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Patent 2667944 Summary

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(12) Patent Application: (11) CA 2667944
(54) English Title: AROMATIC DI-ACID-CONTAINING POLY (ESTER AMIDE) POLYMERS AND METHODS OF USE
(54) French Title: POLYMERES DE POLYESTER AMIDE CONTENANT UN DIACIDE AROMATIQUE ET PROCEDES POUR LES UTILISER
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • C08L 77/12 (2006.01)
  • A61L 17/10 (2006.01)
  • A61L 31/14 (2006.01)
  • A61L 31/16 (2006.01)
  • A61K 47/48 (2006.01)
(72) Inventors :
  • GOMURASHVILI, ZAZA D. (United States of America)
  • KATSARAVA, RAMAZ (Georgia)
  • JENKINS, TURNER DANIEL (United States of America)
  • TURNELL, WILLIAM (United States of America)
(73) Owners :
  • MEDIVAS, LLC (United States of America)
(71) Applicants :
  • MEDIVAS, LLC (United States of America)
(74) Agent: MBM INTELLECTUAL PROPERTY LAW LLP
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2006-10-25
(87) Open to Public Inspection: 2007-05-03
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US2006/041441
(87) International Publication Number: WO2007/050583
(85) National Entry: 2009-04-24

(30) Application Priority Data:
Application No. Country/Territory Date
60/730,611 United States of America 2005-10-26
60/738,335 United States of America 2005-11-18
60/839,867 United States of America 2006-08-23

Abstracts

English Abstract

The present invention provides biodegradable, biocompatible aromatic di-acid- containing poly(ester amide) (PEA) polymers with thermo-mechanical properties that can be readily tailored by selection of various combinations and proportions of the di-acid residues in the polymers. The polymers are suitable for use in production of drug-releasing biodegradable particles and implantable surgical devices, such as stents and internal fixation devices. The polymer compositions and surgical devices biodegrade in vivo by enzymatic action to release bioactive agents in a controlled manner over time as well as biocompatible breakdown products, including one to multiple different amino acids.


French Abstract

La présente invention concerne des polymères de polyester amide (PEA) biodégradables contenant un diacide aromatique biocompatible. Ces polymères présentent des propriétés thermomécaniques qui peuvent facilement être adaptées en sélectionnant diverses combinaisons et proportions des résidus de diacide dans les polymères. Lesdits polymères sont conçus pour être utilisés dans la production de particules biodégradables à libération de médicament et de dispositifs chirurgicaux implantables, tels que des endoprothèses et des dispositifs de fixation interne. Les compositions de polymère et les dispositifs chirurgicaux se biodégradent in vivo par action enzymatique afin de libérer des agents bioréactifs de manière contrôlée dans le temps, ainsi que des produits de dégradation biocompatibles, y compris un à plusieurs acides aminés différents.

Claims

Note: Claims are shown in the official language in which they were submitted.





CLAIMS



1. A polymer composition comprising at least one or a blend of poly(ester
amide) (PEA)
polymers having a chemical formula described by general structural formula (I)

Image
wherein, n is about 20 to about 150; each R1 is independently selected from
residues of .alpha.,.omega.-
bis (o,m, or p-carboxyphenoxy) (C1-C8) alkane, 3,3'-
(alkenedioyldioxy)dicinnamic acid or
4,4'-(alkanedioyldioxy)dicinnamic acid; the R3s in each n monomer are
independently
selected from the group consisting of hydrogen, (C1-C6) alkyl, (C2-C6)
alkenyl, (C2-C6)
alkynyl, (C6-C10) aryl (C1-C6) alkyl and -(CH2)2S(CH2); and R4 is
independently selected
from the group consisting of (C2-C20) alkylene, (C2-C20) alkenylene, (C2-C8)
alkyloxy, (C2-
C20) alkylene, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of general
formula(II), and
combinations thereof;

Image
or a chemical structure described by general structural formula (III),
Image

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1, n is about
20 to
about 150, R1 is a combination of about 0.1 part to about 0.9 part of
.alpha.,.omega.-bis(o, m or p-
carboxyphenyloxy)-(C1-C8)alkane, 3,3'-(alkenedioyldioxy)dicinnamic acid or
4,4'-
(alkanedioyldioxy)dicinnamic acid and about 0.9 part to about 0.1 part
selected from (C2-




C20) alkylene, (C2-C20) alkenylene, or mixtures thereof; R2 is hydrogen, or
(C6-C10) aryl (C1-
C6) alkyl or a protecting group; each R3 is independently hydrogen, (C1-C6)
alkyl, (C2-C6)
alkenyl, (C2-C6) alkynyl and (C6-C10) aryl (C1-C6) alkyl and-(CH2)2S(CH2);
each R4 is
selected from the group consisting of (C2-C20) alkylene, (C2-C20) alkenylene,
(C2-C8)
alkyloxy (C2-C20) alkylene, bicyclic-fragments of 1,4:3,6-dianhydrohexitols of
general
formula III, and combinations thereof; and R5 is independently (C2-C20) alkyl
or (C2-C20)
alkylene.


2. The composition of claim 1, wherein the R3 is CH2Ph.


3. The composition of claim 1, wherein the R3 is selected from hydrogen, CH2-
CH(CH3)2, CH3, CH(CH3)2, CH(CH3)-CH2-CH3, CH2-C6H5, or (CH2)2SCH3.


4. The composition of claim 1, wherein all of the R3s are selected from
hydrogen,
CH2-CH(CH3)2, CH3, CH(CH3)2, CH(CH3)-CH2-CH3, CH2-C6H5,-(CH2)3, or
(CH2)2SCH3).

S. The composition of claim 1, wherein at least one of the R1s is the residues
of .alpha.,.omega.-bis
(4-carboxyphenoxy) propane.


6. The composition of claim 1, wherein at least one of the R1s is the residues
of .alpha.,.omega.-bis
(4-carboxyphenoxy) hexane.


7. The composition of claim 1, wherein at least one of the R1s is the residues
of .alpha.,.omega.-bis
(4-carboxyphenoxy) methane.


8. The composition of claim 1, wherein at least one of the R1s is the residues
of the 4,4'-
(alkanedioyldioxy)dicinnamic acid.


9. The composition of claim 1, wherein at least one of the R1s is the residues
of the 4,4'-
(adipoyldioxy)dicinnamic acid.


10. The composition of claim 1, wherein at least one of the R1s is the
residues of the 4,4'-
(sebacoyldioxy)dicinnamic acid.


11. The composition of claim 1, wherein at least one of the R1s is the
residues of the 3,3'-
(alkanedioyldioxy)dicinnamic acid.


12. The composition of claim 1, wherein at least one of the R1s is the
residues of the 3,3'-
(adipoyldioxy)dicinnamic acid.





13. The composition of claim 1, wlierein from about 0.1 part to about 0.9 part
of R4 is the
1,4:3,6-dianhydrohexitol.


14. The composition of claim 1, wherein the 1,4:3,6-dianhydrohexitol is
derived from D-
glucitol, D-mannitol, or L-iditol.


15. The composition of claim 1, wherein the 1,4:3,6-dianhydrohexitol is
1,4:3,6-
dianhydrosorbitol (DAS).


16. The composition of claim 1, wherein the composition biodegrades over a
period of
about 14 days to about six years.


17. The composition of claim 1, wherein the composition biodegrades to form
from one
to multiple different amino acids.


18. The composition of claim 1, wherein the polymer has a molecular weight in
the range
from about 15 000 Da to about 600 000 Da.


19. The composition of claim 1, wherein the polymer has a glass transition
temperature
(Tg) in the range from about 22°C to about 120°C.


20. The composition of claim 1, wherein a film of the polymer has tensile
stress of about
20 MPa to about 90 Mpa at yield.


21. The composition of claim 1, wherein a film of the polymer has a percent
elongation of
about 5 % to about 400 % at yield.


22. The composition of claim 1, wherein a film of the polymer has a Young's
modulus in
the range from about 400 MPa to about 2000 MPa at yield.


23. The composition of claim 1, wherein the composition further comprises an
effective
amount of at least one bioactive agent dispersed in the polymer.


24. The composition of claim 23, wherein the composition includes from about 5
to about
150 molecules of the bioactive agent per polymer molecule chain.


25. The composition of claim 23 wherein the at least one bioactive agent is
covalently
bonded to the polymer.





26. The composition of claim 23, wherein the at least one bioactive agent is
released from
the composition at a controlled rate substantially as a result of
biodegradation of surface area
of the composition.


27. The composition of claim 23, wherein at least two bioactive agents are
dispersed in
the composition.


28. The composition of claim 1, wherein the polymer has a molecular weight in
the range
from about 15 000 Da to about 600 000 Da.


29. A method comprising fabricating a biodegradable, biocompatible surgical
device
using a composition of claim 1.


30. The method of claim 29, wherein the composition further comprises a
bioactive agent
dispersed in the polymer.


31. The method of claim 29, wherein the surgical device biodegrades under
physiological
conditions over a time selected from about 14 days to about six years.


32. The composition of claim 29, wherein the surgical device is an internal
fixation
device.


33. The composition of claim 32, wherein the surgical device is a vascular
stent or
dialysis shunt.


34. A device comprising a composition of claim 1, wherein the device
completely
biodegrades under physiological conditions within about two days to about six
years to
produce substantially biocompatible breakdown products.


35. The device of claim 34, wherein the device further comprises a bioactive
agent
dispersed in the polymer.


36. The device of claim 34, wherein the device is an implantable internal
fixation device.

37. The device of claim 35, wherein the internal fixation device is a surgical
suture.


38. The device of claim 34, wherein the internal fixation device is a surgical
screw.


39. The device of claim 34, wherein the internal fixation device is an
implantable plate.





40. The device of claim 34, wherein the internal fixation device is an
implantable rod.

41. The device of claim 34, wherein the surgical device is an implantable
vascular stent.

42. The device of claim 34, wherein the device is an implantable dialysis
shunt.


43. A method comprising implanting a surgical internal fixation device
comprising a
composition of claim 1 into an internal body site to fix the internal body
site while the
composition biodegrades, creating substantially biocompatible breakdown
products.


44. The method of claim 41, wherein the device completely biodegrades within
about two
days to about six years.


45. The method of claim 41, wherein the composition further comprises a
bioactive agent
dispersed in the polymer and the bioactive agent is released to surrounding
tissue during
biodegradation of the device.


Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
AROMATIC DI-ACID-CONTAINING
POLY (ESTER AMIDE) POLYMERS AND METHODS OF USE
FIELD OF THE INVENTION

[0001] The invention relates, in general, to drug delivery systems and, in
particular, to
polymer delivery compositions that incorporate aliphatic amino acids into a
biodegradable
polynier baclcbone.

BACKGROUND INFORMATION

[0002] The earliest drug deliveiy systems, first introduced in the 1970s, were
based on
polymers formed from lactic and glycolic acids. Today, polymeric materials
still provide the
most important avenues for research, primarily because of their ease of
processing and the
ability of researchers to readily control their chemical and physical
properties via molecular
synthesis. Basically, two broad categories of polyn7er systems, both lcnown as
"microspheres" because of their size and shape, have been studied: reservoir
devices and
matrix devices. The former involves the encapsulation of a pharmaceutical
product within a
polymer sliell, whereas the latter describes a system in which a drug is
physically entrapped
within a polymer network.

[0003] The release of inedications from either categoYy of polymer device
traditionally has
been diffusion-controlled. Currently, however, modem research is aimed at
investigating
biodegradable polymer systems. These drug deliverers, for exainple
polyhydoxyalkanoates,
degrade into biologically acceptable compounds, often through the process of
hydrolysis, and
leave their incorporated medications behind. This erosion process occurs
either in bulk
(wherein the matrix degrades uniformly) or at the polymer's surface (whereby
release rates
are related to the polymer's surface area). The degradation process itself
involves the
brealcdown of these polymers into lactic and glycolic acids. These acids are
eventually
reduced by the Kreb's cycle to carbon dioxide and water, which the body can
easily expel.
[0004] Amino Acid based Bioanalogous Biopolymers (AABB) - a new family of
hydrophobic a-amino acid based polymers recently has been developed.
Poly(ester amides),
(PEAs), poly(ester urethanes) (PEURs), and poly(ester ureas) (PEUs) with
linear structures,
which are based on a-amino acids, fatty dicarboxylic acids and aliphatic diols
have been
synthesized via an Active Polycondensation (APC) niethod. The APC method
mainly is
conducted in solution under mild temperatures without use of any toxic
catalyst. Using this


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
method, a large variety of AABB polymers with a broad range of physical and
thenno-
nlechanical properties and biodegradation profiles have been reported und
studied. See
review paper and references therein by R. Katsarava (Macromol. S)Imp. (2003)
199:419-429).

[0005] In particular, a-amino acid-based poly(ester amide) (PEA) and
poly(ester urethane)
(PEUR) polymers demonstrate enzyme-inediated surface degradation (G.
Tsitlanadze, et al. J.
Biomatef . Sci. Polynz. Edn. (2004) 15:1-24 and T. Kartvelishvili, at al.
Macroinol, Cliena.
Plrys. (1997) 198: 1921-1932) and PEAs show a low inflammation profile (K.
DeFife et al.
Transcatheter Cardiovascular Therapeutics - TCT 2004 Conference. Poster
presentation.
Washington DC. (2004)). These properties malce PEAs and PEURs excellent
materials for a
variety of different medical and pharmaceutical applications.

[0006] A. Conix in 1957 reported the synthesis of aromatic polyanhydrides with
excellent
film and fiber-forming properties and high melting temperatures (up to 267 C)
based on 1,3-
bis(4-carboxyphenoxy)propane (CPP) (A. Conix, Malcromol. Chem, 24, 76-78,
(1957)).
However, these polymers were unsuitable for use in textiles due to the
hydrolytic instability
of anhydride linkage. CPP as di-acid monomer was again revisited by R.
Langer's team (A.J.
Domb and R.L. Langer. J. Polym. Sci.: Paf tA: Polvm. Claeni. (1987) 25:3373-
3386) in the
mid 1980s, and erodible biocompatible copolyanhydrides based on CPP and
aliphatic
dicarboxylic acids were designed.

[0007] FDA-approved controlled-delivery polymer wafer - Gliadel (Guilford
Pharmaceutical Corp, Baltimore, Md), is the combination of a copolyanhydride
matrix
consisting of CPP and sebacic acid (in 20 to 80 molar ratios,) in which the
anticancer agent is
physically admixed (W. Dang et al. J. Contr. Rel. (1996) 42:83-92). Hydrolytic
degradation
products of Gliadel wafer (iri addition to the anticancer agent) are
ultimately the starting di-
acids: sebacic acid and CPP. Clinical investigations of Gliadel implants in
rabbit brains have
shown limited toxicity, initial activity and fast excretion of decomposition
products - the free
acids (A.J. Domb et al. Biomaterials. (1995) 16:1069-1072).

[0008] More recently, CPP was disclosed as a monomer useful in preparation of
bioabsorbable stents for vascular applications by "Advanced Cardiovascular
Systems, Inc", in
patent WO 03/080147 Al, 2003 and polymer particles in co-pending provisional
application
Serial No. 60/684,670, filed May 25, 2005.

[0009] Another aromatic biodegradable di-acid monomer based on trans-4-hydroxy-

cinnamic acid has been recently described. The monomer with general name 4,4'-


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WO 2007/050583 PCT/US2006/041441
(alkanedioyldioxy) dicinnainic acid inherently contains two hydrolytically
labile ester groups,
and is expected to undergo specific (enzyinatic) and nonspecific (chemical)
hydrolysis (M
Nagata, Y. Sato. Polynaer. (2004) 45:87-93).

