U.S. patent application number 12/046378 was filed with the patent office on 2008-06-26 for biodegradable, anionic polymers derived from the amino acid l-tyrosine.
This patent application is currently assigned to Rutgers, The State University of New Jersey. Invention is credited to Durgadas Bolikal, Shuiyum Guan, Joachim B. Kohn.
Application Number | 20080152690 12/046378 |
Document ID | / |
Family ID | 26734912 |
Filed Date | 2008-06-26 |
United States Patent
Application |
20080152690 |
Kind Code |
A1 |
Kohn; Joachim B. ; et
al. |
June 26, 2008 |
BIODEGRADABLE, ANIONIC POLYMERS DERIVED FROM THE AMINO ACID
L-TYROSINE
Abstract
Polymers with a hydrolytically labile polymer backbones with
non-toxic biocompatible diphenolic repeating units having the
structure: ##STR00001## wherein R.sub.9 is an alkyl, aryl or
alkylaryl group with up to 18 carbon atoms having a pendent
carboxylic acid group or the benzyl ester thereof; and non-toxic
biocompatible diphenolic repeating units having the structure:
##STR00002## wherein R.sub.12 is an alkyl, aryl or alkylaryl group
with up to 18 carbon atoms having a pendent carboxylic acid ester
group selected from straight and branched alkyl and alkylaryl
esters containing up to 18 carbon atoms and ester derivatives of
biologically and pharmaceutically active compounds covalently
bonded to the polymer, provided that said ester group is not a
benzyl group or a group that is removed by hydrogenolysis.
Implantable medical devices and treatment methods using the
polymers are also disclosed.
Inventors: |
Kohn; Joachim B.;
(Piscataway, NJ) ; Bolikal; Durgadas; (Edison,
NJ) ; Guan; Shuiyum; (Edison, NJ) |
Correspondence
Address: |
FOX ROTHSCHILD LLP;PRINCETON PIKE CORPORATE CENTER
997 LENOX DRIVE, BUILDING #3
LAWRENCEVILLE
NJ
08648
US
|
Assignee: |
Rutgers, The State University of
New Jersey
New Brunswick
NJ
|
Family ID: |
26734912 |
Appl. No.: |
12/046378 |
Filed: |
March 11, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09350423 |
Jul 8, 1999 |
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12046378 |
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09056050 |
Apr 7, 1998 |
6120491 |
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09350423 |
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60064656 |
Nov 7, 1997 |
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Current U.S.
Class: |
424/423 ;
424/443; 424/486; 525/132; 528/125; 528/208; 528/219;
623/11.11 |
Current CPC
Class: |
A61L 17/10 20130101;
A61L 27/58 20130101; C08G 63/6858 20130101; A61L 31/06 20130101;
C07K 14/001 20130101; A61L 27/18 20130101; C08G 63/672 20130101;
C08G 64/045 20130101; C08G 64/1641 20130101; A61P 41/00 20180101;
A61L 27/18 20130101; C08G 69/44 20130101; C08G 64/12 20130101; C08G
64/183 20130101; A61L 31/148 20130101; C08L 69/00 20130101; C08G
69/10 20130101; C08L 69/00 20130101; A61L 31/06 20130101; A61K
9/204 20130101; C08G 63/6856 20130101; A61K 38/00 20130101 |
Class at
Publication: |
424/423 ;
528/219; 528/125; 528/208; 525/132; 424/443; 424/486;
623/11.11 |
International
Class: |
A61F 2/02 20060101
A61F002/02; C08G 65/38 20060101 C08G065/38; C08G 8/02 20060101
C08G008/02; A61K 9/70 20060101 A61K009/70; A61P 41/00 20060101
A61P041/00; A61K 9/14 20060101 A61K009/14; C08G 63/06 20060101
C08G063/06; C08F 12/24 20060101 C08F012/24 |
Goverment Interests
GOVERNMENT LICENSE RIGHTS
[0002] The U.S. government has a paid-up license in this invention
and the right in limited circumstances to require the patent owner
to license others on reasonable terms as required by the terms of
Grant Nos. GM-39455 and GM-49849 awarded by the National Institutes
of Health.
Claims
1. A polymer with a hydrolytically labile polymer backbone
comprising non-toxic biocompatible diphenolic repeating units
having the structure: ##STR00017## wherein R.sub.9 is an alkyl,
aryl or alkylaryl group with up to 18 carbon atoms having a pendent
carboxylic acid group or the benzyl ester thereof; and non-toxic
biocompatible diphenolic repeating units having the structure:
##STR00018## wherein R.sub.12 is an alkyl, aryl or alkylaryl group
with up to 18 carbon atoms having a pendent carboxylic acid ester
group selected from the group consisting of straight and branched
alkyl and alkylaryl esters containing up to 18 carbon atoms and
ester derivatives of biologically and pharmaceutically active
compounds covalently bonded to said polymer, provided that said
ester group is not a benzyl group or a group that is removed by
hydrogenolysis.
2. The polymer of claim 1, characterized by said polymer having the
structure: ##STR00019## wherein each R.sub.7 is independently an
alkylene group containing up to 4 carbon atoms; A is a C.dbd.O
group or a ##STR00020## group, wherein R is selected from the group
consisting of saturated and unsaturated, substituted and
unsubstituted alkyl, aryl and alkylaryl groups containing up to 18
carbon atoms; k is between about 5 and about 3,000; and x is
greater than 0 and less than 1 and f ranges from 0 to less than
1.
3. The implantable medical device of claim 2, wherein f is 0.
4. The polymer of claim 2, wherein f ranges between about 0.05 and
about 0.95.
