Feature Article

Liquid, Injectable, Hydrophobic and

Biodegradable Polymers as Drug Delivery
Vehicles

Brian G. Amsden

New delivery approaches to achieve minimally invasive, sustained and local release of drugs
are needed for more effective treatment of conditions such as cancer and ischemia. Hydro-
phobic, biodegradable, liquid injectable polymers possess a number of potential advantages
for this purpose. This review examines various
approaches that have been explored for the prep-
aration of these types of polymers, their ability to
control the release of various drugs ranging from
low-molecular-weight hydrophobic compounds
to protein therapeutics, and finally their degra-
dation rates and the tissue response to them upon
implantation.

Introduction

Advances in biotechnology and drug development have

resulted in an increase in the number of active pharma-
ceutical agents that are difficult to administer by conven-
tional means due to their low aqueous solubility or
degradation and instability in the aqueous environment.
Moreover, there is an increased demand for loco-regional
administration combined with sustained and controlled
release in the treatment of conditions such as ischemia,
chronic pain, and cancer. To overcome these disadvantages,
a number of different formulation approaches have been
investigated that can be injected directly into the required
site.[1,2] Among these, viscous, amorphous, liquid or low
melting point, hydrophobic and biodegradable polymers
possess distinct advantages, including: facile incorporation
of thermally sensitive drugs such as proteins and peptides
by simple mixing, injectability through standard gage
B. G. Amsden
Department of Chemical Engineering, Queen’s University,
Kingston, Ontario, Canada
E-mail: brian.amsden@chee.queensu.ca
needles and thus administration via minimally invasive
means, no need for device retrieval, restricted water
penetration, which may provide enhanced stability for
drugs incorporated as solid particles, and the viscous,
amorphous nature of the polymer may limit irritation
when implanted in soft tissue.
In the past, oily vehicle parenterals have been used, such
as: olive oil, sesame oil, and castor oil. These vehicles are
slowly cleared from the injection site, through absorption
into the capillaries or lymphatic system, by phagocytosis,
and by in situ metabolism. Disadvantages of these
formulations are possible reactions to the vehicle itself such
as allergic reactions, cyst formation, pulmonary embolism
following translocation of oil droplets, and localized
lymphadenopathy.[3] A possible solution to these disadvan-
tages is the use of a biodegradable, synthetic, liquid polymer.
In this review, the various biodegradable, liquid polymer
compositions that have been explored will be outlined and
the various advantages and disadvantages of the approaches
described. The review is restricted to those polymers that

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remain liquid upon injection. Other liquid polymer
approaches, such as in situ setting through crystallization,[4]
gel formation,[5] or solute leaching,[6,7] are not considered
and have been discussed in recent reviews.[1,2]
General Concepts
To ensure that the polymer used is a liquid at temperatures
reasonable for injection into patients, it must have a low
molecular weight. At sufficiently low molecular weights,
the polymer chains in the melt are not entangled with each
other. As molecular weight increases, there exists a
particular molecular weight for each polymer at which
chain entanglement occurs, called the critical entangle-
ment length (Me). Below Me, the polymer melt viscosity is
typically Newtonian, and given by[8]
1 tomers, hydrogels, and low viscosity polymers
h ¼ KL Mw (1)
where KL is a constant. Hence, as the polymer molecular
weight increases, the viscosity increases. Above Me, the
polymer melt viscosity is given by
3:4
h¼ KH M w (2)
in which KH is a constant. Above Me, chain entanglements
result in marked increases in melt viscosity as molecular
weight increases by acting as temporary crosslink points
providing additional resistance to chain movement. Thus,
it is important to ensure that the molecular weight used is
below Me to ensure a viscosity low enough to permit
injection through a needle.
Molecular weight also influences the melting point of the
polymer, with the melting point decreasing as molecular
weight increases. If the polymer chosen, for reasons of
degradability perhaps, is semi-crystalline, molecular
weight can also be manipulated to ensure that it is
amorphous at its operating temperature of 37 8C.
To ensure that it can flow readily through a needle, the
polymer must also possess a low glass transition tempera-
ture. The glass transition temperature dependence of the
melt viscosity can be described using the Williams-Landel-
Ferry equation,[8]
!