[0010] Despite these advances in the ai-t, there is a need for more and better
varieties of
biocoinpatible polymer compositions and methods for delivering therapeutic
molecules, such
as drugs and other bioactive agents, at a controlled rate of therapeutic or
palliative release,
while affording enhanced thermo-mechanical and pliysical properties.

SUMMARY OF THE INVENTION

[0011] The present invention is based on the discovery of new aromatic di-acid-
containing
poly(ester ainide) (PEA) polymer compositions witli significant iniprovement
in thermo-
mechanical properties. Bis(a-amino acid)-a,to-allcylene-diester is a type of
diamine
monomer, useful for active polycondensation (APC), and which inherently
contains two
aliphatic ester linkages. Such ester groups can be enzymatically recognized by
various
esterases, thus making the polymer biodegradable. Condensation of diamine
monomers, for
example, with activated di-acid esters, results in a PEA macromolecule with
ester and amide
linkages. Incorporation of a,co-bis(4-carboxyphenoxy)alkane, 3,3'-
(alkanedioyldioxy)dicinnamic acid or 4,4'-(alkanedioyldioxy)dicinnamic acid as
the di-acid
residue in at least one of the bis(a-amino acid)-based building blocks in the
invention PEA
polymers confers high glass transition temperature (Tg) on the polymer. In
addition, the
invention PEA polymer compositions optionally can include a second, C-
protected
adirectional amino acid-based monomer to introduce additional flexibility into
the polymer.
[0012] Accordingly in one embodiment, the invention provides polymer
compositions
containing at least one or a blend of poly(ester amide) (PEA) polymers having
a chemical
formula described by general structural formula (I)

O 0 H O O H
C-R1-C-N-C-C-O-R 4-0-C-C-N
R3 R3 H n
Formula (I)

wherein, n is about 20 to about 150; each Rl is independently selected from
residues of a,O)-
bis (o,na, orp-carboxyphenoxy)-(C1-C$) alkane, 3,3'-
(alkenedioyldioxy)dicinnamic acid or
4,4'-(alkanedioyldioxy)dicinnamic acid; the R3s in each n monomer are
independently


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
selected from the group consisting of hydrogen, (C1-C6) allcyl, (C2-C6)
alkenyl, (C2-C6)
alkynyl, (C6-C10) aryl (C1-C6) alkyl and -(CH2)2S(CH3); R4 is independently
selected from
the group consisting of (C2-C20) allcylene, (C2-C20) allcenylene, (C2-C$)
allcyloxy, (C2-C20)
allcylene, bicyclic-fragnients of 1,4:3,6-diaiihydrohexitols of general
forinula(II), and
combinations tliereof;

CH O
HaC/ ~CH2
O CH

Formula (II)

or a chemical structure described by general structtual formula (III),
O 10 H O 4 O H 0 1 0 H 5
C-R -C-N-C-C-O-R -O-C-C-N C-R -C-N-C-R -N
H R3 3 H m H C
11 -O-FRe2 H p
O n
Forniula (III)

wherein m is about 0.1 to about 0.9; p is about 0:9 to about 0.1, n is about
10 to
about 150, Rl is a combination of about 0.1 part to about 0.9 part of a,ce -
bis(o,m orp-
carboxy phenoxy)-(CI-C$) alkane, 3,3'-(alkenedioyldioxy)dicinnamic acid or
4,4'-
(alkenedioyldioxy)dicinnainic acid and about 0.9 part to about 0.1 part
selected from (C2 -
C20) alkylene, (C2-C20) alkenylene, or mixtures thereof; R2 is hydrogen, or
(C6-C10) aryl (C1-
C6) allcyl or a protecting group; each R3 is indeperndently hydrogen, (C1-C6)
alkyl, (C2-C6)
alkenyl, (C2-C6) alkynyl and (C6-C 10) aryl (CI-C6) alkyl and -(CH2)2S(CH3);
each R4 is
selected from the group consisting of (C2-C20) alkylene, (C2-C20) alkenylene,
(C2-C8)
alkyloxy (C2-C20) alkylene, bicyclic-fiagments of 1,4:3,6-dianhydrohexitols of
general
fonnula III, and combinations thereof; and R5 is independently (C1-C2o) alkyl
or (C2-C20)
alkenyl.

[0013] In another embodiment, the invention provides methods for fixing an
internal body
part in a subject by implanting into an internal body site a surgical internal
fixation device
fabricated using an invention polyiner composition containing a a,eo-bis(4-
carboxyphenoxy)
alkane, 3,3'-(alkenedioyldioxy)dicinnamic acid or 4,4'-
(alkanedioyldioxy)dicinnamic acid-


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
containing PEA polymer to fix the internal body site while the coinposition
biodegrades to
release substantially biocompatible brealc down products.

[0014] In yet another embodiment, the invention provides biodegradable,
biocompatible
surgical devices fabricated using an invention PEA polymer coinposition.

A BRIEF DESCRIPTION OF THE FIGURES

[0015] Fig. 1 is a iH NMR (500 MHz, DMSO-d6) spectrum of an invention PEA
polymer
containing 50% of CCP as the di-acid building block (polymer #3 in Table 1).

[0016] Fig. 2 is a graph showing a Differential Scaiming Calorimetry trace of
an invention
PEA polyiner (polymer #3 in Table 1), first heating, heating rate 10 C/min.

A DETAILED DESCRIPTION OF THE INVENTION

[0017] The invention is based on the discovery that an active ester of an a,co-
bis(4-
carboxyphenoxy) alkanoic di-acid is useful for active polycondensation and
synthesis of
copoly(ester amides) (PEAs) in which the ap-bis(o,rrz, orp-carboxyphenoxy)
alkanoic acid is
used to at least partially displace the aliphatic dicarboxylic acids used in
fabrication. Such
aromatic di-acid-containing PEA polymers have significant improvement in
thermo-
mechanical properties. While each of the building blocks contributes to the
properties of any
given PEA polymer, in the present invention selection of the di-acid residues
in the bis-(a-
amino acid)-diol-diester containing monomers is exploited to control the
thermo-mechanical
properties of the polymers. Incorporation of an aromatic residue, a,co-bis(4-
carboxyphenoxy)
alkane, 3,3'-(alkenedioyldioxy)dicinnamic acid or 4,4'-
(alkanedioyldioxy)dicinnamic acid, in
the place of at least a portion of the aliphatic dicarboxylic acid residues in
the diester-diamine
based monomers confers relatively high glass transition temperature (Tg) on
the polymer.
The isomers 4,4'- and 3,3'-(alkanedioyldioxy)dicinnamic acid are newly
discovered to be
useful as di-acid monomer for PEA synthesis. Use of a residue of a saturated
or unsaturated
alkyl diol in the monomers provides elongation properties of the resulting
polymer. A
second, L-lysine-based monomer optionally can be included in an invention
polymer to
introduce an additional diol residue that can be selected to further control
the thermo-
mechanical properties of the polymer.


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[0018] The biodegradable polymers containing unsaturated groups have potential
for
various applications. For example, unsaturated groups can be converted into
other fu.nctional
groups such as epoxy or alcohol - usefitl for further modifications. Their
crosslinlcing could
enliance thermal and mechanical properties of polyiner. Cinnamate is known to
undergo
reversible [2 + 2] cycloaddition upon W irradiation at wavelengtlis over 290
nm, without
presence of photoinitiator, a property that makes the polyiner self-photo-
crosslinlcable (Y.
Nalcayama, T. Matsuda. J. Polynz. Sci. PaytA: Polyin. Claefn. (1992) 30:2451-
2457). In
addition, the cimiainoyl group is metabolized in the body and has been proven
to be non-toxic
(Citations in paper of M Nagata, Y. Sato. Polynaer (2004) 45:87-93).

[0019] The invention aromatic di-acid-containing PEA polymers exhibit a
combination of
hydrophobicity, relatively high glass transition tenlperature (Tg) to confer
sufficient stiffness
for the polymers to be extruded, and sufficient elongation properties to
prevent brittleness. In
certain embodiments, individual monomer units in the invention aromatic di-
acid -containing
PEA polymer compositions can be based on and break down during biodegradation
to yield
one of multiple different a-amino acids, as disclosed herein.

[0020] Like other PEA polymers, the invention aromatic di-acid-containing PEA
polymer
coinpositions can be used to deliver in vivo at least one bioactive agent that
is dispersed in
the polymer of the composition. The invention PEA polymer compositions
biodegrade in
vivo by enzymatic action so as to release the at least one bioactive agent(s)
from the polymer
in a controlled manner over time. Thus the invention provides new PEA polymers
suitable for
certain applications requiring a combination of hydrophobicity, relatively
high glass
transition temperature (Tg), and elongation or flexibility properties.
Moreover, since
theoretically the bis(a-amino acid)-diol-diester co-monomers in the invention
PEA polymers
may each contain a different one of the multiple amino acids disclosed herein
in each bis(a-
amino acid) building block, the invention PEA polymer compositions may break
down to
produce from one to niultiple different of such a-amino acids.

[0021] More particularly, in one embodiment, the invention provides polyiner
compositions comprising a PEA polymer having a chemical formula described by
general


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WO 2007/050583 PCT/US2006/041441
structural formula (I):

0 10 H O 4 O H
11
C-R -C-N-C-C-O-R -O-C-C-N
H R3 R3 H n
Formula (I)

wherein, n is about 10 to about 150; each R' is independently selected from
residues of a,co-bis (o,na, orp-carboxyphenoxy) (C1-C$) alkane, 3,3'-
(allcenedioyldioxy)dicinnamic acid or 4,4'-(alkanedioyldioxy)dicinnamic acid;
the R3s in
eacli n monomer are independently selected from the group consisting of
hydrogen,. (C1-C6)
allcyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C10) aryl (C1-C6) alkyl and-
(CHZ)2S(CH3); R4 in
each n monomer is independently selected fiom the group consisting of (C2-Czo)
alkylene,
(C2-C20) alkenylene, (C2-Cs) alkyloxy, (C2-CZO) alkylene, bicyclic-fragments
of 1,4:3,6-
dianhydrohexitols of general formula(II), and combinations thereof;

CH O
H2C/ ~CH2
O CH

Formula (II)

or a chemical structure described by general structural formula (III),
O 10 H O 4 O H 0 0 H 5
C-R -C-N-C-C-O-R-O-C-C-N C-R'-C-N-C-R -N
R3 R3 H m H ~-O-R2 H
O pn
Formula (I1I)

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1, n is about
20 to
about 150, R1 is a combination of about 0.1 part to about 0.9 part of a,0)-bis-
(o,n1; ot- p-
carboxyphenyloxy)-(C1-C$) alkane, 3,3'-(alkenedioyldioxy)dicinnamic acid or
4,4' -
(alkanedioyldioxy)dicinnamic acid and about 0.9 part to about 0.1 part
selected from (C2 -
C20) alkylene, (CZ-Czo) alkenylene, or mixtures thereof; RZ is llydrogen, or
(C6-Cio) aryl (CI-
C6) alkyl or a protecting group; each R3 is independently hydrogen, (C1-C6)
alkyl, (C2-C6)
alkenyl, (C2-C6) alkynyl and (C6-CIo) aryl (C1-C6) alkyl and -(CH2)2S(CH3);
each R4 is


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
selected from the group consisting of (C2-C2o) allcylene, (C2-C20) alkenylene,
(C2-C8)
alkyloxy (C2-C20) allcylene, bicyclic-fragments of 1,4:3,6-dianhydrohexitols
of general
formula III, and combinations thereof; and RSis independently (C1-C2o) alkyl
or (C2-C20)
alkenyl.

[0022] A typical protecting group is t-butyl, or others as are known in the
art. The
bicyclic-fragments of 1,4:3,6-dianhydrohexitols can be derived from "sugar
alcohols", such
as D-glucitol, D-mannitol, or L-iditol, for exainple isosorbide (1,4:3,6-
dianhydrosorbitol).
[0023] In one embodiment, the R3 s are -(CH2)3-, and the compound released by
biodegradation of the polymer is an imino acid, analogous to pyrrolidine-2-
carboxylic acid.
[0024] In certain embodiments, RS is independently (C3-C6) alkyl or (C3-C6)
allcenyl, for
example -(CH2)4-.

[0025] The chemical formula of the class of a,co-bis(o, rn, orp-
carboxyphenoxy) (C i to C8)
alkanoic di-acids useful in the practice of the invention is described by
structural formula (
IV)

HOOC COOH
-0-(CH2)n`0 Formula (IV)

wherein, n = 1 to 8.

[0026] Known examples of di-acids of a,w-bis(4-carboxyphenoxy) (C1-C$) alkanes
suitable for use in practice of the invention include CPP (1,3-bis(4-
carboxyphenoxy)propane)
(n = 3), (Compound 1), which has the following formula:

HOOC 0 O-(CH2)3 OaCOOH
(Compound 1)

A second lcnown a,o)-bis(4-carboxyphenoxy) (C1-C$) alkanoic di-acid is (1,6-
bis (4-
carboxyphenoxy) hexane) CPH (Formula (IV), n = 6). This compound has been
reported to
be a useful monomer for biodegradable implants (M. J. Kipper et al.
Biosnaterials (2002)
23:4405-4412). However, use of di-esters of CPH in preparation of the
invention polymers
generates a PEA polymer with lower Tg and strength measurements at failure
than does CPP.
Potentially promising third compound of this group of di-acids is bis(4-


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
carboxyphenoxy)methane, (Formula (IV), n= 1), reported recently as useful di-
acid for
biodegradable co-poly(anhydrides) synthesis. (J.P. Jain et al. J. Controlled.
Release. (2005)
103: 541-563

[00271 The chemical formula of the 4-hydroxycinnamic acid based di-acids, with
general
name 4,4'-(a,o)-allcanedioyldioxy) dicinnamic acid, usefiil in the practice of
the invention is
described by structural fomzula (V)

O O
HOOC // \ /-O-C-(CH2)õC-O \ / \ COOH
Formula (V)

wherein, n= 2 to 12;

[0028] Known examples of di-acids of 4,4'-(a,(e-alkanedioyldioxy)dicinnamic
acid group,
suitable for use in practice of the invention include 4,4'-
(adipoyldioxy)dicinnamic acid,
whicli has the following formula (compound 2), (M Nagata, Y. Sato. PolyTneT .
(2004) 45: 87-
93)

O O
HOOC IT \ /-O-C-(CH2)a C-O COOH
(Conlpound 2)

[0029] The chemical formula of the 3-hydroxycinnamic acid based di-acids, with
general
name 3,3'-(a,(o-allcanedioyldioxy)dicinnamic acid, useful in the practice of
the invention, is
described by structural formula (VI).

HOOC
O COOH
- -
CACH2)n CO -
O O \ /
Formula (VI)
whereiri, n = 2 to 12


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[0030] For example, Compound 3 described here is 3,3'-(adipoyldioxy)dicinnamic
acid,
(compotuid 3):

HOOC COOH
JOC-(CH2)4" O -
\ /
(Compound 3)

The meta-isomers introduce more disorder in polymer chain packing than the
para-isomers.
Therefore, inonomers and polymers containing the compounds of Formula VI are
expected to
be more soluble in the reaction mixture and polymerization requires lower
temperature. This
combination of properties contributes to formation of higher molecular weight
polymers than
when the para-isomers are used.

[0031] The n monomers in the invention PEA polymers of structure (I) can be
identical, in
which case the polymer is referred to herein as a"homo-polymer." Alternatively
the n repeat
unit in the invention PEA polymers of structure (I) can be different, being
fabricated using
different combinations of building blocks (i.e., diols, di-acids and a-amino
acids), in which
case the polymer is referred to herein as a "co-polymer". The in-repeat unit
in the invention
PEA polymers of structure (III), which include an L-lysine-based p-repeat unit
can be either
identical or different.

