U.S. patent application number 13/063944 was filed with the patent office on 2011-11-10 for bioresorbable polymers synthesized from monomer analogs of natural metabolites.
This patent application is currently assigned to RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY. Invention is credited to Durgadas Bolikal, Joachim B. Kohn.
Application Number | 20110275782 13/063944 |
Document ID | / |
Family ID | 42039850 |
Filed Date | 2011-11-10 |
United States Patent
Application |
20110275782 |
Kind Code |
A1 |
Kohn; Joachim B. ; et
al. |
November 10, 2011 |
BIORESORBABLE POLYMERS SYNTHESIZED FROM MONOMER ANALOGS OF NATURAL
METABOLITES
Abstract
New bioresorbable polymers are synthesized from monomer analogs
of natural metabolites In particular, polymers are polymerized from
analogs of amino acids that contribute advantageous synthesis,
processing and material properties to the polymers prepared
therefrom, including particularly advantageous degradation profiles
##STR00001##
Inventors: |
Kohn; Joachim B.;
(Piscataway, NJ) ; Bolikal; Durgadas; (Edison,
NJ) |
Assignee: |
RUTGERS, THE STATE UNIVERSITY OF
NEW JERSEY
New Brunswick
NJ
|
Family ID: |
42039850 |
Appl. No.: |
13/063944 |
Filed: |
September 16, 2009 |
PCT Filed: |
September 16, 2009 |
PCT NO: |
PCT/US09/57216 |
371 Date: |
July 22, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61097494 |
Sep 16, 2008 |
|
|
|
Current U.S.
Class: |
528/208 ;
548/496; 560/39 |
Current CPC
Class: |
A61L 27/18 20130101;
C08G 64/12 20130101; A61L 27/58 20130101; A61L 27/18 20130101; C08L
77/00 20130101 |
Class at
Publication: |
528/208 ; 560/39;
548/496 |
International
Class: |
C08G 63/00 20060101
C08G063/00; C07D 209/20 20060101 C07D209/20; C07C 229/28 20060101
C07C229/28 |
Claims
1. A polymer comprising at least 10 mol % of a repeating unit
having a structure selected from Formula I and Formula Ia
##STR00014## for which the variables are defined as follows: Ar is
a phenyl ring optionally substituted with from one to four
substituents independently selected from the group consisting of
halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl,
nitro, sulfoxide and sulfonyl; R.sub.1 is selected from the group
consisting of a bond and optionally substituted alkyl, heteroalkyl,
alkenyl and heteroalkenyl groups containing from one to ten carbon
atoms; X.sub.1, X.sub.2 and X.sub.3 are independently selected from
the group consisting of O, S and NR.sub.3; R.sub.2 is selected from
the group consisting of hydrogen and alkyl groups contain-ing from
one to thirty carbon atoms, or R.sub.2a is an alkylene group
covalently bonded to both the NR.sub.2 nitrogen atom and AA, so
that --N--R.sub.2a-AA- define a heterocyclic ring; R.sub.3 is
selected from the group consisting of hydrogen and alkyl groups
contain-ing from one to thirty carbon atoms; AA has a pendant
COOR.sub.4 group in which R.sub.4 is selected from the group
consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups
containing up to 30 carbon atoms and alkyl-terminated poly(alkylene
oxide) groups of molecular weight 100 to 10,000; and AA and
X.sub.3H of Formula I are selected so that
(R.sub.2--HN-)AA-X.sub.3H defines an --X.sub.3H substituted amino
acid and AA and X.sub.3H of Formula Ia are selected so that
##STR00015## defines an X.sub.3H-- substituted amino acid; wherein
said polymer has a glass transition temperature or crystalline
melting temperature greater than 37.degree. C. when fully hydrated
in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at 37.degree. C.
and said Formula I and Ia variables are selected so that monomers
comprising said Formula I and Formula Ia repeating units have a
solubility in said PBS solution at 37.degree. C. of at least about
3 mg/mL.
2. The polymer of claim 1, wherein AA and X.sub.3 are selected so
that ##STR00016## defines an amino acid selected from the group
consisting of hydroxy-tryptophan, mercapto-tryptophan,
hydroxy-proline and mercapto-proline.
3. A polymer comprising at least 10 mol % of repeating units having
a structure selected from Formula I and Formula Ia ##STR00017## for
which the variables are defined as follows: Ar is a phenyl ring
optionally substituted with from one to four substituents
independently selected from the group consisting of halogen,
halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro,
sulfoxide and sulfonyl; R.sub.1 is selected from the group
consisting of a bond and optionally substituted alkyl, heteroalkyl,
alkenyl and heteroalkenyl groups containing from one to ten carbon
atoms; X.sub.1, X.sub.2 and X.sub.3 are independently selected from
the group consisting of O, S and NR.sub.3; R.sub.2 is selected from
the group consisting of hydrogen and alkyl groups contain-ing from
one to thirty carbon atoms, or R.sub.2a is an alkylene group
covalently bonded to both the NR.sub.2 nitrogen atom and AA, so
that --N--R.sub.2a-AA- define a heterocyclic ring; R.sub.3 is
selected from the group consisting of hydrogen and alkyl groups
containing from one to thirty carbon atoms; AA has a pendant
COOR.sub.4 group in which R.sub.4 is selected from the group
consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups
containing up to 30 carbon atoms and alkyl-terminated poly(alkylene
oxide) groups of molecular weight 100 to 10,000; and AA and
X.sub.3H of Formula I are selected so (R.sub.2--HN-)AA-X.sub.3H
defines an --X.sub.3H substituted amino acid and AA and X.sub.3H of
Formula Ia are selected so ##STR00018## defines an X.sub.3H--
substituted amino acid; wherein and said polymer has a glass
transition temperature or crystalline melting temperature greater
than 37.degree. C. when fully hydrated in phosphate buffered saline
(PBS) (0.1M, pH 7.4) at 37.degree. C. and said Formula I and Ia
variables are selected so that monomers comprising said Formula I
and Formula Ia repeating units have a solubility in said PBS
solution at 37.degree. C. of less than about 3 mg/mL.
4. The polymer of claim 3, wherein AA and X.sub.3 are selected so
that ##STR00019## defines an amino acid selected from the group
consisting of hydroxy-tryptophan, mercapto-tryptophan,
mercapto-phenylalanine, thryronine and thyroxine.
5. A polymer comprising at least 10 mol % of repeating units having
a structure selected from Formula I and Formula Ia ##STR00020## for
which the variables are defined as follows: Ar is a phenyl ring
optionally substituted with from one to four substituents
independently selected from the group consisting of halogen,
halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro,
sulfoxide and sulfonyl; R.sub.1 is selected from the group
consisting of a bond and optionally substituted alkyl, heteroalkyl,
alkenyl and heteroalkenyl groups containing from one to ten carbon
atoms; X.sub.1, X.sub.2 and X.sub.3 are independently selected from
the group consisting of O, S and NR.sub.3; R.sub.2 is selected from
the group consisting of hydrogen and alkyl groups containing from
one to thirty carbon atoms, or R.sub.2a is an alkylene group
covalently bonded to both the NR.sub.2 nitrogen atom and AA, so
that --N--R.sub.2a-AA- define a heterocyclic ring; R.sub.3 is
selected from the group consisting of hydrogen and alkyl groups
containing from one to thirty carbon atoms; AA has a pendant
COOR.sub.4 group in which R.sub.4 is selected from the group
consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups
containing up to 30 carbon atoms and alkyl-terminated poly(alkylene
oxide) groups of molecular weight 100 to 10,000; and AA and
X.sub.3H of Formula I are selected so that
(R.sub.2--HN-)AA-X.sub.3H defines an --X.sub.3H substituted amino
acid and AA and X.sub.3H of Formula Ia are selected so that
##STR00021## defines an X.sub.3H-- substituted amino acid; wherein
said polymer has a glass transition temperature or crystalline
melting temperature less than about 37.degree. C. when fully
hydrated in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at
37.degree. C. and said Formula I and Ia variables are selected so
that monomers comprising said Formula I and Formula Ia repeating
units have a solubility in said PBS solution at 37.degree. C.
greater than about 3 mg/mL.
6. The polymer of claim 5, wherein (R.sub.2--HN-)AA-X.sub.3H
defines an amino acid selected from the group consisting of
hydroxy-leucine, mercapto-leucine, hydroxy-isoleucine,
mercapto-isoleucine and mercapto-valine.
7. A polymer comprising at least 10 mol % of repeating units having
a structure selected from Formula I and Formula Ia ##STR00022## for
which the variables are defined as follows: Ar is a phenyl ring
optionally substituted with from one to four substituents
independently selected from the group consisting of halogen,
halomethyl, halomethoxy, methyl, methoxy, thiomethyl, nitro,
sulfoxide and sulfonyl; R.sub.1 is selected from the group
consisting of a bond and optionally substituted alkyl, heteroalkyl,
alkenyl and heteroalkenyl groups containing from one to ten carbon
atoms; X.sub.1, X.sub.2 and X.sub.3 are independently selected from
the group consisting of O, S and NR.sub.3; R.sub.2 is selected from
the group consisting of hydrogen and alkyl groups containing from
one to thirty carbon atoms, or R.sub.2a is an alkylene group
covalently bonded to both the NR.sub.2 nitrogen atom and AA, so
that --N--R.sub.2a-AA- define a heterocyclic ring; R.sub.3 is
selected from the group consisting of hydrogen and alkyl groups
containing from one to thirty carbon atoms; AA has a pendant
COOR.sub.4 group in which R.sub.4 is selected from the group
consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups
containing up to 30 carbon atoms and alkyl-terminated poly(alkylene
oxide) groups of molecular weight 100 to 10,000; and AA and
X.sub.3H of Formula I are selected so that
(R.sub.2--HN-)AA-X.sub.3H defines an --X.sub.3H substituted amino
acid and AA and X.sub.3H of Formula Ia are selected so that
##STR00023## defines an X.sub.3H-- substituted amino acid; wherein
said polymers have a glass transition temperature or crystalline
melting temperature less than about 37.degree. C. when fully
hydrated in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at
37.degree. C. and said Formula I and Ia variables are selected so
that monomers comprising said Formula I and Formula Ia repeating
units have a solubility in said PBS solution at 37.degree. C. of
less than about 3 mg/mL.
8. The polymer of claim 7, wherein AA and X.sub.3H of Formula I are
selected so that (R.sub.2--HN-)AA-X.sub.3H defines an amino acid
selected from the group consisting of cysteine, threonine, serine,
lysine and mercapto-alanine.
9. The polymer of claim 3, wherein said Formula I and Formula Ia
variables are selected to provide a polymer with an equilibrium
water content in said PBS solution at 37.degree. C. of less than
about 20 wt %.
10. (canceled)
11. The polymer of claim 3, wherein AA and X.sub.3H of Formula I
are selected so that (R.sub.2--HN-)AA-X.sub.3H defines an alpha
amino acid, and wherein AA and X.sub.3H of Formula Ia are selected
so that ##STR00024## defines an alpha-amino acid.
12. The polymer of claim 11, wherein said alpha amino acid is a
naturally-occurring amino acid.
13. The polymer of claim 11, wherein said alpha amino acid is an
essential amino acid.
14. The polymer of claim 3, comprising two different repeating
units having the structures of Formula I or Formula Ia, wherein
said polymer comprises a first repeating unit in which R.sub.4 is
hydrogen, so that COOR.sub.4 is a pendant free carboxylic acid
group, and a second repeating unit in which R.sub.4 is an alkyl
group containing up to 30 carbon atoms so that COOR.sub.4 is a
pendant carboxylate group.
15. The polymer of claim 14, wherein between about 1 and about 50%
of the AA groups have pendant free carboxylic acid groups.
16. The polymer of claim 3, wherein at least 50% of the Ar groups
are substituted with two to four atoms selected from the group
consisting of iodine atoms and bromine atoms.
17. The polymer of claim 3, wherein R.sub.1 is
--CH.sub.2--CH.sub.2--.
18. The polymer of claim 3, wherein X.sub.1, X.sub.2 and X.sub.3
are all oxygen.
19. The polymer of claim 3, characterized by being a polycarbonate,
polyester, poly(phosphazine), poly(phosphoester),
poly(iminocarbonate), polyether, polyurethane, poly(carbamate),
poly(thiocarbonate), poly(carbonodithionate) or
poly(thiocarbamate).
20. The polymer of claim 3, characterized by being a polyalkylene
oxide block copolymer.
21. The polymer of claim 3, wherein R.sub.1 is
--CH.sub.2--CH.sub.2-- or --CH.dbd.CH--, X.sub.1, X.sub.2 and
X.sub.3 are O and Ar is a phenyl group optionally substituted with
two to four atoms selected from the group consisting of iodine
atoms and bromine atoms.
22. A polymer according to claim 3 comprising a repeating unit
having a structure selected from Formula II and Formula IIa:
##STR00025## wherein A is selected from the group consisting of:
##STR00026## wherein R.sup.10 is selected from the group consisting
of H, and optionally substituted alkyl, heteroalkyl, alkenyl and
heteroalkenyl groups containing from one to 30 carbon atoms, and
R.sup.12 is selected from the group consisting of optionally
substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups
containing from one to 18 carbon atoms and alkylaryl,
heteroalkylaryl, alkenylaryl and heteroalkenylary groups containing
from three to 12 carbon atoms.
23. A polymer according to claim 3, further comprising polyalkylene
oxide block repeating unit having a structure according to Formula
III: B-A.sup.2 (III) wherein B is
--O--((CHR.sup.6).sub.p--O).sub.q--; each R.sup.6 is independently
H or C.sub.1 to C.sub.3 alkyl; p is an integer in the range of one
to about 4; q is an integer in the range of one to about 100; and
A.sup.2 is selected from the group consisting of: ##STR00027##
wherein R.sup.10 is selected from the group consisting of H and
optionally substituted alkyl, heteroalkyl, alkenyl and
heteroalkenyl groups containing from one to 30 carbon atoms, and
R.sup.12 is selected from the group consisting of optionally
substituted alkyl, heteroalkyl, alkenyl and heteroalkenyl groups
containing from one to 18 carbon atoms and alkylaryl,
heteroalkylaryl, alkenylaryl and heteroalkenylary groups containing
from three to 12 carbon atoms.