h
C1 T
Tg
log ¼
 (3)
hTg C1 þ T
Tg
in which C1 and C2 are constants for a given polymer, and hTg
is the melt viscosity of the polymer at its glass transition
temperature. For many linear amorphous polymers, C1 and
C2 can be approximated as 17.44 and 51.6, respectively.[8] As
the glass transition temperature decreases, for example, by
designing the polymer so as to possess flexible linkages in
Macromol. Biosci. 2010, 10, 825–835
826 ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
B. G. Amsden
Brian Amsden obtained his PhD in Chemical
Engineering from Queen’s University in 1996,
in the area of therapeutic protein delivery from
hydrogels and polymer microspheres. He worked
for Angiotech Pharmaceuticals from 1996-97 as a
Research Associate, leading projects involving
the formulation of paclitaxel for localized deliv-
ery to treat post-operative adhesions and psor-
iasis, and participating in projects developing
degradable microsphere and micellar formu-
lations of paclitaxel for intra-articular delivery
and systemic delivery, respectively. He left
Angiotech to join the Faculty of Pharmacy at
the University of Alberta and is currently a Pro-
fessor in the Department of Chemical Engineer-
ing at Queen’s University where he has been
since July 2000. His current research interests
include the development of biodegradable elas-
for the local delivery of small molecules, pep-
tides, and proteins, and as scaffolds for soft and
connective tissue regeneration.
the backbone or through elimination of polymer chain
interactions by inclusion of a plasticizer, the viscosity
decreases. Furthermore, hTg is also molecular weight
dependent, decreasing as molecular weight increases.
For biodegradability, most polymer designs include
hydrolyzable linkages such as esters or anhydrides. For
these polymers, degradation rate is then dependent on the
relative rates of water diffusion into the bulk of the polymer
and the kinetics of the hydrolysis reaction.[9] The rate of
water penetration is determined by the diffusivity of water
into the polymer and the relative hydrophobicity of the
polymer. Water diffusivity into polymers is dependent on
polymer chain flexibility, increasing as chain flexibility
increase, and hence as glass transition temperature
decreases.[10] Degradation rates are also influenced by the
nature of the drug incorporated; hydrophilic drugs will act in
an osmotic fashion to draw water into the polymer bulk,
whereas hydrophobic drugs can act as plasticizers or can
retard water penetration into the bulk.[11] The hydrolysis
kinetics are determined by the susceptibility of the linkage to
hydrolysis; for example, anhydrides undergo hydrolysis
much faster than do esters.[12] Moreover, esters and
anhydrides are susceptible to auto-catalyzed hydrolysis, as
they generate acidic degradation products that catalyze the
hydrolysis, and hence the internal pH may decrease more
rapidly than the pH at the surface of the implanted polymer.
Poly(ortho ester)s
The first descriptions of biodegradable, liquid polymers to
be used for drug delivery were from Heller et al. concerning
poly(ortho ester)s (POE).[13,14] Much of the early work was
DOI: 10.1002/mabi.200900465
Liquid, Injectable, Hydrophobic and Biodegradable Polymers as . . .

Scheme 1. Structures of poly(ortho esters) developed by Heller et al.[16] Top: poly(ortho ester) class III, prepared through the transester-
ification reaction of 1,2,6-hexanetriol and trimethyl orthoacetate. Bottom: poly(ortho ester) class IV.[18] R represents the chemical group that
arises from the choice of diol used (e.g., 1,10-decanediol or triethylene glycol), while R0 represents the diol initiator used during the ring-
opening polymerization to yield either oligo(lactide) (shown above), or oligo(glycolide).

done using the poly(ortho ester) family prepared through
the transesterification reaction of 1,2,6-hexanetriol and
trimethyl orthoacetate, designated POE III (Scheme 1).
These polymers degraded by hydrolysis of the ester linkages
yielding acetic acid and the original triol as degradation
products. The degradation rate of the polymer was
controllable by incorporating acidic or basic compounds.
Moreover, they were injectable, sterilizable, and possessed
good biocompatibility when injected into the ocular
subconjunctival space.[15] However, this polymerization
approach required long reaction times, control of the
molecular weight was unachievable, and it was very
difficult to scale up and so further development of POE III
was abandoned.[16]
To overcome these problems, a new class of poly(ortho
ester)s was developed, designated POE IV. These polymers
were prepared through polyaddition of polyols with a
diketene acetal, 3,9-diethylidene-2,4,8,10-tetraoxaspir-
o[5.5]undecane (DETOSU). Examples of polyols used
included 1,10-decanediol or triethylene glycol to provide
backbone flexibility, and oligo(lactic acid) or oligo(glycolic
acid) (termed latent acid diols) to provide controllable
degradation rates (Table 1). The structure of these polymers
is provided in Scheme 1. It can be appreciated that a large
number of different poly(ortho ester)s can be prepared in
this fashion through utilization of different diols. The
nature of the diol used influenced the physical properties of
the final polymer. For example, the use of 1,10-decanediol
resulted in a hydrophobic polymer while triethylene glycol
resulted in more hydrophilic polymers. The glass transition
temperature of the polymers was also determined by choice
of the diol used. For example, inclusion of trans-cyclohex-
anedimethanol, which imparts rigidity to the polymer
backbone, increased the polymer glass transition tempera-
ture, whereas inclusion of longer chain alkane diols
decreased the polymer glass transition temperature;[16,17]
glass transition temperatures as low as
46 8C have been
reported.[17] Control over the molecular weight of POE IV
polymers was achieved by using an excess of diol relative to
the diketene acetal or through the use of a chain-stopper
monofunctional alcohol, such as, for example, 1-decanol.[17]
The number-average molecular weight for injectable
purposes was maintained below 5 000 Da, and the
polydispersities ranged from 1.6 to 1.9.[17]
The degradation of POE IV is believed to occur in the
following sequence. First, the lactide or glycolide segment is
hydrolyzed yielding a shorter polymer chain possessing a
carboxylic acid end group. Further cleavage results in the
liberation of free lactic or glycolic acid. These acidic groups
then catalyze hydrolysis of the ortho ester groups. The final
products of the degradation of this poly(ortho ester) class
are the original diol used (e.g., triethylene glycol or 1,10-