[0032J As used herein, the term "residue of a di-acid" means a portion of a
dicarboxylic-
acid, as described herein, that excludes the two carboxyl groups of the di-
acid. As used
herein, the term "residue of a diol" means a portion of a diol, as described
herein, which
excludes the two hydroxyl groups of the diol. The corresponding di-acid or
diol containing
the "residue" thereof is used in synthesis of the co-polym.er compositions.
The residue of the
di-acid or diol is reconstituted in vivo (or under siinilar conditions of pH,
aqueous media, and
the like) to the corresponding diol or di-acid upon release from the polymer
composition by
biodegradation in a controlled manner that depends upon the properties of the
a,co-bis (o,na,
orp-carboxyphenoxy) alkane-containing polymer used in the composition, which
properties
are as described herein, for example in the Examples.

[00331 As used herein, the terms "a-amino acid-containing", and "a-amino acid"
mean a
chemical compound containing an amino group, a carboxyl group and R3 groups as
defined
herein. As used herein, the terms "biological a-amino acid-containing" and
"biological


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WO 2007/050583 PCT/US2006/041441
amino acid" mean the a-ainino acid(s) used in synthesis are naturally
occurring L-
phenylalanine, leucine, glycine, alanine, valine, isoleucine, lysine, or
methionine, or a
mixture thereof. Additional adirectional biological ainino acids used in
fabrication of
invention co-polymers may include lysine and oniithine, but are oriented in
the co-polynier
baclcbone adirectionally (i.e., in a non-biological orientation) such that the
carboxyl group of
the amino acid (which may also be substituted by an R2 otlier than H) is
pendent rather than
being incorporated into a peptide bond. Additional adirectional amino acids
can be
incorporated into the invention compositions by varying the R5 group as
described herein.
[0034] As used herein the term "bioactive agent" ineans a bioactive agent as
disclosed
herein that is not incorporated into the polyiner backbone, but is dispersed
within the PEA
polyiner in the invention composition. One or more such bioactive agents may
optionally be
inncluded in the invention polymer compositions. As used herein to refer to
the bioactive
agent(s), the term "dispersed" means the bioactive agents are intermixed or
dissolved in,
homogenized with, and/or covalently bound or conjugated to a PEA polymer in
invention an
invention composition, for example attached to a functional group in the PEA
polymer of the
composition or to the surface of a polymer particle or surgical device made
using the
invention polymer composition.

[0035] The tenn, "biodegradable, biocompatible" as used herein to describe the
invention
PEA polymer composition.s means the polymer is capable of being broken down
into
innocuous products in the normal functioning of the body. This is particularly
true when the
amino acids used in fabrication of the PEA polymers are biological L-a-amino
acids. These
PEA polymer compositions include llydrolyzable ester and enzymatically
cleavable amide
linkages that provide biodegradability, and are typically chain terminated,
predominantly
with amino groups. Optionally, the amino termini of the polymers can be
acetylated or
otherwise capped by conjugation to any other acid-containing, biocompatible
molecule, to
include without restriction organic acids, bioinactive biologics, other
polymers and bioactive
agents as described herein. In one embodiment, the entire polymer composition,
and any
particles, or surgical device made thereof, is substantially biodegradable.

[0036] In one alternative, at least one of the a-amino acids used in
fabrication of the
invention polymers is a biological a-amino acid. For example, when the R3s are
CH2Ph, the
biological a-amino acid used in synthesis is L-phenylalanine. In alternatives
wherein the R3s
are CH2-CH(CH3)2, the polymer contains the biological a-amino acid, L-leucine.
By varying


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
the R3s within co-monomers as described herein, other biological a-anzino
acids can also be
used, e.g., glycine (when the R3s are H), alanine (when the R3s are CH3),
valine (when the
R3s are CH(CH3)2), isoleucine (wlien the R3s are CH(CH3)CH2CH3), phenylalanine
(when the
R3s are CH2-C6H5),, or methionine (when the R3s are -(CH2)2SCH3, and mixtures
thereof.
When the R3s are -(CH2)3- (as 2-pyrrolidinecarboxylic acid), a a-imino acid
can be used. In
yet another alteniative embodiment, all of the various a-amino acids contained
in the
invention aromatic di-acid-containing PEA polyiners are biological a-amino
acids, as
described herein.

[0037] The terni "aryl" is used with reference to stnictural formulas herein
to denote a
phenyl radical or an ortho-fused bicyclic carbocyclic radical having about
nine to ten ring
atoms in which at least one ring is aromatic. In certain embodiments, one or
more of the ring
atoms can be substituted with one or more of nitro, cyano, halo,
trifluoromethyl, or
trifluoromethoxy. Exainples of aryl include, but are not limited to, phenyl,
napllthyl, and
nitrophenyl.

[0038] The term "alkenylene" is used with reference to structural foimulas
herein to mean
a divalent branched or unbranched hydrocarbon chain containing at least one
unsaturated
bond in the main chain or in a side chain.

[0039] In addition, the polymer molecules may optionally have a bioactive
agent
conjugated tliereto via a linker or incoiporated into a crosslinker between
molecules.
[0040] Further, the aromatic di-acid-containing PEA polymer compositions
suitable for
use in the practice of the invention bear functionalities that allow the
option of covalent
attachment of bioactive agent(s) to the polymer. For example, a polymer
bearing free
carboxyl groups can readily react with an amino moiety, thereby covalently
bonding a
peptide to the polymer via the resulting amide group. As will be described
herein, the
biodegradable polymer and a bioactive agent may contain numerous complementary
functional groups that can be used to covalently attach the bioactive agent to
the
biodegradable polymer.

[0041] Further examples of PEA polymers related to those contemplated for use
in the
practice of the iiivention and methods of synthesis include those set forth in
U.S. Patent Nos.
5,516, 881; 5,610,241; 6,476,204; and 6,503,538; and in U.S. Application Nos.
10/096,435;
10/101,408; 10/143,572; 10/194,965 and 10/362,848.


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0042] In certain embodiments, particles or a surgical device made from or
containing the
invention aromatic di-acid-containing PEA polyiner composition, as described
herein, plays
an active role in the treatnient processes at the site of implant or use by
holding the polyiner
and any bioactive agents dispersed therein at the site for a period of time
sufficient to allow
the subject's endogenous processes to slowly release particles or polynier
molecules from the
composition. Meanwhile, the subject's endogenous processes biodegrade the
polynier so as
to release bioactive agents dispersed in the polymer. The fragile optional
bioactive agents are
protected by the more slowly biodegrading polymer to increase half-life and
persistence of
the bioactive agent(s) locally at the site of use, e.g., implant. A detailed
description of
methods of making polymer particles using related PEA polymers may be found in
co-
pending U.S. application Serial No. 11/344,689, filed January 31, 2006.

[0043] In addition, the invention PEA polyniers disclosed herein (e.g., those
having
structural formulae (I, and II)), upon enzymatic degradation, provide a-amino
acids, such as
biological a-amino acids, and other breakdown products that can be readily
metabolized.
When biodegradation products are sparingly water-soluble di-acid monomers,
elimination
proceeds via solubilization in a biological environment as a slow process. The
aliphatic di-
acid sebacic acid will most likely par-ticipate in the P-oxidation pathway,
yielding acetic-coA,
which could be used in a typical biosynthetic pathway. Aromatic di-acids, such
as CPP, are
eliminated without further metabolic transformation. (D.S. Katti, et al. Adv.
Drug deliv. Rev.
(2002) 54(7): 933-961). Uptake of the polymer with bioactive agent is safe:
stadies have
shown that the subject can metabolize/clear the polymer degradation products.
The invention
PEA polymer compositions are, therefore, substantially non-inflammatory to the
subject both
at the site of implant and systemically, apart from any trauma caused by
implantation itself.
[0044] The invention PEA polymers and compositions preferably have weight
average
molecular weights ranging from 15,000 to 600,000 Daltons; these polymers
typically have
inherent viscosities at 25 C, determined by standard viscosimetric methods,
ranging from 0.3
to 3.5, preferably ranging from 0.4 to 2.0

[0045] The molecular weights and polydispersities herein are deterinined by
gel
permeation chromatography (GPC) using polystyrene standards. More
particularly, number
and weight average molecular weights (Mn and M,,,) are determined, for
example, using a
Model 510 gel permeation chromatographer (Water Associates, Inc., Milford, MA)
equipped
with a high-pressure liquid chromatographic pump, a Waters 486 UV detector and
a Waters
2410 differential refractive index detector. Solution of 0.1% LiC1 in N,N-
dimethylacetamide


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
(DMAc) is used as the eluent (1.0 mL/min). The polystyrene (PS) standards,
which have a
narrow molecular weight distribution, were used for calibration of GPC curves.

[0046] Methods for making PEA polymers containing a-anlino acids in the
general
fonnula are well k.nown in the art. For example, for the embodiment of the
polymer of
forinula (I), a a-amiiio acid can be converted into a bis(a-amino acid)-diol-
diester monomer,
for example, by condensing the a-amino acid with a diol as described herein.
As a result,
ester bonds are formed. Then, the bis(a-amino acid)-diol-diester is entered
into a
polycondensation reaction with a di-acid, such as sebacic acid, or a,co-bis(4-
carboxyphenoxy)
alkanoic di-acid, to obtain the final polymer having both ester and amide
bonds.
Alternatively, instead of the di-acid, an activated di-acid derivative, e.g.,
di-(p-nitrophenyl)
ester, can be used for polymers of chemical structure (I) or (III).

[0047] More particularly, synthesis of the unsaturated poly(ester-amide)s
(UPEAs) useful
as polymers of the structure (I) or (III) as described above will be described
wherein

0
II II II C
~ C---
l(a) -C-R-C is \
H I
O
[0048] for example, and/or (b) R3 is -CH2-CH=CH-CH2-. In cases where (a) is
present
and (b) is not present, R3 is -C4H8- or -C6H12-. 111 cases where (a) is not
present and (b) is
present, Ri is -C4H8- or -C$Hl6-.

[0049] The UPEAs can be prepared by solution polycondensation of either (1) di-
p-
toluene sulfonic acid salt of bis(a-amino acid) diesters, comprising at least
1 double bond in
the diol residue, a di-p-toluene sulfonic acid salt of a bis(a-amino acid)-
alkylene-diesters,
comprising a diol of structural formula (II), and di-p-nitrophenyl esters of
saturated
dicarboxylic acid or (2) two di-p-toluene sulfonic acid salt of bis(a-amino
acid) alkylene-
diesters, comprising no double bonds in the diol residues, and di-p-
nitrophenyl ester of
unsaturated dicarboxylic acid or (3) two di-p-toluene sulfonic acid salts of
bis (a-amino
acid)-diol-diesters, comprising at least one double bond in one of the diol
residues in the
polymer general structural formula, the other diol residue having stn.ictural
fonnula (II), and
di-nitrophenyl esters of unsaturated dicarboxylic acids.


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0050] Salts of p-toluene sulfonic acid are lrnown for use in synthesizing
polymers
containing amino acid residues. The aryl sulfonic acid salts are used instead
of the free base
because the aryl sulfonic salts of bis(a-amino acid)-alkylene-diesters are
easily purified
through recrystallization and render the amino groups as stable ammonium
tosylates
tliroughout worlcup. In the polycondensation reaction, the nucleophilic alnino
group is
readily revealed through the addition of an organic base, such as
trietllylamine, so the
polymer product is obtained in higli yield.

[0051] For unsaturated polymers of structure (I or II), the di-p-nitrophenyl
esters of
unsaturated dicarboxylic acid can be synthesized from p-nitrophenol and
unsaturated
dicarboxylic acid chloride, e.g., by dissolving triethylamine and p-
nitrophenol in acetone and
adding unsaturated dicarboxylic acid chloride dropwise witli stirring at below
- 65 C and
pouring into water to precipitate product. Suitable acid chlorides included
fumaric, maleic,
mesaconic, citraconic, glutaconic, itaconic, ethenyl-butane dioic and 2-
propenyl-butanedioic
acid chlorides.

[0052] The di-aryl sulfonic acid salts of bis(a-amino acid)-diesters of
saturated and
unsaturated diols can be prepared by admixing a-amino acid, aryl sulfonic acid
(e.g., p-
toluene sulfonic acid monohydrate) and saturated or unsaturated diol in
toluene, heating to
reflux temperature, until water evolution is minimal, then cooling. The
unsaturated diols
include, for example, 2-butene- 1,4-diol and 1, 1 8-octadec-9-en-diol.

[0053] Saturated di-p-nitrophenyl esters of dicarboxylic acid and saturated di-
p-toluene
sulfonic acid salts of bis(a-amino acid)-alkylene-diesters can be prepared as
described in U.
S. Patent No. 6,503,538 Bl.

[0054] Although the invention PEA polymer compositions comprise poly(ester
amides)
(PEAs) made by polycondensation of components as described above, in the
present
invention, the components include a di-p-toluenesulfonic acid salt of bis(a-
amino acid)-
1,4:3,6-dianhydrosorbitol diester; a dip-toluenesulfonic acid salt of bis(a-
amino acid)-linear
aliphatic a,co-diol diester and a di p-nitrophenyl ester of aliphatic (fatty)
dicarboxylic acid.
The di-p-nitrophenyl esters of dicarboxylic acids are used because the p-
nitrophenyl ester is a
very good leaving group that can promote the condensation reaction to move to
the right of
the reaction equation so the polymer product is obtained in high yield. In
addition, the di-p-
nitrophenyl esters are stable throughout workup and can be handled and dried
in open
atmosphere.


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WO 2007/050583 PCT/US2006/041441
[00551 The, di-aryl sulfonic acid salts of bis(a-amino acid) diol-diesters of
unsaturated
diols can be prepared by admixing a-amino acid, p-aiyl sulfonic acid (e.g. p-
toluene sulfonic
acid nzonohydrate) and saturated or unsaturated diol in toluene, heating to
reflux temperature,
until water evolution is minimal, then cooling. The unsaturated diols include,
for exaniple, 2-
butene-1,4-diol and 1,18-octadec-9-en-diol.

[0056] A working exainple of a diamine monomer having stnictural fonnula
(III), in U.S.
Patent No. 6,503,538 is provided by substituting p-toluene sulfonic acid salt
of bis(L-
phenylalanine)-2-butene-1,4-diester for (III) in Example 1 of U.S. Patent No.
6,503,538 or by
substituting bis (p-nitrophenyl) fumarate for (V) in Example 1 of U.S. Patent
No. 6,503,538
or by substituting p-toluene sulfonic acid salt of bis(L-phenylalanine)-2-
butene-1,4-diester for
III in Example 1 of U.S. Patent No. 6,503,538 and also substituting bis(p-
nitrophenyl)
fumarate for (V) in Example 1 of U.S. Patent No. 6,503,538.

[0057] In unsaturated PEA, the following hold: Aminoxyl radical e.g., 4-amino
TEMPO
can be attached using carbonyldiimidazol, or suitable carbodiimide, as a
condensing agent.
Optionally, bioactive agents, as described herein, can be attached via a
double bond
functionality, preferably one that does not occur in a residue of a bioactive
agent in the
polymer backbone. Hydrophilicity, if desired, can be iniparted by bonding to
poly(ethylene
glycol) mono- or diacrylate.

