confining cell
growth to within the channel areas.
Finally, cell-cell interactions and their role in maintaining cell viability
and function needed to be considered in order to allow an effect scaffold to
become established. Recent work had focused on the use of fibroblasts co-cultured
with hepatocytes as a means of preventing such phenomena.
Tomographic imaging
The use of tomographic imaging for the in-process monitoring of the movement
of solids and semi-solids within processing equipment was outlined by Professor
Richard Williams (University of Leeds).
This method involved placing multiple electrodes in a circular arrangement around
the container in question. By measuring the impedance between respective pairs
of electrodes it was possible to rapidly build a three dimensional image of
the contents of that container, discrimination being based on differences in
impedance between the material and the medium (eg, air).
The method allowed a rapid, inexpensive and easily scalable means of observing
a range of systems including biological tissues and body parts, cyclone separation
of powders, particle-liquid mixing, fluidised beds, powder flow through pipes
and hoppers and slurry systems.
Given the difficulties in ascertaining the processes that occurred during a
particular operation, as opposed to examining the end product, Professor Williams
suggested that tomography represented a potentially highly useful tool for pharmaceutical
manufacture.
Spectroscopic imaging
The use of spectroscopic imaging methods was outlined by Mr Don Clark (Pfizer
Ltd), including Raman chemical imaging and NIR (near infrared) imaging. These
techniques involved rastering over the sample surface and measuring the composition
spectroscopically. The different components of the sample were then colour coded
to obtain an image that allowed discrimination between different components
on a microscopic scale.
A number of examples were presented, including the examination of two batches
of tablets that had exhibited differing dissolution properties, despite the
ingoing components (drug, Avicel and calcium phosphate) all meeting specifications.
Raman chemical imaging allowed observation of differences in the manner in which
the drug was distributed within the two tablets. More specifically, the batch
showing poor dissolution showed the drug to be embedded within regions rich
in Avicel, while the batch showing favourable dissolution showed the particles
to be adjacent to the calcium phosphate. It had therefore been suggested that
association with calcium phosphate optimised drug release. To test this hypothesis,
the drug had been milled with calcium phosphate prior to tableting; this had
led to all the batches meeting dissolution specifications.
Thermoanalytical technique
The use of thermally stimulated current as a means of studying pharmaceuticals
was outlined by Professor Colette Lacabanne (Université Paul Sabatier,
France).
This was a thermoanalytical technique that involved the application of a polarising
current to a sample at a specified temperature. This current caused the dipoles
within the sample to reorientate in the direction of the field and was immediately
followed by rapid cooling to “freeze” the dipoles in the polarised
orientation. The material was then heated and the depolarisation current measured
as a function of temperature.
As each dipolar species would reorientate in a characteristic manner, the method
allowed not only discrimination between differing species but also insights
into the molecular mobilities involved.
Examples included the study of structural relaxation in amorphous materials,
where the glass transition could be easily discerned by the change in depolarisation
current over a narrow temperature range. However, the technique also allowed
the effects of ageing on the depolarisation process to be ascertained, providing
a tool for the prediction of the long-term storage behaviour of the amorphous
material.