Table 1. Physical properties of POE IV polymers developed as injectable delivery systems.

Polymer Mn; M w; Tg h at 37 -C Ref.

Da Da -C Pa  s

DETOSU/1,10decanediol/1,10 decanediol dilactate 5 200 9 700
25 148a) [17]

a)
4 500 7 400
33 70.8
3 800 6 100
46 60.9a)
DETOSU/triethylene glycol/triethylene glycol monoglycolide 6 410 8 850
25 1 200–1 300b) [24]

a)
Complex viscosity; b)Zero-shear viscosity.

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 B. G. Amsden

decandiol), pentaerythritol, propionic acid, and lactic or

glycolic acid.[18] This process of degradation is supported by
in vitro degradation data showing that the mass loss of high
molecular weight poly(ortho ester)s prepared using 1,10-
decanediol, 1,10-decanediol dilactate, and DETOSU polymer
was closely matched by the release of lactic and propionic
acid.[19] The resulting degradation also appears to proceed
predominantly via surface erosion, as the surface contains
more water; however some bulk erosion also occurs. The
degradation rates of the POE IV polymers depend on their
monomer composition. Increasing the amount of oligolac-
tide diol in the polymer increased the in vitro degradation
rate of high molecular weight POE IV polymers prepared
using 1,10-decanediol and 1,10-decanediol dilactate.[19] The
same effect would be expected for low-molecular-weight
polymers. Moreover, the use of an oligoglycolide diol would
be expected to further increase the degradation rate given
that polyglycolide is more hydrophilic and degrades faster
than polylactide.[20] Similarly, the hydrophilicity of the diol
can be utilized to control the degradation rate. For example,
low-molecular-weight poly(ortho ester)s composed of
DETOSU, triethylene glycol, and triethylene glycol glycolide
degraded much more rapidly than those composed of
DETOSU, decanediol and triethylene glycol glycolide when
implanted subcutaneously in mice; the former degraded
within 2 days while the latter degraded completely
between 23 and 25 days.[16]
The in vivo biocompatibility of these injectable polymers
has been examined and reported after ocular implantation
in rabbits,[21] and implantation into the periodontal pocket
in humans.[22] In both cases the polymer was composed of
DETOSU, 1,10-decanediol, and 1,10-decanediol dilactate, Figure 1. A) Representative release profiles of various drugs
and had a weight-average molecular weight of 5 000 to loaded into POE IV polymers composed of DETOSU, triethylene
6 000 Da. The implants were well tolerated, with only mild glycol, and triethylene glycol diglycolide.[23,24] B) A closer com-
parison of the release of positively charge drugs from the POE IV
inflammatory responses reported. Interestingly, the degra-
polymer showing that their release rates are approximately linear
dation rate of the implants depended on the ocular and essentially identical beyond an initial period. The solid lines
implantation site, with polymer lifetimes ranging from represent a linear regression to the data. (LYS ¼ lysozyme,
5 weeks after subconjunctival implantation to 6 months BSA ¼ bovine serum albumin, and VEGF ¼ vascular endothelial
following suprachoroidal or intracameral implantation. growth factor).
The differences in degradation rate were not discussed, but
may be due to differences in local tissue movement. In the (VEGF)[24] from poly(ortho ester)s composed of DETOSU,
subconjunctical space, the polymer may have been exposed triethylene glycol, and triethylene glycol diglycolide. Their
to mechanical stress as a result of eye movement, resulting release rates are shown in Figure 1. For all the drugs but
in a physical erosion of the polymer, whereas in the VEGF, release began with an initial faster, burst phase,
suprachoroidal or intracameral space, the extent of followed by a nearly linear release period. The release
mechanical stresses would likely have been much smaller. profiles of the low-molecular-weight bupivacaine (288.43
A number of different drugs or drug analogs have been Da) and the higher molecular weight lysozyme (LYS,
incorporated into injectable POE IV polymers, and their 14.7 kDa) are essentially the same, up to about 30 h, after
release rates monitored. For example, in vitro and in vivo which time the lysozyme release is much slower (Figure 1A).
release studies have been undertaken with the local Despite exhibiting an initial lag period, VEGF (VEGF, 45 kDa)
anaesthetic bupivacaine,[23] while in vitro release has been was released at essentially the same rate as well (Figure 1B).
demonstrated using protein drug analogs such as bovine By contrast, bovine serum albumin (BSA, 67 kDa) was
serum albumin,[23,24] lysozyme and lactalbumin,[24] and the released much more slowly (Figure 1A). These release
angiogenic protein vascular endothelial growth factor characteristics cannot be explained by the different size and