Geszeral snetlzod forPreparation of Dip-nitNopheizyl ester of CPP (Compound 4)
O2N rN O-C ~ f O-(GH2)3-O C-O NO2
~

(Compound 4)

[0058] Preparation of this compound has been carried out by two different
methods. In
the direct condensation method CPP, condensation of CPP with p-nitrophenol is
accomplished using thionyl chloride as condensing reagent. CPP, p-nitrophenol,
and a few
drops of DMF in dry chlorobenzene are added to thionyl chloride and heated to
about 80 C
under slow nitrogen gas flow until the reaction mixture becomes homogenous.
The cooled
solution was diluted with hexanes and kept over night at 0 C. Separated yellow
crystals
collected by filtration, washed with hexane are re-crystallized from acetone.


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WO 2007/050583 PCT/US2006/041441
[0059] Two step synthesis via acid chloride was also developed, as described
in detail in
Exainple 1 herein, using oxalyl chloride. Briefly, CPP and a few drops of
pyridine are
suspended dry chloroform. At room temperature, oxalyl chloride solution in
dichloromethane
is added and the solution is heated to reflux for about another 6 hours. After
cooling, a clear
reaction solution is filtered under exclusion of moisture and then diluted
with hexanes.
Yellow crystals separated from the filtrate were collected and dried under
vacuum at room
tenzperature. In a second step, to a chilled (0 C) solution of p-nitrophenol
and triethylamine
in dry etllylacetate, a solution of CPP-dichloride in ethylacetate is added
dropwise. Then, the
solvent is evaporated, and solid product is washed, dried and recrystallized
from acetone.
[0060] The description and methods of synthesis of related PEA polyiners are
set forth in
U.S. Patent Nos. 5,516, 881; 6,476,204; 6,503,538; and in U.S. Application
Nos. 10/096,435;
10/101,408; 10/143,572; 10/194,965; 10/362,848, 10/346,848, 10/788,747, the
entire content
of each of which is incorporated herein by reference.

[0061] The aromatic di-acid-containing PEA polymers described herein have
weight
average molecular weights ranging from 15,000 to 600,000 Daltons; these
polymers and
copolymers typically have inherent viscosities at 25 C, determined by
standard viscosimetric
methods, ranging from 0.3 to 4.0, preferably ranging from 0.4 to 2Ø

[0062] The aromatic di-acid-containing PEA polymers described herein can be
fabricated
in a variety of molecular weights and a variety of relative proportions of the
two bis(a-amino
acid)-alkylene-diester containing units and optional L-lysine based monomer.
The
appropriate molecular weight for a particular use is readily determined by one
of skill in the
art based on the guidelines coiitained herein and the thermo-mechanical
properties disclosed.
Thus, e.g., a suitable molecular weight will be on the order of about 15,000
to about 600,000
Daltons, for example about 15,000 to about 400,000, or about 15,000 to about
300,000.
[0063] The invention PEA polymers useful in the invention coinpositions,
biodegradable
surgical devices and methods of use biodegrade by enzymatic action at the
surface.
Therefore, the polymers,for example particles thereof, facilitate in vivo
release of a bioactive
agent dispersed in the polymer at a controlled release rate, which is specific
and constant over
a prolonged period. Additionally, since PEA polymers break down in vivo via
enzymes
without production of adverse side products, the polymers in the invention
compositions and
surgical devices, such as those that produce biological a-amino acids upon
break down, are
substantially non-inflammatory.


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0064] Synthesis of the unsaturated poly(ester-amide)s (UPEAs) useful as
biodegradable
polymers of the stiucture (I) as described above will now be described.
Conzpounds having
the stiucture (II) can be made in similar fashion to the compound (VII) of U.
S. Patent No.
6,503,538 B1, except that R4 of (III) of 6,503,538 and/or Rl of (V) of
6,503,538 is (C2-C20)
alkenylene as described above. Unsaturated copolyiners, co-UPEAs containing
different feed
ratios of two diamiue monomers R4 of (III) of 6,503,538 will have combinations
of above
described (C2-C2o) alkenylene and residue of 1,4:3,6-dianhydrohexitols. And/or
Rl in (V) of
6,508,538 is (C2-CZO) alkenlylene or combinations of alkenylene and fatty acid
residues with
various feed ratios. Reaction is carried out, for example, by adding dry
triethylaniine to a
mixture of said (III) and (IV) of 6,503,538 and said (V) of 6,503,538 in dry
N,N-
dimethylacetamide, at room temperature, then increasing the temperature to 80
C and stirrixig
for 16 hours, then cooling the reaction solution to room temperature, diluting
with etlianol,
pouring into water, separating polymer, washing separated polymer with water,
drying to
about 30 C under reduced pressure and then purifying up to negative test on p-
nitrophenyl
and p-toluene sulfonic acid. A preferred reactant (IV) of 6,503, 538 is p-
toluene sulfonic acid
salt of L-lysine benzyl ester, the benzyl ester protecting group is preferably
removed from (I)
to confer biodegradability, but it should not be removed by hydrogenolysis as
in Example 22
of U.S. Patent No. 6,503,538 because hydrogenolysis would saturate the desired
double
bonds; rather the benzyl ester group should be converted to an acid group by a
method that
would preserve unsaturation, e.g., by treatment with fluoroacetic acid or
gaseous HF.
Alternatively, the lysine reactant (IV) of 6,503, 538 can be protected by a
protecting group
different from benzyl which can be readily removed in the finished product
while preset ving
unsaturation, e.g., the lysine-based reactant can be protected witli t-butyl
(e.g., the reactant
can be t-butyl ester of lysine) and the t-butyl can be converted to the "H"
form (free
carboxylic acid) while preserving unsaturation by treatment of the product
(II) with acid.
[0065] In unsaturated compounds having structural formula (I) or (III), the
following hold:
An amino substituted aminoxyl (N-oxide) radical bearing group e.g., 4-ainino
TEMPO, can
be attached using carbonyldiimidazole, or suitable carbodiimide, as a
condensing agent.
Bioactive agents, and the like, as described herein, optionally can be
attached via the double
bond functionality. Hydrophilicity can be imparted by bonding to poly(ethylene
glycol)
diacrylate.

[0066] Polymers contemplated for use in the practice of the invention can be
synthesized
by a variety of methods well known in the art. For example, tributyltin (IV)
catalysts are


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
cominonly used to fomz polyesters such as poly(caprolactone), poly(glycolide),
poly(lactide),
and the lilce. However, it is understood that a wide variety of catalysts can
be used to foml
polymers suitable for use in the practice of the invention.

[0067] Such poly(caprolactones) contenzplated for use have an exemplary
structtual
formula (VII) as follows:

O
11
O-C-(CH2)5
n
Formula (VII)

[0068] Poly(glycolides) contemplated for use have an exemplary structural
forinula (VIII)
as follows:

O H
O-C-C
H n

Formula (VIII)

[0069] Poly(lactides) contemplated for use have an exemplary structural
formula (IX) as
follows:

0 Me
O-C-C
H n

Formula (IX)

[0070] An exemplary synthesis of a suitable poly(lactide-co-s-caprolactone)
including an
aininoxyl moiety is set forth as follows. The first step involves the
copolymerization of
lactide and 8-caprolactone in the presence of benzyl alcohol using stannous
octoate as the


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
catalyst to form a polymer of structural foxmula (X).

O O
Me
CHzOH+nO O .+-I3z O
~Me
O
O H O
O CHzO C-C-O C-(CH2)5-O H
~e n m
Formula (X)

[0071] The hydroxy terminated polyiner chains can then be capped with maleic
anhydride
to form polymer chains having structural formula (Xl):

O H 0 O 0 11
CH2O C-C-O C-(CH2)5-O C-C=C-C-OH
Me n im H H
Formula (XI)

[0072] At this point, 4-amino-2,2,6,6-tetramethylpiperidine-l-oxy can be
reacted with the
carboxylic end group to covalently attach the aininoxyl moiety to the
copolymer via the
amide bond which results from the reaction between the 4-amino group and the
carboxylic
acid end group. Alternatively, the maleic acid capped copolymer can be grafted
with
polyacrylic acid to provide additional carboxylic acid moieties for subsequent
attachment of
further aminoxyl groups.

[0073] Due to the versatility of the aromatic di-acid-containing PEA polymers
used in the
invention compositions, the relative amounts of stiffness and elongation
properties of the
polymers can be controlled by varying the proportions of the two bis(a-amino
acid)-
containing, the lysine-based unit and other building blocks of the polymer.
For exainple,
Table 1 llerein illustrates the differences in Tg, tensile stress at yield,
percent elongation and
Young's modulus of a film of PEA polymers of structural formula (I) and how
relative
proportions of the aliphatic di-acid to a,co-bis (4-carboxyphenoxy) alkanoic-
diacid, 3,3'-
(alkenedioyldioxy)dicinnamic acid or 4,4 -(a,co-alkanedioyldioxy)dicinnamic
acid in the
invention polymers affect the various properties. For example, Table 1
illustrates the
mechanico-thermal characteristics and tensile properties of a 0.125 mm thick
film of the
invention PEA of Formula (III), (where R3 is CH2-CH(CH3)2 L-Leucine, R2 is CH2-
Ph and R4
is -(CHZ)6- hexane diole,) containing various Rl feed ratios of CPP to sebacic
acid.


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WO 2007/050583 PCT/US2006/041441
TABLE 1
Polymer CPP to Yield Tga) Tma Mw PDI Tensile % Young's
# sebacic [%] [ C] [ C] X10"3 Stress at Elong Modulus
acid Break [MPa]
feed [MPa]
ratio %
1 25 78 35 - 64 1.56 40.4 327 1205
2 35 66 37 224 70 1.81 21.6 217 772
3 50 79 45.5 287 82 1.66 51.5 6.1 1309
4* 50 52 73 232 69 1.58 24.4 6.3 672
*hexanediol in scheme is replaced with 50% (mol) isosorbide, (Compound 6).
DSC Measureinents were taken from second heating, heating rate 10 C/min.
GPC Measurements were carried out in DMAc, (PS).

[0074] Further, as shown in polymer #4 in Table 1, replacement of a portion of
aliphatic
diol feed with a.1,4:3,6-dianhydrohexitol will fiifther raise the glass
transition temperature
(Tg) of the polymer. In general, the invention aromatic di-acid-containing PEA
polymers
formed as described herein, for example, in the Examples herein, can be
expected to have the
following thermo-mechanical properties.

1. A glass transition temperature in the range from about 22 C to about 120 C,
for example, in the range from about 35 C to about 80 C, from about 37 C to
about
73 C;
2. A film of the polymer with an average thickness of about 0.125 mm will have
a tensile stress at yield of about 25 MPa to about 90 MPa, for example, about
20 MPa to
about 50 MPa, or about 21.6 MPa to about 51.5 MPa;
3. A film of the polymer with an average thickness of about 0.125 mm will have
a percent elongation of about 2% to about 400%, for example about 5% to about
350%
or about 6.1 % to about 327%; and
4. A film of the polymer with an average thickness of about 0.125 mm will have
a Young's modulus in the range from about 400 MPa to about 2000 MPa, for
example
about 500 MPa to about 2000 MPa, or about 672 MPa to about 1309 MPa.

Thus, by judicious choice of the content and relative proportions of the three
building block
units, one skilled in the art can obtain an invention bis (a-amino acid)-
containing PEA
polymer that is both biodegradable and biocompatible and which possesses a
wide range of
thermo-mechanical properties.


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WO 2007/050583 PCT/US2006/041441
[0075] In certain embodiments, a bioactive agent can be covalently bound to
the
biodegradable polymers via a wide variety of suitable functional groups. For
example, when
the biodegradable polymer is a polyester, the carboxylic group chain end can
be used to react
with a complimentary moiety on the bioactive agent, such as hydroxy, amino,
thio, and the
like. A wide variety of suitable reagents and reaction conditions are
disclosed, e.g., in
March's Advanced Organic Chemistry, Reactions, Mechanisms, and Structure,
Fifth Edition,
(2001); and Comprehensive Organic Transformations, Second Edition, Larock
(1999).
[0076] In other embodiments, a bioactive agent can be dispersed into the,
polymer by
"loading" onto the polymer without formation of a chemical bond or the
bioactive agent can
be linked to any free functional group in the polymers, such as an amine,
hydroxyl (alcohol),
or thiol, and the like, to form a direct linkage. Such a linkage can be formed
from suitably
functionalized starting materials using synthetic procedures that are known in
the art.

[0077] For example, a polymer of the present invention can be linked to the
bioactive
agent via a carboxyl group (e.g., COOH) of the polymer. Specifically, a
compound of
structures (I and II) can react with an amino functional group of a bioactive
agent or a
hydroxyl functional group of a bioactive agent to provide a biodegradable,
biocompatible
polymer having the bioactive agent attached via an amide linkage or ester
linkage,
respectively. In another embodiment, the carboxyl group of-the polymer can be
transformed
into an acyl halide, acyl anhydride/"mixed" anhydride, or active ester.

[0078] Alternatively, the bioactive agent may be attached to the polymer via a
linker.
Indeed, to improve surface hydrophobicity of the biodegradable polymer, to
improve
accessibility of the biodegradable polymer towards enzyme activation, and to
improve the
release profile of the biodegradable polymer, a linker may be utilized to
indirectly attach the
bioactive agent to the biodegradable polymer. In certain embodiments, the
linker compounds
include poly(ethylene glycol) having a molecular weight (Mw) of about 44 to
about 10,000,
preferably 44 to 2000; amino acids, such as serine; polypeptides with repeat
units from 1 to
100; and any other suitable low molecular weight polymers. The linker
typically separates
the bioactive agent from the polymer by about 5 angstroms up to about 200
angstroms.

[0079] In still further embodiments, the linker is a divalent radical of
formula W-A-Q,
wherein A is (C1-C24) alkyl, (C2-C24) alkenyl, (C2-C24) alkynyl, (C2-C20)
alkyloxy, (C3-C8)


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
cycloalkyl, or (C6-Clo) aryl, and W and Q are each independently N(R)C(=O)-, -
C(=O)N(R)-, -OC(=0)-, -C(=0)O, -0-, -S-, -S(O), -S(O)2-, -S-S-, -N(R)-, -C(=0)-
, wherein
each R is independently H or (C1-Q) alkyl.

[0080] As used herein, the term "alkyl", as applied to the linkers described
herein, refers
to a straight or branched chain hydrocarbon group including methyl, ethyl, n-
propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.

[0081] As used herein, "alkenyl", as applied to the linkers described herein,
refers to
straight or branched chain hydrocarbon groups having one or more carbon-carbon
double
bonds.

[0082] As used herein, "alkynyl", as applied to the linkers described herein,
refers to
straight or branched chain hydrocarbon groups having at least one carbon-
carbon triple bond.
[0083] As used herein, "aryl", as applied to the linkers described herein,
refers to aromatic
groups having in the range of 6 up to 14 carbon atoms.

[0084] In certain embodiments, the linker may be a polypeptide having from
about 2 up to
about 25 amino acids. Suitable peptides contemplated for use include poly-L-
lysine, poly-L-
glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-
L-threonine,
poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-
arginine, poly-L-
lysine-L-tyrosine, and the like.

[0085] The linker can be attached first to the polymer or to the bioactive
agent. During
synthesis of polymers having bioactive agents indirectly attached via a
linker, the linker can
be either in unprotected form or protected from, using a variety of protecting
groups well
known to those skilled in the art.

[0086] In the case of a protected linker, the unprotected end of the linker
can first be
attached to the polymer or the bioactive agent. The protecting group can then
be de-protected
using Pd/H2 hydrogenolysis for saturated polymers, mild acid or base
hydrolysis for
unsaturated polynlers, or any other common de-protection method that is kliown
in the art.


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
The de-protected linker can then be attached to the bioactive agent. An
exanlple using
poly(ethylene glycol) as the linker is shown in Scheme 1.

