Formulating Proteins and Peptides: Designing for Delivery
By: Cindy H. Dubin, Contributor
Protein and peptide therapeutics
have become an important class of
drugs due to advancements in
molecular biology and recombinant
technology. There are more than 100
biopharmaceutical products approved and
generating revenue of more than $56
billion dollars, according to researchers at
Lipocine Inc., a Salt Lake City, Utah-based drug delivery company. A safe,
effective and patient friendly delivery of
these agents is the key to their commercial
success.
Currently, most proteins are
administered parenterally; various delivery
strategies and specialized companies have
evolved over the past few years to improve
delivery of proteins and peptides.
Polymeric depot and PEGylation
technologies have overcome some of the
issues associated with parenteral delivery.
Considerable research has been focused
on non-invasive routes, such as
pulmonary, oral and transdermal, to
increase patient compliance.
Yet, delivery via non-invasive routes
remains challenging due to their poor
absorption and enzymatic instability. In
the case of oral administration, for
example, the barriers to peptide
bioavailability after oral administration are
intestinal membrane permeability, size,
intestinal and hepatic metabolism and
lastly solubility. Structurally modifying
the compound or site-specific delivery are
just some of the approaches being used to
overcome limitations via oral delivery.
While there is much excitement
surrounding the potential of proteins and
peptides, the complex structure of these
therapeutic substances require special
formulation and delivery strategies,
creating special challenges for drug
developers and their formulation
technology and delivery device partners.
One formulation trend is emerging:
Designing for delivery has become the
goal of many formulators when it comes
to proteins and peptides. According to Dr.
Tom Tice, Vice President of Research for
Brookwood Pharmaceuticals, Inc., a
subsidiary of SurModics, Inc., “The drug
delivery folks have had their technologies
around and were just waiting to deliver
proteins and peptides. We are now
developing proteins and peptides that
match to the existing delivery systems and
as a result we get better dosing regimens,
improved stability, optimized solubility, and
optimized formulation manufacturing.”
Patricia Haller, PhD, Director, GMP
Manufacturing and Process Development
at American Peptide Company, Inc., says
that small modifications in the peptide
sequence or counter-ion can alter their
compatibility with existing delivery
systems without compromising the
affinity and potency of the peptide drug.
“These requests from clients are not
uncommon and can be accommodated
during manufacture,” she says.
Drug Delivery Technology February 2008 Vol 8 No 2
34
AMERICAN PEPTIDE
COMPANY, INC. —
CONCENTRATING ON THE
COUNTER-ION
According to Scott Caton, Senior
Manager, GMP Quality Control for
American Peptide, the number-one
challenge in helping clients with
formulation is the solubility of
hydrophobic peptides. Much of these
solubility issues come from the general
chemistry of the peptide, but there are
steps within manufacturing that can
increase solubility. One of these steps is
the type and concentration of the counter-ion. The specific concentration of the
counter-ion can be difficult to control, but
understanding the minimum counter-ion
concentration needed to be soluble can
help with formulation development.
“Clients are looking at us to help
them in the early stages of their
formulation hurdles. They are carefully
looking at several different issues that
directly affect the stability and solubility
of their API,” says Shawn Shirzadi, Vice
President, Quality. “Clients are coming to
us in various stages of the drug
development process. Most of our clients
are in Phase I and Phase II of
development, although we have some late-development stage clients. The early-stage
clients are where a majority of the
formulation-related questions and
concerns come from. Some clients do not
have experience with peptides or
formulation development. Based on our
experience with peptides and the drug
development process, we help our clients
with these questions and their
development work through stability and
forced degradation studies, impurities
identification and solubility issues.”
“Most of our clients are in the
development of cancer fighting
therapeutics,” says Gary Hu, Vice
President, Sales and Marketing. “With all
the published genome mapping
information available, clients are able to
find and develop specific peptides that
target new technologies to help combat
cancer. The other area of therapeutic
development is dealing with autoimmune
diseases.”
The peptides that American Peptide
manufactures contain a counter-ion or
they are requested as a specific salt form.
The most common counter-ion is acetate.
An additional counter-ion sometimes
requested is TFA, says Mr. Caton. In some
peptides, the varying concentration of
acetate directly affects solubility.