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828 ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/mabi.200900465
Liquid, Injectable, Hydrophobic and Biodegradable Polymers as . . .
therefore diffusivity of the molecules within the polymer
matrix, but appear to be dependent on the overall charge of
the molecule. Bupivacaine (pKa ¼ 8 [25]), LYS (pHi ¼ 11 [25]),
and VEGF (pHi ¼ 8.9 [26]) are all positively charged, whereas
BSA (pHi ¼ 4.7 [27]) is negatively charged, at the pH
conditions existing within the degrading polymer. This
influence of molecular charge was noted by Weert et al.
when examining protein release from the polymers.[24]
They postulated that the more basic proteins effectively
catalyze the degradation of the poly(ortho ester), enhancing
their release, which is controlled by the polymer degrada-
tion rate. This explanation is supported by the fact that the
bupivacaine is also released at the same rate as the
positively charged proteins.
In vitro release experiments have also been undertaken
with poly(ortho ester)s composed of DETOSU, 1,10-decan-
ediol, and 1,10-decanediol dilactate (molar ratios of
100:50:50) using tetracycline.[28] Tetracycline release from
this more hydrophobic polymer lasted longer (approxi-
mately 15 days), but exhibited a more sigmoidal release
pattern. This formulation was tested in humans for
treatment of infection in the periodontal pocket.[22] Despite
the formulation being apparently well tolerated by the
patients, the polymer was not retained at the injection site,
with only 2 out of 24 sites having the formulation present
by day 11.
A drawback of the use of these polymers with respect to
drug delivery is that the accumulation of acidic degradation
products within the polymer resulted in a drop in pH to less
than 5.2 within a day within triethylene glycol-based
poly(ortho ester)s.[24] This drop in pH has been cited as the
cause of both protein aggregation and VEGF denaturation
through hydrolysis when released from these polymers.[24]
Attempts to overcome this denaturation could include the
incorporation of basic compounds, as has been done
previously with earlier POE polymers to control their
degradation rate.[15] Nevertheless, such attempts to control
the acidic microenvironment within poly(lactide-co-glyco-
lide) microspheres has been somewhat unsuccessful as pH
varies throughout the interior of the polymer,[29] and so the
use of these injectable polymers may need to be restricted to
drugs that are not acid sensitive.
Poly(ester)s
A series of patents assigned to Ethicon Inc., describe the
preparation and use of liquid or low melting point,
biodegradable poly(a-hydroxy acid)s as injectable delivery
systems.[30–33] All the patents describe the preparation of
low-molecular-weight co- or terpolymers of e-caprolactone
with either lactide, para-dioxanone, or trimethylene
carbonate through ring-opening polymerization. The e-
caprolactone is considered a necessary comonomer because
Macromol. Biosci. 2010, 10, 825–835
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
it imparts a low glass transition temperature and thus a low
viscosity to the final polymer (the glass transition
temperature of poly(e-caprolactone) is
60 8C [34]). Proper-
ties of examples of these polymers are given in Table 2. The
data in Table 2 illustrate the degree of control over the final
viscosity of the polymers achieved through copolymeriza-
tion and by manipulation of the molecular weight.
Polymer viscosity can also be controlled by the choice of
initiator used. For low-molecular-weight polymers, the
initiator comprises a significant portion of the overall
macromolecule. In the examples in Table 2 taken from
Bezwada et al.[32] and Scopelianos et al.,[33] the initiator used
was propylene glycol, whereas the initiator used by
Sharifpoor et al. was 1-octanol.[35] It has been demonstrated
that the length of alkanol initiators used, and the presence
of carbon-carbon double bonds in the middle region of the
initiator used, influences the melt viscosity of the final low-
molecular-weight polymer, all other parameters being kept
constant. For primary alcohol initiators, the longer the
chain length of the initiator the lower the melt viscosity of
the polymer, until a chain length of eight carbons, after
which there was no noticeable effect. The use of secondary
alcohols resulted in higher viscosities while the use of an
unsaturated alcohol, also reduced the melt viscosity of the
polymer.[36,37] The influence of the initiator is explained in
terms of the flexibility of the overall polymer chain; the
more flexible the polymer chain, the more readily it orients
in the direction of the applied force, thus exhibiting a lower
viscosity. Increasing the number of carbons in an alkane
portion of the polymer increases its chain flexibility, while
bulky pendant groups increase steric hindrance for bond
rotation about the chain and decrease chain flexibility. The
presence of unsaturated groups along the backbone results
in eased rotation of the neighboring carbon groups on the
backbone in the melt.[38]
The architecture of the polymer also has been used to
manipulate its viscosity. The use of polyol initiators such as
glycerol or pentaerythritol in the ring-opening polymeriza-
tion leads to star polymers, and low-molecular-weight star-
shaped polymers possess a lower melt viscosity than their
linear counterparts of equal molecular weight.[38] This
approach was taken by Sokolsky-Papkov and Domb, who
used castor oil, a triglyceride of ricinoleic acid, as an initiator
in a polycondensation reaction of L- and D,L-lactic acid to
form a star polymer with three arms (Scheme 2); the
polymer has a castor oil core with radiating poly(lactic acid)
blocks and the length of the poly(lactic acid) blocks is
controlled by the feed ratio of lactic acid to castor oil.[39,40]
The viscosity of the polymers formed was determined
primarily by the molecular weight and were viscous liquids
due to the unsaturated group along the ricinoleic acid
backbone and the low molecular weight (Table 2). There
was also an influence of the stereoregularity of the polymer
on viscosity; the poly(L-lactic acid) had a higher viscosity at a
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 B. G. Amsden