5. The polymer of claim 2, wherein k is between 2 and about
200.
6. The polymer of claim 2, wherein x is between about 0.5 and about
0.75.
7. The polymer of claim 1 or 2, wherein R.sub.9 has a structure
selected from the group consisting of: ##STR00021## wherein R.sub.2
is hydrogen or a benzyl group and a and b are independently 0, 1 or
2.
8. The polymer of claim 7, where in R.sub.9 has the structure:
##STR00022## wherein a is 2 and b is 1.
9. The polymer of claim 1 or 2, wherein said pendent group of
R.sub.9 comprises a pendant benzyl carboxylate group.
10. The polymer of claim 1 or 2, wherein said pendent group of
R.sub.9 comprises a pendant carboxylic acid group.
11. The polymer of claim 1 or 2, wherein R.sub.12 has a structure
selected from the group consisting of: ##STR00023## wherein R.sub.2
is selected from the group consisting of straight and branched
alkyl and alkylaryl groups containing up to 18 carbon atoms and
derivatives of biologically and pharmaceutically active compounds
covalently bonded to said polymer; and c and d are independently 0,
1 or 2.
12. The polymer of claim 11, wherein R.sub.12 has the structure:
##STR00024## wherein c is 2 and d is 1.
13. The polymer of claim 1 or 2, wherein said ester group of said
pendent carboxylic acid ester group of R.sub.12 is a
straight-chained alkyl group selected from the group consisting of
ethyl, butyl, hexyl and octyl groups.
14. A block copolymer comprising the polymer of claim 1, block
copolymerized with poly(alkylene oxide) repeating units, each
poly(alkylene oxide) repeating unit comprising between about 5 and
about 3,000 alkylene oxide groups comprising an alkylene group
containing up to 4 carbon atoms.
15. The polymer of claim 2 or 14, wherein said alkylene group is
ethylene.
16. The polymer of claim 14, wherein each poly(alkylene oxide)
repeating unit contains between about 20 and about 200 alkylene
oxide groups.
17. The polymer of claim 2, wherein A is a ##STR00025## group,
wherein R.sub.8 is selected from the group consisting of
--CH.sub.2--C(.dbd.O)--, --CH.sub.2--CH.sub.2--C(.dbd.O)--,
--CH.dbd.CH-- and (--CH.sub.2--)z, wherein z is an integer between
2 and 8, inclusive.
18. The polymer of claim 17, wherein R.sub.8 is selected from the
group consisting of substituted and unsubstituted aryl and
alkylaryl groups containing from 6 to 12 carbon atoms.
19. A medical device comprising the polymer of claim 10, adapted
for implantation into the body of an animal.
20. The medical device of claim 19, wherein the device is in the
form of a suture, bone implant, vascular graft or stent.
21. The medical device of claim 19, wherein the surface of said
device is coated with said polymer.
22. The medical device of claim 19, comprising a biologically or
pharmaceutically active compound in combination with said polymer,
wherein said active compound is present in an amount sufficient for
therapeutically effective site-specific or systemic drug
delivery.
23. The medical device of claim 22, wherein said biologically or
pharmaceutically active compound is covalently bonded to said
polymer.
24. An implantable medical device in the form of a sheet consisting
essentially of the polymer of claim 10 for use as a barrier for
surgical adhesion prevention.
25. A method for site-specific or systemic drug delivery comprising
implanting in the body of a patient in need thereof an implantable
drug delivery device comprising a therapeutically effective amount
of a biologically or pharmaceutically active compound in
combination with the polymer of claim 10.
26. The method of claim 25, wherein said biologically or
pharmaceutically active compound is covalently bonded to said
polymer.
27. The method of claim 25, wherein said biologically or
pharmaceutically active compound is physically admixed with a
biologically or pharmaceutically active agent.
28. A method for preventing the formation of adhesions between
injured tissues comprising inserting a barrier between said injured
tissues a sheet consisting essentially of the polymer of claim
10.
29. A controlled drug delivery system comprising a biologically or
pharmaceutically active agent physically coated with the polymer of
claim 10.
30. A controlled drug delivery system comprising a biologically or
pharmaceutically active agent physically embedded or dispersed into
a polymeric matrix form from the polymer of claim 10.
31. A controlled drug delivery system comprising a biologically or
pharmaceutically active agent covalently bonded to the polymer of
claim 10.
32. A method of regulating cellular attachment, migration and
proliferation on a polymeric substrate comprising contacting living
cells, tissues or biological fluids containing living cells with
the polymer of claim 10.
33. The method of claim 32, wherein said polymer is in the form of
a coating on a medical implant.
34. The method of claim 32, wherein said polymer is in the form of
a film.
35. The method of claim 32, wherein said polymer is in the form of
a polymeric tissue scaffold.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a Continuation of U.S. patent
application Ser. No. 09/350,423 filed Jul. 8, 1999, which, in turn,
is a Continuation of U.S. patent application Ser. No. 09/056,050
filed Apr. 7, 1998, now U.S. Pat. No. 6,120,491, which claims the
benefit of U.S. Provisional Patent Application Ser. No. 60/064,656
filed on Nov. 7, 1997. The disclosures of all three applications
are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0003] The present invention relates to biodegradable anionic
polycarbonates and polyarylates having pendent carboxylic acid
groups, and to block copolymers thereof with poly (alkylene
oxides). The present invention further relates to species of the
above-listed polymers having pendent carboxylic acid ester groups,
and, more specifically, to pendent benzyl ester groups and the
selective removal of such benzyl esters to form pendent carboxylic
acid groups by palladium (Pd)-catalyzed hydrogenolysis of the
benzyl esters. The present invention further relates to
polycarbonates, polyarylates, and poly (alkylene oxide) block
copolymers thereof that are homopolymers and copolymers of
tyrosine-derived diphenol monomers having pendent benzyl
carboxylate groups.
