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Amino acid containing degradable polymers and their potential in controlled drug delivery.
Aylvin A. Dias R&D Manager Drug Delivery
DSM Biomedical, Geleen, The Netherlands
Biodegradable polymers allow for avoidance of re-interventions related to removal of the drug
delivery implant, and therefore minimize risk of complications and adverse events associated with
long term implantable materials. However, it should be noted that these benefits have to be weighed
against potential risks caused by degradation products and intermediates.
The manner in which degradation proceeds has an influence on drug release behavior and can
influence the form that the polymer has to adopt. Surface versus bulk degradation is dependent on
whether the degradation is via a hydrolytic mechanism (e.g., ester hydrolysis) or via an enzymatic
mechanism. In case of degradation by hydrolysis, bulk degradation takes place, but can be controlled
by exerting control over the rate of water penetration and material swelling, which is governed by the
hydrophilicity of the polymer. In the case of enzyme or cellular mediated biodegradation the
mechanism is mainly via surface degradation and erosion.
Enzymatic degradation can occur via hydrolytic or oxidative mechanisms. These degradation
mechanisms can occur as a result of the inflammatory foreign body response that occurs upon
implantation of the polymeric drug delivery system. Enzymes typically involved in biodegradation are
esterases, proteases, elastases and peroxidases.
Thus in the design of degradable polymer-based drug delivery systems, it is worthwhile evaluating
both chemically degradable and enzymatically biodegradable polymers, and scrutinize the in vitro and
in vivo testing results to define the optimal system to proceed with.
Amino acid-based biodegradable polymers
Amino acid containing polymers have emerged as novel biodegradable materials in the drive to find
materials that breakdown into safe, metabolizable and/ or excretable building blocks.
However the effect of using amino acid is that many cases it involves their incorporation into the
polymer via ester, amide, urethane and urea bonds. Most of these bonds do not hydrolyse readily by
purely chemical means and often require biocatalytic or cell mediated reactions on order to ensure
complete degradation. In this lecture we explore the consequence of using amino acid building blocks
on the degradation, both hydrolytic, enzymatic and macrophage mediated degradation. This will be
done with novel polyester amides and polyester urethanes.
Amino acid based polyester urethanes
The developments of degradable polyester urethanes initially began with the utilization of aliphatic
polyesters diols and then evolved to the use isocyanates (eg butanie di-isocyanate) that degraded to
natural diamines (eg putrescine). This eventually lead to the use of amino acids that were
incorporated as key building blocks in the form of lysine di-isocyanate or as chain extenders.
We describe novel thermoset polyester urethane acrylate photopolymer that can be used as drug
delivery matrices where crosslink density block copolymer character and end groups can be used to
tailor drug release.
- Chemical composition
- Mwt between crosslinks (Crosslink density)
R1 = CH3, H
R2 = OH, protected esters, peptides, proteins
or bioactive molecules
Figure 1: Amino acid based biodegradable polyesterurethane acrylates for drug delivery.
Amino acid-based polyesteramides
Amino acid based polyesteramides (4) are based on
diols as shown in Figure 2.
-amino acids, aliphatic dicarboxylic acids and
Among this class of polymers it is the AA-BB heterochain polymers that offer the greatest versatility in
terms of molecular level design to tailor drug release properties.
Figure 2: Amino acid based biodegradable polyesteramides for drug delivery
These polyesteramides degrade enzymatically as can be demonstrated with chymotrypsin, esterases
and lipases. In addition macrophage mediated degradation reveal the suggest a susceptibility of
these polymers to the foreign body reaction. These polyester amides have been chemically modified
and formulated to deliver a wide variety of small molecule drugs and biologics from a variety of forms
ranging from solid monoliths to coatings and nanoparticles. Their main advantage is related to the
fact that they predominantly degrade by an enzymatic mechanism; because of consequential surface
erosion degradation, drug release follows mainly zero-order kinetics. These amino acid based
polyester amides have extensively been tested preclinically and showed good tissue and blood
compatibility. These amino acid-based polyester amide polymers are currently in human clinical
studies as biodegradable coatings for drug eluting stents. Serum mediated degradation followed by
HPLC-MS reveal typical breakdown products consistent with enzymatic hydrolysis.
Amino acid based biodegradable polymers represent the next frontier in the use of polymers for drug
delivery. The amino acid building blocks provide the possibility of tailoring the degradation to be occur
either mainly via hydrolysis or enzymatically.
Both the amino acid based polyesterurethanes and polyesteramides show reduced pH drop upon
degradation when compared to conventional degradable aliphatic polyesters.
1. DSM Patents: WO2008/ 055666, & WO 2007/107358.
2. Gomursahvili Z, Zhang H, Da J, Jenkins TD, Hughes J, Wu M, Lanbert L, Grako KA, Defife
KM, Macpherson K, Vassilev V, Katsarava R, and Turnell WG, From drug eluting stents to
biopharmaceuticals: Poly(esteramide) a versatile new bioabsorbable biopolymer. ACS
Synposium series 977; Polymers for Biomedical Applications Eds Mahapatro A and
Kulshresthra AS, ISBN 978-0-8412-3966-1, 2008