24.-25. (canceled)
26. A load-bearing medical implant comprising the polymer of claim
3.
27. A drug delivery implant, embolotherapy product, hernia repair
mesh, envelope of the implantation of a cardiac device, bridging
material, tissue sealant, adhesion prevention material, graft for
nerve regeneration, implantable organ support or tissue engineering
scaffold comprising the polymer of claim 5.
28.-33. (canceled)
34. A compound having the structure of formula IV or formula IVa:
##STR00028## for which the variables are defined as follows: Ar is
a phenyl ring that optionally substituted with from one to four
substituents independently selected from the group consisting of
halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl,
nitro, sulfoxide and sulfonyl; R.sub.1 is selected from the group
consisting of optionally substituted alkyl, heteroalkyl, alkenyl
and heteroalkenyl groups containing from one to ten carbon atoms;
X.sub.1, X.sub.2 and X.sub.3 are independently selected from the
group consisting of O, S and NR.sub.3; R.sub.2 is selected from the
group consisting of hydrogen and alkyl groups containing from one
to thirty carbon atoms bonded only to N, or R.sub.2a is an alkylene
group covalently bonded to both the NR.sub.2 nitrogen atom and AA,
so that --N--R.sub.2a-AA- define a heterocyclic ring; R.sub.3 is
selected from the group consisting of hydrogen and alkyl groups
containing from one to thirty carbon atoms; AA has a pendant
COOR.sub.4 group in which R.sub.4 is selected from the group
consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups
containing up to 30 carbon atoms and alkyl-terminated poly(alkylene
oxide) groups of molecular weight 100 to 10,000; and AA and
X.sub.3H of Formula I are selected so that
(R.sub.2--HN-)AA-X.sub.3H defines an --X.sub.3H substituted amino
acid and AA and X.sub.3H of Formula Ia are selected so ##STR00029##
defines an X.sub.3H-- substituted amino acid; wherein said Formula
IV and Formula IVa variables are selected so that said compound has
a solubility in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at
37.degree. C. greater than about 3 mg/mL.
35. A compound having the structure of formula IV or formula IVa:
##STR00030## for which the variables are defined as follows: Ar is
a phenyl ring that is optionally substituted with from one to four
substituents independently selected from the group consisting of
halogen, halomethyl, halomethoxy, methyl, methoxy, thiomethyl,
nitro, sulfoxide and sulfonyl; R.sub.1 is selected from the group
consisting of optionally substituted alkyl, heteroalkyl, alkenyl
and heteroalkenyl groups containing from one to ten carbon atoms;
X.sub.1, X.sub.2 and X.sub.3 are independently selected from the
group consisting of O, S and NR.sub.3; R.sub.2 is selected from the
group consisting of hydrogen and alkyl groups containing from one
to thirty carbon atoms bonded only to N, or R.sub.2a is an alkylene
group covalently bonded to both the NR.sub.2 nitrogen atom and AA,
so that --N--R.sub.2a-AA- define a heterocyclic ring; R.sub.3 is
selected from the group consisting of hydrogen and alkyl groups
containing from one to thirty carbon atoms; AA has a pendant
COOR.sub.4 group in which R.sub.4 is selected from the group
consisting of hydrogen, alkyl, heteroalkyl and alkylaryl groups
containing up to 30 carbon atoms and alkyl-terminated poly(alkylene
oxide) groups of molecular weight 100 to 10,000; and AA and
X.sub.3H of Formula I are selected so that
(R.sub.2--HN-)AA-X.sub.3H defines an --X.sub.3H substituted amino
acid and AA and X.sub.3H of Formula Ia are selected so ##STR00031##
defines an X.sub.3H-- substituted amino acid; wherein said Formula
IV and Formula IVa variables are selected so that said compound has
a solubility in phosphate buffered saline (PBS) (0.1 M, pH 7.4) at
37.degree. C. less than about 3 mg/mL.
36.-40. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application claims priority benefit under 35
U.S.C. .sctn.119(e) of U.S. Provisional Patent Application Ser. No.
61/097,494 filed Sep. 16, 2008, the disclosure of which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to new bioresorbable polymers
synthesized from monomer analogs of natural metabolites. In
particular, the present invention relates to polymers polymerized
from analogs of amino acids that contribute advantageous synthesis,
processing and material properties to the polymers prepared
therefrom, including particularly advantageous degradation
profiles.
[0003] U.S. Pat. No. 5,099,060 discloses diphenolic monomers based
on 3-(4-hydroxy-phenyl) propionic acid and L-tyrosine alkyl esters
(desaminotyrosyl-tyrosine alkyl esters). Subsequent related patents
involve variations of this basic monomer structure, including
halogenated radiopaque diphenolic monomers, such as the
3,5-di-iododesaminotyrosyl-tyrosine esters (I.sub.2DTR, wherein R
is an alkyl group, e.g., E=ethyl, H=hexyl, O=octyl, etc.) disclosed
by U.S. Patent Application Publication No. 20060034769. The
disclosures of both publications are incorporated herein by
reference. These monomers, although useful in many applications,
have several limitations:
[0004] In the context of these teachings, the term "degradation" is
defined as the process leading to the chemical cleavage of the
polymer backbone, resulting in a reduction in polymer molecular
weight and mechanical strength. The rate of polymer degradation
under physiological conditions is predominantly determined by the
type of bonds used to link the individual polymer repeat units
together. Hence, polyanhydrides, e.g., polymers containing the
highly labile anhydride linkage, will tend to degrade faster than
polyesters. In contrast, the term "resorption" is defined as the
process leading to a reduction of the mass of an implanted device.
The rate of resorption is predominantly governed by the solubility
of the polymer itself or its degradation products. The resorption
of an implant is complete, once the entire mass of the implant has
been removed from the implant site. Degradation and resorption do
not always go hand-in-hand. Just for the purpose of providing an
illustrative example, a sugar cube in water will "resorb" (e.g.,
lose mass and ultimately disappear) without any chemical
degradation process. Likewise, comparing the degradation and
resorption profiles of two different polyanhydrides, one can expect
that both polymers will degrade when exposed to aqueous media, but
the polymer degrading into more soluble degradation products will
be losing mass faster and will, therefore, be the polymer that will
resorb faster when implanted in a patient.
[0005] Use of monomers having two phenolic hydroxyl groups, as
disclosed in the above mentioned patent applications, tend to limit
the resulting homopolymers to fully aromatic backbone structures.
Such polymers have generally good mechanical properties--but slow
degradation rates. Moreover, when the monomers are sparingly
soluble in water, the degradation products formed during polymer
degradation are often also sparingly soluble in water. This
property can slow or prevent the degrading polymer from being
resorbed at a time scale that is concomitant with polymer
degradation. Hence, such polymers will tend to have some use
limitations as medical implant materials when the processes of
degradation and resorption need to occur concomitantly. The
previously described homopolymers prepared from the previously
described sparingly-soluble monomers will not have any significant
weight loss while the degradation of the homopolymer backbone
results in reduction in the polymer molecular weight and loss of
mechanical strength. As a result, implantable medical devices and
drug delivery implants prepared from the previously described
homopolymers that are intended to be resorbed are still
substantially undissolved at the end of their useful life as
measured by reduction in polymer molecular weight or mechanical
strength.
[0006] This is particularly a problem for drug delivery implants
and implantable medical devices that are intended to be replaced as
part of a long-term treatment regimen. For example, a polymeric
implant for the delivery of birth control hormones is intended to
be replaced at the terminal stage of polymer degradation when
essentially all of the hormones have been released as a consequence
of polymer backbone degradation and mass loss. However, implants
formed with many of the previously described homopolymers will not
only be substantially undissolved when a replacement device must be
implanted, significant mass will remain when the next replacement
device is due for implantation. This creates the untenable
situation where patient would be expected to endure having several
depleted polymeric drug delivery implants in their body at various
stages of resorption while replacement devices continue to be
implanted at a periodic rate.
[0007] Homopolymers of non-aromatic amino acids have been prepared.
Examples are polyglycine, polyalanine, polyserine, polyleucine.
However, despite their apparent potential as biomaterials, such
poly(amino acids) have actually found few practical applications. A
major problem is that most of the poly(amino acids) are highly
intractable (e.g., non-processable by conventional thermal or
solvent fabrication methods), which limits their utility.
[0008] The elegant synthesis of a copolymer derived from lactic
acid and lysine was reported by Barrera et al., Macromol., (28),
425-432 (1995). The lysine residue was utilized to chemically
attach a cell-adhesion promoting peptide to the copolymer.
[0009] Other polymers of amino acids and hydroxy acids are
disclosed by U.S. Pat. No. 3,773,737. The non-aromatic copolymers
were random copolymers prepared from cyclic monomers by
ring-opening polymerization. The composition of the copolymers is
highly dependent on the relative reactivity of the two types of
cyclic monomers and on the exact polymerization conditions used. It
is hard to control the composition and hard to predict the polymer
properties. Also, there may be large batch-to-batch variations in
the polymer microstructure and sequence. Further, most previous
reports only described polymers of relatively low molecular weight
(M.sub.W<10,000).
[0010] There are very few degradable polymers for medical uses that
have been successfully commercialized. Poly(glycolic acid) (PGA),
poly(lactic acid) (PLA) and their copolymers are representative
examples. However, these polymers degrade to form tissue-irritating
acids. Polymers of tyrosine and hydroxy acids such as glycolic acid
and lactic acid have also been prepared and are disclosed by U.S.
Pat. No. 6,284,862. There still remains a need for bioresorbable
polymers suitable for use as tissue-compatible materials.
[0011] For example, many investigators in the emerging field of
tissue engineering have proposed to engineer new tissues by
transplanting isolated cell populations on biomaterial scaffolds to
create functional new tissues in vivo. Bioresorbable materials
whose degradation and resorption rates can be tailored to
correspond to the rate of tissue growth are needed. It is desirable
that libraries of many different materials be available so that the
specific polymer properties can be optimally matched with the
requirements of the specific application under development.
SUMMARY OF THE INVENTION
[0012] This need is met by preferred embodiments of the present
invention. Embodiments of the present invention provide novel
classes of aliphatic-aromatic monomers and bioresorbable polymers
derived therefrom that hydrolytically degrade under physiological
conditions. In preferred embodiments the monomers are dipeptides of
tyrosine analogs and amino acids with substituent groups through
which the monomers can be polymerized. Monomer solubility and the
mechanical properties of the polymer can be varied by selection of
the amino acid which is incorporated into the dipeptide
monomer.
[0013] An embodiment therefore provides polymers that include one
or more repeating units having the structure of Formula I and/or
Formula Ia:
##STR00002##
for which the variables are defined as follows:
[0014] Ar is a phenyl ring that is unsubstituted or substituted
with from one to four substituents independently selected from
halogen atoms, halomethyl groups, halomethoxy groups, methyl,
methoxy, thiomethyl, nitro, sulfoxide and sulfonyl;
R.sub.1 is selected from a bond and saturated and unsaturated,
substituted and unsubstituted alkyl, heteroalkyl, alkenyl and
heteroalkenyl groups containing from one to 10 carbon atoms;
[0015] X.sub.1, X.sub.2 and X.sub.3 are independently selected from
O, S and NR.sub.3;
[0016] R.sub.2 is selected from hydrogen and alkyl groups
containing from one to thirty carbon atoms bonded only to the
Formula I nitrogen atom, and R.sub.2a is an alkylene group
covalently bonded to both the Formula Ia nitrogen atom and AA to
define a heterocyclic ring;
[0017] R.sub.3 is selected from hydrogen and alkyl groups
containing from one to thirty carbon atoms;
[0018] AA has a pendant COOR.sub.4 group in which R.sub.4 is
selected from hydrogen, alkyl, heteroalkyl and alkylaryl groups
containing up to 30 carbon atoms and alkyl-terminated poly(alkylene
oxide) groups of molecular weight 100 to 10,000; and
[0019] AA and X.sub.3 of Formula I are selected so that
(R.sub.2--HN-)AA-X.sub.3H defines an X.sub.3H-- substituted amino
acid, and AA and X.sub.3 of Formula Ia are selected so that
##STR00003##
defines an X.sub.3H-- substituted amino acid.
(R.sub.2--HN-)AA-X.sub.3H is optionally N-alkyl substituted.
[0020] According to one embodiment, R.sub.2 and R.sub.3 are
independently selected from alkylene groups containing from one to
six carbon atoms. According to another embodiment, the R.sub.4
groups contain 18 carbon atoms or less.
[0021] Alkyl, heteroalkyl, alkenyl and heteroalkenyl groups are
straight-chained or branched. The heteroalkyl and heteroalkenyl
groups contain from one to eight heteroatoms. Heteroatoms are
independently selected from O, S and N-methyl. Examples of
alkyl-terminated poly(alkylene oxides) include methoxy-terminated
poly(ethylene glycols) (PEG) of molecular weight 400 to 4,000,
methoxy-terminated poly(propylene glycols) (PPG), and
methoxy-terminated block copolymers of PEG and PPG.
[0022] Aromatic rings may be optionally substituted with from 1 to
4 of the identified groups as long as the substitution patterns are
chemically feasible. Any combination of substituents containing
more than two nitro groups is potentially explosive and expressly
excluded from these teachings.
[0023] Polymers that include repeating units of Formula I and/or
Formula Ia may be referred to herein as "polymers of Formula I and
Formula Ia" or "Formula I and Ia polymers." Polymers of Formula I
and Formula Ia include polymers containing either or both Formula I
and Formula Ia repeating units. Other repeating units may be
present, including repeating units derived from
desaminotyrosyl-tyrosine monomers, including the monomers disclosed
by U.S. Pat. No. 5,099,060.
[0024] The present invention more specifically provides Formula I
and Formula Ia polymers wherein AA and X.sub.3 are selected so that
(R.sub.2--HN-)AA-X.sub.3H and
##STR00004##
represent an alpha-amino acid wherein (R.sub.2--HN-)AA-X.sub.3H is
optionally N-alkyl substituted. In a more specific embodiment, the
alpha amino acid is a naturally-occurring amino acid. Alpha-amino
acids from which the polymers of the present invention may be
prepared include, but are not limited to, cysteine, threonine,
serine, lysine, thyronine, thyroxine, hydroxy-proline,
mercapto-proline, hydroxy-leucine, mercapto-leucine,
hydroxy-isoleucine, mercapto-isoleucine, hydroxy-tryptophan,
mercapto-tryptophan, mercapto-alanine, mercapto-valine and
mercapto-phenylalanine.