Table 2. Physical properties of poly(a-hydroxy acid)s developed as liquid injectable delivery systems (CL ¼ e-caprolactone, PDO ¼ para-
dioxanone, LLA ¼ L-lactide, DLLA ¼ D,L-lactide, CO ¼ castor oil, TMC ¼ trimethylene carbonate, HLA ¼ monohexyl-substituted lactide,
diHLA ¼ dihexyl-substituted lactide).

Monomers Composition Mn Mw [h]a) Tg Viscosity Ref.

mol-% Da Da dL  g
1 -C ha) T

Pa  s -C

CL:PDO 60:40 1 990 3 230 0.19 7.62 25 [32]

50:50 1 850 3 290 0.22 11.2 25
CL:PDO 50:50 0.08 1.6 37 [33]
0.14 3.2 37
0.22 9.2 37
CL:LLA 50:50 0.14 37 37 [33]
CL:TMC 50:50 0.14 3.4 37 [33]
CL:TMC 88:12 1 550 2 810
67 1.1 37 [35]
50:50 1 400 2 525
62 2.7 37
LLA:CO 55:45 3 300 4 800 12.7 37 [39,40]
62:38 2 600 3 670 4.3 37
52:48 52:48 3 250 4 650 5.5 37
56:44 2 800 3 800 2.0 37
29:71 2 100 2 800 0.9 37
mHLA 100 4 800 6 000
17 715 25 [41]
diHLA 100 4 500 5 620
42 40 25

a)
[h] ¼ inherent viscosity in a 0.1 g  dL
1 hexafluorisopropyl alcohol solution at 25 8C,h ¼ zero-shear viscosity.

