as depot systems for sustained release of low molecular weight therapeutic
proteins are attractive options for pharmaceutical industry. These are of
particular industrial interest because many hydrogels can be produced solely by
mixing aqueous solutions. Thus, the relatively “delicate” proteins (e.g.
immunoglobulins) can be formulated without compromising their integrity and
stability1. Besides full-sized immunoglobulins, the amenable
architecture of antibodies has made it possible to develop more than 60
alternative antibody formats2. More than thirteen have proceeded
into clinical development3.
The antibody formats with molecular weights less than 50 kDa are of
interest to the formulators for development as depot systems because of their
relative short circulation half-life that requires frequent subcutaneous or intravenous
dosing. The most commonly used depot systems are inserts, coatings,
microparticles, based on natural products or synthetic polymers; and hydrogels4.
Currently an increasing number of antibody formulations are developed as high
concentrated liquid formulations (50 to 150 mg/ml) that can be self
administered5. However, the advantage is contrasted by the
manufacturing complexities that require special equipment and novel
a manufacturer’s point of view, hydrogels appear to be an attractive format as
compared to other depot systems since hydrogels are typically produced by a
simple mixing procedure of biocompatible materials in aqueous solutions at
ambient temperature. Hydrogels are elastic, hydrophilic, cross-linked,
3-dimensional networks, composed of natural or synthetic polymeric, water
insoluble materials that can bind a high amount of water6. Their
high-water content and their mechanical properties of soft matter and porous
structures make them especially suitable for loading with therapeutic proteins7.
However, hydrogels suffer from limited loading capacity; short time period
(hours to days) in which hydrogels release their hydrophilic cargo and the
relative high plasma concentrations needed to achieve a therapeutic effect. This
may limit the use of hydrogels for antibodies but the same is not true for
several alternative antibody formats namely Fab, Fab2, Fab3, scFv, triabodies,
diabodies, minibodies, nanobodies, Bi-specific T-cell engagers (BiTE),
dual-affinity re-targeting antibodies (DARTs) and single-domain antibodies
which often possess plasma half-lives of less than one day and can be highly
In order to
develop advanced and cost-effective depot formulations, the properties of
hydrogels need to be optimized. Apart from pharmaceutical criteria (formulator/
manufacturer point of view) safety issues are equally important. From the drug
developer’s point of view, hydrogel building blocks should be FDA approved and
the cargo molecule should be stable and not interact with the hydrogel during
the manufacturing process and during the entire release period at body
temperature9. The manufacturing process should be simple without the
use of heat or organic solvents leading to a formulation that can be
sterile-filtered and injected within seconds through a 27G or 30G needle. The
hydrogel depot formulations should represent a platform technology, which could
serve for a variety of drugs or drug categories. Loading capacities should be
ideally at least 10% and drug product shelf-life at 2-8°C should be at minimum
two years10. The reality is, however, quite different. Many delivery
systems currently developed by research groups in academic institutions aim at
increasing complexity rather than simplicity. Academic researchers tend to work
on innovative and rather complicated delivery systems, whereas industrial
research is focused on ease of production, cost of goods and manufacturing,
process scalability, process robustness, and on reducing the number of
excipients to the bare minimum. Collaborations between academia and industry
need to be fostered to keep exchanging ideas, acknowledging all aspects needed
for the development of a depot formulation, such as drug metabolism and
pharmacokinetics, pharmacology, and toxicology.
challenge of hydrogel formulations is their hydrophilicity and high-water
content, which typically results in relatively rapid drug release of
hydrophilic molecules (hours or days).
The concepts to prolong the release duration to weeks/months include
accentuating the interactions between the drug and the hydrogel matrix, or
incorporation of a diffusion barrier to retard the drug release. These
strategies have been successfully implemented for hydrophobic drugs in InGell
gamma by InGell Labs (Groningen, The Netherlands) wherein the depot system
based on the gamma technology releases its hydrophobic cargo over a period of
days to weeks11. For hydrophilic drugs, such as antibodies and other
immunoglobulins, the challenges are far greater. In addition to short release
period, challenges concerning use of hyaluronidase to widen the injection space
and their loading capacities (1-5% by weight) are significantly important.
Typical antibody dose ranges between 2 to 6 mg/kg, which translates into a
plasma concentration of 50-150 µg/ml12. Depending on the plasma half-life,
this concentration will, however, only be a fraction of that when released over
the course of a week or even a month. A depot formulation for therapeutic
proteins is therefore especially useful for highly potent drugs. An alternative
solution to increase the loading capacity by use of highly concentrated
crystalline/ solid amorphous protein solutions and to pre-administer an IV
bolus dose followed by subcutaneous depot maintenance dose to achieve
clinically relevant steady state concentrations.
enormous academic research on hydrogel-based drug delivery systems, the number
of hydrogels approved by the FDA or those in clinical development is limited.
One of the few marketed hydrogels used for subcutaneous drug delivery is
“Supprelina LA” by Endo Pharmaceuticals Solutions Inc., Dublin, Ireland, for
sustained delivery formulation for histrelin acetate13. Another is
Eligard™ 7.5 mg, (Novelon therapeutics, US) a polymeric matrix formulation for
controlled delivery of leuprolide acetate, for over a month14. A
platform technology from Foresee Pharmaceuticals Co., Ltd., Taipei, Taiwan, is
a stabilized injectable formulation, for controlled-release formulations of
small molecules, peptides, and proteins. Amongst the various successful
research products, Foresee's FP-001(LHRH agonist), is in clinical phase III
study for advanced prostate carcinoma therapeutics and FP02C-14-001 (MMP-12
inhibitor) is in phase I study15. Another platform sustained release
technology BEPO® developed by MedinCell (Jacou, France) claimed as a
game changer by the company is a simple yet flexible technology. BEPO® on subcutaneous injection forms a fully
bioresorbable depot that can provide
controlled release of therapeutic molecules for days, weeks or months and
therefore can be used for treatment of chronic and short term illnesses16.
proteins that require intravitreal injections, a hydrogel formulation is
particularly attractive to improve patient convenience and compliance. For
example, the anti-VEGF Fab-fragment ranibizumab (LucentisR) and the anti-VEGF
monoclonal antibody bevacizumab (AvastinR) are clinically used to for
age-related macular degeneration and proliferative diabetic retinopathy. Both
treatments need to be administered via intravitreal injection every four to six
weeks17. Many academic groups have developed intravitreal depot
formulations for ranibizumab and bevacizumab so as to extend the duration to
months instead of weeks. Considering the
extreme uncomforting injection procedure, any reduction in the injection
frequency would be an instant marketing advantage. Besides ophthalmological
applications, hydrogels have been researched for anti-cancer mAbs such as a
trastuzumab (HerceptinR) hydrogel for breast cancer therapy18.
progress in hydrogel technologies is evident, the commercialization of hydrogel
formulations remains challenging. Scale up and cost-effective manufacturing
using safe and established excipients need special mention. Hydrogels for
biologicals are at present scarcely developed beyond the clinical evaluation
phases. The future of “next generation” hydrogels for biologicals will thus
depend on the success of suitable molecule formats especially those that are
highly potent or exhibit short plasma half-lives in addition to the medical
needs, the general benefit/risk balance, and overall costs.
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