[0025] Included among the polymer embodiments of the Formula I and
Formula Ia are four distinct polymer embodiments. According to the
first polymer embodiment, AA and X.sub.3 are selected so that the
degradation products of polymers of Formula I and Formula Ia resorb
more quickly under physiological conditions than comparable
polymers of desaminotyrosyl-tyrosine alkyl esters and the polymers
have intrinsic physical properties suitable for use in load-bearing
medical implants such as vascular or coronary stents. One example
of comparable polymers of desaminotyrosyl-tyrosine alkyl esters are
polymers with structural similarities that provide essentially the
same molecular weight.
[0026] For purposes of the present invention, "physiological
conditions" are defined as storage in phosphate buffered saline
solution (PBS), 0.1 M, pH 7.4 at 37.degree. C., and polymers that
resorb more quickly are defined as containing at least 10 mol % of
monomers comprising either the Formula I or Formula Ia repeating
units having a PBS solubility under physiological conditions of at
least about 3 mg/mL, e.g., preferably, at least about 5 mg/mL, to
provide the desired rate of resorption. The monomer comprising
either Formula I or Formula Ia repeating units may contain other
moieties or substituents, provided that the requisite degree of PBS
solubility is conserved. All of this is readily determined by one
of ordinary skill in the art without undue experimentation.
Embodiments according to the present invention include polymers
containing up 90 mol % of said monomer, and polymers consisting
entirely of said monomers. Other monomers and repeating units may
be used to design polymers with a desirable rate of resorption.
[0027] "Load-bearing medical implants" are defined as implantable
medical devices that are required by their intended use to
withstand forces caused by compression, bending, or stretching of
the implant. Because of the significant variations in shape, size,
and use of load-bearing medical implants, the physicomechanical
properties of polymers suitable for load-bearing implants cannot be
described in precise terms, except for the following requirements:
As a general rule, load-bearing medical implants can only be
fabricated from (i) amorphous polymers having glass transition
temperatures greater than 37.degree. C. when fully hydrated under
physiological conditions and (ii) from crystalline or partially
crystalline polymers that have a crystalline melting temperature
greater than 37.degree. C. when fully hydrated under physiological
conditions. In addition, the equilibrium water content when fully
hydrated under physiological conditions is typically less than 20
wt %, preferably less than 10 wt % and more preferably less than 5
wt %. These required polymer properties can be achieved by
carefully optimizing the chemical composition of the polymer
backbone structure, including Formula I repeating units, Formula Ia
repeating units, other repeating units, and combinations
thereof.
[0028] Examples of Formula I and Formula Ia polymers according to
the first polymer embodi-ment include, but are not limited to,
polymers in which AA and X.sub.3 of Formula I are selected so that
(R.sub.2--HN-)AA-X.sub.3H defines the amino acid cysteine, and AA
and X.sub.3 of Formula Ia are selected so that:
##STR00005##
defines an amino acid selected from cis-hydroxy-proline,
trans-hydroxy-proline, cis-mercapto-proline and
trans-mercapto-proline.
[0029] According to the second polymer embodiment of the invention,
AA and X.sub.3 are selected so that the degradation products of the
polymers of Formula I and Formula Ia do not necessarily resorb
significantly more quickly under physiological conditions than
comparable polymers of desaminotyrosyl-tyrosine alkyl esters. That
is, they resorb at about the same rate or slower. However, polymers
according to this embodiment still have intrinsic physical
properties suitable for use in load-bearing medical implants.
[0030] Polymers according to this embodiment are defined as
containing at least 10 mol % of monomers comprising either Formula
I or Formula Ia repeating units having a PBS solubility under
physiological conditions of less than about 3 mg/mL to provide the
desired slow rate of resorption, and having the requisite glass
transition or crystalline melting temperature and equilibrium water
content for the desired load-bearing intrinsic physical properties.
The solubility may be as low as 0.01 mg/mL. Examples of polymers
according to the second polymer embodiment include, but are not
limited to, polymers in which AA and X.sub.3 of Formula I are
selected so (R.sub.2--HN-)AA-X.sub.3H defines an amino acid
selected from mercaptophenylalanine, 5-hydroxytryptophan,
thryronine and thyroxine.
[0031] According to the third polymer embodiment of the invention,
AA and X.sub.3 are selected so that the degradation products of the
polymers of Formula I and Formula Ia do not necessarily resorb
significantly more quickly under physiological conditions than
comparable polymers of desaminotyrosyl-tyrosine alkyl esters and
the polymers do not have intrinsic physical properties suitable for
use in load-bearing medical implants. Polymers according to this
embodiment have utility in other uses for biocompatible polymers,
such as drug delivery implants, bridging materials, tissue
sealants, adhesion prevention materials, tissue scaffolds where
rigidity is not essential, and the like.
[0032] Polymers lacking intrinsic physical properties suitable for
use in load-bearing medical implants include, if the polymer is
amorphous, a glass transition temperature less than 37.degree. C.
when fully hydrated under physiological conditions and, if the
polymer is crystalline, a crystal-line melting temperature less
than 37.degree. C. when fully hydrated under physiological
conditions. In addition, the equilibrium water content when fully
hydrated under physiological conditions is typically greater than
20 wt %.
[0033] Polymers according to this embodiment are defined as being
polymerized from at least 10 mol % of monomers that comprising
either Formula I or Formula Ia repeating units having a PBS
solubility under physiological conditions effective to provide the
desired slower rate of resorption, and have the requisite glass
transition or crystalline melting temperature and equilibrium water
content for the desired intrinsic physical properties. That is, the
monomers have a PBS solubility under physiological conditions of
less than about 3 mg/mL, wherein the solubility may be as low as
0.01 mg/mL. Polymers according to this embodiment of the invention
include, but are not limited to, polymers in which AA and X.sub.3
of Formula I are selected so that (R.sub.2--HN-)AA-X.sub.3H defines
an amino acid selected from hydroxy-leucine, mercapto-leucine,
hydroxy-isoleucine, mercapto-isoleucine and mercapto-valine.
[0034] According to the fourth polymer embodiment of the invention,
AA and X.sub.3 are selected so that the degradation products of
polymers of Formula I and Formula Ia resorb more quickly under
physiological conditions than comparable polymers of
desaminotyrosyl-tyrosine alkyl esters and the polymers do not have
intrinsic physical properties suitable for use in load-bearing
medical implants. Polymers according to this embodiment are defined
as being polymerized from at least 10 mol % of monomers comprising
either Formula I or Formula Ia repeating units having a PBS
solubility under physiological conditions to provide the desired
rate of resorption, and having the requisite glass transition or
crystalline melting temperature and equilibrium water content for
the desired intrinsic physical properties. Examples of polymers
according to this embodiment of the invention include, but are not
limited to, polymers in which AA and X.sub.3 of Formula I are
selected so (R.sub.2--HN-)AA-X.sub.3H defines an amino acid
selected from cysteine and serine.
[0035] Independent of each polymer embodiment, the same Formula I
and/or Formula Ia repeating units can provide both the desired
resorption properties and the intrinsic physical properties. In the
alternative, one set of Formula I and/or Formula Ia repeating units
are selected to provide the desired rate of resorption and combined
with a second set of Formula I and/or Formula Ia repeating units
selected to provide intrinsic physical properties. Additional
repeating units can be present that also contribute to the desired
degradation properties and intrinsic physical properties, such as
repeating units with pendant free carboxylic acid groups, including
repeating units of Formula I and Formula Ia with pendant free
carboxylic acid groups. The selection of appropriate repeating
units for each polymer embodiment is readily determined by one of
ordinary skill in the art without undue experimentation.
[0036] Independent of each polymer embodiment, the present
invention provides polymers according to Formula I and Formula Ia
in which X.sub.1 and X.sub.2 are O, wherein the polymers are
prepared from monomers that are formed from the reaction products
of a hydroxy-phenylalkanoic or alkenoic acid and an amino acid.
R.sub.1 is preferably ethylene so that the phenylalkanoic acid is
desaminotyrosine (DAT), also referred to as
4-hydroxy-phenylpropanoic acid. When X.sub.1 and X.sub.2 are O and
R.sub.1 is ethylene, the Formula I and Formula Ia polymers are
referred to as "DAT derivatives."
[0037] More specifically, Formula I and Formula Ia polymers are
provided independent of each embodiment that are formed from
monomers that are amide, thioamide or imide reaction products of
phenylalkanoic acid, preferably DAT, and amino acid starting
materials, with modification as needed. DAT and the phenylalkanoic
acid analogs thereof unexpectedly contribute useful physical
properties to the Formula I and Ia polymers that are not obtained
from polymers formed from monomers combining two or more amino
acids. Therefore, "phenyl-alkanoic acid analogs of DAT" are defined
as compounds contributing at least one advantageous physical
property to the Formula I and Ia polymers that are also obtained
with Formula I and Ia polymers that are DAT derivatives. For
purposes of the present invention, a "derivative" of a compound is
defined as the product of a reaction in which the compound is a
reactant. Thus, a "DAT derivative" is a compound produced by
reacting DAT with a co-reactant, etc.
[0038] The advantageous physical properties in no particular order
of importance include DAT's lack of a chiral center, so that DAT,
unlike amino acids, does not give rise to diastereomers when
coupled with amino acids. Also, because the COOH on DAT is not
linked to a chiral carbon, there is no racemization during coupling
to make the monomer. Furthermore, DAT is easier to iodinate than an
aromatic amino acid such as tyrosine when a radio-opaque polymer is
desired. In addition, despite not being a nutrient, DAT is
naturally found in the body as an end-stage metabolite and is
excreted in urine. As a natural constituent of human metabolism,
DAT has low toxicity, attributable in part to being a
closely-related analog of the essential amino acid L-tyrosine. More
significantly, DAT is an end stage metabolite; there is no cause
for concern that DAT may be further converted to other metabolites.
In addition to being non-toxic, DAT's aromatic ring imparts good
mechanical properties to polymers, and removal of the tyrosine
amino group gives better polymer processing properties compared to
amino acids.
[0039] The present invention also provides independent of any
polymer embodiment, copolymers having two different repeating units
with the structure of Formula I or Formula Ia, wherein the
copolymer has a first repeating unit in which R.sub.4 is hydrogen,
so that COOR.sub.4 is a pendant free carboxylic acid group, and a
second repeating unit in which R.sub.4 is an alkyl group containing
up to 30 carbon atoms, so that COOR.sub.4 is a pendant alkyl ester
group. Among the copolymers provided are copolymers in which
between about 1 and about 50% of the AA groups have pendant free
carboxylic acid groups. Among other copolymers provided are
copolymers in which greater than about 5% but less than about 33%
of the AA groups have pendant free carboxylic acid groups.
According to one embodiment R.sub.4 is an alkyl group containing
less than 18 carbon atoms
[0040] This is not to say that polymer embodiments according to the
present invention do not include polymers having Formula I or
Formula Ia repeating units with pendant free carboxylic acid
groups. Monomers comprising Formula I or Formula Ia repeating units
with pendant free carboxylic acid groups have increased solubility
in PBS under physiological conditions than their ester
counterparts. Thus, one determining factor for whether a polymer
according to the present invention falls within the first polymer
embodiment or the second polymer embodiment is the molar fraction
of repeating units with pendant free carboxylic acid groups. This
is also one determining factor for whether a polymer according to
the present invention falls within the third polymer embodiment or
the fourth polymer embodiment. Furthermore, the solubility of a
particular monomer can be modulated to less solubility in PBS by
variation in the chain length of R.sub.3 and R.sub.4. This is
independent of the effect of these groups on the load bearing
capacity of the subsequent polymer, e.g., long side chains will
lower solubility and may or may not affect wet Tg and/or Tm.
[0041] Thus, a highly esterified or fully esterified version of a
polymer according to the present invention may fall within the
second or third polymer embodiment, while a less esterified
counterpart with more pendant free carboxylic acid groups may fall
within the first or fourth polymer embodiment. Stated another way,
one of ordinary skill in the art can design or modify a polymer to
have a molar fraction of monomeric repeating units with pendant
free carboxylic acid groups so that the polymer falls within the
first polymer embodiment rather than the second polymer embodiment,
or within the fourth polymer embodiment rather than the third
polymer embodiment.
[0042] Furthermore, polymers according to the present invention
with pendant free carboxylic acid groups have higher glass
transition temperatures or crystalline melting temperatures than
their unsubstituted counterparts. Thus, polymers with higher molar
fractions of monomeric repeating units with pendant fee carboxylic
acid groups tend to fall within the first polymer embodiment.
[0043] Polymers with a sufficient number of aromatic rings
sufficiently substituted with bromine or iodine are inherently
radio-opaque. The present invention therefore also provides,
independent of any particular polymer embodiment, polymers
according to Formula I and Ia in which the aromatic rings are
substituted with at least one iodine or bromine atom, on at least
one and preferably on both ring positions ortho to X.sub.1. In a
more specific aspect of each embodiment, at least 50% of the Ar
groups are substituted with from two to four iodine atoms, bromine
atoms, or combinations thereof.
[0044] This is not to say that polymer embodiments according to the
present invention do not include polymers having Formula I or
Formula Ia repeating units in which the aromatic rings are bromine-
or iodine-substituted. Polymers comprising Formula I or Formula Ia
repeating units with bromine- or iodine-substituted aromatic rings
have higher glass transition temperatures or crystalline melting
temperatures than their unsubstituted counterparts. Thus, another
determining factor for whether a polymer according to the present
invention falls within the first polymer embodiment or the second
polymer embodiment is the molar fraction of repeating units with
bromine or iodine substituted aromatic rings. This is also another
determining factor for whether a polymer according to the present
invention falls within the third polymer embodiment or the fourth
polymer embodiment.
[0045] Thus, a highly bromine or iodine ring-substituted version of
a polymer according to the present invention may fall within the
first or second polymer embodiment, while a less substituted
counterpart may fall within the third or fourth polymer embodiment.