[0004] Diphenols are monomeric starting materials for
polycarbonates, polyiminocarbonates, polyarylates, polyurethanes,
and the like. Commonly owned U.S. Pat. Nos. 5,099,060 and 5,198,507
disclose amino acid-derived diphenol compounds, useful in the
polymerization of polycarbonates and polyiminocarbonates. The
resulting polymers are useful as degradable polymers in general,
and as tissue-compatible bioerodible materials for medical uses, in
particular. The suitability of these polymers for this end use
application is the result of their polymerization from diphenols
derived from the naturally occurring amino acid, L-tyrosine. The
disclosures of U.S. Pat. Nos. 5,099,060 and 5,198,507 are hereby
incorporated by reference. These previously-known polymers are
strong, water-insoluble materials that can best be used as
structural implants.
[0005] The same monomeric L-tyrosine derived diphenols were also
used in the synthesis of polyarylates as described in commonly
owned U.S. Pat. No. 5,216,115, and in the synthesis of poly
(alkylene oxide) block copolymers with the aforementioned
polycarbonates and polyarylates, which is disclosed in commonly
owned U.S. Pat. No. 5,658,995. The disclosures of U.S. Pat. Nos.
5,216,115 and 5,658,995 are also hereby incorporated by
reference.
[0006] The polycarbonates, polyarylates and poly (alkylene oxide)
block copolymers thereof cannot be prepared by conventional
solution processes from monomers having free carboxylic acid
groups. Therefore, one must selectively incorporate removable
protecting groups that can be cleaved after the polymer is formed,
without significant degradation of the polymer backbone. The
protecting groups are needed to prevent cross-reaction of these
otherwise free carboxylic acid groups (i) with the phosgene used in
the preparation of polycarbonates and (ii) with the carbodiimide
reagents used in the preparation of polyarylates.
[0007] The resulting polymers with protected carboxylic acid groups
are limited in application because of their slow rate of
degradation and significant hydrophobicity. The free acid form of
the polymers, in which the ester protecting groups have been
removed from the pendent carboxylic acid chains of the diphenols,
would be less hydrophobic and thus would be expected to exhibit
somewhat increased degradation rates.
[0008] In polycarbonates, polyarylates and poly (alkylene oxide)
block copolymers thereof prepared from tyrosine-derived diphenol
monomers, the backbone contains bonds that are designed to degrade
in aqueous media (acidic, neutral, or basic). Thus, the selective
removal of any carboxylic acid protecting groups is a challenge.
For polyarylates and poly (alkylene oxide) block copolymers
thereof, the ester protecting groups cannot be removed by
conventional hydrolysis techniques without complete degradation of
the polymer backbone. For polycarbonates and poly (alkylene oxide)
block copolymers thereof, the ester protecting groups cannot be
removed by conventional hydrolysis techniques without massive
degradation of the polymer backbone. Since cleavage of the pendent
ester groups becomes slower (relative to backbone cleavage) as the
bulkiness of the pendent group increases, conventional hydrolysis
of methyl and ethyl ester pendent chains is accompanied by a
dramatic loss of molecular weight, while attempts to remove bulkier
ester pendent chains by either basic or acidic hydrolysis of
polycarbonates results in total destruction of the polymer and the
recovery of oligomeric species only. Thus, conventional hydrolysis
of polycarbonates and poly (alkylene oxide) block copolymers
thereof is of marginal value if applied to methyl or ethyl ester
pendent chains and is entirely unsuitable for the removal of
bulkier pendent chains.
[0009] There exist several needs that can be addressed by the
incorporation of free carboxylic acid groups to the above mentioned
polymer systems. First, the presence of free carboxylic acid groups
on polymeric surfaces allows for the modification of the surface
properties via the chemical attachment of selected pendent chains,
the attachment of biologically active molecules, or the attachment
of drugs moieties. Second, the presence of free carboxylic acid
groups by itself is a strong regulator of cell attachment, growth
and migration on polymeric surfaces. This is of particular
importance in the design of medical implant materials that are used
in tissue engineering applications where the exact control of cell
attachment, spreading and proliferation is a key to the success of
the tissue engineering implant.
[0010] There exists a need for degradable, biocompatible polymer
systems whose design includes the convenient formation of a pendent
carboxylic acid group at each monomeric repeat unit without
significant backbone degradation. A second need is the need to
control the polymer degradation rate through small changes in
polymer composition.
SUMMARY OF THE INVENTION
[0011] These needs are met by the present invention. It has now
been found that the incorporation of pendent carboxylic acid groups
within the polymer bulk has a dramatic and previously unrecognized
accelerating effect on the rate of polymer backbone degradation and
resorption both in vitro and in vivo. Thus, the present invention
makes it possible to modulate the rates of degradation and
resorption to such a surprising extent that rod-like devices can be
formulated that resorb completely from about 5 hours all the way to
3 years post implantation-simply by modifying the percentage of
pendent carboxylic acid pendent chains available along the polymer
backbone.
[0012] The present invention makes it possible to create pendent
carboxylic acid groups on the polymer surface without concomitant
backbone cleavage. This is in important difference relative to
conventionally used medical polymers such as poly (lactic acid),
poly (glycolic acid), polycaprolactone and others where the polymer
backbone has to be cleaved (with the associated reduction in
molecular weight and physical strength) in order to create
chemically reactive attachment sites at the polymer surface. Thus,
the present invention significantly improves the versatility and
utility of the above mentioned polymer systems, specifically
polycarbonates, polyarylates, and the respective poly (alkylene
oxide) copolymers thereof.