[0087] Scheme 1: Poly(ethylene glycol) enlployed as the linker between polymer
and
bioactive agent.
O

n
O
R
n

O
R
n

wherein .rvvnr represents the
polymer; R can be a bioactive
agent; and n can range from 1 to 200; preferable from 1 to 50.

[0088] The following illustrates synthesis of a polymer composition according
to the
invention (wherein the bioactive agent is an aminoxyl). A polyester can be
reacted with an
amino substituted aminoxyl (N-oxide) radical bearing group, e.g., 4-amino-
2,2,6,6-
tetramethylpiperidine-l-oxy, in the presence of N,N'-carbonyldiimidazole or
suitable
carbodiimide to replace the hydroxyl moiety in the carboxyl group at the chain
end of the
polyester with an amino substituted aminoxyl (N-oxide) radical bearing group,
so that the
amino moiety covalently bonds to the carbon of the carbonyl residue of the
carboxyl group to
form an amide bond. The N,N'-carbonyldiimidazole or suitable carbodiimide
converts the
hydroxyl moiety in the carboxyl group at the chain end of the polyester into
an intermediate
activated moiety which will react with the aminoxyl, e.g., 4-amino-2,2,6,6-
tetramethylpiperidine-l-oxy. The aminoxyl reactant is typically used in a mole
ratio of
reactant to polyester ranging from 1:1 to 100:1. The mole ratio of N,N'-
carbonyldiimidazole
to aminoxyl is preferably about 1:1.


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0089] A typical reaction is as follows. A polyester is dissolved in a
reaction solvent and
reaction is readily carried out at the temperature utilized for the
dissolving. The reaction
solvent may be any in which the polyester will dissolve. When the polyester is
a polyglycolic
acid or a poly(glycolide-L-lactide) (having a monoiner mole ratio of glycolic
acid to L-lactic
acid greater than 50:50), highly refined (99.9+% pure) dimethyl sulfoxide at
115 C to 130 C
or hexafluoroisopropanol at room temperature suitably dissolves the polyester.
When the
polyester is a poly-L-lactic acid, a poly-DL-lactic acid or a poly(glycolide-L-
lactide) (having
a monomer mole ratio of glycolic acid to L-lactic acid 50:50 or less than
50:50),
tetrahydrofuran, methylene chloride and cliloroform at room temperature to 50
C suitably
dissolve the polyester.

[0090] The reaction is typically carried out to, substantial coinpletion in 30
minutes to 5
hours. When a polyglycolic acid or a poly(glycolide-L-lactide) from a glycol-
rich monomer
mixture constitutes the polyester, 2 to 3 hours of reaction time is preferred.
When a poly-L-
lactic acid is the polyester, the reaction is readily carried out to
substantial completion at
room temperature for one hour. The reaction is preferably carried out under an
inert
atmosphere with dry nitrogen purging so as to drive the reaction towards
completion.

[0091] The product may be precipitated froin the reaction inixture by adding
cold non-
solvent for the product. For example, aminoxyl-containing polyglycolic acid
and aminoxyl-
containing poly(glycolide-L-lactide) formed from glycolic acid-rich monomer
mixture are
readily precipitated from hot dimethylsulfoxide by adding cold methanol or
cold
acetone/methanol mixture and then recovered, e.g., by filtering. When the
product is not
readily precipitated by adding cold non-solvent for the product, the product
and solvent may
be separated by using vacuum techniques. For example, aminoxyl-containing poly-
L-lactic
acid is advantageously separated from solvent in this way. The recovered
product is readily
further purified by washing away water and by-products (e.g. urea) with a
solvent which does
not dissolve the product, e.g., methanol in the case of the modified
polyglycolic acid,
polylactic acid and poly(glycolide-L-lactide) products herein. Residual
solvent from such
washing may be removed using vacuum drying.

[0092] While the optional bioactive agent(s) can be dispersed within the
polymer matrix
without chemical linkage to the polymer carrier, it is also contemplated that
one or more
bioactive agents or covering molecules can be covalently bound to the
biodegradable
polymers via a wide variety of suitable functional groups. For example, a free
carboxyl
group can be used to react with a complimentary moiety on a bioactive agent or
covering


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
molecule, such as a hydroxy, amino, or thio group, and the lilce. A wide
variety of suitable
reagents and reaction conditions are disclosed, e.g., inMarclz's Advanced
Organic Chenzistry,
Reactions, Meclianisnzs, and Structure, Fifth Edition, (2001); and
Cofnprelaeiasive Organic
Ti=ansfornnations, Second Edition, Larock (1999).

[0093] In other einbodiments, one or more bioactive agent can be linlced to
any of the
polymers of stnictures (I and II) through an amide, ester, ether, amino,
ketone, thioether,
sulfinyl, sulfoiiyl, or disulfide linlcage. Such a linkage can be formed fiom
suitably
functionalized starting materials using synthetic procedures that are known in
the art.
[0094] For example, in one embodiment a polyiner can be linked to a bioactive
agent or
adjuvant via a free carboxyl group (e.g., COOH) of the polymer. Specifically,
a coinpound of
structures (I) and (II) can react with an amino functional group or a hydroxyl
fitnctional
group of a bioactive agent to provide a biodegradable polymer having the
bioactive agent
attached via an amide linkage or ester linkage, respectively. In another
enibodiment, the
carboxyl group of the polymer can be-benzylated or transformed into an acyl
halide, acyl
anhydride/"mixed" anhydride, or active ester. In other embodiments, the free -
NH2 ends of
the polymer molecule can be acylated to assure that the bioactive agent will
attach only via a
carboxyl group of the polyiner and not to the free ends of the polyiner.
~
[0095] The invention aromatic di-acid-containing PEA polymer compositions can
be
formulated into particles to provide a variety of properties. The particles
can have a variety
of sizes and structures suitable to meet differing therapeutic goals and
routes of
administration using methods described in full in co-pending U.S. application
Serial No.
11/344,689, filed January 31, 2006.

[0096] Water soluble covering molecule(s), such as poly(ethylene glycol)
(PEG);
phosphatidylcholine (PC); glycosaminoglycans including heparin;
polysaccharides including
chitosan, alginates and polysialic acid; poly(ionizable or polar amino acids)
including
polyserine, polyglutamic acid, polyaspartic acid, polylysine and polyarginine;
as described
herein, and targeting molecules, such as antibodies, antigens and ligands, are
bioactive agents
that can also be conjugated to the polymer on the exterior of particles or
surgical devices
formed from the invention polymer compositions after production to block
active sites
thereon not occupied by a bioactive agent or to target delivery of the
particles to a specific
body site as is known in the art. The molecular weights of PEG molecules on a
single
particle can be substantially any molecular weight in the range from about 200
to about


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
200,000, so that the molecular weights of the various PEG molecules attached
to the particle
can be varied.

[0097] Alternatively, a bioactive agent or covering molecule can be attached
to the
polymer via a 1ii-Acer molecule. Indeed, to improve surface hydropliobicity of
the
biodegradable polymer, to improve accessibility of the biodegradable polymer
towards
enzynie activation, and to inzprove the release profile of the bioactive
agents from the
biodegradable polymer, a linker may be utilized to indirectly attach a
bioactive agent to the
biodegradable polymer. In certain embodiments, the linlcer compounds include
poly(ethylene
glycol) having a molecular weight (Mw) of about 44 to about 10,000, preferably
44 to 2000;
ainino acids, such as serine; polypeptides with repeat nuinber from 1 to 100;
and any other
suitable low molecular weight polymers. The linker typically separates the
bioactive agent
from the polymer by about 5 angstroms up to about 200 angstroms.

[0098] In still further embodiments, the linker is a divalent radical of
fomiula W-A-Q,
wherein A is (C1-C24) alkyl, (C2-C24) alkenyl, (C2-Cz4) alkynyl, (C2-C20)
alkyloxy, (C3-C$)
cycloalkyl, or (CG-Clo) aryl, and W and Q are each independently N(R)C(=0)-, -
C(=O)N(R)-, -OC(=0)-, -C(=O)O, -0-, -S-, -S(O), -S(0)2-, -S-S-, -N(R)-, -C(=0)-
, wherein
each R is independently H or (C1-Q) alkyl.

[0100] As used to describe the above linkers, the term "alkyl" refers to a
straight or
branched chain hydrocarbon group including methyl, ethyl, n-propyl, isopropyl,
n-butyl,
isobutyl, tert-butyl, n-hexyl, and the like.

[0101] As used to describe the above linkers, "alkenyP" refers to straight or
branched chain
hydrocarbyl groups having one or more carbon-carbon double bonds.

[0102] As used to describe the above liiilcers, "alkynyl" refers to straight
or branched chain
hydrocarbyl groups having at least one carbon-carbon triple bond.

[0103] As used to describe the above linkers, "aryl" refers to aromatic groups
having in
the range of 6 up to 14 carbon atoms.

[0104] In certain embodiments, the linker may be a polypeptide having from
about 2 up to
about 25 amino acids. Suitable peptides contemplated for use include poly-L-
glycine, poly-
L-lysine, poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-
ornithine,


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-
lysine-L-
plienylalanine, poly-L-arginine, poly-L-lysine-L-tyrosine, and the like.

[0105] In one enlbodiment, a bioactive agent can covalently crosslink the
polymer, i.e. the
bioactive agent is bound to more than one polymer molecule, to form an
intermolecular
bridge. This covalent crosslinking can be done with or witliout a linlcer
containing a
bioactive agent.

[0106] A bioactive agent molecule can also be incorporated into an
intramolecular bridge
by covalent attachment between two sites on the same polymer molecule.

[0107] A linear polymer polypeptide conjugate is made by protecting the
potential
nucleophiles on the polypeptide backbone and leaving only one reactive group
to be bound to
the polyiner or polymer linker construct. Deprotection is performed according
to methods
well lcnown in the art for deprotection of peptides (Boc and Fmoc chemistry
for example).
[0108] In one embodiment of the present invention, a bioactive agent is a
polypeptide
presented as a retro-inverso or partial retro-inverso peptide.

[0109] In otller embodiinents, a bioactive agent may be mixed with a
photocrosslinkable
version of the polymer in a matrix, and, after crosslinking, the material is
dispersed (ground)
to form particles having an average diameter in the range from about 0.1 to
about 10 m.
Polymer - Bioactive agent Linkage

[0110] In one embodiment, the polymers used to make the invention PEA polymer
compositions as described herein have one or more bioactive agent directly
linked to the
polymer. The residues of the polymer can be linked to the residues of the one
or more
bioactive agents. For example, one residue of the polymer can be directly
linked to one
residue of a bioactive agent. The polymer and the bioactive agent can each
have one open
valence. Alternatively, more than one bioactive agent, multiple bioactive
agents, or a mixture
of bioactive agents having different therapeutic or palliative activity can be
directly linlced to
the polymer. However, since the residue of each bioactive agent can be linked
to a
corresponding residue of the polymer, the number of residues of the one or
more bioactive
agents can correspond to the number of open valences on the residue of the
polyzner.

[0111] As used herein, a "residue of a polyiner" refers to a radical of a
polymer having
one or more open valences. Any synthetically feasible atom, atoms, or
functional group of


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
the polymer (e.g., on the polymer backbone or pendant group) is substantially
retained when
the radical is attached to a residue of a bioactive agent. Additionally, any
synthetically
feasible fitnctional group (e.g,, carboxyl) can be created on the polymer
(e.g., on the polymer
backbone as a pendant group or as chain termini) to provide the open valence,
provided
bioactivity of the baclcbone bioactive agent is substantially retained when
the radical is
attached to a residue of a bioactive agent. Based on the linlcage that is
desired, those slcilled
in the art can select suitably functionalized starting materials that can be
used to derivatize
the PEA polymers used in the present invention using procedures that are known
in the art.
[0112] As used herein, a "residue of a compound of structural formula (*)"
refers to a
radical of a compound of polyiner formulas (I and III) as described herein
having one or more
open valences. Any synthetically feasible atom, atoms, or functional group of
the conipound
(e.g., on the polyiner backbone or pendant group) can be removed to provide
the open
valence, provided bioactivity of the backbone bioactive agent is substantially
retained when
the radical is attached. Additionally, any synthetically feasible fiinctional
group (e.g.,
carboxyl) can be created on the compound of formulas (I and III) (e.g., on the
polymer
backbone or pendant group) to provide the open valence, provided bioactiv.ity
of the
baclcbone bioactive agent is substantially retained when the radical is
attached to a residue of
a bioactive agent. Based on the linkage that is desired, those skilled in the
art can select
suitably functionalized starting materials that can be used to derivatize the
compound of
formulas (I and III) using procedures that are known in the art.

[0113] For example, the residue of a bioactive agent can be linked to the
residue of a
compound of structural formulas (I and III) through an amide (e.g., -N(R)C(=O)-
or
C(=O)N(R)-), ester (e.g., -OC(=O)- or -C(=O)O-, ether (e.g., -0-), amino
(e.g., -N(R)-),
ketone (e.g., -C(=0)-), thioether (e.g., -S-), sulfinyl (e.g., -S(O)-),
sulfonyl (e.g., -S(0)2-),
disulfide (e.g., -S-S-), or a direct (e.g., C-C bond) linlcage, wherein each R
is independently H
or (CI-C6) alkyl. Such a linkage can be formed from suitably functionalized
starting
materials using synthetic procedures that are known in the art. Based on the
linkage that is
desired, those skilled in the art can select suitably functional starting
material to derivatize
any residue of a compound of structural formulas (I and III) and thereby
conjugate a given
residue of a bioactive agent using procedures that are known in the art. The
residue of the
optional bioactive agent can be linked to any synthetically feasible position
on the residue of
a compound of structural formulas (I and P. Additionally, the invention also
provides


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
compounds having more tlian one residue of a bioactive agent directly linlced
to a coinpound
of structural formulas (I and III).

[0114] The nuinber of bioactive agents that can be linked to the polymer
molecule can
typically depend upon the molecular weight of the polymer. For example, for a
compound of
structural fonnula (I), wherein n is about 5 to about 150, preferably about 2
to about 70,
bioactive agent molecules (i.e., residues thereof) can be directly linked to
the polymer (i.e.,
residue thereof) by reacting the bioactive agent with temlinal groups of the
polyiner. On the
other hand, for a compound of structural formula (III) up to an additional 150
bioactive
agents can be linked to the polymer by reacting the bioactive agent with the
pendant group on
the adirectional amino acid-containing unit, for example wherein R2= H in an L-
lysine-
containing unit. In unsaturated polyiners, additional bioactive agents can
also be reacted with
double (or triple) bonds in the polymer.

[0115] The invention polymer composition, either in the form of particles or
surgical
devices, or not, can be covalently attached directly to the bioactive agent,
rather than being
dispersed or "loaded" into the polymer without chemical attachment, using any
of several
methods well knowii in the art and as described hereinbelow. The amount of
bioactive agent
is generally approximately 0.1 % to about 60% (w/w) bioactive agent to polymer
composition,
more preferably about 1% to about 25% (w/w) bioactive agent, and even more
preferably
about 2% to about 20% (w/w) bioactive agent. The percentage of bioactive agent
will depend
on the desired dose and the condition being treated, as discussed in more
detail below.

[0116] In addition to serving as a stand-alone delivery system for bioactive
agents when
directly administered in vivo in the form of implantable particles, the
invention PEA polyiner
compositions can be used in the fabrication of various types of surgical
devices. In this
embodiment, the invention polymer composition used in fabrication of the
surgical device is
effective for controlled delivery to surrounding tissue of any bioactive
agents dispersed in the
polymer in the invention polymer composition, for exaniple, covalently
attached to the
surface thereof.