Stated another way, one of ordinary skill in the art can design or
modify some polymers to fall within the first or second embodiment
rather than the third or fourth embodiment by increasing the level
of bromine or iodine ring substitution. While not every polymer
according to the present invention can be moved between the first
and fourth polymer embodiments or the second and third poly-mer
embodiments by adjusting or selecting the degree of iodine or
bromine ring-substitution, one of ordinary skill in the art will
readily recognize the polymers that can be modified or designed in
this manner. Furthermore it is important to note that the level of
bromine or iodine substitution may not be subject to modification
if it is necessary for the polymer to be radio-opaque or
radio-transparent.
[0046] In terms of the prior art, the new polymers of the present
invention, including the polymers of all four polymer embodiments,
are similar to the desaminotyrosyl-tyrosine alkyl ester polymers
disclosed in U.S. Pat. No. 5,099,060. An important difference is
that the tyrosine alkyl ester unit has been replaced by another
amino acid ester selected for its contribution to the resorbability
of the polymeric implant, or for its contribution to the intrinsic
physical properties of the polymer related to suitability for use
in load bearing medical implants, or both.
[0047] The present invention is thus based in part on the
recognition that valuable polymers are obtained when DAT and its
analogs are kept constant and the monomer and polymer properties
are modified by varying the amino acid coupled to the DAT or DAT
analog that otherwise would not be obtained if at the same time the
DAT or DAT analog was replaced by amino acids or other amino acid
analogs. The new monomers, the resulting polymers, and their
respective properties represent new and valuable biomaterials in
addition to the desamino-tyrosyl-tyrosine alkyl ester monomers and
the polymers polymerized therefrom disclosed before.
[0048] New polymers are formed from DAT--amino acid monomers in the
same fashion as the desaminotyrosyl-tyrosine alkyl ester--derived
polymers disclosed before. In particular, polymers according to the
present invention include polycarbonates, polyesters,
polyphosphazines, polyphosphoesters and polyiminocarbonates, having
the structure of Formula II and IIa:
##STR00006##
[0049] wherein X.sub.1, X.sub.2, X.sub.3, Ar, R.sub.1, R.sub.2,
R.sub.2a, AA, and the embodiments thereof, are the same as
described above with respect to Formula I and Formula Ia and A is
selected from:
##STR00007##
[0050] wherein R.sup.10 is selected from H, saturated and
unsaturated, substituted and unsubstituted alkyl, heteroalkyl,
alkenyl and heteroalkenyl groups containing from one to 18 carbon
atoms, and R.sup.12 is selected from saturated and unsaturated,
substituted and unsubstituted alkyl, heteroalkyl, alkenyl and
heteroalkenyl groups containing from one to 18 carbon atoms and
alkylaryl, hetero-alkylaryl, alkenylaryl and heteroalkenylary
groups containing from three to 12 carbon atoms.
[0051] Polymers according to the present invention include
polyethers, polyurethanes, polycarbamates, polythiocarbonates,
polycarbonodithionates and polythiocarbamates. Polycarbonates,
specifically poly(amide carbonates), as well as polyurethanes,
polycarbamates, polythiocarbonates, polycarbonodithionates and
polythiocarbamates are prepared by the process disclosed by U.S.
Pat. No. 5,198,507, the disclosure of which is incorporated by
reference. Polyesters, specifically poly(ester amides), are
prepared by the process disclosed by U.S. Pat. No. 5,216,115, the
disclosure of which is incorporated herein by reference.
Polyiminocarbonates are prepared by the process disclosed by U.S.
Pat. No. 4,980,449, the disclosure of which is incorporated by
reference. Polyethers are prepared by the process disclosed by U.S.
Pat. No. 6,602,497, the disclosure of which is incorporated by
reference.
[0052] Independent of any particular polymer embodiment, the
present invention also provides polymers that include a recurring
unit according to Formula I, Formula Ia, Formula II and/or Formula
IIa that are copolymerized with any number of other recurring
units. For example the present invention provides polymers having a
recurring unit according to Formula I, Formula Ia, Formula II
and/or Formula IIa that are block copolymerized with recurring
polyalkylene oxide block units having a structure according to
Formula III:
B-A.sup.2 (III)
wherein B is --O--((CHR.sup.6).sub.p--O).sub.q--; each R.sup.6 is
independently H or C.sub.1 to C.sub.3 alkyl; p is an integer
ranging between about one and about 4; q is an integer ranging
between about one and about 100; and A.sup.2 is the same as A in
Formula II and IIa. Block copolymers according to the present
invention include copolymers containing molar fractions of alkylene
oxide between about 0.1 and about 25%. Other block copolymers
according to the present invention contain molar fractions of
alkylene oxide between about 0.5 and about 10%. Yet other block
copolymers according to the present invention contain molar
fractions of alkylene oxide between about 1 and about 5%.
[0053] This is not to say that polymer embodiments according to the
present invention do not include polymers that are poly(alkylene
oxide) block copolymers. Polymers that are block-copolymerized with
poly(alkylene oxides) tend to have lower glass transition
temperatures or crystalline melting temperatures than their
counterparts without poly(alkylene oxide) blocks. Thus, another
determining factor for whether a polymer according to the present
invention falls within the first polymer embodiment or the second
polymer embodiment instead of the third polymer embodiment or the
fourth polymer embodiment is whether the polymer is block
copolymerized with poly(alkylene oxide) and molar fraction of
poly(alkylene oxide) blocks.
[0054] Thus, a poly(alkylene oxide) block copolymer may fall within
the third or fourth polymer embodiment, while a counterpart polymer
with a lesser degree of block copolymerization, or one that is free
of poly(alkylene oxide) blocks may fall within the first or second
polymer embodiment, while a less substituted counterpart may fall
within the third or fourth polymer embodiment. Stated another way,
one of ordinary skill in the art can design or modify some polymers
to fall within the first or second embodiment rather than the third
or fourth embodiment by decreasing or eliminating poly(alkylene
oxide) block copolymerization.
[0055] Independent of any particular polymer embodiment, the
present invention also provides copolymers with two different
repeating units with the structure of Formula I and/or Formula II,
wherein the copolymer has a first repeating unit in which R.sub.2
is hydrogen, and a second repeating unit in which R.sub.2 is an
alkyl group containing from one to thirty carbon atoms. Copolymers
with repeating units in which R.sub.2 is alkyl are referred to as
N-substituted copolymers and are prepared from N-substituted
monomers by the methods disclosed by U.S. patent application Ser.
No. 11/873,979, the disclosure of which is incorporated herein by
reference. In one embodiment, R.sub.4 is an alkyl group containing
from one to six carbon atoms
[0056] This is not to say that polymer embodiments according to the
present invention do not include polymers having N-substituted
Formula I or Formula Ia repeating units. Polymers comprising
N-substituted Formula I or Formula Ia repeating units tend to have
lower glass transition temperatures or crystalline melting
temperatures than their unsubstituted counterparts. Thus, another
determining factor for whether a polymer according to the present
invention falls within the first polymer embodiment or the second
polymer embodiment is the molar fraction of N-substituted repeating
units. This is also another determining factor for whether a
polymer according to the present invention falls within the third
polymer embodiment or the fourth polymer embodiment.
[0057] Thus, a highly N-substituted version of a polymer according
to the present invention may fall within the third or fourth
polymer embodiment, while a less substituted counter-part with may
fall within the first or second polymer embodiment. Stated another
way, one of ordinary skill in the art can design or modify some
polymers to fall within the first or second embodiment rather than
the third or fourth embodiment by decreasing the level of
N-substitution. This can be done in combination with increasing the
level of bromine or iodine ring substitution. While not every
polymer according to the present invention can be moved between the
first and fourth polymer embodiments or the second and third
polymer embodiments by adjusting or selecting the degree of
N-substitution, alone or in combination with adjusting or selecting
the level of iodine or bromine ring-substitution and degree of
poly(alkylene oxide) block copolymerization, one of ordinary skill
in the art will readily recognize the polymers that can be modified
or designed in this manner.
[0058] N-substituted copolymers according to the present invention
include copolymers in which the molar fraction of N-substituted
monomer is between about 1 and about 90%. N-substituted copolymers
according to the present invention also include copolymers with a
molar fraction of N-substituted monomer between about 5 and about
25%. Yet other N-substituted co-polymers according to the present
invention include copolymers with a molar fraction of N-substituted
monomer between about 7.5 and about 12.5%.
[0059] According to another aspect of the present invention,
monomer compounds are provided having the structure of Formula IV
and Formula IVa:
##STR00008##
for which the variables are defined as follows:
[0060] Ar is a phenyl ring that is unsubstituted or substituted
with from one to four substituents independently selected from the
group consisting of halogen atoms, halo-methyl groups, halomethoxy
groups, methyl, methoxy, thiomethyl, nitro, sulfoxide and
sulfonyl;
[0061] R.sub.1 is selected from a bond and saturated and
unsaturated, substituted and unsubstituted alkyl, heteroalkyl,
alkenyl and heteroalkenyl groups containing from one to 12 carbon
atoms;
[0062] X.sub.1, X.sub.2 and X.sub.3 are independently selected from
the group consisting of O, S and NR.sub.3;
[0063] R.sub.2 is selected from the group consisting of hydrogen
and alkyl groups containing from one to thirty carbon atoms bonded
only to N, or R.sub.2a is an alkylene group covalently bonded to
both the nitrogen atom and AA, so that --N--R.sub.2a-AA- define a
heterocyclic ring;
[0064] R.sub.3 is selected from the group consisting of hydrogen
and alkyl groups containing from one to thirty carbon atoms;
[0065] AA has a pendant COOR.sub.4 group in which R.sub.4 is
selected from the group consisting of hydrogen, alkyl, heteroalkyl
and alkylaryl groups containing up to 30 carbon atoms and
alkyl-terminated poly(alkylene oxide) groups of molecular weight
100 to 10,000; and
[0066] AA and X.sub.3H of Formula IV are selected so that
(R.sub.2--HN-)AA-X.sub.3H define an amino acid and AA and X.sub.3H
of Formula IVa are selected so that
##STR00009##
define an X.sub.3H-- substituted amino acid. According to one
embodiment:
##STR00010##
defines a proline ring.
[0067] According to one embodiment, R.sub.2 and R.sub.3 are
independently selected from alkylene groups containing from one to
six carbon atoms. According to another embodiment, the R.sub.4
groups contain 18 carbon atoms or less.
[0068] Independent of any particular polymer embodiment, polymers
according to the present invention include polymers in which the
thermal decomposition temperature is greater than the glass
transition temperature or the crystalline melt temperature. Such
polymers can be melt-processed and can be shaped into different
three-dimensional structures for specific uses by conventional
polymer-forming techniques such as extrusion and injection molding.
The solvent-casting and compression molding techniques described in
earlier patents disclosing polymers polymerized from
tyrosine-derived diphenol compounds can also be used for all
polymers provided by the present invention, regardless of whether
they can be melt-processed.
[0069] Therefore, according to another aspect of the present
invention, blood-contacting or tissue-implantable medical devices
are provided, formed from the polymers of the present invention.
Preferably, the devices are formed by thermal fabrication. Such
devices include hernia repair devices. Load-bearing medical devices
are formed from the first and second polymer embodiments, while
medical devices that are not load-bearing may be formed from all
four polymer embodiments.
[0070] Load-bearing medical devices formed from the first and
second polymer embodiments of the present invention include stents
for the treatment of a body lumen including, but not limited to,
any blood vessels, the esophagus, urinary tract, bile tract, and
the ventricles of the central nervous system (brain and spinal
cord). Preferred stents are formed from or coated with radio-opaque
polymers according to the first and second polymer embodiments of
the present invention, so that fluoroscopic imaging can be used to
guide positioning of the device. One radio-opaque, bioresorbable
stent provided by the present invention is formed from a
bioresorbable polymer with sufficient halogen atoms to render the
stent inherently visible by X-ray fluoroscopy during stent
placement.
[0071] Included among the medical devices formed from the polymers
of the present invention are embolotherapy products. Embolotherapy
products provided by the present invention include particulate
formulations of biocompatible, bioresorbable polymers according to
all four polymer embodiments of the present invention. Among the
embolotherapy products provided by the present invention are
embolotherapy products formed from the radio-opaque polymers
provided by the present invention that contain a sufficient number
of halogen atoms to render the embolotherapy product inherently
radio-opaque.
[0072] Another specific application for which polymers provided by
the present invention are particularly useful is the fabrication of
scaffolds for tissue engineering on which isolated cell populations
are transplanted to engineer new tissues. The polymers are formed
into porous devices as described by Mikos et al., Biomaterials, 14,
323-329 (1993) or Schugens et al., J. Bio-med. Mater. Res., 30,
449-462 (1996) or U.S. Pat. No. 6,103,255 to allow for the
attachment and growth of cells as described in Bulletin of the
Material Research Society, Special Issue on Tissue Engineering
(Guest Ed.: Joachim Kohn), 21(11), 22-26 (1996). Thus the present
invention also provides tissue scaffolds having a porous structure
for the attachment and proliferation of cells either in vitro or in
vivo formed from polymers provided by the present invention. Which
polymer embodiment disclosed herein should be used to fabricate the
scaffold will depend upon the degree of rigidity and rate of
resorption required by the intended scaffold use.
[0073] Another specific application for which polymers provided by
the present invention may be used is the fabrication of implantable
drug delivery devices where a pharmaceutically active moiety is
admixed within the polymeric matrix for slow release, including
devices for ophthalmic drug delivery. The polymers provided by the
present invention are combined with a quantity of a biologically or
pharmaceutically active compound sufficient to be therapeutically
effective as a site-specific or systemic drug delivery system as
described by Gutowska et al., J. Biomater. Res., 29, 811-21 (1995)
and Hoffman, J. Contr. Rel., 6, 297-305 (1987). Accordingly, the
present invention also provides a method for site-specific or
systemic drug delivery by implanting in the body of a patient in
need thereof an implantable drug delivery device containing a
therapeutically effective amount of a biologically or a
physiologically active compound (e.g., a drug) in combination with
a polymer provided by the present invention.
[0074] Independent of any particular polymer embodiment, the
polymers provided by the present invention have good film-forming
properties. An important phenomena observed for the polymers
provided by the present invention having poly(alkylene oxide) block
copolymer segments is the temperature dependent phase transition of
the polymer gel or the polymer solution in aqueous solvents. As the
temperature increases, the gel of the polymers undergo a phase
transition to a collapsed state, while polymer solutions
precipitate at a certain temperature or within certain temperature
ranges. The polymers of the present invention having poly(alkylene
oxide) segments, and especially those that undergo a phase
transition at about 30 to 40.degree. C. on heating can be used as
biomaterials for drug release and clinical implantation materials.
