Pharmaceuticals
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Medicines
in print
S In August 2015, the world’s
pritam (levetiracetam) might
look like a normal tablet, but
according to its manufacturer
Aprecia Pharmaceuticals,
in Ohio, US, this 3D printed pill
for epilepsy patients has a higher,
more consistent dose and dissolves
more quickly than if it had been
manufactured via conventional
means. Its approval by the US
Food and Drug Administration
(FDA) is significant because it
shows a medicine can be produced
commercially using 3D printing.
‘Knowing that one drug has been
approved takes away a big barrier,’
says Stephen Hilton, lecturer
in pharmaceutical sciences and
biochemistry at University College
London (UCL), UK, who is exploring
3D printing in drug discovery. ‘A lot
of companies will want to invest now
because there is a market and they
can see the technology works.’
3D printing has become
increasingly popular for
manufacturing toys, hearing aids and
car parts, among other things, with a
worldwide annual value of $1–2bn.
The technology – also known as
additive manufacturing – involves
making a 3D object by depositing
successive layers of material on top of
each other as directed by a computer-
generated digital model. Plastics,
metals and even biomaterials, such as
36 Chemistry&Industry • Issue 1 • 2016
first 3D printed medicine was
approved for use in the US –
heralding a new technological
era for the healthcare sector.
Katrina Megget reports
cells, are some of the materials that
are used.
What is so useful about 3D
printing is that the digital design
can be tweaked to change the final
product. Hearing aids, for instance,
can be customised by scanning
the ear cavity of each patient. ‘It’s
amazingly exciting,’ says Hilton.
‘There’s a lot of hype [about 3D
printing] but a lot of potential as well.
In theory, we can make anything we
want.’
The idea of 3D printed drugs is
not new. In 1997, a collaboration
between scientists at pharma
firm Therics, Ohio, US, and
at Massachusetts Institute of
Technology (MIT) in Boston, US,
demonstrated they could print
pharmaceutical-grade pills ‘as a
new way of formulating drugs with
unprecedented dosage control’.
However, 3D printing analyst,
Terry Wohlers, based in
Colorado, US, believes
that at that time the
business case for
3D-printed drugs was
not strong enough
as Therics returned the
pharmaceutical rights back to MIT.
But he is optimistic: ‘I’ve long felt the
opportunity of 3D printing custom
pills and tablets is significant. I can
envision a future where most drugs
are manufactured in this way.’
In the case of Spritam, the drug is
produced using ZipDose 3D printing
technology, combining powder and
liquid mixtures to create a porous pill
that dissolves quickly on contact with
liquid. The process involves spreading
a thin layer of powder followed by
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droplets of liquid, according to a
pre-programmed design, which is
repeated for 20–40 layers. On drying,
the printed regions bind together.
The pills can accommodate high
drug loads of up to 1000mg, while
still having the ability to dissolve
quickly. Generally, a fast-melt pill
made through standard tablet
compression technology cannot
have a dose beyond 50mg without
affecting its dissolving speed. ‘Aprecia
chose to focus on 3D printing
because the process enables new
types of structures to be made, and
these structures can exhibit new
or different functionality when
compared with the objects made
by prior techniques,’ says Thomas
West, Aprecia’s project director and
manager of intellectual property.
Aprecia, which holds more
than 50 patents for its 3D printing
technology, has three other
2016 • Issue 1 • Chemistry&Industry
investigational drugs in its pipeline.
In the main, these are drugs aimed
at the central nervous system, which
will also be produced by the ZipDose
technology.
According to Swathi Allada,
research analyst at consultant Frost
& Sullivan, the healthcare industry
is expected to be one of the top
industries driving the growth of
3D printing over the next decade,
reaching a $6bn market by 2025.
37
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Several research institutes and start-
ups are working in this space but
a lot of groundwork is still needed
before 3D printing can realise its full
potential in pharmaceuticals, she
says.
Much of the research in this area
is being done in universities, many
of which are launching start-ups to
commercialise their findings. One
is Hilton’s lab at UCL, which has
recently set up the company FabRx.
With numerous patents pending,
there is only so much Hilton can say,
but the group is exploring 3D drug
delivery mechanisms, shape-release
profiles, and dual layer printing with
two drugs, as well as 3D-printed
bacteria and lab equipment such as
flasks and flow reactors.
One of the main areas the UCL
team is investigating is the printing
and analysis of drug doses, and its
relationship with tablet shape. ‘We
are working towards printing drugs
in such a way as to be able to give the
right dose to each patient, effectively
personalising the treatment. This is
where there will be inroads in the
pharmaceutical industry,’ Hilton says.