[0117] In one embodiment, the invention aromatic di-acid-containing PEA
polymer
composition has sufficient stiffness to be fabricated in the form of a
biodegradable,
biocompatible surgical device, including but not limited to internal fixation
devices, such as
surgical suture, surgical screws, implantable plates, and implantable rods, or
as a vascular
stent or dialysis shunt. Any method known in the art for fabrication of
biodegradable


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WO 2007/050583 PCT/US2006/041441
polymer surgical devices, such as extrusion, injection molding,_ casting, or
solution
processing (dry and wet spinning), and the like, can be used for this purpose.
Such
biodegradable, biocompatible surgical devices slowly biodegrade, for exainple
over a period
of from about 14 days to few years, for exaniple one year, three years or six
years, depending
on device thiclaiess and_ combination of building blocks in the PEA polymer to
create
substantially biocompatible breakdown products.

[0118] Accordingly, in another embodiment the invention provides metliods for
treating a
subject in need thereof comprising iinplanting an invention surgical device at
an iiiterior body
site so that the device slowly biodegrades, for exainple completely. Any
dispersed bioactive
agent, as described herein, dispersed in the polymer from which the device is
fabricated will
be slowly released to tissue surrounding a site of implantation during
biodegradation of the
device, for example to promote healing or alleviate pain therein. For
exainple, the bioactive
agent released from the surgical device, for example when fabricated as a
vascular stent,
promotes endogenous healing processes at the wound site by contact with the
surroundings
into which the surgical device is implanted. In embodiments wherein the device
is fabricated
of a polymer designed to be completely biodegradable, no additional surgery is
required to
remove the implanted surgical device due to its biodegradation properties.

[0119] In another embodiment, the invention aromatic di-acid-containing PEA
polymer
composition can be fabricated in the form of a biodegradable, biocompatible
pad, sheet or
wrap of any desired surface area. For example, the polyiner can be woven or
formed as a tliin
slieet of randomly oriented fibers by electrospinning to produce nanofibers of
the polymer.
Such pads, sheets and wraps can be used in a number of types of wound
dressings for
treatment of a variety of conditions, for example by promoting endogenous
healing processes
at a wound site. Such wound dressings can be implanted at an interior body
site or applied to
a body surface, depending upon the needs of the subject. For example, such a
wound
dressing can be applied to the surface of burned or injured skin. The
invention PEA polymer
in such a wound dressing biodegrades over time, releasing a bioactive agent
dispersed therein
to be absorbed into a wound site where it acts intracellularly, either within
the cytosol, the
nucleus, or both, of a target cell. Alternatively, the bioactive agent caii
bind to a cell surface
receptor molecule to elicit a cellular response without entering the cell. A
detailed
description of wound dressings, wound healing implants and surgical device
coatings made
using related PEA polymers is found in co-pending U.S. Patent Application
Serial No.
11/128,903, filed May 12, 2005.


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
(0120] Bioactive agents contenlplated for dispersion within the polymers used
in the
invention aromatic di-acid-containing PEA polyiner compositions include anti-
proliferants,
rapamycin and any of its analogs or derivatives, paclitaxel or any of its
taxene analogs or
derivatives, everolimus, sirolimus, tacrolimus, or any of its -linius named
family of drugs,
and statins such as sinivastatin, atorvastatin, fluvastatin, pravastatin,
lovastatin, rosuvastatin,
geldanamycins, such as 17AAG (17-allylamino-l7-demetlloxygeldanamycin);
Epothilone D
and other epothilones, 17-dimethylaminoethylamino-17-demethoxy-geldanamycin
aild other
polylcetide inhibitors of heat shock protein 90 (Hsp90), cilostazol, and the
like.

[0121] Suitable bioactive agents for dispersion in the invention aromatic di-
acid-
containing PEA polymer compositions and particles made therefrom also can be
selected
from those that promote endogenous production of a therapeutic natural wound
healing agent,
such as nitric oxide, which is endogenously produced by endothelial cells.
Alternatively the
bioactive agents released from the polymers during degradation may be directly
active in
promoting natural wound healing processes by endothelial cells. These
bioactive agents can
be any agent that donates, transfers, or releases nitric oxide, elevates
endogenous levels of
nitric oxide, stimulates endogenous synthesis of nitric oxide, or serves as a
substrate for nitric
oxide synthase or that inhibits proliferation of smooth muscle cells. Such
agents include, for
example, aminoxyls, furoxans, nitrosothiols, nitrates and anthocyanins;
nucleosides such as
adenosine and nucleotides such as adenosine diphosphate (ADP) and adenosine
triphosphate
(ATP); neurotransmitter/neitromodulators such as acetylcholine and 5-
hydroxytryptamine
(serotoninl5-HT); histamine and catecholamines such as adrenalin and
noradrenalin; lipid
molecules such as sphingosine-1-phosphate and lysophosphatidic acid; amino
acids such as
arginine and lysine; peptides such as the bradykinins, substance P and calcium
gene-related
peptide (CGRP), and proteins such as insulin, vascular endothelial growtlr
factor (VEGF),
and thrombin.

[0122] A variety of bioactive agents, coating molecules and ligands for
bioactive agents
can be attached, for example covalently, to the surface of the polymer
particles. Bioactive
agents, such as targeting antibodies, polypeptides (e.g., antigens) and drugs
can be covalently
conjugated to the surface of the polymer particles. In addition, coating
molecules, such as
polyethylene glycol (PEG) as a ligand for attachment of antibodies or
polypeptides or
phosphatidylcholine (PC) as a means of blocking attaclnnent sites on the
surface of the
particles, can be surface-conjugated to the particles to prevent the particles
from sticking to


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
non-target biological molecules and surfaces in a subject to which the
particles are
administered.

[0123] For example, small proteinaceous motifs, such as the B domain of
bacterial Protein
A and the fiinetionally equivalent region of Protein G are lrnown to bind to,
and thereby
capture, antibody molecules by the Fc region. Such proteinaceous motifs can be
attached as
bioactive agents to the invention polymers and conlpositions, especially to
the surface of the
polymer particles described herein. Such molecules will act, for exainple, as
ligands to attach
antibodies for use as targeting ligands or to capture antibodies to hold
precursor cells or
capture cells out of the blood stream. Therefore, the antibody types that can
be attached to
polyiner coatings using a Protein A or Protein G functional region are those
that contain an
Fc region. The capture antibodies will in turn bind to and hold precursor
cells, such as
progenitor cells, near the polymer surface while the precursor cells, which
are preferably
bathed in a growth medium within the polymer, secrete various factors and
interact with other
cells of the subject. In addition, one or more bioactive agents dispersed in
the polymer
particles, such as the bradykinins, may activate the precursor cells.

[0124] In addition, bioactive agents for attaching precursor cells or for
capturing
progenitor endothelial cells (PECs) from a blood stream in a subject to which
the polymer
compositions are administered are monoclonal antibodies directed against a
known precursor
cell surface marker. For example, complementary determinants (CDs) that have
been
reported to decorate the surface of endothelial cells include CD31, CD34,
CD102, CD105,
CD106, CD109, CDwl30, CD141, CD142, CD143, CD144, CDw145, CD146, CD147, and
CD166. These cell surface markers can be of varying specificity and the degree
of specificity
for a particular cell/developmental type/stage is in many cases not fitlly
characterized. In
addition, these cell marker molecules against which antibodies have been
raised will overlap
(in terms of antibody recognition) especially with CDs on cells of the same
lineage:
monocytes in the case of endothelial cells. Circulating endothelial progenitor
cells are some
way along the developmental pathway from (bone marrow) monocytes to mature
endothelial
cells. CDs 106, 142 and 144 have been reported to mark mature endothelial
cells with some
specificity. CD34 is presently known to be specific for progenitor
endotlielial cells and
therefore is currently preferred for capturing progenitor endothelial cells
out of blood in the
site into which the polymer particles are implanted for local delivery of the
active agents.
Examples of such antibodies include single-chain antibodies, chimeric
antibodies,


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
inonoclonal antibodies, polyclonal antibodies, antibody fragments, Fab
fragments, IgA, IgG,
IgM, IgD, IgE and humanized antibodies, and active fragments thereof.

[0125] The following bioactive agents and small molecule drugs will be
particularly
effective for dispersion within the invention aromatic di-acid-containing PEA
polymer
compositions when selected for their suitable therapeutic or palliative effect
in treatinent of a
wound or interior body condition of interest.

[0126] In one enibodiinent, the suitable bioactive agents are not limited to,
but include,
various classes of compounds that facilitate or contribute to wound healing
when presented in
a time-release fashion. Such bioactive agents include wound-healing cells,
including certain
precursor cells, which can be protected and delivered by the biodegradable
polymer in the
invention compositions. Such wound healing cells include, for example,
pericytes and
endothelial cells, as well as inflammatory healing cells. To recruit such
cells to the site of an
implanted device coniprising an invention PEA polymer in vivo, the invention
aromatic di-
acid-containing PEA polymer compositions, such as implantable surgical devices
or particles
thereof used in the invention methods of use can include ligands for such
cells, such as
antibodies and smaller molecule ligands, that specifically bind to "cellular
adhesion
molecules" (CAMs). Exemplary ligands for wound healing cells include those
that
specifically bind to Intercellular adhesion molecules (ICAMs), such as ICAM-1
(CD54
antigen); ICAM-2 (CD102 antigen); ICAM-3 (CD50 antigen); ICAM-4 (CD242
antigen);
and ICAM-5; Vascular cell adhesion molecules (VCAMs), such as VCAM-1 (CD106
antigen); Neural cell adhesion molecules (NCAMs), such as NCAM-1 (CD56
antigen); or
NCAM-2; Platelet endothelial cell adhesion molecules PECAMs, such as PECAM-1
(CD31
antigen); Leukocyte-endothelial cell adhesion molecules (ELAMs), such as LECAM-
1; or
LECAM-2 (CD62E antigen), and the like.

[0127] In another aspect, the suitable bioactive agents include extra cellular
matrix
proteins, macromolecules that can be dispersed into the polymer particles used
in the
invention aromatic di-acid-containing PEA polymer compositions, e.g., attached
either
covalently or non-covalently. Examples of useful extra-cellular matrix
proteins include, for
example, glycosaminoglycans, usually linked to proteins (proteoglycans), and
fibrous
proteins (e.g., collagen; elastin; fibronectins and laminin). Bio-mimics of
extra-cellular
proteins can also be used. These are usually non-huinan, but biocoinpatible,
glycoproteins,
such as alginates and chitin derivatives. Wound healing peptides that are
specific fragments
of such extra-cellular matrix proteins and/or their bio-mimics can also be
used.


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WO 2007/050583 PCT/US2006/041441
[0128] Proteinaceous growtli factors are another category of bioactive agents
suitable for
dispersion in the invention aromatic di-acid-containing PEA polymer
compositions and
methods of use described herein. Such bioactive agents are effective in
promoting wound
healing and otller disease states as is known in the art, for example,
Platelet Derived Growth
Factor-BB (PDGF-BB), Tumor Necrosis Factor-alpha (TNF-alpha), Epidennal Growth
Factor (EGF), Keratinocyte Growth Factor (KGF), Thymosiii B4; and, various
angiogenic
factors such as vascular Endotlielial Growth Factors (VEGFs), Fibroblast
Growth Factors
(FGFs), Tumor Necrosis Factor-beta (TNF -beta), and Insulin-like Growth Factor-
1 (IGF-1).
Many of these proteinaceous growth factors are available commercially or can
be produced
recombinantly using techniques well known in the art.

[0129] Alternatively, expression systems coniprising vectors, particularly
adenovirus
vectors, incorporating genes encoding a variety of biomolecules can be
dispersed in the
invention aromatic di-acid-containing polyiner compositions and particles
thereof for timed
release delivery. Methods of preparing such expression systems and vectors are
well kn.own
in the art. For example, proteinaceous growth factors can be dispersed into
the invention
bioactive compositions for administration of the growth factors either to a
desired body site
for local delivery, by selection of particles sized to form a polymer depot,
or systemically, by
selection of particles of a size that will enter the circulation. Growth
factors, such as VEGFs,
PDGFs, FGF, NGF, and evolutionary and functionally related biologics, and
angiogenic
enzymes, such as thrombin, may also be used as bioactive agents in the
invention.

[0130] Small molecule drugs are yet another category of bioactive agents
suitable for
dispersion in the invention aroinatic di-acid-containing PEA polymer
compositions and
methods of use described herein. Such drugs include, for example,
antimicrobials and anti-
inflammatory agents as well as certain healing promoters, such as, for
example, vitamin A
and synthetic inhibitors of lipid peroxidation.

[0131] A variety of antibiotics can be dispersed as bioactive agents in the
invention
aromatic di-acid-containing PEA polymer compositions to indirectly promote
natural healing
processes by preventing or controlling infection. Suitable antibiotics include
many classes,
such as aminoglycoside antibiotics or quinolones or beta-lactams, such as
cefalosporins, e.g.,
ciprofloxaciil, gentamycin, tobramycin, erythromycin, vancomycin, oxacillin,
cloxacillin,
methicillin, lincomycin, ampicillin, and colistin. Suitable antibiotics have
been described in
the literature.


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0132] Suitable antimicrobials inchide, for example, Adriamycin PFS/R.DF
(Phannacia
and Upjolul), Blenoxane (Bristol-Myers Squibb Oncology/Inlmunology),
Cerubidine
(Bedford), Cosmegen (Merclc), DaunoXomeO (NeXstar), Doxil (Sequus),
Doxon.ibicin
Hydrochloride (Astra), Idamycin PFS (Phannacia and Upjohn), Mithracin
(Bayer),
Mitamycin (Bristol-Myers Squibb Oncology/Immunology), Nipen (SuperGen),
Novantrone (Immunex) and Rubex (Bristol-Myers Squibb Oncology/Iminunology).
In
one embodiment, the peptide can be a glycopeptide. "Glycopeptide" refers to
oligopeptide
(e.g. heptapeptide) antibiotics, characterized by a multi-ring peptide core
optionally
substituted with saccharide groups, such as vancomycin.

[0133] Examples of glycopeptides included in this category of antimicrobials
may be
found in "Glycopeptides Classification, Occurrence, and Discovery," by Raymond
C. Rao
and Louise W. Crandall, ("Bioactive agents and the Pharmaceutical Sciences"
Volume 63,
edited by Ramakrishnan Nagarajan, published by Marcal Dekker, Inc.).
Additional examples
of glycopeptides are disclosed in U.S. Patent Nos. 4,639,433; 4,643,987;
4,497,802;
4,698,327, 5,591,714; 5,840,684; and 5,843,889; in EP 0 802 199; EP 0 801 075;
EP 0 667
353; WO 97/28812; WO 97/38702; WO 98/52589; WO 98/52592; and in J. Amer.
Clzeni.
Soc.(1996) 118: 13107-13108;.I. Amer. Chenz. Soc. (1997) 119:12041-12047;
and,I. Amer.
Chenz. Soc. (1994) 116:4573-4590. Representative glycopeptides include those
identified as
A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575,
AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin, Azureomycin, Balhimyein,
Chloroorientiein, Chloropolysporin, Decaplanin, -demethylvancomycin,
Eremomycin,
Galacardin, Helvecardin, Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289,
MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270,
MM56597, MM56598, OA-7653, Orenticin, Parvodicin, Ristocetin, Ristomycin,
Synmonicin, Teicoplanin, UK-68597, UD-69542, UK-72051, Vancomycin, and the
like. The
tenn "glycopeptide" or "glycopeptide antibiotic" as used herein is also
intended to include
the general class of glycopeptides disclosed above on which the sugar moiety
is absent, i.e.
the aglycone series of glycopeptides. For example, removal of the disaccharide
moiety
appended to the phenol on vancomycin by mild hydrolysis gives vancomycin
aglycone. Also
included within the scope of the tenn "glycopeptide antibiotics" are synthetic
derivatives of
the general class of glycopeptides disclosed above, including alkylated and
acylated
derivatives. Additionally, within the scope of this tenn are glycopeptides
that have been
further appended with additional saccharide residues, especially
aminoglycosides, in a
manner similar to vancosamine.