Specific applications include films and sheets for the prevention
of adhesion and tissue reconstruction, as well as injectable drug
delivery systems that exist as a solution at room temperature and
that precipitate to form a solid drug release device upon injection
into the patient.
[0075] Therefore, the present invention also provides sheets or
coatings for application to exposed or injured tissues for use as
barrier for the prevention of surgical adhesions as described by
Urry et al., Mat. Res. Soc. Symp. Proc., 292, 253-64 (1993), which
are formed from the poly(alkylene oxide) block copolymers provided
by the present invention. In addition, the present invention also
provides a method for preventing the formation of adhesions between
injured tissues by inserting as a barrier between the injured
tissues a sheet or a coating of the poly(alkylene oxide) block
copolymers provided by the present invention.
[0076] The poly(alkylene oxide) segments decrease the surface
adhesion of the polymers provided by the present invention. As the
molar fraction of poly(alkylene oxide) increases, the surface
adhesion decreases. Coatings containing polymers with poly(alkylene
oxide) segments provided by the present invention may thus be
prepared that are resistant to cell attachment and are useful as
non-thrombogenic coatings on surfaces in contact with blood. Such
polymers also resist bacterial adhesion in this and in other
medical applications as well. The present invention therefore also
provides blood contacting devices and medical implants having
surfaces coated with the poly(alkylene oxide) block copolymers
provided by the present invention.
[0077] The coated surfaces are preferably polymeric surfaces.
Methods provided by the present invention therefore further include
implanting in the body of a patient a blood-contacting device or
medical implant having a surface coated with a polymer provided by
the present invention containing poly(alkylene oxide) block
copolymer segments.
[0078] By varying the molar fraction of poly(alkylene oxide)
segments in the block copolymers provided by the present invention,
the hydrophilic/hydrophobic ratios of the polymers can be
attenuated to adjust the ability of the polymer coatings to modify
cellular behavior. Increasing levels of poly(alkylene oxide)
inhibit cellular attachment, migration and proliferation, while
increasing the amount of pendent free carboxylic acid groups
promotes cellular attachment, migration and proliferation. The
present invention therefore also provides methods for regulating
cellular attachment, migration and proliferation by contacting
living cells, tissues, or biological fluids containing living cells
with the polymers provided by the present invention.
[0079] Through pendant free carboxylic acid groups, derivatives of
biologically and pharmaceutically active compounds, including
drugs, can be attached to the polymer backbone by covalent bonds
linked to the carboxylic acid pendent chain. This provides for the
sustained release of the biologically or pharmaceutically active
compound by means of hydrolysis of the covalent bond between the
drug and the polymer backbone. The present invention therefore also
provides polymers according to the depicted formulas in which
R.sub.4 is a biologically or pharmaceutically active compound
covalently attached to the polymer backbone.
[0080] Other features of the present invention will be pointed out
in the following description and claims, which disclose the
principles of the invention and the best modes which are presently
contemplated for carrying them out.
BRIEF DESCRIPTION OF THE DRAWINGS
[0081] FIG. 1 depicts a method according to the present invention
in which desaminotyrosyl tyrosine is coupled with serine ethyl
ester using a carbodiimide coupling agent.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0082] The present invention introduces a novel class of monomers
and copolymers polymerized therefrom in which an amino acid and an
amino acid derivative are coupled together to form the new monomers
depicted in formula IV and formula IVa:
##STR00011##
[0083] X.sub.1, X.sub.2, X.sub.3, Ar, R.sub.1, R.sub.2, R.sub.2a,
AA and the embodiments thereof are the same as described above with
respect to Formula I and Formula Ia. The new monomers are then
polymerized to form the new, useful polymers depicted in Formula I,
Formula Ia, Formula II and Formula IIa. The Formula IV and Formula
IVa monomers are prepared following standard procedures of peptide
chemistry such as disclosed in J. P. Greenstein and M. Winitz,
Chemistry of the Amino Acids, (John Wiley & Sons, New York
1961) and Bodanszky, Practice of Peptide Synthesis
(Springer-Verlag, New York, 1984).
[0084] Specifically, the monomers are prepared by coupling an
aromatic compound having the structure of formula V:
##STR00012##
with an amino acid having the structure of Formula VIa or Formula
VIb:
##STR00013##
[0085] More specifically, the two compounds are coupled by means of
carbodiimide-mediated coupling reactions in the presence of
hydroxybenzotriazole according to the procedure disclosed in U.S.
Pat. Nos. 5,587,507 and 5,670,602, the disclosures of both of which
are hereby incorporated by reference. Suitable carbodiimides are
disclosed therein. The preferred carbodi-imide is
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
(EDCI.HCl). The crude monomers can be recrystallized twice, first
from 50% acetic acid and water and then from a 20:20:1 ratio of
ethyl acetate, hexane and methanol, or, alternatively, flash
chromatography on silica gel is used, employing a 100:2 mixture of
methylene chloride:methanol as the mobile phase.
[0086] Monomers according to one embodiment of the present
invention have a molecular weight less than 1000. According to
another embodiment the monomer molecular weight is less than
500.
[0087] Using the reaction coupling desaminotyrosine and serine as
an example, a schematic view of the synthetic route is shown in
FIG. 1.
[0088] Desaminotyrosine and serine are but two examples of suitable
reactants. The other Formula V aromatic compounds and the other
Formula VIa and Formula VIb amino acids can be substituted for
desaminotyrosine and serine, respectively, in the depicted reaction
scheme.
[0089] According to one embodiment, X.sub.1, X.sub.2 and R.sub.1
are selected so that Formula V defines a hydroxy-phenylalkanoic or
alkenoic acid. Examples of Formula V acids include
4-hydroxy-cinnamic acid, 4-hydroxy-benzoic acid,
4-hydroxy-phenylethanoic acid, 4-hydroxy-phenyl-propanoic acid
(DAT), 4-hydroxy-phenylbutanoic acid and the like.
[0090] According to another embodiment, R.sub.2, R.sub.2a, AA and
X.sub.3 are selected so that Formula VIa and Formula VIb define an
alpha-amino acid. The Formula VIa alpha-amino acid is optionally
N-alkyl substituted. In a more specific embodiment, the alpha amino
acid is a naturally-occurring amino acid. In an even more specific
embodiment, the alpha amino acid is an essential amino acid. Even
more specifically, R.sub.2, AA and X.sub.3 may be selected to
define an amino acid selected from cysteine, threonine, serine,
lysine, thyronine, thyroxine, hydroxy-proline, mercapto-proline,
hydroxy-leucine, mercapto-leucine, hydroxy-isoleucine,
mercapto-isoleucine, hydroxy-tryptophan, mercapto-tryptophan,
mercapto-alanine, mercapto-valine and mercapto-phenylalanine.
[0091] According to another embodiment, the monomer of Formula IV
or Formula IVa is an amide dimer of a hydroxyphenyl alkanoic or
alkenoic acid and an amino acid. Specific examples of this
embodiment of Formula IV and IVa monomers include
desaminotyrosyl-serine, 3,5-diiododesaminotyrosyl-thyroxine,
desaminotyrosyl-cysteine, desamino-tyrosyl-hydroxyproline and the
like.
[0092] For purposes of the present invention, a "combination of
variables" refers to the combin-ation of X.sub.1, X.sub.2, X.sub.3,
R.sub.1, R.sub.2, R.sub.2a, R.sub.3, R.sub.4 and AA variables in
Formula I, Formula Ia, Formula II, Formula IIa, Formula IV, Formula
IVa, Formula V, Formula VIa and Formula VIb. The present invention
provides polymers with combinations of variables and degrees of
poly(alkylene oxide) block copolymerization that possess
degradation product solubility and the intrinsic physical polymer
properties related to suitability for use in load-bearing and
non-load-bearing medical implants within one of the four polymer
embodiments disclosed herein.
[0093] The combination of variables that achieve this result can be
readily determined without undue experimentation by one of ordinary
skill art guided by the present specification with the objective of
achieving a polymer with one of the four combinations of
degradation product solubility and intrinsic physical polymer
properties described herein. Once appropriate variable combinations
are selected, the synthesis of monomers and the polymerization of
monomers into polymers is essentially conventional. Thioamide
monomers (X.sub.2.dbd.S) can be prepared using the method described
by A. Kjaer (Acta Chemica Scandinavica, 6, 1374-83 (1952)). The
amide group in the monomers or polymers can also be converted to
thioamide groups using the fluorous analog of the Lawesson's
reagent (f.sub.6LR) described by Kaleta, et al., Org. Lett., 8(8),
1625-1628 (2006). The second method is preferable, since it allows
the formation of the monomer first then allows the conversion of
the amide group to the thioamide group. The present invention also
includes polymers in which other carboxyl groups, such as the
COOR.sub.4 group, are replaced with thio groups.
[0094] For the conversion of the tyrosine derived amide monomers to
the corresponding thio-amides, the phenolic groups of the monomers
are first protected by converting them to the diacetyl esters as
shown in the above-referenced U.S. application Ser. No. 11/873,979
by treating the monomer with Ac.sub.2O/pyridine. The protected
monomer is then reacted with f.sub.6LR followed by base hydrolysis
to the thioamide. The transformation can also be carried out on the
polymer using a similar procedure.
[0095] The N-substituted monomers and polymers of the present
invention (R.sub.2=one to thirty carbon atom alkyl) can be prepared
by substituting commercially-available N-substituted starting
materials for the starting materials of monomers containing
unsubstituted amide groups, or by substituting monomers containing
amide groups using non-N-substituted starting materials. Such
conversions are described in the above-referenced U.S. patent
application Ser. No. 11/873,979, which discloses in one embodiment
the preparation of N-substituted alpha-amino acid com-pounds of
Formula IVb from alanine, cysteine, glycine, histidine, isoleucine,
phenylalanine, serine, threonine, tryptophan, tyrosine and valine
that are subsequently coupled to 4-hydroxy-phenylalkanoic acids to
provide N-substituted monomers having the structure of formula IV.
According to a disclosed embodiment, R.sub.2 contains from one to
six carbon atoms.
[0096] Because the DAT and DAT analogs are non-chiral, unless
otherwise indicated the products of this invention are R,S
enantiomers. Preferably, however, when a chiral product is desired,
the chiral product corresponds to the L-amino acid derivative.
Alternatively, chiral products can be obtained via purification
techniques which separates enantiomers from an R,S mixture to
provide for one or the other stereoisomer. Such techniques are well
known in the art.
[0097] Polymers according to the present invention may contain a
plurality of repeating units containing an N-substituted amide
group, wherein the N-substituents and degree of N-substitution are
effective to render the polymer processable by a desired processing
method. Preferably, the minimum degree of N-substitution is used.
This can range from one to three mole percent to render a
non-soluble polymer soluble in a given solvent to up to about 25
mole percent to make the same polymer thermally processable, for
example, injection moldable. This can be readily determined by one
of ordinary skill in the art without undue experimentation.
N-methyl substituents are preferred. In certain circumstances, the
degree of N-substitution may also be selected to determine whether
the polymer falls within the first or second polymer embodiment
rather than the third or fourth polymer embodiment.
[0098] The monomer compounds are polymerized to form bioerodable
polymers for medical uses. The monomers can be used in any
conventional polymerization process using the monomer --X.sub.1H
and --X.sub.3H groups, including those processes that synthesize
polymers traditionally considered hydrolytically stable and
non-biodegradable. This includes polyesters, poly-carbonates,
polyiminocarbonates, polyarylates, polyurethanes, poly(urethane
carbonates), polyphosphazines, polyphosphoesters, polyethers,
polycarbamates, polycarbonodithionates, polythiocarbonates and
polythiocarbamates, as well as random block copolymers of these
polymers with poly(alkylene oxides) as described in U.S. Pat. No.
5,658,995, the disclosure of which is incorporated herein by
reference.
[0099] It is also understood that in the presentation of the
various polymer formulae that the polymer structures represented
may include homopolymers and heteropolymers, which include
stereoisomers. Homopolymer is used herein to designate a polymer
comprised of all the same type of monomers. Heteropolymer is used
herein to designate a polymer comprised of two or more different
types of monomer, which is also called a copolymer. A heteropolymer
or co-polymer may be of kinds known as block, random and
alternating. Further, with respect to the presentation of the
various polymer formulae, products according to embodiments of the
present invention may be comprised of a homopolymer, heteropolymer
and/or a blend of such polymers and repeating units may be present
other than those depicted by Formula I and Formula Ia.
[0100] Polyiminocarbonates are synthesized from dihydroxy and
diphenol monomers via one of the appropriate methods disclosed by
U.S. Pat. No. 4,980,449, the disclosure of which is incorporated by
reference. According to one method, part of the dihydroxy or
diphenol compound is converted to the appropriate dicyanate, then,
equimolar quantities of the dihydroxy or diphenol compound and the
dicyanate are polymerized in the presence of a strong base catalyst
such as a metal alkoxide or metal hydroxide.
[0101] The monomers compounds of formula IV and formula IVa may
also be reacted with phosgene or phosgene-like reactants to form
polycarbonates with --O--C(.dbd.O)--O-- linkages. The method is
essentially the conventional method for polymerizing diols into
polycarbonates. Suitable processes, associated catalysts and
solvents are known in the art and are taught in Schnell, Chemistry
and Physics of Polycarbonates, (Interscience, New York 1964), the
teachings of which are also incorporated herein by reference.
Because X.sub.1 and X.sub.3 are independently selected from O, S
and NR.sub.3, the reaction of the formula IV and formula IVa
monomers with phosgene will also produce urethane linkages
(--NR.sub.3--(C.dbd.O)--NR.sub.3--), carbonodithioate linkages
(--S--(C.dbd.O)--S--), carbamate linkages
(--O--(C.dbd.O)--NR.sub.3--), thiocarbonate linkages
(--S--(C.dbd.O)--O--) and thiocarbamate linkages
(--S--(C.dbd.O)--NR.sub.3--).