[0013] Thus, a new method has now been discovered for preparing new
polymeric materials in which the ester of pendent carboxylic acid
groups is selectively removed from the polymer backbone. The
resulting polymers contain pendent carboxylic acid groups on some
or all of their monomeric repeating subunits. The pendent
carboxylic acid groups impart increased hydrophilicity to the
polymers and result in unexpected useful new properties.
Polycarbonates, polyarylates, and poly (alkylene oxide) block
copolymers thereof, with pendent carboxylic acid groups have been
prepared.
[0014] In particular, it has now been discovered that benzyl esters
of pendent polymer carboxylic acid groups may be selectively
removed by palladium-catalyzed hydrogenolysis in
N,N-dimethylformamide (DMF) or similar solvents such as
N,N-dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) to form
pendent carboxylic acid groups. Although this reaction is very well
known in the literature for the removal of benzyl esters from
monomeric or low molecular weight compounds, the present
application of this approach to the selective removal of benzyl
ester groups from biodegradable polycarbonates and polyarylates is
heretofore unknown. By varying the molar ratio of monomeric
repeating subunits having pendent benzyl carboxylate groups to the
monomeric repeating subunits having other alkyl or alkylaryl
carboxylate groups within a polymer, the molar ratio of monomeric
repeating subunits having pendent carboxylic acid groups within a
polymer may be varied after completion of the selective removal of
the benzyl carboxylate groups.
[0015] Therefore, according to one aspect of the present invention,
polymers are provided having monomeric repeating units defined in
Formula I as follows:
##STR00003##
[0016] Formula I represents a diphenolic unit wherein R.sub.9 is an
alkyl, aryl or alkylaryl group with up to 18 carbons with the
specific proviso that this group contains as part of its structure
a carboxylic acid group or the benzyl ester thereof. R.sub.9 can
also contain non-carbon atoms such as nitrogen and oxygen. In
particular, R.sub.9 can have a structure related to derivatives of
the natural amino acid tyrosine, cinnamic acid, or
3-(4-hydroxyphenyl) propionic acid. In these cases, R.sub.9 assumes
the specific structures shown in Formulae II and III.
##STR00004##
[0017] The indicators a and b in Formulae II and III can be
independently 0, 1, or 2. R.sub.2 is hydrogen or a benzyl
group.
[0018] A second diphenolic subunit of the polymer is defined in
Formula IV. In this second diphenolic subunit, R.sub.12 is an
alkyl, aryl or alkylaryl group substituted with a carboxylic acid
ester group, wherein the ester is selected from straight and
branched alkyl and alkylaryl esters containing up to 18 carbon
atoms, and ester derivatives of biologically and pharmaceutically
active compounds covalently bonded to the polymer, provided that
the ester group is not a benzyl group or any other chemical moiety
that may potentially be cleaved by hydrogenolysis. R.sub.12 can
also contain non-carbon atoms such as nitrogen and oxygen. In
particular, R.sub.12 can have a structure related to derivatives of
the natural amino acid tyrosine, cinnamic acid, or
3-(4-hydroxyphenyl) propionic acid.
##STR00005##
[0019] For derivatives of tyrosine, 3-(4-hydroxyphenyl) propionic
acid and cinnamic acid, R12 assumes the specific structures shown
in Formulae V and VI:
##STR00006##
[0020] The indicators c and d can be independently 0, 1 or 2.
R.sub.1 is selected from straight and branched alkyl and alkylaryl
groups containing up to 18 carbon atoms, and ester derivatives of
biologically active compounds covalently bonded to the diphenol,
provided that R.sub.1 is not a benzyl group.
[0021] Some polymers of this invention may also contain blocks of
poly (alkylene oxide) as defined in Formula VII. In Formula VII,
R.sub.7 is independently an alkylene group containing up to 4
carbons and k is between about 5 and 3,000.
--O--R.sub.7--(O--R.sub.7).sub.k Formula VII
[0022] A linking bond, designated as "A" is defined to be
either
##STR00007##
where R.sub.8 is selected from saturated and unsaturated,
substituted and unsubstituted alkyl, aryl and alkylaryl groups
containing up to 18 carbon atoms. Thus, polymers in accordance with
the present invention have the structure of Formula VIII:
##STR00008##
[0023] In formula VIII, x and f are the molar ratios of the various
subunits. X and f can range from 0 to 0.99. It is understood that
the presentation of Formula VIII is schematic and that the polymer
structure presented by Formula VIII is a true random copolymer
where the different subunits can occur in any random sequence
throughout the polymer backbone. Formula VIII provides a general
chemical description of polycarbonates when A is
##STR00009##
[0024] and of polyarylates when A is
##STR00010##
[0025] Furthermore, several limiting cases can be discerned: When
x=0, the polymer contains only benzyl ester pendent chains which,
after hydrogenolysis as described below, will provide pendent
carboxylic acid groups at each diphenolic repeat unit. If x is any
fraction greater than 0 but smaller than 1, a copolymer is obtained
that contains a defined ratio of benzyl ester and non-benzyl ester
carrying pendent chains. After hydrogenolysis, a copolymer is
obtained that contains a defined ratio of carboxylic acid groups as
pendent chains.
[0026] If f=0, the polymers do not contain any poly (alkylene
oxide) blocks. The frequency at which poly (alkylene oxide) blocks
can be found within the polymer backbone increases as the value of
f increases.