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0134] The term "lipidated glycopeptide" refers specifically to those
glycopeptide
antibiotics that have been synthetically modified to contain a lipid
substituent. As used
herein, the term "lipid substituent" refers to any substituezit contains 5 or
more carbon atoms,
preferably, 10 to 40 carbon atoms. The lipid substituent may optionally
contain from 1 to 6
heteroatoms selected from halo, oxygen, nitrogen, sulfiir, and phosphorous.
Lipidated
glycopeptide antibiotics are well known in the art. See, for exaniple, in U.S.
Patent Nos.
5,840,684, 5,843,889, 5,916,873, 5,919,756, 5,952,310, 5,977,062, 5,977,063,
EP 667, 353,
WO 98/52589, WO 99/56760, WO 00/04044, WO 00/39156, the disclosures of which
are
incorporated herein by reference in their entirety.

[0135] Anti-inflaminatory bioactive agents are also useful for dispersion in
used in
invention aromatic di-acid-containing PEA polymer compositions and methods.
Depending
on the body site and disease to be treated, such anti-inflammatory bioactive
agents include,
e.g. analgesics (e.g., NSAIDS and salicyclates), steroids, antirheumatic
agents,
gastrointestinal agents, gout preparations, hormones (glucocorticoids), nasal
preparations,
ophthalmic preparations, otic preparations (e.g., antibiotic and steroid
combinations),
respiratory agents, and skin & mucous membrane agents. See, Playsician's
DeskReference,
2005 Edition. Specifically, the anti-inflammatory agent can include
dexamethasone, which is
chemically designated as (119, 16I)-9-fluro-11,17,21-trihydroxy-l6-
methylpregna-1,4-diene-
3,20-dione. Alternatively, the anti-inflammatory bioactive agent.can be or
include sirolimus
(rapamycin), which is a triene macrolide antibiotic isolated from Streptomyces
hygroscopzcus.

[0136] The polypeptide bioactive agents included in the invention compositions
and
methods can also include "peptide mimetics." Such peptide analogs, referred to
herein as
"peptide mimetics" or "peptidomimetics," are coinmonly used in the
pharmaceutical industry
with properties analogous to those of the template peptide (Fauchere, J.
(1986) Adv. Bioactive
agent Res., 15:29; Veber and Freidinger (1985) TINS, p. 392; and Evans et al.
(1987) J. Med.
Chena., 30:1229) and are usually developed with the aid of computerized
inolecular
modeling. Generally, peptidomimetics are structurally similar to a paradigm
polypeptide
(i.e., a polypeptide that has a biochemical property or pharmacological
activity), but have one
or more peptide linkages optionally replaced by a linkage selected from the
group consisting
of: - -CH2NH--, --CH2S--, CH2--CH2--, --CH=CH-- (cis and trans), --COCH2--, --
CH(OH)CHZ--, and --CH2SO--, by methods known in the art and further described
in the
following references: Spatola, A.F. in Chemistiy and Biochemistfy ofAinino
Acids, Peptides,


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
and Pf-oteins, B. Weinstein, eds., Marcel Deldcer, New York, p. 267 (1983);
Spatola, A.F.,
Vega Data (March 1983), Vol. 1, Issue 3, "Peptide Baclcbone Modifications"
(general
review); Morley, J.S., Trends. Pharrii. Sci., (1980) pp. 463-468 (general
review); Hudson, D.
et al., Int. .I. Pept. Prot. Res., (1979) 14:177-185 (--CH2 NH--, CH2CH2--);
Spatola, A.F. et
al., Life Sci., (1986) 38:1243-1249 (--CH2-S--); Harm, M. M., J. Cheni. Soc.
Perkin Trans I
(1982) 307-314 (--CH=CH--, cis and trans); Almquist, R.G. et al., J. Med.
Chenz., (1980)
23:2533 (--COCH2--); Jennings-Wliie, C. et al., Tetf ahedi=on Lett., (1982)
23:2533 (--
COCH2--); Szelke, M. et al., European Appln., EP 45665 (1982) CA: 97:39405
(1982)
(--CH(OH)CH2--); Holladay, M. W. et al., Tetrahedron Lett., (1983) 24:4401-
4404 (--
C(OH)CH2--); and Hruby, V.J., Life Sci., (1982) 31:189-199 (--CHZ-S--). Such
peptide
mimetics may have significant advantages over natural polypeptide embodiments,
including,
for example: more economical production, greater chemical stability, enhanced
pharmacological properties (half-life, absorption, potency, efficacy, etc.),
altered specificity
(e.g., a broad-spectrum of biological activities), reduced antigenicity, and
others.

[0137] Additionally, substitution of one or more amino acids within a peptide
(e.g., witli a
D-lysine in place of L-lysine) may be used to generate more stable peptides
and peptides
resistant to endogenous peptidases. Alternatively, the synthetic polypeptides
covalently
bound to the biodegradable polymer, can also be prepared from D-amino acids,
referred to as
inverso peptides. When a peptide is assembled in the opposite direction of the
native peptide
sequence, it is referred to as a retro peptide. In general, polypeptides
prepared from D-amino
acids are very stable to enzymatic hydrolysis. Many cases have been reported
of preserved
biological activities for rett o-inverso or partial retYo-inverso polypeptides
(US patent,
6,261,569 Bl and references therein; B. Fromme et al, Endocrinology
(2003)144:3262-3269.
[0138] Any suitable and effective amount of the at least one bioactive agent
can be
released with time from the invention polymer composition, including those in
a
biodegradable internal fixation device, stent, or dialysis shunt, or in a
depot formed from
particles thereof introduced in vivo. The suitable and effective amount of the
bioactive agent
will typically depend, e.g., on the specific aromatic di-acid-containing PEA
polymer and type
of particle or polymer/bioactive agent linlcage, if present. Typically, up to
about 100% of the
bioactive agent(s) can be released from the invention polymer in vivo.
Specifically, up to
about 90%, up to 75%, up to 50%, or up to 25% thereof can be released from the
polymer.
Factors that typically affect the release rate from the polymer are the types
of


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WO 2007/050583 PCT/US2006/041441
polynier/bioactive agent linlcage, and the nature and amount of additional
substances present
in the formulation.

[0139] In addition to humans, the invention aromatic di-acid-containing PEA
polymer
compositions, as well as particles and surgical devices fabricated therefrom,
are also intended
for use in veterinary practice, including a variety of mainmalian patients,
such as pets (for
exanlple, cats, dogs, rabbits, and ferrets), faml animals (for example, swine,
horses, inules,
dairy and meat cattle) and race horses.

[0140] In certain embodiments, the bioactive agent(s) used in the invention
conlpositions,
devices and methods of administration will coinprise an "effective aniount" of
one or more
bioactive agents of interest. That is, an amount of a bioactive agent will be
incorporated into
the polymer that will produce a sufficient therapeutic or palliative response
in order to
prevent, reduce or elinzinate symptoms. The exact amount necessary will vary,
depending on
the subject to which the composition is being administered; the age and
general condition of
the subject; the capacity of the subject's immune system, the degree of
therapeutic or
palliative response desired; the severity of the condition being treated or
investigated; the
particular bioactive agent selected and mode of administration of the
composition, among
other factors. An appropriate effective amount can be readily determined by
one of skill in
the art. Thus, an "effective amount" will fall in a relatively broad range
that can be
determined through routine trials. For example, for purposes of the present
invention, an
effective amount will typically range from about 1 g to about 100 mg, for
example from
about 5 g to about 1 mg, or about 10 gg to about 500 gg of the bioactive
agent delivered.
[0141] The following examples are meant to illustrate, but not to limit the
invention.

EXAMPLE 1
Materials:

[0142] 4-hydroxybenzoic acid, 1,3-dibromopropane, p-nitrophenol, thionyl
chloride,
oxalyl chloride, triethylamine, and anliydrous N,N-dimethylformamide (DMF)
were
purchased from Aldrich Chemicals (St. Louis, MO), and used without further
purification.
Chloroform and chlorobenzene were dried over 4A molecular sieves. Other
solvents and
reagents: diethyl ether, ethyl acetate, sodium carbonate, sodium sulfate were
purchased from
Fisher Chemicals (UK).


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
Materials Characterization

101431 NMR spectra were recorded by a Brulcer AMX-500 spectrometer (Numega R.
Labs, San Diego, CA) operating at 500 MHz for 'H NMR spectroscopy. Deuterated
solvents
CDCl3 or DMSO-d6 (Cambridge Isotope Laboratories, Cambridge, MA) were used
with
tetramethylsilane (TMS) as internal standard.

[0144] Melting points of monomers were determined on automatic Mettler Toledo
FP62
Melting Point Apparatus (Mettler-Toledo International, Inc). Thermal
properties of
monomers and polymers were characterized on Mettler Toledo DSC 822e
differential
scanning calorimeter. Samples were placed in aluminum pans. Measurements were
carried
out at a scanning rate of 10 C/min under nitrogen flow.

[0145] The nuniber and weight average molecular weights (Mw and Mn) and
molecular
weight distribution of synthesized polymers were determined by Mode1515 gel
permeation
chromatography (Waters Associates, Milford, MA) equipped with a high pressure
liquid
chroinatographic pump, a Waters 2414 refractory index detector with 0.1 % of
LiCI solution
in DMAc used as eluent (1.0 mL/min). Two Styragel HR 5E DMF type columns
(Waters
Associates) were connected and calibrated with polystyrene standards.

[0146] Tensile strength, % elongation at brealc, and Young's Modulus were
measured on
tensile strength machine (Chatillon TCD200) integrated with a PC and Nexygen
FM software
(Amatek, Largo, FL, ) at a crosshead speed of 100 mm/min. The load capacity
was 501bs.
The film (4 x 1.6 cm) had a dumbbell shape and thickness of about 0.125 mm.

Monomer synthesis: -
CPP synthesis (Compound 1)

[0147] Into a round bottom flask equipped with magnetic stirrer and reflux
condenser, 30
g (0.2172 mol) of 4-hydroxybenozoyc acid was dissolved in 220 mL of 2M sodium
hydroxide solution. Then 11.1 mL (0.1086 mmol) of 1,3-dibromopropane was
introduced
and the reaction nlixture was heated to reflux wliile being stirred. Heating
continued for 16
hours and then the cooled solution was poured into 700 mL of 1M HCI. A white
paste
formed and was filtered. An off-white solid obtained by filtration was
suspended in
H20/Etanol 1:1 solution, re-filtered and dried in an oven under vacuum. Yield
was 21.3 g
(62%) white solid collected with melting point (mp) of 310 C obtained as
described above


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
conipared to a literature mp of 310 C (Aldrich Chemicals). Product was
reciystallized from
DMF:water, 1:1 w/w.

Di p-nitrophenyl ester of CPP (Compound 4)

O2N r_) O-C O-(CH2)3'O C-O NO2
(Compound 4)

[0148] Preparation of this compound has been carried out by two different
methods:
[0149] Method A: Direct condensation of CPP with p-nitrophenol, using thionyl
chloride
as condensing reagent.

[0150] A three-neck round-bottom flask, equipped with magnetic stirrer,
addition funnel,
reflux condenser, and nitrogen in- and outlet was charged with 7.9 g. (25
mmol) of CPP
(compound 1), 7.3 g (52.5 mmol) of p-nitrophenol, and a few drops of DMF and
100 mL of
dry chlorobenzene. To this mixture a solution of 4 ml (54.8 mmol) thionyl
chloride in 10 mL
of chlorobenzene was added drop-wise at ambient teniperature for 20 n1in. time
period. Then
the reaction mixture was heated to 79 C while a slow stream of nitrogen was
introduced to
evacuate formed gases. After 8 h, the reaction mixture became homogenous. Tlie
cooled
solution was diluted with 120 mL hexane and left over night at 0 C. Yellow
crystals of
compound 2 were collected by filtration, washed with hexane and dried in
vacuunl over night
at 45 C. Yield was 10.3g, (74 %.). Recrystallization from acetone yielded pale
yellow
crystals, mp 161.6 C.

[0151] 1H NMR, 6 (DMSO-d6, 500 MHz): 8.33 (d, 4H, Ar), 8.10 (d, 4H, Ar), 7.58
(d, 4H,
Ar), 7.17 (d, 4H, Ar), 4.29 (t, 4H, -O-CH2-), 2.27 (m, 2H, -CHZ-CHZ-).

[0152] Method B: Because thionyl chloride is a controlled substance no longer
readily
available, a two step synthesis via acid chloride was developed, illustrated
in this example
using oxalyl chloride.

[0153] First step: syntlaesis of CPP-dichloride: 9.2g (29.1 mmol) of CPP and a
few drops
of pyridine were suspended into 120 mL of dry chloroform in 500 mL round-
bottom flask.
Using an addition funnel, at room temperature, 35 mL of 2 M oxalyl chloride
solution
(Aldrich) in dichloromethane was added dropwise with stirring. Stirring was
continued for 1
h and the solution was heated to reflux for another 6 hours: the white
suspension turned into a


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
yellow homogeneous solution. After cooling, a clear reaction solution was
filtered through
glass frit under inert atniosphere to remove tliei-ino-mechanical iinpurities
and the filtrate was
diluted with. 500 niL of hexane. Yellow crystals separated fiom the filtrate
after standing over
night, being, filtered under argon, placed in round-bottom flask and dried
under vacuum at
room temp. Crude product with the yield of 9.8 g. (95%) was converted to
activated ester,
without further recrystallization.

[0154] Second step: condensation of CPP-dich.lof ide with p-nitrophenol To the
chilled
(0 C) solution of 8 g (57.5 inmol) of p-nitrophenol and 8.1 mL of
triethylamine in 100 mL of
dry ethylacetate a solution of 9.8 g (27.8 mmol) CPP-dichloride in 150 mL of
ethylacetate
was added dropwise over 30 min. Then, the reaction mixture was warmed to room
temperature for 8 hours before heating to 45 C for another 2 hours.
Ethylacetate was
evaporated and obtained solid product was first washed with acidified water
(pH 2-3), then
with deionized water and dried. Yield was 9.0 g (92%). Product was
recrystallized from
acetone.

Synthesis of di p-nitrophenyl esters ofsebacic acid (Compound 5)

[0155] Di-p-nitrophenyl ester of sebacic acid was prepared by reacting of
sebacoyl
chloride with p-nitrophenol as described previously (Katsarava et al. J.
Polyin. Sci. Part A:
Polym. Chem. (1999) 37. 391-407):

0 0 _ O
CI-C-(CH2)$-C-CI + 02N OH - OZN r~\ O-C-(CH2)$-C-O NO2
Triethylamine '0'

(Compound 5)

[0156] For the polymerization other required monomers were bis-electrophiles
based on
amino acids and aliphatic diols, both of which were synthesized according to
previously
published procedures.