[0102] Other methods adaptable for use to prepare the polycarbonate
and other phosgene-derived polymers of the present invention are
disclosed in U.S. Pat. Nos. 6,120,491, and 6,475,477 the
disclosures of which are incorporated by reference. The
polycarbonates and other phosgene derivatives may also be prepared
by dissolving the Formula IV and/or Formula Iva monomer in
methylene chloride containing 0.1M pyridine or triethylamine A
solution of phosgene in toluene at a concentration between about 10
and about 25 wt %, and preferably about 20 wt %, is added at a
constant rate, typically over about two hours, using a syringe pump
or other means. The reaction mixture is quenched by stirring with
tetrahydrofuran (THF) and water, after which the polymer is
isolated by precipitation with isopropanol. Residual pyridine (if
used) is then removed by agitation of a THF polymer solution with a
strongly acidic resin, such as AMBERLYST 15.
[0103] The monomer compounds of Formula IV and/or Formula IVa may
also be directly reacted with aliphatic or aromatic dicarboxylic
acids in the carbodiimide mediated process disclosed by U.S. Pat.
No. 5,216,115 using 4-(dimethylamino) pyridinium-p-toluene
sulfonate (DPTS) as a catalyst to form the aliphatic or aromatic
poly(ester amides) when both X.sub.3 groups are O. The disclosure
of U.S. Pat. No. 5,216,115 is incorporated by reference.
Dicarboxylic acids according to one embodiment of the present
invention have the structure of Formula VII:
HOOC--R.sub.5--COOH (VII)
in which, for the aliphatic copolymers, R.sub.5 is selected from
saturated and unsaturated, substituted and unsubstituted alkyl or
heteroalkyl groups containing up to 30 carbon atoms, and preferably
from 2 to 12 carbon atoms. Heteroalkyl groups contain up to eight
N, O, P or S atoms. For aromatic copolymers R.sub.5 is selected
from aryl and alkylaryl groups containing up to 24 carbon atoms and
preferably from 13 to 20 carbon atoms, and optionally may also
include up to eight N, O, P or S atoms. For both aliphatic and
aromatic copolymers, N-heteroatoms may be N-substituted to reduce
polymer T.sub.g and melt viscosity.
[0104] The process forms polymers with
--X.sub.3--C(.dbd.O)--R.sub.5--C(.dbd.O)--X.sub.1-- linkages,
R.sub.5 may be selected so the dicarboxylic acids employed as the
starting materials are either important naturally-occurring
metabolites or highly biocompatible compounds. Aliphatic
dicarboxylic acid starting materials therefore include the
intermediate dicarboxylic acids of the cellular respiration pathway
known as the Krebs Cycle. The dicarboxylic acids include
.alpha.-ketoglutaric acid, succinic acid, fumaric acid and
oxaloacetic acid (R.sub.5 of formula VII is
--CH.sub.2--CH.sub.2--C(.dbd.O)--, --CH.sub.2--CH.sub.2--,
--CH.dbd.CH-- and --CH.sub.2--C(.dbd.O)--, respectively).
[0105] Another naturally-occurring aliphatic dicarboxylic acid is
adipic acid (R.sub.5 is (--CH.sub.2--).sub.4), found in beet juice.
Still yet another biocompatible aliphatic dicarboxylic acid is
sebacic acid (R.sub.5 is (--CH.sub.2--).sub.8), which has been
studied extensively and has been found to be nontoxic as part of
the clinical evaluation of
poly(bis(p-carboxyphenoxy)propane-co-sebacic acid anhydride) by
Laurencin et al., J. Biomed. Mater. Res., 24, 1463-81 (1990).
[0106] Other biocompatible aliphatic dicarboxylic acids include
oxalic acid (R.sub.5 is a bond), malonic acid (R.sub.5 is
--CH.sub.2--), glutaric acid (R.sub.5 is (--CH.sub.2--).sub.3),
pimelic acid (R.sub.5 is (--CH.sub.2--).sub.5), suberic acid
(R.sub.5 is (--CH.sub.2--).sub.6) and azelaic acid (R.sub.5 is
(--CH.sub.2--).sub.7). R.sub.5 can thus represent
(--CH.sub.2--).sub.Q, where Q is between 0 and 8 inclusive. Among
the suitable aromatic dicarboxylic acids are terephthalic acid,
isophthalic acid and bis(p-carboxy-phenoxy) alkanes such as
bis(p-carboxyphenoxy) propane.
[0107] R.sub.5 can also have the structure of Formula VIII:
--(CH.sub.2--).sub.aO--[(CH.sub.2--).sub.aCHR.sub.4--O--].sub.m(CH.sub.2-
--).sub.a (VIII)
[0108] wherein a is from 1 to 3, inclusive, m is from 1 to 500,000,
inclusive, and R.sub.4 is hydrogen or a lower alkyl group
containing from one to four carbon atoms. R.sub.4 is preferably
hydrogen, a is preferably 1, and m is preferably between about 10
and about 100, and more preferably between about 10 and about
50.
[0109] The diacids of Formula VIII are formed by the oxidation of
poly(alkylene oxides) according to well-known methods. One example
of such a compound is biscarboxymethyl poly(ethylene glycol), which
is commercially available.
[0110] R.sub.5 can also have the structure of Formula IX:
--R.sub.3--C(.dbd.O)--O[(--CH.sub.2).sub.a--CHR.sub.4--O--].sub.mC(.dbd.-
O)--R.sub.3 (IX)
[0111] wherein a, m and R.sub.4 and the preferred species thereof
are the same as described above with respect to Formula VIII.
R.sub.3 is selected from a bond or straight and branched alkyl and
alkylaryl groups containing up to 30 carbon atoms, including
embodiments containing up to 18 carbon atoms.
[0112] The dicarboxylic acids of Formula IX are poly(alkylene
oxides) bis-functionalized with dicarboxylic acids having the
structure of Formula VII wherein R.sub.5 is the same as described
above for Formula VII and preferably contains up to 12 carbon
atoms.
[0113] The poly(alkylene oxides) of Formula IX that are
bis-functionalized with dicarboxylic acids are prepared by the
reaction of a non-functionalized poly(alkylene oxide) with an
excess of either the dicarboxylic acid (mediated by a coupling
agent such as dicyclohexyl carbodiimide), the anhydride (e.g.
succinic anhydride) in the presence of pyridine or triethylamine,
or a dicarb-oxylic acid chloride (e.g. adipoyl chloride) in the
presence of an acid acceptor like triethylamine.
[0114] Polymers prepared from the Formula IV and Formula IVa
starting materials of the present invention with at least one
bromine- or iodine-substituted aromatic ring are radio-opaque, such
as the polymers prepared from radiopaque diphenol compounds
prepared according to the disclosure of U.S. Pat. No. 6,475,477, as
well as he disclosure of co-pending and commonly-owned U.S. patent
application Ser. No. 10/592,202, the disclosures of both of which
are incorporated herein by reference. The iodinated and brominated
diphenol monomers of the present invention can also be employed as
radio-opacifying, biocompatible non-toxic additives for other
polymeric biomaterials.
[0115] Bromine and iodine substituted aromatic monomers of the
present invention are prepared by well-known iodination and
bromination techniques that can be readily employed by those of
ordinary skill in the art guided by the above referenced granted
patent and pending application (now published) without undue
experimentation. The halogenated aromatic compounds from which the
halogenated aromatic monomers of the present invention are prepared
undergo ortho-directed halogenation. The term, "ortho-directed", is
used herein to designate orientation of the halogen atom(s)
relative to the X.sub.1 group of the DAT or DAT analog, or the
X.sub.3 group if the amino acid has an aromatic ring.
[0116] Random or block copolymers of the Formula I, Formula Ia,
Formula II and Formula IIa polymers of the present invention with a
poly(alkylene oxide) may be prepared according to the method
disclosed in U.S. Pat. No. 5,658,995, the disclosure of which is
also incorporated by reference. The poly(alkylene oxide) is
preferably a poly(ethylene glycol) block/unit typically having a
molecular weight of less than about 10,000 per unit. More
typically, the poly(ethylene glycol) block/unit has a molecular
weight less than about 4000 per unit. The molecular weight is
preferably between about 1000 and about 2000 per unit.
[0117] The molar fraction of poly(ethylene glycol) units in block
copolymers may range from grater than zero to less than 1, and is
typically greater than zero up to about 0.5, inclusive. More
preferably the molar fraction is less than about 0.25 and yet more
prefer-ably less than about 0.1. In more preferred variations, the
molar fraction may vary from greater than about 0.001 to about
0.08, and most preferably, between about 0.025 and about 0.035.
[0118] Unless otherwise indicated, the molar fractions reported
herein are based on the total molar amount of poly(alkylene glycol)
and non-glycol units in the polymers
[0119] The polymer glass transition temperature tends to increase
as the degree of halogenation and the molar fraction of free
carboxylic acid units increase. Higher weight percentages of
poly(alkylene oxide) are typically used in polymers with higher
levels of iodination or with higher molar fractions of free
carboxylic acid units to maintain the polymer glass transition
temperature within the desired range for the end use application.
N-alkylation provides an alternative means for lowering the polymer
glass transition temperature so that the amount of poly(alkylene
oxide) may be lowered or eliminated without adversely affecting the
polymer melt properties.
[0120] The Formula I, Formula Ia, Formula II and Formula IIa
polymers have weight--average molecular weights above about 20,000,
preferably above 40,000 and more preferably above about 80,000,
calculated from gel permeation chromatography (GPC) relative to
polystyrene standards using tetrahydrofuran (THF) as the eluent
without further correction. Stated another way, the polymers
preferably have between about 30 and 50 of the repeating units
depicted in Formula I, Formula Ia, Formula II and Formula IIa.
[0121] The polymers of the present invention are defined as
including polymers polymerized from formula IV and formula IVa
monomers having pendent free carboxylic acid groups
(R.sub.4.dbd.H). However, it is not possible to polymerize polymers
having pendent free carboxylic acid groups from corresponding
monomers with pendent free carboxylic acid groups without
cross-reaction of the free carboxylic acid group with the
co-monomer. Accordingly, polymers in accordance with the present
invention having pendent free carboxylic acid groups are prepared
from homopolymers and copolymers of benzyl and tert-butyl ester
monomers of the present invention having the structure of formula
IV or formula IVa in which R.sub.4 is a benzyl or tert-butyl
group.
[0122] The benzyl ester homopolymers and copolymers may be
converted to corresponding free carboxylic acid homopolymers and
copolymers through the selective removal of the benzyl groups by
the palladium catalyzed hydrogenolysis method disclosed by
co-pending and commonly owned U.S. Pat. No. 6,120,491, the
disclosure of which is incorporated herein by reference. The
tert-butyl ester homopolymers and copolymers may be converted to
corresponding free carboxylic acid homopolymers and copolymers
through the selective removal of the tert-butyl groups by the
acidolyis method disclosed by U.S. application Ser. No. 10/592,202,
also incorporated herein by reference. The catalytic hydrogenolysis
or acidolysis is necessary because the lability of the polymer
backbone prevents the employment of harsher hydrolysis
techniques.
[0123] The molar fraction of free carboxylic acid units in the
polymers of the present invention can be adjusted according to the
present invention to modify the degradation of devices made from
such polymers. For example, polymers with lower amounts of free
carboxylic acid will have longer lifetimes in the body. Further, by
otherwise adjusting the amount of free carboxylic acid in the
polymers across the range of preferred molar fraction, the
resulting polymers can be adapted for use in various applications
requiring different device lifetimes. In general, the higher the
molar fraction of free carboxylic acid units, the shorter the
lifetime of the device in the body and more suitable such devices
are for applications wherein shorter lifetimes are required.
[0124] After polymerization, appropriate work up of the polymers in
accordance with preferred embodiments of the present invention may
be achieved by any of a variety of known methods commonly employed
in the field of synthetic polymers to produce a variety of useful
articles with valuable physical and chemical properties, all
derived from tissue compatible monomers. The useful articles can be
shaped by conventional polymer thermo-forming techniques such as
extrusion and injection molding when the degradation temperature of
the polymer is above the glass transition or crystalline melt
temperature, or conventional non-thermal techniques can be used,
such as compression molding, injection molding, solvent casting,
spin casting, wet spinning Combinations of two or more methods can
be used. Shaped articles prepared from the polymers are useful,
inter alia, as degradable biomaterials for medical implant
applications.
[0125] In one embodiment, the medical device is a stent. It is
contemplated that a stent may comprise many different types of
forms. For instance, the stent may be an expandable stent. In
another embodiment, the stent may be configured to have the form of
a sheet stent, a braided stent, a self-expanding stent, a woven
stent, a deformable stent, or a slide-and-lock stent. Stent
fabrication processes may further include two-dimensional methods
of fabrication such as cutting extruded sheets of polymer, via
laser cutting, etching, mechanical cutting, or other methods, and
assembling the resulting cut portions into stents, or similar
methods of three-dimensional fabrication of devices from solid
forms.
[0126] In certain other embodiments, the polymers are formed into
coatings on the surface of an implantable device, particularly a
stent, made either of a polymer of the present invention or another
material, such as metal. Such coatings may be formed on stents via
techniques such as dipping, spray coating, combinations thereof,
and the like. Further, stents may be comprised of at least one
fiber material, curable material, laminated material, and/or woven
material. The medical device may also be a stent graft or a device
used in embolotherapy.
[0127] Details of stent products and fabrication in which the
polymers of the present invention may be employed are disclosed in
co-pending and commonly-owned U.S. patent application Ser. No.
10/952,202 filed Sep. 27, 2004, the disclosure of which is
incorporated by reference. Stents are preferably fabricated from
the radiopaque polymers of the present invention, to permit
fluoroscopic positioning of the device.
[0128] The highly beneficial combination of properties associated
with the polymers provided by the present invention means these
polymers are well-suited for use in producing a variety of
resorbable medical devices besides stents, especially implantable
medical devices that are preferably radiopaque, biocompatible, and
have various times of bioresorption. Polymers are provided that are
biocompatible for their intended end use and degrade under
physiological conditions into degradation products that are also
non-toxic in the intended end use of the polymer.