[0027] According to another aspect of the invention, a method is
provided for the preparation of the above-defined polymers by:
[0028] preparing a reaction mixture of a polymer having the
structure of Formula VIII, in which R9 has a pendent
benzyl-protected carboxylic acid group, in an anhydrous reaction
solvent consisting essentially of one or more solvents selected
from DMF, DMA and NMP;
[0029] and contacting the reaction mixture with a palladium
catalyst in the presence of a hydrogen source so that the benzyl
ester groups are selectively removed by hydrogenolysis.
[0030] Benzyl group removal by hydrogenolysis in the present
invention has been successfully performed upon polycarbonates,
polyarylates and poly (alkylene oxide) block copolymers thereof
when a benzyl ester protecting group was present. The polymers may
be homopolymers of the first repeating subunit of Formula I, or the
polymers may be copolymers of the first repeating subunit of
Formula I and a second repeating subunit having a structure of
Formula IV. The polymers may also contain poly (alkylene oxide)
blocks as defined in Formula V and the linking bond "A" may be
##STR00011##
where R.sub.8 is selected from saturated and unsaturated,
substituted and unsubstituted alkyl, aryl and alkylaryl groups
containing up to 18 carbon atoms.
[0031] The present invention incorporates the discovery that pure
DMF, DMA, or NMP are necessary as the reaction solvent. It was a
surprising and unexpected result that no reaction was observable in
methylene chloride, methanol, or solvent mixtures containing
various ratios of methylene chloride, methanol, and DMF. Another
unexpected result was that the reaction medium has to be anhydrous
and that the solvents have to be dried to ensure complete removal
of all benzyl ester groups in the hydrogenolysis reaction. In
preferred methods in accordance with the present invention, the
palladium catalyst is palladium on barium sulfate. This catalyst is
recoverable and reusable, thereby dramatically reducing the cost of
the hydrogenolysis.
[0032] Preferred methods in accordance with the present invention
also use 1,4-cyclohexadiene, a transfer hydrogenolysis reagent, in
combination with hydrogen gas as a hydrogen source. It has been
unexpectedly discovered that at ambient pressure the hydrogenolysis
can be accelerated dramatically by the exposure of the reaction
mixture to a combination of 1,4-cyclohexadiene and hydrogen gas. If
desired, the reaction can be performed at high pressure in a PARR
hydrogenolysis apparatus. At high pressure conditions, the addition
of 1,4-cyclohexadiene is not required to ensure complete removal of
all benzyl ester groups from the polymers.
[0033] The benzyl carboxylate polycarbonate homopolymers and
copolymers of the present invention are novel and non-obvious
intermediate compounds having utility in the preparation of
polycarbonates having pendent carboxylic acid groups. Likewise, the
benzyl carboxylate polyarylate homopolymers and copolymers of the
present invention are novel and non-obvious intermediate compounds
having utility in the preparation of polyarylates having pendent
carboxylic acid groups.
[0034] The polymers of the present invention having pendent
carboxylic acid groups meet the need for processible biocompatible
biodegradable polymers. Therefore, the present invention also
includes implantable medical devices containing the polymers of the
present invention having pendent carboxylic acid groups. In one
embodiment of the present invention, the polymers are combined with
a quantity of a biologically or pharmaceutically active compound
sufficient for effective site-specific or systemic drug delivery as
described by Gutowska et al., J. Biomater. Res., 29, 811-21 (1995)
and Hoffman, J. Controlled Release, 6, 297-305 (1987). The
biologically or pharmaceutically active compound may be physically
admixed, embedded in or dispersed in the polymer matrix. In another
embodiment of the present invention, the polymer is in the form of
a sheet or a coating applied to exposed injured tissue for use as a
barrier for the prevention of surgical adhesions as described by
Urry et al., Mat. Res. Soc. Symp. Proc., 292, 253-64 (1993).
[0035] Another aspect of the present invention 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 atherapeutically effective amount of a
biologically or pharmaceutically active compound in combination
with a polymer of the present invention. Yet another aspect of the
present invention 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 a polymer of the
present invention.
[0036] As noted above, 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.
[0037] In addition, the pendent carboxylic acid groups of the
polymers in the present invention provide the polymers with a pH
dependent dissolution rate. This further enables the polymers to be
used as coatings in gastrointestinal drug release carriers to
protect some biologically and pharmaceutically active compounds
such as drugs from degrading in the acidic environment of the
stomach. The copolymers of the present invention having a relative
high concentration of pendent carboxylic acid groups are stable and
water insoluble in acidic environments but dissolve/degrade rapidly
when exposed to neutral or basic environments. By contrast,
copolymers of low acid to ester ratios are more hydrophobic and
will not degrade/resorb rapidly in either basic or acidic
environments. Therefore, another aspect of the present invention
provides a controlled drug delivery system in which a biologically
or pharmaceutically active agent is physically coated with a
polymer of the present invention.
[0038] The polymers prepared from tyrosine-derived diphenol
compounds having pendent carboxylic acid groups are more
hydrophilic. Therefore, the polymers of the present invention
having carboxylic acid groups will be more readily resorbable under
physiological conditions than the previously known polycarbonates
and polyarylates. The polymers of the present invention, because
they are more hydrophilic, have a higher water uptake, and when the
monomeric subunits having carboxylic acid groups predominate, they
are more soluble in aqueous media. When the monomeric repeating
subunits having pendent carboxylic acid groups do not predominate,
the polymers may slowly dissolve in aqueous media with slower
degradation. The dissolution/degradation rates are highly pH
dependent.
[0039] As noted above, the pendent carboxylic acid groups on the
polymers of the present invention can function to regulate cell
attachment, growth and migration on the polymer surfaces.