given molecular weight than did the poly(D,L-lactic acid),
likely due to enhanced polymer-polymer chain interac-
tions.
While bulky pendant groups decrease polymer chain
flexibility, resulting in increased viscosity, flexible pendant
groups increase polymer chain flexibility. This fact has been
exploited by Trimaille et al., who have synthesized alkyl-
substituted lactide (Scheme 3) and used these monomers to
prepare viscous liquid polymers through ring-opening
polymerization.[41] The viscosity of the poly-(hexyl-sub-
stituted lactide) thus prepared decreased as the degree of
hexyl substitution increased (Table 2).
Examples of the in vitro degradation rate of poly(a-
hydroxy acid) approaches examined in the literature are
given in Figure 2. These polymers degraded through a bulk
degradation process, producing the characteristic weight
loss profile; an initial period in which little weight loss is
observed, followed by a period in which weight loss
increases markedly.[11] In the data of Tomkins et al.
(Figure 2A),[42] the 2 800 Da star poly[(e-caprolactone)-co-
(D,L-lactide)] (SCP) degraded at a faster rate than the 1 400 Da
poly(e-caprolactone) (PCL) because of the incorporation of
the hydrophilic lactide monomer in the SCP. Moreover, the
SCP was amorphous while the PCL was semi-crystalline,
and crystalline regions resist hydrolysis and slow down the
rate at which water can penetrate the polymer.[20] In the
approach of Trimaille et al. [41], the grafting of a single hexyl
pendant group to the lactide monomer reduced the glass
transition temperature of the resulting polymer to the point
where the 4 500 Da polymer was a viscous liquid (Table 2);
however, the increased hydrophobicity that was generated
reduced the overall degradation rate from that of poly(D,L-
lactide) of the same molecular weight (Figure 2B). The
increase in degradation rate that resulted from grafting two
hexyl groups to the lactide was due to the significant (25 8C)
drop in glass transition temperature. This degree of
decrease in glass transition temperature allowed for an
increase in water diffusion through the polymer, leading to
increased hydrolysis. Despite possessing low-molecular-
weight, the hydrophobic castor oil central core resulted in a
slow degradation rate of the star-poly(lactic acid) approach
of Sokolsky-Papkov (Figure 2C). Moreover, there was no
influence of lactic acid stereoregularity on the degradation
rate, likely because each polymer was amorphous as the

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830 ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/mabi.200900465
Liquid, Injectable, Hydrophobic and Biodegradable Polymers as . . .
Scheme 2. Polycondensation reaction of castor oil and lactic
poly(lactic acid) according to Sokolsky-Papkov and Domb.[39]
poly(L-lactic acid) blocks were too short to promote
crystallization.
Examples of the release of low-molecular-weight drug
salts from viscous liquid poly(a-hydroxy acids) are shown in
Figure 3A, while the release of vitamin B12 is shown in
Figure 3B. The drug salt release rates vary from 1 week to
3 weeks, and are incomplete for the higher initial drug salt
loadings of 10%. The incomplete release could be due to
interaction between the positively charged tetracycline or
tamsulosin, and the negatively charged polymer degrada-
tion products, although this is a tentative explanation, as
the degradation rates appear to be slow (Figure 2C). Another
possibility is that the dissolved drug salt within the
polymer depots eventually precipitated from solution as
the free base form of the drug and the limited solubility of
the free base form in the aqueous surrounding medium
produced a much slower release rate. Furthermore, there is
not much influence of initial tamsulosin HCl loading on the
release rate, until day 10. Beyond day 10, the tamsulosin HCl
is released at a greater rate normalized to the initial drug
loading from the depots containing 5% drug than from the
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ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
depots containing 10% drug. This result is
in agreement with the lack of influence of
loading on ofloxacin release from linear
poly[(e-caprolactone)-co-lactide] of Bez-
wada et al.[32]
By comparison, vitamin B12, a neutral,
highly water soluble compound, was
completely released from poly[(tri-
methylene carbonate)-co-(e-caprolac-
tone)] depots (Figure 3B).[35] The release
of vitamin B12 increased as the polymer
vehicle viscosity decreased; the viscosity
at 37 8C of the 1 500 Da, 50:50 poly-
[(trimethylene carbonate)-co-(e-caprolac-
tone)] was 2.7 Pa  s (Table 2), while that of
the poly(trimethylene carbonate) was
16.8 Pa  s.[35] The vitamin B12 was mixed
into the polymer at only 1 wt.-%. Its
release thus has been explained in terms
of an osmotic pressure driven mechan-
ism. Upon immersion into water, water
penetrates the polymer as a diffusional
front, until it reaches a particle. The water
dissolves the particle, creating a satu-
rated solution. As a result of the increase
in the water activity gradient, water
begins to be drawn toward the dissolving
particle, generating a pressure equal to
the osmotic pressure of the drug solution.
The pressure begins to push on the
acid yielding a star
polymer, generating a pore that ulti-
mately reaches the surface. This release
mechanism may also be occurring for the
drug salt loaded depots in Figure 3A.
To date, none of these polymers have been used in the
delivery of protein therapeutics. This is likely because these
hydrolyzable polyesters will degrade to generate an acidic
microenvironment, detrimental to the stability of the
entrapped protein. Indeed, Trimaille et al. reported that
tetracycline HCl was degraded within the poly(monohexyl-
substituted lactide) vehicle, and attributed this degradation
to the acidic microenvironment that is generated during
polymer hydrolysis.[41]
There has been little data published on the biocompat-
ibility of these polyester liquid vehicles. Ekholm et al. have
reported that low-molecular-weight amorphous pastes of
poly[(e-caprolactone)-co-(D,L-lactide)] induced a severe
inflammatory response when implanted in the abdominal
muscle of rats.[43] Although not discussed by these authors,
the severe inflammatory response is likely due to the rapid
degradation and concomitant release of a high local
concentration of acidic degradation products. Sokolsky-
Papkov et al. have reported on the in vivo delivery of
bupivacaine, a local anesthetic, from their star poly(lactic
www.mbs-journal.de 831
 B. G. Amsden