[0129] For example the polymers are suitable for use in resorbable
implantable devices with and without therapeutic agents, device
components and/or coatings with and without therapeutic agents for
use in other medical systems, for instance, the musculoskeletal or
orthopedic system (e.g., tendons, ligaments, bone, cartilage
skeletal, smooth muscles); the nervous system (e.g., spinal cord,
brain, eyes, inner ear); the respiratory system (e.g., nasal cavity
and sinuses, trachea, larynx, lungs); the reproductive system
(e.g., male or female reproductive); the urinary system (e.g.,
kidneys, bladder, urethra, ureter); the digestive system (e.g.,
oral cavity, teeth, salivary glands, pharynx, esophagus, stomach,
small intestine, colon), exocrine functions (biliary tract, gall
bladder, liver, appendix, recto-anal canal); the endocrine system
(e.g., pancreas/islets, pituitary, parathyroid, thyroid, adrenal
and pineal body), the hematopoietic system (e.g., blood and bone
marrow, lymph nodes, spleen, thymus, lymphatic vessels); and, the
integumentary system (e.g., skin, hair, nails, sweat glands,
sebaceous glands).
[0130] The polymers described herein can thus be used to fabricate
wound closure devices, hernia repair meshes, gastric lap bands,
drug delivery implants, envelopes for the implantation of cardiac
devices, devices for other cardiovascular applications,
non-cardiovascular stents such as biliary stents, esophageal
stents, vaginal stents, lung-trachea/bronchus stents, and the
like.
[0131] In addition, the resorbable polymers are suitable for use in
producing implantable, radiopaque discs, plugs, and other devices
used to track regions of tissue removal, for example, in the
removal of cancerous tissue and organ removal, as well as, staples
and clips suitable for use in wound closure, attaching tissue to
bone and/or cartilage, stopping bleeding (homeostasis), tubal
ligation, surgical adhesion prevention, and the like. Applicants
have also recognized that the resorbable polymers of the present
invention are well-suited for use in producing a variety of
coatings for medical devices, especially implantable medical
devices.
[0132] Further, in some preferred embodiments, the present polymers
may be advantageously used in making various resorbable orthopedic
devices including, for example, radiopaque biodegradable screws
(interference screws), radiopaque biodegradable suture anchors, and
the like for use in applications including the correction,
prevention, reconstruction, and repair of the anterior cruciate
ligament (ACL), the rotator cuff/rotator cup, and other skeletal
deformities.
[0133] Other resorbable devices that can be advantageously formed
from the polymers of the present invention, include devices for use
in tissue engineering. Examples of suitable resorbable devices
include tissue engineering scaffolds and grafts (such as vascular
grafts, grafts or implants used in nerve regeneration). The present
resorbable polymers may also be used to form a variety of devices
effective for use in closing internal wounds. For example
biodegradable resorbable sutures, clips, staples, barbed or mesh
sutures, implantable organ supports, and the like, for use in
various surgery, cosmetic applications, and cardiac wound closures
can be formed.
[0134] Various resorbable devices useful in dental applications may
advantageously be formed according to embodiments of the present
invention. For example devices for guided tissue regeneration,
alveolar ridge replacement for denture wearers, and devices for the
regeneration of maxilla-facial bones may benefit from being
radiopaque so that the surgeon or dentist can ascertain the
placement and continuous function of such implants by simple X-ray
imaging.
[0135] The polymers of the present invention are also useful in the
production of bioresorbable, inherently radiopaque polymeric
embolotherapy products for the temporary and therapeutic
restriction or blocking of blood supply to treat tumors and
vascular malformations, e.g., uterine fibroids, tumors (i.e.,
chemoembolization), hemorrhage (e.g., during trauma with bleeding)
and arteriovenous malformations, fistulas and aneurysms delivered
by means of catheter or syringe. Details of embolotherapy products
and methods of fabrication in which the polymers of the present
invention may be employed are disclosed in co-pending and
commonly-owned U.S. patent application Ser. No. 10/952,274 filed
Sep. 27, 2004, the disclosure of which is incorporated by
reference. Embolotherapy treatment methods are by their very nature
local rather than systemic and the products are preferably
fabricated from the radiopaque polymers of the present invention,
to permit fluoroscopic monitoring of delivery and treatment.
[0136] The present polymers are further useful in the production of
a wide variety of therapeutic agent delivery devices. Such devices
may be adapted for use with a variety of therapeutics including,
for example, pharmaceuticals (i.e., drugs) and/or biological agents
as previously defined and including biomolecules, genetic material
and processed biologic materials, and the like. Any number of
transport systems capable of delivering therapeutics to the body
can be made, including devices for therapeutic delivery in the
treatment of cancer, intravascular problems, dental problems,
obesity, infection, and the like.
[0137] In certain embodiments, any of the aforementioned devices
described herein can be adapted for use as a therapeutic delivery
device (in addition to any other functionality thereof). Controlled
therapeutic delivery systems may be prepared, in which a
therapeutic agent, such as a biologically or pharmaceutically
active and/or passive agent, is physically embedded or dis-persed
within a polymeric matrix or physically admixed with a polymer of
the present invention. Controlled therapeutic agent delivery
systems may also be prepared by direct application of the
therapeutic agent to the surface of an implantable medical device
such as a bioresorbable stent device (comprised of at least one of
the present polymers) without the use of these polymers as a
coating, or by use of other polymers or substances for the
coating.
[0138] When R.sub.4 is hydrogen, the COOR.sub.4 pendant groups of
the polymers of the present invent-tion may also be derivatized by
the covalent attachment of a therapeutic agent. Depending upon the
moieties present on the underivatized therapeutic agent, the
covalent bond may be an amide bond or an ester bond. Typically, the
therapeutic agent is derivatized at a primary or secondary amine,
hydroxyl, ketone, aldehyde or carboxylic acid group. Chemical
attachment procedures are described by U.S. Pat. Nos. 5,219,564 and
5,660,822; Nathan et al., Bio. Cong. Chem., 4, 54-62 (1993) and
Nathan, Macromol., 25, 4476 (1992), the disclosures of which are
incorporated by reference.
[0139] The therapeutic agent may first be covalently attached to a
monomer, which is then polymerized, or the polymerization may be
performed first, followed by covalent attachment of the therapeutic
agent. Hydrolytically stable conjugates are utilized when the
therapeutic agent is active in conjugated form. Hydrolyzable
conjugates are utilized when the therapeutic agent is inactive in
conjugated form.
[0140] Therapeutic agent delivery compounds may also be formed by
physically blending the therapeutic agent to be delivered with the
polymers of the present invention using conventional techniques
well-known to those of ordinary skill in the art. For this
therapeutic agent delivery embodiment, it is not essential that the
polymer have pendent groups for covalent attachment of the
therapeutic agent.
[0141] The polymer compositions of the present invention containing
therapeutic agents, regard-less of whether they are in the form of
polymer conjugates or physical admixtures of polymer and
therapeutic agent, are suitable for applications where localized
delivery is desired, as well as in situations where a systemic
delivery is desired. The polymer conjugates and physical admixtures
may be implanted in the body of a patient in need thereof, by
procedures that are essentially conventional and well-known to
those of ordinary skill in the art.
[0142] Implantable medical devices may thus be fabricated that also
serve to deliver a thera-peutic agent to the site of implantation
by being fabricated from or coated with the therapeutic agent
delivery system of the present invention in which a polymer of the
present invention has a therapeutic agent physically admixed
therein or covalently bonded thereto, such as a drug-eluting stent.
Embolotherapeutic particles may also be fabricated for delivery of
a therapeutic agent.
[0143] Examples of biologically or pharmaceutically active
therapeutic agents that may be cova-lently attached to the polymers
of the present invention include acyclovir, cephradine, procaine,
ephedrine, adriamycin, daunomycin, plumbagin, atropine, quinine,
digoxin, quinidine, bio-logically active peptides, chlorin e.sub.6,
cephradine, cephalothin, proline and proline analogs such as
cis-hydroxy-L-proline, malphalen, penicillin V and other
antibiotics, aspirin and other non-steroidal anti-inflammatories,
nicotinic acid, chemodeoxycholic acid, chlorambucil, anti-tumor and
anti-proliferative agents, including anti-proliferative agents that
prevent restenosis, hormones such as estrogen, and the like.
Biologically active compounds, for the purposes of the present
invention, are additionally defined as including cell attachment
mediators, biologically active ligands, and the like.
[0144] The invention described herein also includes various
pharmaceutical dosage forms containing the polymer-therapeutic
agent combinations of the present invention. The combination may be
a bulk matrix for implantation or fine particles for administration
by traditional means, in which case the dosage forms include those
recognized conventionally, e.g. tablets, capsules, oral liquids and
solutions, drops, parenteral solutions and suspensions, emulsions,
oral powders, inhalable solutions or powders, aerosols, topical
solutions, suspensions, emulsions, creams, lotions, ointments,
transdermal liquids, etc.
[0145] The dosage forms may include one or more pharmaceutically
acceptable carriers. Such materials are non-toxic to recipients at
the dosages and concentrations employed, and include dil-uents,
solubilizers, lubricants, suspending agents, encapsulating
materials, penetration enhancers, solvents, emollients, thickeners,
dispersants, buffers such as phosphate, citrate, acetate and other
organic acid salts, anti-oxidants such as ascorbic acid,
preservatives, low molecular weight (less than about 10 residues)
peptides such as polyarginine, proteins such as serum albumin,
gelatin, or immunoglobulins, other hydrophilic polymers such as
poly(vinylpyrrolidinone), amino acids such as glycine, glutamic
acid, aspartic acid, or arginine, monosaccharides, disaccharides,
and other carbohydrates, including cellulose or its derivatives,
glucose, mannose, or dextrines, chelating agents such as EDTA,
sugar alcohols such as mannitol or sorbitol, counter-ions such as
sodium and/or nonionic surfactants such as tween, pluronics or
PEG.
[0146] Therapeutic agents to be incorporated in the polymer
conjugates and physical admixtures of the invention may be provided
in a physiologically acceptable carrier, excipient stabilizer,
etc., and may be provided in sustained release or timed release
formulations supplemental to the polymeric formulation prepared in
this invention. Liquid carriers and diluents for aqueous
dispersions are also suitable for use with the polymer conjugates
and physical admixtures.
[0147] Subjects in need of treatment, typically mammalian, using
the polymer-therapeutic agent combinations of this invention, can
be administered dosages that will provide optimal efficacy. The
dose and method of administration will vary from subject to subject
and be dependent upon such factors as the type of mammal being
treated, its sex, weight, diet, concurrent medication, overall
clinical condition, the particular compounds employed, the specific
use for which these compounds are employed, and other factors which
those skilled in the medical arts will recognize. The
polymer-therapeutic agent combinations of this invention may be
prepared for storage under conditions suitable for the preservation
of therapeutic agent activity as well as maintaining the integrity
of the polymers, and are typically suitable for storage at ambient
or refrigerated temperatures.
[0148] Depending upon the particular compound selected, transdermal
delivery may be an option, providing a relatively steady delivery
of the drug, which is preferred in some circumstances. Transdermal
delivery typically involves the use of a compound in solution, with
an alcoholic vehicle, optionally a penetration enhancer, such as a
surfactant, and other optional ingredients. Matrix and reservoir
type transdermal delivery systems are examples of suitable
transdermal systems. Transdermal delivery differs from conventional
topical treatment in that the dosage form delivers a systemic dose
of the therapeutic agent to the patient.
[0149] The polymer-drug formulations of this invention may also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes may be used in any of the
appropriate routes of administration described herein. For example,
liposomes may be formulated that can be administered orally,
parenterally, transdermally or via inhalation. Therapeutic agent
toxicity could thus be reduced by selective delivery to the
affected site. For example if the therapeutic agent is liposome
encapsulated, and is injected intravenously, the liposomes used are
taken up by vascular cells and locally high concentrations of the
therapeutic agent could be released over time within the blood
vessel wall, resulting in improved action of the therapeutic agent.
The liposome encapsulated therapeutic agents are preferably
administered parenterally, and particularly, by intravenous
injection.
[0150] Liposomes may be targeted to a particular site for release
of the therapeutic agent. This would obviate excessive dosages that
are often necessary to provide a therapeutically useful dosage of a
therapeutic agent at the site of activity, and consequently, the
toxicity and side effects associated with higher dosages.
[0151] Therapeutic agents incorporated into the polymers of this
invention may desirably further incorporate agents to facilitate
their delivery systemically to the desired target, as long as the
delivery agent meets the same eligibility criteria as the
therapeutic agents described above. The active therapeutic agents
to be delivered may in this fashion be incorporated with
antibodies, antibody fragments, growth factors, hormones, or other
targeting moieties, to which the therapeutic agent molecules are
coupled.
[0152] The polymer-therapeutic agent combinations of this invention
may also be formed into shaped articles, such as valves, stents,
tubing, prostheses, and the like. Cardiovascular stents may be
combined with therapeutic agents that prevent restenosis
Implantable medical devices may be combined with therapeutic agents
that prevent infection.
[0153] Therapeutically effective dosages may be determined by
either in vitro or in vivo methods. For each particular compound of
the present invention, individual determinations may be made to
determine the optimal dosage required. The range of therapeutically
effective dosages will naturally be influenced by the route of
administration, the therapeutic objectives, and the condition of
the patient. For the various suitable routes of administration, the
absorption efficiency must be individually determined for each drug
by methods well known in pharmacology. Accordingly, it may be
necessary for the therapist to titer the dosage and modify the
route of administration as required to obtain the optimal
therapeutic effect.
[0154] The determination of effective dosage levels, that is, the
dosage levels necessary to achieve the desired result, will be
within the ambit of one skilled in the art. Typically, applications
of compound are commenced at lower dosage levels, with dosage
levels being increased until the desired effect is achieved. The
release rate from the formulations of this invention is also varied
within the routine skill in the art to determine an advantageous
profile, depending on the therapeutic conditions to be treated.
[0155] A typical dosage might range from about 0.001 mg/k/g to
about 1,000 mg/k/g, preferably from about 0.01 mg/k/g to about 100
mg/k/g, and more preferably from about 0.10 mg/k/g to about 20
mg/k/g. Advantageously, the compounds of this invention may be
administered several times daily, and other dosage regimens may
also be useful.
[0156] In practicing the methods of this invention, the
polymer-therapeutic agent combinations may be used alone or in
combination with other therapeutic or diagnostic agents. The
compounds of this invention can be utilized in vivo, ordinarily in
mammals such as primates such as humans, sheep, horses, cattle,
pigs, dogs, cats, rats and mice, or in vitro.