Therefore, according to yet another aspect of the present
invention, a method is provided for regulating cellular attachment,
migration and proliferation on a polymeric substrate by contacting
living cells, tissues or biological fluids containing living cells
with the polymers of the present invention having pendent
carboxylic acid groups. The degree of copolymerization, i.e., the
ratio of pendent carboxylic acid groups to pendent ester groups,
can be attenuated to provide polymers that promote cellular
attachment, migration and proliferation, as well as polymers that
inhibit attachment, migration and proliferation.
[0040] A more complete appreciation of the invention and many other
intended advantages can be readily obtained by reference to the
following detailed description of the preferred embodiment 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 DRAWING
[0041] FIG. 1 depicts percent mass retention vs. time of poly
(0.5DT-0.5DTE carbonate) poly (DT carbonate)(-*-) and poly (DTE
carbonate) polymer compositions in vitro under physiological
conditions.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0042] The method of the present invention provides polycarbonates
and polyarylates, as well as poly (alkylene oxide) block polymers
thereof, having pendent carboxylic acid groups on some or all of
their monomeric subunits. The polymers having pendent carboxylic
acid groups are prepared by the hydrogenolysis of polymeric
starting materials having corresponding pendent benzyl carboxylate
groups. The benzyl carboxylate polymeric starting materials are
polymerized from diphenol compounds having benzyl ester protected
pendent carboxylic acid groups, alone, or in combination with
diphenol compounds having other ester-protected carboxylic acid
groups. In particular, the benzyl carboxylate diphenols have the
structure of Formula Ia:
##STR00012##
wherein R.sub.9 is the same as described above with respect to
Formula I, but limited to the species that contains as part of its
structure a benzyl ester protected carboxylic acid group. The
benzyl carboxylate diphenols preferably have the structure of
Formula Ia in which R.sub.9 has the structure of Formula II or
Formula III in which R.sub.2 is a benzyl group. Among the preferred
diphenols are compounds in which Rg has the structure of Formula II
in which a and b are independently one or two. Most preferably, a
is two and b is one. These most preferred compounds are tyrosine
dipeptide analogues known as desaminotyrosyl-tyrosine alkyl or
alkylaryl esters. In this preferred group the diphenols can be
regarded as derivatives of tyrosyl-tyrosine dipeptides from which
the N-terminal amino group has been removed.
[0043] Diphenol compounds having other ester-protected carboxylic
acid groups have the structure of Formula IVa:
##STR00013##
wherein R.sub.12 is the same as described above with respect to
Formula IV. R.sub.12 preferably has the structure of Formula V or
Formula VI. More preferably, R.sub.12 has the structure of Formula
V in which c and d are preferably independently one or two. Most
preferably, c is two and d is one.
[0044] Methods for preparing the diphenol monomers are disclosed in
commonly owned U.S. Pat. Nos. 5,587,507 and 5,670,602, the
disclosures of both of which are hereby incorporated by reference.
The preferred desaminotyrosyl-tyrosine esters are the ethyl, butyl,
hexyl, octyl and benzyl esters. For purposes of the present
invention, desaminotyrosyl-tyrosine ethyl ester is referred to as
DTE, desaminotyrosyl-tyrosine benzyl ester is referred to as DTBn,
and the like. For purposes of the present invention, the
desaminotyrosyl-tyrosine free acid is referred to as DT.
[0045] The polymers of the present invention may be homopolymers
with each monomeric subunit having a pendent carboxylic acid group
prepared by the hydrogenolysis of corresponding benzyl carboxylate
homopolymers. Copolymers of diphenol monomers having pendent
carboxylic acid ester groups, and diphenol monomers having pendent
carboxylic acid groups can also be incorporated into the basic
backbone structure of the polymers by the hydrogenolysis of
corresponding copolymers of benzyl ester monomers and monomers
having pendent esters other than benzyl carboxylates.
[0046] Thus, for example, poly (DT carbonates) are prepared by the
hydrogenolysis of poly (DTBn carbonates), poly (DT-DTE carbonate)
copolymers are prepared by the hydrogenolysis of poly (DTBn-DTE
carbonate) copolymers, and so forth. One can thus vary within
polymers the molar ratios of the monomeric subunits having pendent
alkyl and alkylaryl ester groups and the monomeric subunits having
pendent carboxylic acid groups.
[0047] Polymers in accordance with the present invention include
homopolymers of a repeating unit having a pendent carboxylic acid
group. Such homopolymers have the structure of Formula VIII in
which x and f are both zero and R.sub.9 is the same as described
above with respect to Formula I with the proviso that it is limited
to species having pendent carboxylic acid groups. The homopolymers
are prepared by the hydrogenolysis of corresponding homopolymers
having the structure of Formula VIII in which x and f are both zero
and R.sub.9 is the same as described above with respect to Formula
I, with the proviso that it is limited to species having pendent
benzyl carboxylate groups.
[0048] Polymers in accordance with the present invention also
include copolymers having pendent carboxylic acid groups with the
structure of Formula VIII in which f is zero, x is a number greater
than zero but less than one, R.sub.12 is the same as described
above with respect to Formula IV and R.sub.9 is the same as
described above with respect to Formula I, with the proviso that it
is limited to species with pendent carboxylic acid groups. In
copolymers in accordance with the present invention, x is
preferably between about 0.50 and about 0.90 and more preferably
between about 0.60 and about 0.80.