Scheme 3. Structures of monohexyl-substituted lactide (mHLA)

(left), dihexyl-substituted lactide (diHLA), and the poly(hexyl-
substituted lactide)s formed through ring-opening polymeri-
zation (ROP) of these monomers.[41]

acid) depots;[40] however, the tissue response to the implant

was not assessed.
A different approach to obtaining liquid, hydrophobic
polymers containing hydrolyzable ester linkages was
taken by Nathan et al. Scheme 4.[44,45] This approach
comprised a polycondensation reaction between a poly-
basic acid, such as succinic anhydride, with a mono-
substituted fatty acid. A representative approach is
illustrated in Scheme 3, showing the formation of a
branched, ester linked, fatty acid polymer from the reaction
of glyceryl monolinoleate with succinic anhydride. The
resulting polymer was a viscous liquid with a number-
average molecular weight of 2 260 Da and a weight-average
molecular weight of 3 955 Da; the viscosity of the polymer
was not disclosed. Examples of other fatty acids that were
used in the polymerization process included glyceryl
monostearate, glyceryl monooleate, glyceryl monodecano-
ate, and glyceryl monolaurate. These fatty acids were also
copolymerized with each other. Furthermore, the hydro-
philicity of the polymer could be increased by copolymer-
ization of poly(ethylene glycol) diol.[44] In an in vivo
experiment, 2 115 Da poly[(monostearoyl glycerol)-co-
(glyceryl monolinoleate/succinate)] was implanted into
bone defects in rabbits by injection. In two of the four
Figure 2. Weight loss during in vitro degradation of low-molecular-
implants, bone regeneration was observed at 8 weeks.[45] weight, viscous liquid poly(a-hydroxy acid)s. A) Data from Tomkins
No other description of tissue response was provided. et al., comparing the degradation rate of 1 400 Da 1-octanol-
initiated PCL to 2 800 Da star poly[(e-caprolactone)-co-(D,L-lactide)]
(50:50 mol:mol) (SCP) and blends of the SCP and PCL of
Poly(carbonate)s different wt.-% SCP.[42] B) Data from Trimaille et al. comparing
the degradation rate of 4 500 Da poly(D,L-lactide) (PLA) to poly-
Recognizing that the acidic degradation products of (monohexyl-substituted lactide) (PmHLA) and poly(dihexyl-
injectable polyesters adversely affects incorporated acid substituted lactide) (PdiHLA).[41] C) Data from Sokolsky-Papkov
sensitive drugs, such as proteins and peptides, we have et al., for three-armed star poly(lactic acid) initiated with castor
recently explored the potential of low-molecular-weight oil, illustrating the influence of lactic acid stereoregularity.[39]

Macromol. Biosci. 2010, 10, 825–835

832 ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/mabi.200900465
Liquid, Injectable, Hydrophobic and Biodegradable Polymers as . . .

Figure 4. In vitro release of VEGF from 1 600 Da poly(trimethylene

carbonate). The VEGF was mixed in as <50 mm solid particles also
comprising 95% trehalose and 4.9% serum albumin. The total
particle loading was 1 wt.-%, consisting of approximately 500 ng
of VEGF.[46]

microenvironmental pH within this degrading polymer

remains near neutral, eliminating the likelihood of acid
degradation of drugs entrapped within the polymer. The
low glass transition temperature ensures that the polymer
is injectable; zero shear viscosity of poly(trimethylene
carbonate) ranges from 0.66 Pa  s for a 600 Da polymer to
123 Pa  s for a 2 400 Da polymer.[47]
As shown in Figure 3B, vitamin B12 was released in a
sustained fashion from 1 500 Da poly(trimethylene carbo-
nate). Building on this result, VEGF was co-lyophilized with
trehalose and serum albumin to yield particles containing
95% trehalose, 4.9% albumin, and 0.1% VEGF.[46] These
Figure 3. In vitro release of low-molecular-weight drugs from particles were incorporated into 1 600 Da poly(trimethy-
viscous liquid poly(a-hydroxy acid)s. A) drug salt release; PmHLA
lene carbonate) at a loading of 1 wt.-% and released in vitro.
refers to 4 500 Da poly(monohexyl-substituted lactide). The tetra-
cycline HCl data are from Trimaille et al.[41] (10% refers to the
loading of drug), while the tamsulosin data are from Sokolsky-
Papkov and Domb for release from 3 250 Da star poly(D,L-lactic
acid).[39] B) vitamin B12 release from 1 500 Da poly(trimethylene
carbonate) and 50:50 poly[(trimethylene carbonate)-co-(e-capro-
lactone)];[35] TMC refers to trimethylene carbonate. The lines are
meant as visual aids only.