[0157] A major advantage of using the radiopaque, bioresorbable
polymers of the instant invention in therapeutic agent delivery
applications is the ease of monitoring release of a therapeutic
agent and the presence of the implantable therapeutic delivery
system. Because the radiopacity of the polymeric matrix is due to
covalently attached halogen substituents, the level of radiopacity
is directly related to the residual amount of the degrading
therapeutic agent delivery matrix still present at the implant site
at any given time after implantation. In preferred embodiments the
rate of therapeutic release from the degrading therapeutic delivery
system will be correlated with the rate of polymer resorption. In
such preferred embodiments, the straight-forward, quantitative
measurement of the residual degree of radio-opacity will provide
the attending physician with a way to monitor the level of
therapeutic release from the implanted therapeutic delivery
system.
[0158] The following non-limiting examples set forth herein below
illustrate certain aspects of the invention. All parts and
percentages are by mole percent unless otherwise noted and all
temperatures are in degrees Celsius unless otherwise indicated. All
solvents were HPLC grade and all other reagents were of analytical
grade and were used as received, unless otherwise indicated.
EXAMPLES
Example 1
Preparation of the Ethyl Ester of Amino Acids
[0159] Ethyl esters of amino acids were prepared by reaction of the
amino acid with ethanol and thionyl chloride as described in a
literature procedure (Bodanszky, Practice of Peptide Synthesis
(Springer-Verlag, New York 1984). The products were characterized
using HPLC, .sup.1H NMR, elemental analysis and melting point. In
most cases esters were used as the hydrochloride salt with in situ
free base generation with triethylamine Free bases of the esters
were also prepared and isolated in some cases by treating with 5M
aqueous potassium carbonate. When available esters were obtained
from commercial sources.
Example 2
Synthesis of Desaminotyrosyl Serine Ethyl Ester
[0160] To a single-necked 500 mL round-bottomed flask equipped with
an addition funnel and a magnetic stirrer was added
3-(4-hydroxyphenyl)propionic acid (10.0 g, 60.2 mmol), serine-ethyl
ester hydrochloride (10.7 g, 63.2 mmol), hydroxybenzotriazole
hydrate (0.81 g, 6.0 mmol), and tetrahydrofuran (50 mL). The flask
was cooled in an ice-water bath and triethylamine (8.85 mL, 63.4
mmol) was added drop wise over a period of 10 minutes and the
reaction mixture was stirred for 30 more minutes and then
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (12
g, 50 mmol) was added and stirred at ice-water bath temperature for
1 hour.
[0161] The reaction mixture was further stirred at room temperature
for 4 hours. Distilled water (150 mL) was added to the reaction
flask and was transferred to a separatory funnel and extracted
twice with 100 mL ethyl acetate. The combined extract was washed
twice with 0.2 M hydrochloric acid solution (100 mL), twice with
0.5 M sodium bicarbonate solution (100 mL). After drying over
anhydrous magnesium sulfate and stirring with 100-mesh activated
carbon, the solution was filtered. Solvent was removed by rotary
evaporation and the monomer was dried under vacuum. The syrupy
product obtained was stirred with hexane (100 mL) for 6 h. The
product was obtained as white powder (yield 72%). The identity of
the product as desamino-tyrosyl serine ethyl ester was con-firmed
by elemental analysis and .sup.1H NMR spectroscopy and had a
melting point of 85-88.degree. C.
Examples 3 and 4
Synthesis of DAT-hydroxyproline ethyl ester and DAT-threonine ethyl
ester
[0162] Using the procedure of Example 2, ethyl esters of
trans-hydroxyproline and threonine were coupled to
desaminotyrosine. The resulting monomers were characterized as in
Example 1 by elemental analysis, .sup.1H NMR spectroscopy and
HPLC.
TABLE-US-00001 Table of reagents used for the preparation of
monomers (DAT-AA ethyl ester) Amino AA-ethyl DAT HOBt Triethyl-
EDCI Yield acid ester.cndot.HCl, (g) (g) (g) amine (g) (g) (%)
Serine 21.43 20 1.63 12.8 25.4 49.3 Threonine 5.22 4.5 0.37 2.88
5.71 54.0 tHyp 9.89 8.0 0.65 5.12 10.2 43.3 5-HTrp 5.23 2.9 0.24
1.86 3.69 69.8 Thyronine 0.65* 0.34 0.03 -- 0.43 61.2 *thyronine
ethyl ester free base was used
Examples 5 and 6
Synthesis of I.sub.2DAT-thyronine ethyl ester and
I.sub.2DAT-5-hydroxyhyptophan ethyl ester
[0163] Thyronine ethyl ester hydrochloride and 5-hydroxytryptophan
ethyl ester hydrochloride were prepared and converted to the
corresponding free base with 5M aqueous potassium carbonate
solution. Using the procedure of Example 2, thyronine ethyl ester
and 5-hydroxytryptophan ethyl esters were coupled with diiodo-DAT
{3-(3,5-diiodo-4-hydroxyphenyl))propionic acid} to get the
corresponding diiodinated monomers. The monomers were also
characterized as in Example 2.
TABLE-US-00002 Table of reagents used for the iodinated monomers
(I.sub.2DAT-AA ethyl esters) Amino AA-ethyl Triethyl- % acid ester
I.sub.2DAT HOBt amine EDCI yield tHyp 9.8 20 0.65 5.08 10.1 65
5-HTrp 8.05 11.28 0.36 2.87 5.69 54 Thyronine 5.07* 6.57 0.21 --
3.33 57 *thyronine ethyl ester free base was used
Example 7
Polymerization of Diiododesaminotyrosyl Thyronine Ethyl Ester Using
Triphosgene
[0164] In a 100 mL round-bottomed flask equipped with a magnetic
stirrer and a syringe pump, were placed 1.5 g (2.1 mmol)
diiododesaminotyrosyl thyronine ethyl ester, 15 mL of methylene
chloride, and 0.66 g (8.3 mmol) of pyridine, the resulting solution
was stirred and to the stirred solution was added 0.25 gram of
triphosgene dissolved in 1 mL of methylene chloride over a period
of 3 h using a syringe pump. The product was isolated by
precipitation with 2-propanol. The product was dried in vacuum oven
at 40.degree. C. and characterized by GPC (Mw=65 KDa) and DSC
(glass transition temperature=67.degree. C.) and by .sup.1H NMR
spectroscopy. This polymer could be compression molded into thin
films using a hot press. The compression molded films showed a
tensile modulus of ca 290 kpsi and yield stress of 10.9 kpsi.
Example 8
Copolymer of DTE and DAT-5-hydroxytryptophan ethyl ester
(DHTrpE)
[0165] Into a 100 mL round bottomed flask were added 2.5 g (7.0
mmol) of DTE and 2.5 g of DHTrpE. To the flask were added 30 mL of
methylene chloride and 6.1 mL of pyridine. Most of the solid
dissolved. However, some turbidity was present. This was filtered
with a coarse fluted filter paper into a 3-necked 100 mL round
bottomed flask. 1.42 g of triphosgene in 10 mL of methylene
chloride was added over 3 h. The reaction mixture became viscous.
It was quenched with 10 mL of 9:1 THF-water. The product was
isolated by precipitation with IPA followed by 3 washings with IPA
in a laboratory blender. The product was dried under a stream of
nitrogen and then in vacuum oven. The .sup.1H NMR spectrum showed a
ratio of 1:0.7 of DTE to DHTrpE. The Tg of the polymer was
114.degree. C.
[0166] Another polymerization was also carried out using a 3:1
ratio of DTE (3 g) and DAT-5-hydroxytryptopan ethyl ester (1 g). In
this case a clear solution was obtained and therefore the
polymerization was carried out without filtration. .sup.1H NMR
spectrum of the polymer confirmed 3:1 ratio of DTE to DHTrpE and
the Tg of the polymer was 105.degree. C.
Example 9
Wet Tg and Dry Tg of all the New AA Polymers
[0167] Glass transition temperature of the polymers was determined
by differential scanning calorimetry from the second heat. The wet
Tgs of the polymers were measured using differential mechanical
analyzer (DMA). For this measurement a compression molded film of
the polymer were used. In some cases a film could not be obtained
or the film was too brittle to make a measurement. In such cases
only the dry Tg is reported.
Table showing the dry and wet Tgs of the polymers from the monomers
as shown
TABLE-US-00003 Monomer Dry Tg, .degree. C. Wet Tg, .degree. C.
DAT-serine ethyl ester 58 18-19 DAT-threonine ethyl ester 75 46
DAT-trans-Hydroxyproline ethyl ester 103 >50
DAT-5-hydroxytryptophan ethyl ester:DTE 94 43 (0.7:1)
DAT-5-hydroxytryptophan ethyl ester:DTE 92 40 (1:3) DAT-Thyronine
ethyl ester 84 43 I.sub.2DAT-trans-Hydroxyproline ethyl ester 155
>70 I.sub.2DAT-Thyronine ethyl ester 132 >70
Example 10
Determination of Solubility of Monomers
[0168] About 30 mg of the monomer and 2 mL of PBS (pH 7.4) were
added to a 2 dram vial. The vial was agitated on a vortex mixer for
2 h. If all the solid dissolved, more solid was added and agitation
was continued. The mixture was filtered using a syringe filter to
remove undissolved monomer. The clear filtrate was analyzed by HPLC
by injecting 5 microliter of the filtrate. The area of the peak
obtained was measured. A calibration curve was obtained by
injecting known concentration of the monomer in methanol and
plotting concentration against the area of the peaks obtained.
Using this calibration curve the solubility of the monomer in PBS
at ambient temperature was determined
[0169] To determine the solubility at 37.degree. C., the vials were
placed in an incubator at 37.degree. C. for 2 h. The mixture was
then quickly filtered using syringe filter and then diluted
2.times. with PBS to prevent precipitation of the monomer. The
solubility is determined using procedures similar to that used at
room temperature solubility.
Table showing the solubility of the monomers prepared above in PBS
at 25.degree. C.*
TABLE-US-00004 Solubility, mg/mL, Solubility, Monomer 25.degree. C.
mg/mL, 37.degree. C. DAT-tyrosine ethyl ester (DTE) 0.74 NA
DAT-serine ethyl ester 7.7 14.13 DAT-threonine ethyl ester 10 NA
DAT-trans-Hydroxyproline 12 NA ethyl ester DAT-5-hydroxytryptophan
0.15 0.43 ethyl ester DAT-Thyronine ethyl ester <0.05 NA *with
most monomers a small amount of the by products of the reaction
were present.
Example 11
Preparation of .beta.-Hydroxy Leucine
[0170] .beta.-Hydroxy leucine is prepared using the method of Adam
J. Morgan and co-workers (Morgan et al., Org. Lett, 1, 1949-1952
(1999).
Example 12
.beta.-Hydroxy Leucine ethyl ester hydrochloride
[0171] Into a 100 mL round-bottomed flask equipped with reflux
condenser is added 50 mL ethanol and stirred using magnetic stirrer
under positive nitrogen pressure. The flask is cooled using a dry
ice/IPA bath to -35.degree. C. Using an addition funnel 8.5 mL
(0.12 mol) of thionyl chloride is added over 10 min To the flask is
then added 14.7 g (0.1 mol) of .beta.-Hydroxy Leucine. The cooling
bath is then removed and the flask heated using a heating mantle to
reflux for 10 h. The reaction mixture is concentrated to 20 mL and
then precipitated by adding 50 mL of ether. The product is isolated
by filtration and washed with ether. The product .beta.-Hydroxy
Leucine ethyl ester hydrochloride is characterized by proton NMR
and elemental analysis.
Example 13
Preparation of DAT-.beta.-Hydroxy Leucine ethyl ester
[0172] Into a 250 mL round bottomed flask equipped with an overhead
stirrer, and a thermometer are added 16.6 g (0.100 mol) of
desaminotyrosine, 21.8 g (0.103 mol) of .beta.-Hydroxy Leucine
ethyl ester hydrochloride, 1.3 g (0.010 mol) hydroxybenzotriazole,
and 120 mL of tetrahydrofuran. The flask is cooled using an
ice-water bath to about 5.degree. C. To the flask are then added
10.5 g (0.103 mol) of triethylamine over 5 min followed by 21.1 g
(0.11 mol) of EDCI. The reaction mixture is stirred at 5-10.degree.
C. for 1 h and then at ambient temperature for 5 h.
[0173] To the reaction mixture is then added 240 mL of 0.2 M HCl
and stirred for 10 min It is then transferred to a 50 mL separatory
funnel and extracted with 500 mL of ethyl acetate. The aqueous
layer is separated and discarded. The organic layer is washed with
250 mL of 0.02 M HCl, 5% aqueous NaHCO.sub.3 and 250 mL 20% aqueous
NaCl. After drying over MgSO.sub.4 it is evaporated to dryness and
the viscous oil is stirred with hexane till it solidifies. The
product is characterized .sup.1H NMR, HPLC, and elemental analysis.
The solubility of the monomer in PBS is also determined as
described above.
Example 14
Polymerization of DAT .beta.-Hydroxy Leucine ethyl ester
[0174] Into a 100 mL round bottomed flask are added 6.45 g (20.0
mmol) of DAT .beta.-Hydroxy Leucine ethyl ester, 40 mL of methylene
chloride and 5.93 mL (75.0 mmol) of pyridine. To the resulting
mixture with stirring is added 2.18 g (7.33 mmol) of triphosgene in
10 mL of methylene chloride over 3 h using a syringe pump. The
reaction mixture is quenched with 5 mL of 9:1 THF-water. The
polymer is precipitated with IPA followed by 3 washings with IPA in
a laboratory blender. Polymer is isolated by filtration and dried
under a stream of nitrogen and then in vacuum oven at 40.degree. C.
It is characterized by NMR, DSC (Tg), and mechanical
properties.
[0175] The foregoing illustrates the novel classes of monomers and
bioresorbable polymers derived therefrom with varying mechanical
properties that hydrolytically degrade under physiological
conditions and resorb at varying rates. The foregoing examples and
description of the preferred embodiment should be taken as
illustrating, rather than as limiting, the present invention as
defined by the claims. As will be readily appreciated, numerous
variations and combinations of the features set forth above can be
utilized without departing from the present invention as set forth
in the claims. Such variations are not regarded as a departure from
the spirit and scope of the invention, and all such variations are
intended to be included within the scope of the following
claims.
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