[0049] Copolymers having pendent carboxylic acid groups are
prepared by the hydrogenolysis of corresponding copolymers having
the structure of Formula VIII in which f is zero, x is a number
greater than zero but less than one, R.sub.12 is the same as
described above with respect to Formula IV and R.sub.9 is the same
as described above with respect to Formula I, with the proviso that
it is limited to species with pendent benzyl carboxylate groups. In
preferred copolymers in accordance with the present invention,
R.sub.9 has the structure of either Formula II or Formula III and
R.sub.12 has the structure of either Formula V or Formula VI, in
which R.sub.1, R.sub.2, a, b, c and d are the same as described
above with respect to Formulae II, III, V and VI.
[0050] In more preferred copolymers, R.sub.9 has the structure of
Formula II and R.sub.12 has the structure of Formula V in which a,
b, c and d are independently one or two. Most preferably, a and c
are two and b and d are one.
[0051] When A of Formula VIII is:
##STR00014##
the polymers of the present invention are polycarbonates. The
polycarbonate homopolymer and copolymer starting materials having
pendent benzyl carboxylate groups may be prepared by the method
described by U.S. Pat. No. 5,099,060 and by U.S. patent application
Ser. No. 08/884,108 filed Jun. 27, 1997, the disclosures of both of
which are also incorporated herein by reference. The described
method is essentially the conventional method for polymerizing
diphenols 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 incorporated herein by
reference.
[0052] Polycarbonate homopolymers and copolymers in accordance with
the present invention having pendent carboxylic acid groups, and
the polycarbonates having pendent benzyl carboxylate groups from
which they are prepared, have weight-average molecular weights
ranging between about 20,000 to about 400,000 daltons, and
preferably about 100,000 daltons, measured by gel permeation
chromatography (GPC) relative to polystyrene standards without
further correction.
[0053] When A of Formula VIII is:
##STR00015##
the polymers of the present invention are polyarylates. The
polyarylate homopolymer and copolymer starting materials having
pendent benzyl carboxylate groups may be prepared by the method
described by U.S. Pat. No. 5,216,115, in which diphenol compounds
are reacted with aliphatic or aromatic dicarboxylic acids in
carbodiimide mediated direct polyesterification using
4-(dimethylamino) pyridinium-p-toluene sulfonate (DPTS) as a
catalyst to form aliphatic or aromatic polyarylates. The disclosure
of this patent is also incorporated herein by reference. It should
be noted that R should not be substituted with functional groups
that would cross-react with the dicarboxylic acids.
[0054] Dicarboxylic acids from which the polyarylate starting
materials of the present invention may be polymerized have the
structure of Formula IX:
##STR00016##
in which, for the aliphatic polyarylates, R.sub.8 is selected from
saturated and unsaturated, substituted and unsubstituted alkyl
groups containing up to 18 carbon atoms, and preferably from 4 to
12 carbon atoms. For aromatic polyarylates, R.sub.8 is selected
from aryl and alkylaryl groups containing up to 18 carbon atoms,
but preferably from 8 to 14 carbon atoms. Again, R.sub.8 should not
be substituted with functional groups that would cross-react with
the diphenols.
[0055] R.sub.8 is even more preferably selected so that the
dicarboxylic acids from which the polyarylate starting materials
are polymerized are either important naturally-occurring
metabolites or highly biocompatible compounds. Preferred aliphatic
dicarboxylic acids therefore include the intermediate dicarboxylic
acids of the cellular respiration pathway known as the Krebs Cycle.
These dicarboxylic acids include alpha-ketoglutaric acid, succinic
acid, fumaric acid, maleic acid and oxalacetic acid. Other
preferred biocompatible aliphatic dicarboxylic acids include
sebacic acid, adipic acid, oxalic acid, malonic acid, glutaric
acid, pimelic acid, suberic acid and azelaic acid. Among the
preferred aromatic dicarboxylic acids are terephthalic acid,
isophthalic acid and bis(p-carboxyphenoxy) alkanes such as
bis(p-carboxyphenoxy) propane. Stated another way, R.sub.8 is more
preferably a moiety selected from --CH.sub.2--C(.dbd.O)--,
--CH.sub.2--CH.sub.2--C(.dbd.O)--, --CH.dbd.CH-- and
(--CH.sub.2--).sub.z, wherein z is an integer between two and
eight, inclusive.
[0056] Polyarylate homopolymers and copolymers in accordance with
the present invention having pendent carboxylic acid groups, and
the corresponding polyarylates having pendent benzyl carboxylate
groups from which they are prepared, have weight average molecular
weights between about 20,000 and about 400,000 daltons, and
preferably about 100,000 daltons, measured by GPC relative to
polystyrene standards without further correction.
[0057] Polycarbonates and polyarylates in accordance with the
present invention also include random block copolymers with a poly
(alkylene oxide) having pendent carboxylic acid groups with the
structure of Formula VIII, wherein f is greater than zero but less
than one, R.sub.12 is the same as described above with respect to
Formula IV, k and R.sub.7 are the same as described above with
respect to Formula VII, and R.sub.9 is the same as described above
with respect to Formula I, with the proviso that it is limited to
species having pendent carboxylic acid groups. The value for x is
less than one, but x may or may not be greater than zero.
[0058] The molar fraction of alkylene oxide in the block copolymer,
f, ranges between about 0.01 and about 0.99. The block copolymers
having pendent carboxylic acid groups are prepared by the
hydrogenolysis of corresponding block copolymers having the
structure of Formula VIII, wherein x is greater than zero but less
than one, R.sub.12 is the same as described above with respect to
Formula IV, k and R.sub.7 are the same as described above with
respect to Formula VII, and R.sub.9 is the same as described above
with respect to Formula I, with the proviso that it is limited to
species having pendent benzyl carboxylate groups. Again, the value
for x is less than one, but may or may not be greater than
zero.
