(536a) pH-Responsive Hydrogels for Oral Delivery of Therapeutic Proteins

pH-Responsive Hydrogels for Oral
Delivery of Therapeutic Proteins

Michael C. Koetting and
Nicholas A. Peppas, The University of Texas at Austin, Department of Chemical
Engineering, Austin, TX

Introduction: Therapeutic
delivery of proteins via intravenous injection is an invasive and often painful
method which has been shown to cause low patient compliance with
doctor-recommended treatment.  Delivery via the transmucosal and especially the
oral route is strongly preferred to avoid the pain and embarrassment of
injection and therefore increase patient compliance.  However, several
challenges currently prevent this route from being used.  The protein must
first be protected from proteases and strongly acidic conditions present in the
stomach to arrive in its therapeutic form, must then be released in the 2-3
hour window during which it is in the small intestine, and must finally be
absorbed through the epithelial lining of the small intestine to enter the
bloodstream.  Environmentally-responsive hydrogel systems have shown great
promise as drug delivery vehicles to overcome these obstacles.  Our group has
previously developed copolymer hydrogel delivery vehicles?notably poly(methacrylic
acid) grafted with poly(ethylene glycol), or P(MAA-g-EG)?for the oral
delivery of insulin.  These hydrogels protect the protein through the
gastrointestinal tract and release the protein in the small intestine by
swelling at the higher pH found in the intestine.

            Our current
work is focused on creating a pH-responsive copolymeric hydrogel delivery
vehicle for other proteins, specifically salmon calcitonin which is used to
treat osteoporosis, Paget's disease, and hypercalcaemia.  Calcitonin displays
very different properties than insulin, primarily a high isoelectric point of
8.86 compared to 5.39 for insulin.  As a result, new hydrogel delivery systems
have been investigated as carriers appropriate for the delivery of calcitonin.

Methods and Results:
We have synthesized copolymers of itaconic acid and N-vinylpyrrolidone, designated
as poly(itaconic acid-co-N-vinylpyrrolidone) or P(IA-co-NVP), that
possess pH-dependent swelling properties.  Hydrogel films were synthesized via
UV-initiated free radical polymerization using tetra(ethylene glycol)
dimethacrylate (TEGDMA) as a crosslinker.  The effect of composition on the
swelling profile has been investigated with equilibrium and dynamic pH swelling
studies.  The carriers displayed favorable swelling characteristics for
delivery in the small intestine, remaining collapsed at acidic conditions and
swelling to weight ratios of up to 20 at neutral conditions.  Compositions with
higher itaconic acid content relative to N-vinylpyrrolidone displayed greater
swelling ratios and more anionic properties.  Furthermore, all carriers displayed
faster swelling dynamics than previous formulations of P(MAA-g-EG) or
P(MAA-co-NVP), indicating the potential for greater release of the
loaded drug during the narrow time frame in the small intestine.  Loading and
release studies using P(IA-co-NVP) microparticles sieved to sizes
between 90 and 150 μm
and loaded with bovine serum albumin or salmon calcitonin have also been
performed to demonstrate the suitability of the copolymer as a drug delivery
vehicle.

Conclusions:  The
copolymer hydrogels of P(IA-co-NVP) demonstrate favorable pH-dependent
swelling for efficient oral delivery of drugs to the small intestine.  The
polymer network remains collapsed at low pH, protecting the protein from
proteases in the stomach, and swells rapidly at neutral conditions, releasing
the protein in the small intestine for uptake into the bloodstream.  The
carriers are therefore considered viable candidates for the oral delivery of
various therapeutic proteins such as calcitonin or insulin.

Acknowledgment:     This
work was supported by grant 1R01-EB000246-19 from the National Institutes of
Health.