IN THIS ISSUE - Drug Development & Delivery

called a cold-runner mold, and material in the
cold runner hardens or cures with the part and
is then removed from the part and discarded as
scrap or in the case of stable thermoplastic
formulations, sent to be recycled in a later
molding run after each cycle. Cold runner
systems are generally used for applications in
which materials are inexpensive or when use of
recycled material is acceptable, as they are less
expensive than hot runner systems. However,
materials cannot be reprocessed indefinitely,
especially if thermally labile, and if thermoset
materials are used in cold runner molds, the
material must be discarded.
Hot runner systems use a heated manifold
that is fed by the injection nozzle and keeps the
material molten in the runners in the mold
frame outside the plane of the cavity. The
molten material enters the cavity from the
runners via valve-gates or tips, and there is no
scrap, so costly raw materials losses are
minimized. Only the material in the cavity cools
and hardens on each cycle, and molten material
for the next cycle is forced into the cavity from
the hot runners as fresh material is pumped into
the hot manifold from the barrel nozzle. The
fact that material remains continuously molten
in the mold means that thermally sensitive
materials can be subject to degradation, and the
volume of hot runners should be kept as low as
possible (a few cavity volumes at most) to
F I G U R E 4
In vitro release of dapivirine from an EVA matrix-type IVR made by injection molding (25 mg
dapivirine).
ensure labile material does not have a long
residence time in the molten state.
PHARMACEUTICAL PRODUCTS
BY INJECTION MOLDING
Simple and complex shapes can be
produced by IM, and as such, the process is
used to prepare a wide variety of plastic
medical device parts from caps, seals, closures,
syringes, valves, and even implants. All of
these require formulation of polymers with a
range of additives, such as colorants,
antioxidants, fillers, and plasticizers. Many of
the compounds are pre-prepared by hot-melt
extrusion, pelletized, and the pellets fed to the
injection molder to form the part.
Whereas the halves of a gelatin capsule
that can be filled with API formulation are
traditionally made by hardening a gelatin
solution coated on a shaped metal pin by
dipping it a into gelatin solution, IM can be
used to prepare capsules, for example, the
FlexTab TM technology that Capsugel acquired
in 2011.
More recently, IM has been used to
directly incorporate APIs into shaped plastic
parts, and hence used to prepare drug products.
The majority of drug products prepared by IM
are drug-eluting devices (DED); however, even
more recently, IM has been used to prepare
solid oral dosage forms (SOD). IM offers the
product developer novel delivery features,
specific shaped-part preparation capability, and
potential for life-cycle management of APIs.
Commercial DED prepared by IM include
intravaginal rings (IVR), and several such
devices on the market made of silicones
manufactured using a RIM process. Examples
of such IVR are FemRing ® , Estring ® , and
Progering ® for hormone replacement therapy,
vaginal atrophy, and contraception,
respectively. These are core-sheath reservoir
devices in which a drug-loaded silicone core is
coated with a drug-free silicone sheath to
regulate the rate of release of API from the
device, yielding virtually zero-order (constant)
release kinetics. The sheath is put over the core
in a second injection molding process, making
manufacturing quite complex.
The International Partnership for
Microbicides (IPM) working with Karl
Malcolm and David Wolfson at Queens
University, Belfast, has leveraged silicone
technology in the development of a simpler
IVR containing the non-nucleoside reverse
transcriptase inhibitor dapivirine that does not
have a rate controlling membrane. 1 This IVR is
a device to protect women from HIV
transmission during sexual intercourse with an
infected partner, and is slated to start Phase III
clinical trials in 2012.
The RIM process requires the API and
any other excipients to be suspended in the
silicone liquids prior to injection (silicones are
poor solvents so all added materials are
suspended). Challenges arise from aggregation
and settling of particulate materials in these
fluids, which can cause inhomogeneities and
nozzle blocking.
Particle Sciences uses IM in the
development of EVA and polyurethane DED
for a variety of clients. 2,3 EVA and
polyurethanes are thermoplastic polymers, and
APIs and additives can be co-mixed uniformly
with it prior to IM using hot-melt extrusion to
yield pellets that are stable and can be used
right away or stored for later IM processing.
IVRs are developed first at laboratory scale
using a bench-top molder, and successful
formulations are then scaled to larger molding
units for clinical and then commercial process
development. The in vitro release of dapivirine
Drug Development & Delivery July/August 2012 Vol 12 No 6
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