Using hot melt extrusion, which
blends a heated mixture of a poorly
soluble drug with a polymer and
squeezes it through a small aperture,
the team printed pills in five different
shapes, from pyramids to doughnuts.
The results show that drug release is
not dependent on the surface area but
on the surface area to volume ratio.
Thus a pyramid-shaped pill releases
a drug more slowly than a cube or
sphere. ‘This work has demonstrated
the potential of 3D printing to
manufacture tablet shapes of different
geometries, many of which would
be challenging to manufacture by
powder compaction,’ the team has
reported (International Journal of
Pharmaceutics, 2015, 494 (2), 657).
Meanwhile, Clive Roberts,
professor of pharmaceutical
nanotechnology at Nottingham
University, UK, and his team have
successfully printed a ‘polypill’
containing five drugs, for the
treatment of heart problems.
Using 3D extrusion printing, the
pill has five compartments with
two independently controlled
release profiles, immediate release
and sustained release. The results
38 Chemistry&Industry • Issue 1 • 2016
show the polypill has the intended
release profiles based on the active
ingredient/excipient ratio used.
The research proves a principle,
Roberts says. ‘We can make a polypill.
3D printing can produce viable drug
forms that meet all the criteria of
standard tablets. We have been able
to move from producing a 3D tablet
to making something that cannot
be done by traditional forms of
manufacturing.’ It is this aspect where
the full potential of 3D printing drugs
will be realised, he says.
This concept has been taken a
step further by Lee Cronin, professor
of chemistry at the University of
Glasgow, UK. He envisages a future
where a 3D printer – configured as
a modular liquid-handling robotic
device – will print 3D ‘reactionware’
vessels, like test tubes, with added
solid or gel catalyst layers. Reagents
would then be added via the 3D
printer and react in the vessel,
causing a chemical reaction that
produces the required drug. The
digital design of the reactionware
could be tweaked to print different
shapes, contain different catalysts and
have a range of chemicals added.
In this way, a variety of chemicals
can be produced. For example,
Cronin’s team has converted styrene
to ethylbenzene, and even synthesised
small peptides and protein fragments.
They are also working on the
synthesis of a painkiller as a proof-of-
concept.
This approach could change the
way manufacturers produce drugs, he
says, while the digital recipe for the
medicine could be encrypted to stop
counterfeiters. ‘Our approach, using
configurable “chemorobotics”, allows
us to design, discover and digitise
chemistry. It’s effectively driving a
digital revolution in chemistry,’ he
says. Cronin believes the technology
has the potential to revolutionise how
new drugs are discovered.
The promise of 3D printed drugs
is immense. The technology could
advance the case for personalised
medicine; compliance to treatments
could be improved for both young
and old; and the availability of 3D
printers in the developing world
could mean quicker access to life-
saving medicines.
Many experts speculate a
‘I’ve long felt the opportunity of 3D
printing custom pills and tablets is
significant. I can envision a future where
most drugs are manufactured in this
way.’
Terry Wohlers
scenario in which local pharmacies
could play a central role in 3D
drug printing. This could happen
in as little as five to 10 years, says
Hilton. However, Roberts is a little
more hesitant, saying the structure
of healthcare systems and the
training of pharmacists would
need to be considered; knowing
how slow change is in global
healthcare systems, this would mean
implementation could take decades.
The technology also raises
questions about the pharmaceutical
industry’s future manufacturing
model. Roberts says much will
come down to the business and
clinical case for the technology. At
Aprecia, 3D printing is treated as
a new unit operation within the
traditional framework. The approach
is centralised manufacturing in
scale under the existing regulatory
paradigm, with Spritam distributed
through the same pharmaceutical
supply chain.
3D printing
in healthcare 3D printing is not expected to
will represent replace current manufacturing,
a market worth Roberts says. He believes it could
$6bn by 2025
be a viable alternative for niche
products with smaller patient
populations or for clinical trial drug
manufacturing. While Allada agrees,
she adds that 3D printing could
create huge cost savings on storage,
handling, distribution, labour and
lab equipment, with production
costs dropping by as much as 80%
for 3D printed drugs. She forecasts
large-scale adoption in the industry
by 2025.
3D printing Being first out of the blocks,
could create a
viable alternative Aprecia has identified an opportunity
for niche and has sparked interest across the
products with sector. The race is now on to realise
smaller patient
populations or for
the full potential that the technology
clinical trials can offer.
Katrina Megget is a science writer
based in London, UK
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