Preparation of di p-tolueuesulfouic acid salt of bis-L-leuciue-lzexaue-1, 6-
diester
(Compound 6)

[0157] Synthesis of tosylate salts of diamines as nucleophilic monomers has
been
described previously in U.S. Patents 6,503,538 Bl and in provisional U.S.
application Serial
No. 60/687,570, filed June 3, 2005. Di-p-toluenesulfonic acid salt of bis-L-
leucine-hexane-


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
1,6-diester (Compound 6) was prepared by a modification of the previously
published
method

H O O H
HOTos.H2N-6-C-O-(CHZ)6-O-6-6-NH2.TosOH
CH2 CH2
CH(CH3)2 CH(CH3)2

(Compound 6)

wherein L-leucine (0.132 mol), p-toluenesulfonic acid monoliydrate (0.132 mol)
and 1,6-
hexane diol (0.06 mol) in 250 mL of toluene were placed in a flaslc equipped
with a Dean-
Stark apparatus and overhead stirrer. The heterogeneous reaction mixture was
heated to
reflux for about. 12 h until 4.3 mL (0.24 mol) of water evolved. The reaction
mixture was
then cooled to room temperature, filtered, washed with acetone, and
recrystallized twice from
methanol/toluene 2:1 mixture. Yield and mp obtained as described above were
identical to
published data (R. Katsarava et al. J. Polynz. Sci., Part A: Polyna. Chena.
(1999) 37:391-407).
Preparation of di-p-Toluenesulfonic acid salt of O, 0'-bis(L-leucinyl)-1, 4:
3, 6-
diar2hydNosos bitol-diester (Compound 7).

[0158] Preparation of di-p-Toluenesulfonic acid salt of 0,0'-bis(L-leucinyl)-
1,4:3,6-
dianhydrosorbitol-diester (Compound 6) was carried out analogously to that of
Compound 3
by reacting isosorbide with L-leucine in refluxing toluene in the presence ofp-

toluenesulfonic acid monohydrate with a Dean-Stark equipment as previously
described (Z.
Gomurashvili, et al. J. Macfronaol. Sci. Pure Appl. Chen2. (2000) A37: 215-
227).

0 O H
H 0 O-C-C-NH2'TosOH
HOTos.H2N-C-C-OU~ 0 CH~
CHZ CH(CH3)2
CH(CH3)2

(Compound 7)

Preparation of Di p-toluenesulfonic acid salt of L-lysine benzyl ester
(Compotind 8)

[0159] Di-p-toluenesulfonic acid salt of L-lysine benzyl ester (Compound 7)
was prepared
as described previously in U.S. Patents 6,503,538 Bl by refluxing of benzyl
alcohol,


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
toluenesulfonic acid monohydrate and L-lysine monohydrochloride in toluene,
while
applying azeotropic removal of water.

H
HOTos.H2N-C-(CH2)4 NH2.TosOH
O=C
i
0
CHZ
~ I
~
(Compound 8)
Polymer Synthesis:

[0160] Preparation ofPEA Polyrnef= # 3, in Table 1. To the stirred inixture of
9 mmol of
Compound 6, 3 mmol of Compound 8, 6 inmol of pNP-CPP (Compound 4) and 6 inmol
of
compound 5 in 8.5 mL of anhydrous N,N-dimethylformamide, 12.3 mmol of
triethylainine
was added and heated at 65 C for 24 hours. In all cases the reaction
proceeded
homogenously. The obtained viscous reaction solution was poured into cold
water and
precipitated product was filtered off and thoroughly washed with water. Crude
polymer was
dried, resuspended in 100 mL chloroform, and p-nitrophenyl residue was
extracted with
water several times. The organic phase was dried over sodium sulfate,
filtered, and
concentrated by solvent evaporation. Polymer was precipitated in ethylacetate.
Yields and
polymer properties are as summarized in Table 1 herein.

Polymer characterization

[0161] Four different poly(ester amides) were prepared using the technique
illustrated
above, but with various proportional coinbinations (feed ratios) of sebacic
acid and CPP. The
exemplary aromatic di-acid-containing PEA polymers have properties as
sunlmarized in
Table I herein and have chemical structures described by the following formula
XII:

frO O H H O O H H 0 O H H
11 i i n n i i n 1 n 1 i
CR -C-N-C-C-O-(CH,)s O-C-C-N C-R -C-N-C-(CH2)4 N
CH2 CH2 3 C-O-C6H5 H 1
CH(CH3)2 CH(CH3)2 p n

Formula XII

wherein for sebacic acid (R1= -(CH2)$-) and/or for CPP (R' =-C6H4-O-(CHZ)3-O-
C6H4-).


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0162] In all cases the reaction proceeded homogenously. The polymers
displayed an
increase of glass trailsition temperature (Tg) directly proportional to the
amount of CPP di-
acid residue contained in the polymer (e.g. increase in feed ratio of
CPP:aliphatic di-acid(s)
used in preparation). In addition Tg of the exemplary invention polymers was
above
physiological temperature, in the range from 45 C to 78 C (Table 1). Tg was
also increased
by substitution of an aliphatic linear 1,6-hexanediol residue in the place of
the residue of a bi-
cyclic aliphatic sugar-diol, such as isosorbide (See # 4 in Table 1).

[0163] Differential Scanning Calorimetry heating traces of polymers with more
than 3 5%
CPP di-acid content show the presence of melting endotherms (Fig. 2), a
phenomenon
generally characteristic of semi-crystalline materials. Wetting properties
(hydrophilicity) as
well as capacity for water uptake of the invention PEAs decreases as the
content of CPP di-
acid residues increases.

[0164] By contrast, the elastic properties (% elongation) of the exemplary CCP-
containing
PEA polymers decreased in proportion to the amount of CCP residues in the
polymers, an
effect attributed to the rigid phenyl groups in CCP.

[0165] In addition, it was discovered that increasing the proportion of CPP in
the di-acid
feed ratio to greater than 25 % in PEA polymers decreases solubility of the
polymer in
ethanol. However, the PEA polymer is still soluble in chloroform,
dichloromethane and
aprotic polar solvents like N,N-Dimethylformamide (DMF), N,N-Dimethylacetamide
(DMAc), and diinethylsulfoxide (DMSO).

EXAMPLE 2
Materials

[0166] The compounds trans-3-hydroxycinnamic acid, trans-4-hydroxycinnamic
acid,
adipoyl chloride, sebacoyl chloride, oxalyl chloride (2M in inethylene
chloride) and pyridine
were purchased from Aldich Chemicals (St, Louis, MO), and used without further
purification. Anhydrous solvents, tetrahydrofurane and N'N-dimethylformamide
(DMF,
Aldrich) were used as received.

Monomer synthesis:

Syntlaesis of 3,3'-(adipoyldioxy)dicinnamic acid (Compound 3).


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0167] A solution of 3-Hydroxyciimamic acid (8.2 g, 0.05 mol) dissolved in 100
mL of
2N sodium hydroxide solution was vigorously stirred and cooled to about 5 C.
At once
adipoyl chloride (4.6 g, 0.025 mol) diluted with 25 mL of dry chloroform was
added. After
30 min of stirring, whole precipitate was filtered off, washed with water, in
1N HCI, and
dried. Product recrystallized from DMSO/ethanol/water (pH 2-3) to yield 6.6 g
(56%) of
conipound 3, m.p. 238-239 C (decomp.). Elemental Aiialysis, C24H2208:
Calculated values:
C: 65.75, H: 5.06; Found values: C: 65.27, H: 5.34. Mono-substituted by-
product, 3-
adipoyldioxydicinnamic acid, (about 37% of the overall product, in.p. 192-194
C), gained
from motlier liquor, was presumably formed by partial hydrolysis of adipoyl
chloride during
interfacial reaction.

Syzzthesis of 4,4'-(alkanedioyldioxy)dicinnamic acids

[0168] The procedure is as described with reference to synthesis of 4,4'-
(adipoyldioxy)dicinnamic acid (Compound 2). Adipoyl dichloride (5.49 g) was
dissolved in
20 mL of anhydrous THF and added dropp-wise to an ice cold solution of 14.77 g
(0.09 mol)
p-hydroxycinnamic acid in 80 mL of anhydrous THF and 10 mL of pyridine. The
reaction
mixture was stirred at room temperature for 48 h and then poured into 1 L of
ice-cooled
dilute hydrochloric acid (pH 2-3). The obtained precipitate was washed again
with 1N
hydrochloric acid, then with water and acetone, and dried to yield: 10.2 g
(88%) of white
solid. This product recrystallized in dioxane. Melting point (m.p.) 283 C.
(m.p. from the
literature : 282-283 C), (M. Nagata et al. Macroinol. Biosci. (2003), 3: 412-
419)

[0169] 4,4'-(sebacoyldioxy)dicizznamic acid (Formula V, n = 8) was
recrystallized from
DMF:ethanol (1:1). Yield 92%, m.p. 244.3 C, 'H NMR,(DMSO-d6, 500 MHz) S: 12.34
(s,
2H, -COOH) 7.73 (d, 4H), 7.59 (d, 2H), 7.15 (d, 4H), 6.50 (d, 2H), 2.57 (t,
4H, -O-CH2-),
1.63 (m, 4H), 1.32 (m, 8H).

[0170] Synthesized di-acids were converted into acid chlorides, applying
oxalyl chloride;
the general procedure is as described for diacyl chloride of 4,4'-
(adipoyldioxy) dicinnamic
acid, (Compound 9):

-O /-COCI
CIOC ~ O-C-(CH2)4-C11

(Compound 9)


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0171] To 10 g (22.8 mmol) of Compound 2 suspended in 200 niL dry chloroforin,
a few
drops of pyridine was added and then cooled down on an ice-bath. Using an
addition fiuinel,
81nL of oxalyl chloride was added drop-wise to the reaction solution and
stirring was
continued for 1 hour. Then the reaction mixture was slowly heated up to reflux
temperature
and stiiring continued for another 8 hours. The white acid suspension tunied
into a clear
yellow solution. The reaction mixture was then filtered under nitrogen, and
the filtrate was
diluted wit11200 mL of hexane. Yellow crystalline product formed after
standing over night
at room temperature. The product was filtered and dried in vacuum. Yield 9.1 g
(84 %). M.p.
= 1.35 C, (m.p. from the literature: 135 - 136 C). (M. Nagata, et al,
sacpra).

[0172] Diacyl chloride of 4,4 "-(sebacoyldioxy)dicinnanzic acid.= 1H NMR,
(CDC13, 500
MHz) 8: 7.81 (d, 2H), 7.59 (d, 4H), 7.17 (d, 4H), 6.59 (d, 2H), 2.58 (t, 4H, -
O-CHZ-), 1.78
(m, 4H), 1.40 (m, 8H).

Syrzthesis ofdi-4-niti=opheTzyl esters of4,4'-(alkanedioyldioxy)dicinnarnic
acids, (Formula
XIII):

O2N /\-,O O O O O O N02
O-C-(CH2)n C-O ~
Formula (XIII)

[0173] The general procedure is as follows. To the cliilled (0 C) solution of
8 g (57.5
mmol) of 4-nitrophenol and 8.1 mL of triethylamine in 100 mL of dry
ethylacetate, a solution
of 27.8 mmol of di-acid chloride in 150 mL of ethylacetate was added drop-wise
over 30 min.
Afterwards, the reaction mixture was warmed to room temperature for 8 hours
and then
heated to 45 C for another 2 hours. Reaction mixture was concentrated by
rotavaporization
and the concentrate was washed with acidified 200 mL water (HCI, pH 2-3), then
with
deionized water, filtered and dried.

[0174] Di-(4-nitrophenyl)-ester of 4,4 "-(adipoyldioxy)dicinnanaic acid,
(Fonnula XIII, n
4): Yield (65%), mp = 140-143 C, (from chlorobenzene). 1H NMR, 8(DMSO-d6, 500
MHz):
8.33 (d, 4H), 7.93 (d, 2H), 7.89 (d, 4H), 7.53 (d, 4H), 7.25 (d; 4H), 6.91 (d,
4H), 2.68 (t, 4H),
1.77 (m, 4H).


CA 02667944 2009-04-24
WO 2007/050583 PCT/US2006/041441
[0175] Di-(4-riiti ophenyl)-estet= of 4,4'-(sebacoyldioxy)dicinnarnic acid
(Fonnula XIII, n
8): Yield ( 68%). mp 135-137 C (from ethylacetate; soluble in acetone). 'H
NMR, (DMSO-
d6, 500 MHz), 5: 8.32 (d, 4H), 7.93 (d, 2H), 7.91 (d, 4H), 7.54 (d, 4H), 7.22
(d; 4H) 6.89 (d,
4H), 2.60 (t, 4H), 1.66 (m, 4H), 1.37 (in, 8H).

[0176] Synthesis of PEA with general formula (XIV)
O O H H O O H H 0 O H H
n ~ u i i n u i i u
CR C-N-C-C-O-(CH2)6 O-CC-N C-R -C-N-C-(CH2)4-N
CHZ CH2 3 C-O-C6H5 H 1
CH(CH3)2 CH(CH3)2 p

Formula (XIV)

where R' is a combination of two acids with 1:1 feed ratios: 50% of 4,4'-
(sebacoyldioxy) -
dicinnamic acid (Formula V, n = 8) and 50% of sebacic acid (-(CH2)$-).

[0177] To the stirred mixture of 9 mmol of Compound 6, 3 mmol of Compound 8, 6
inmol
of compound di-(4-nitrophenyl)-ester of 4,4'-(sebacoyldioxy)dicinnamic acid
(Formula XIII,
n = 8) and 6 mmol of bis-p-nitrophenyl sebacinate (Compound 5) in 8.5 mL of
anhydrous
N,N-dimethylformamide were added 12.3 mniol of triethylamine and the mixture
was heated
at 65 C for 24 hours. The obtained viscous reaction solution was poured into
cold water and
precipitated product was filtered off and thoroughly waslled with water. Crude
polymer was
dried and resuspended in 100 mL chloroform and p-nitrophenyl residue extracted
with water
several times. The organic phase was dried over sodium sulfate, filtered,
concentrated by
solvent evaporation. Polymer was precipitated in ethylacetate. Polymer, with
average
molecular weight 35 000 Da and PDI 1.51, yielded 56%. Tg 49 C; Tensile
Properties:
Tensile stress at break=33.9 MPa, 2% Elongation and Young's Modulus=1129 MPa.

[0178] All publications, patents, and patent documents are incorporated by
reference
herein, as though individually incorporated by reference. The invention has
been described
with reference to various specific and preferred embodiments and techniques.
However, it
should be understood that many variations and modifications might be made
while remaining
within the spirit and scope of the invention.

[0179] Although the invention has been described with reference to the above
examples, it
will be understood that modifications and variations are encompassed within
the spirit and
scope of the invention. Accordingly, the invention is limited only by the
following claims.

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Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 2006-10-25
(87) PCT Publication Date 2007-05-03
(85) National Entry 2009-04-24
Dead Application 2010-10-25

Abandonment History

Abandonment Date Reason Reinstatement Date
2009-10-26 FAILURE TO PAY APPLICATION MAINTENANCE FEE

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Reinstatement of rights $200.00 2009-04-24
Application Fee $400.00 2009-04-24
Maintenance Fee - Application - New Act 2 2008-10-27 $100.00 2009-04-24
Registration of a document - section 124 $100.00 2009-07-16
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
MEDIVAS, LLC
Past Owners on Record
GOMURASHVILI, ZAZA D.
JENKINS, TURNER DANIEL
KATSARAVA, RAMAZ
TURNELL, WILLIAM
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Description 
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Abstract 2009-04-24 1 66
Claims 2009-04-24 5 186
Drawings 2009-04-24 2 11
Description 2009-04-24 48 2,772
Cover Page 2009-08-07 1 37
PCT 2009-04-24 1 55
Assignment 2009-04-24 4 121
Correspondence 2009-06-25 1 25
Assignment 2009-07-16 8 273
Correspondence 2009-07-16 4 111
Correspondence 2009-08-27 1 16