poly(trimethylene carbonate) as a delivery vehicle.[46,47]

Poly(trimethylene carbonate) is amorphous and has a glass
transition temperature of from
40 to
17 8C,[48,49] is
readily polymerized via ring-opening polymerization
initiated by various alcohol initiators,[49–53] and has been
demonstrated to be biocompatible when implanted as a
high molecular weight material.[54,55] In contrast to
poly(lactide-co-glycolide) poly(trimethylene carbonate)
undergoes hydrolysis slowly,[54–56] and produces propanol Figure 5. Bioactivity of VEGF released from 1 600 Da poly(tri-
and carbon dioxide as degradation products. Thus, the methylene carbonate) in vitro.[46]

Macromol. Biosci. 2010, 10, 825–835

ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mbs-journal.de 833

Scheme 4. Polycondensation reaction procedure to produce liquid, low-molecular-
weight poly(glyceryl monolinoleate/succinate).[45]
VEGF was released in a sustained manner over a period of
40 to 50 d, with a nearly constant release over the first 18 to
20 d, followed by a monotonically decreasing release rate
(Figure 4). The initially linear release rate was attributed
the osmotic pressure release mechanism described above.
The VEGF remained highly bioactive upon release, as
determined from an endothelial cell-based bioactivity
assay (Figure 5).
Although the stability of acid sensitive drugs was
maintained using this delivery vehicle, 1 600 Da poly-
(trimethylene carbonate) degraded slowly in vivo, reaching
a mass loss of only approximately 55% after 40 weeks
subcutaneous implantation in rats.[47] Poly(trimethylene
carbonate) with a number-average molecular weight of 600
Da was initially rapidly absorbed in vivo, as the low-
molecular-weight fraction of the polydisperse polymer
dissolved in the in vivo aqueous environment, while 2 400
Da poly(trimethylene carbonate) remained essentially non-
degraded, losing only between 5 and 10% of its initial mass
after 40 weeks. In every case, the tissue response to the
implanted material was mild.
Received: December 21, 2009; Revised: February 9, 2010;
Published online: May 17, 2010; DOI: 10.1002/mabi.200900465
Conclusion
Keywords: biodegradable; drug delivery; liquids; tissue response
Liquid, injectable, hydrophobic, and biodegradable poly-
mers have a number of potential advantages as delivery
vehicles for sustained and local delivery. The strategies
explored to date consist primarily of polymers designed to
degrade by hydrolysis. This approach is advantageous in
that degradation can be achieved predictably in vivo and at
Macromol. Biosci. 2010, 10, 825–835
834 ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
B. G. Amsden
reasonable rates. Sustained release of
low molecular hydrophobic and hydro-
philic drugs as well as high molecular
weight proteins have been shown to be
possible. However, the acidic degrada-
tion products have been implicated in
the degradation of the incorporated
drugs, and possibly the less than optimal
tissue response to the implanted tissue in
certain implantation sites where clear-
ance of the degradation products is slow.
This acidity may be used to advantage for
specific drugs. For example, camptothe-
cin, an anti-cancer agent, suffers from
rapid hydrolysis of its lactone ring in
aqueous media to a carboxylate form
that is essentially inactive, whereas at
acidic pH, the lactone ring remains stable
and the drug retains its activity. At
physiological pH more than 80% of the
drug exists as the carboxylate form.[57] A
drug such as camptothecin would be a
good candidate for release from these
polymer vehicles. Nevertheless, the number of drugs that
would benefit from an acidic environment is small.
Alternatively, drug release could be driven to be essentially
complete before significant pH decrease occurs within the
bulk of the polymer. This could be achieved by utilizing the
osmotic pressure release mechanism alone, or perhaps in
combination with the inclusion of basic compounds to
assist in neutralization of acidic polymer degradation
products. Finally, new approaches need to be considered to
generate polymers that are injectable and that biodegrade,
but do not produce significant concentrations of acidic
degradation products. One possible solution would be to
include peptide linkages along the polymer backbone that
are susceptible to enzymatic degradation. This strategy
may result in increased viscosity of the polymer due to
hydrogen bonding between polymer chains, making the
polymer more difficult to inject. However, the enhanced
viscosity may be advantageous as a means of controlling
release rates and to ensure maintenance of a cohesive
polymer mass upon injection.
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