[0059] For preferred polymeric starting materials and the resulting
free acid block copolymers, R.sub.7 is ethylene, k is between about
20 and about 200, and the molar fraction of alkylene oxide in the
block copolymer, f, preferably ranges between about 0.05 and about
0.75. R.sub.7 may also represent two or more different alkylene
groups within a polymer.
[0060] The block copolymers of the present invention having pendent
benzyl carboxylate groups may be prepared by the method described
by U.S. Pat. No. 5,658,995, the disclosure of which is also
incorporated herein by reference. For block copolymers of the
present invention having either pendent carboxylic acid groups or
pendent benzyl carboxylate groups in which x is greater than zero,
the molar fraction of alkylene oxide and block copolymer, f, will
remain between about 0.01 and about 0.99.
[0061] The block copolymers in accordance with the present
invention having pendent carboxylic acid groups, and the block
copolymers having pendent benzyl carboxylate groups from which they
are prepared, have weight-average molecular weights between about
20,000 and about 400,000 daltons, and preferably about 100,000
daltons. The number-average molecular weights of the block
copolymers are preferably above about 50,000 daltons. Molecular
weight determinations are measured by GPC relative to polystyrene
standards without further correction.
[0062] For the copolymers of the present invention having the
structure of Formula VIII in which x is greater than zero, the
pendent carboxylic acid ester group of R.sub.12 can be an ester
derivative of a biologically or pharmaceutically active compound
covalently bonded to the polycarbonate or polyarylate copolymer.
The covalent bond is by means of an amide bond when in the
underivatized biologically or pharmaceutically active compound a
primary or secondary amine is present at the position of the amide
bond in the derivative. The covalent bond is by means of an ester
bond when in the underivatized biologically or pharmaceutically
active compound a primary hydroxyl is present at the position of
the ester bond in the derivative. The biologically or
pharmaceutically active compounds may also be derivatized at a
ketone, aldehyde or carboxylic acid group with a linkage moiety
that is covalently bonded to the copolymer or diphenol by means of
an amide or ester bond.
[0063] Detailed chemical procedures for the attachment of various
drugs and ligands to polymer bound free carboxylic acid groups have
been described in the literature. See, for example, Nathan et al.,
Bio. Cong. Chem., 4, 54-62 (1993). The disclosure of this
publication is incorporated herein by reference.
[0064] Examples of biologically or pharmaceutically active
compounds suitable for use with the present invention include
acyclovir, cephradine, malphalen, procaine, ephedrine, adriamycin,
daunomycin, plumbagin, atropine, quinine, digoxin, quinidine,
biologically active peptides, chlorin e6, cephradine, cephalothin,
cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic
acid, chemodeoxycholic acid, chlorambucil, and the like. The
compounds are covalently bonded to the polycarbonate or polyarylate
copolymer by methods well understood by those of ordinary skill in
the art. Drug delivery compounds may also be formed by physically
blending the biologically or pharmaceutically active compound to be
delivered with the polymers of the present invention having pendent
carboxylic acid groups using conventional techniques well-known to
those of ordinary skill in the art.
[0065] For purposes of the present invention, biologically active
compounds are also defined as including crosslinking moieties, such
as molecules with double bonds (e.g., acrylic acid derivatives),
which can be attached to the pendent carboxylic acid groups for
crosslinking to increase the strength of the polymers. Biologically
active compounds, for purposes of the present invention, are
additionally defined as including cell attachment mediators,
biologically active ligands and the like.
[0066] As noted above, the polymers of the present invention
contain pendent carboxylic acid groups at selected repeating
subunits. For the purposes of the present invention, homopolymers
(Formula VIII, x=0) are defined as containing a pendent carboxylic
acid group at each diphenolic subunit. These homopolymers can be
polycarbonates or polyarylates and may contain polyalkylene oxide
blocks. The homopolymers are best described as new, degradable
polyanions that may have a number of pharmacological and biological
activities. Likewise, for the purposes of the present invention,
copolymers (Formula VIII, 0<x<1) are defined as containing a
pendent carboxylic acid group at some of the diphenolic subunits.
These copolymers can be polycarbonates or polyarylates and may
contain polyalkylene oxide blocks.
[0067] In terms of processability, homopolymers (as defined above)
tend to have very high glass transition temperatures because of
strong intrachain and interchain hydrogen bonding. Homopolymers are
soluble in water because of the high density of free carboxylic
acid groups present and have a pH-dependent solubility profile.
Their solubility is significantly reduced in slightly acidic media.
Homopolymers are also soluble in commonly used organic solvents
such as mixtures of methylene chloride and methanol. Because of
their solubility in both water and organic media, they can be
processed by solvent casting techniques and are good film formers.
Homopolymers can also be processed into porous foams by salt
leaching techniques as described in Freed et al., J. Biomed. Mater.
Res., 27, 11-23 (1993), as long as the aqueous extraction steps are
performed inslightly acidic media (pH 4-5) so that the homopolymers
do not dissolve. Homopolymers can also be processed into porous
foams by phase separation techniques, as described in Schugens et
al., J. Biomed. Meter. Res., 30, 449-462 (1996) as long as a
saturated solution of sodium chloride is used instead of water as
the "non-solvent". The disclosure of these publications is
incorporated herein by reference.
[0068] The copolymers as defined above may contain from about 1 to
about 99 mole percent of monomeric subunits having pendent
carboxylic acid groups. Their properties are strongly affected by
the mole fraction of free carboxylic acid groups present.
Copolymers that have less than 20 molar percent of monomeric
repeating subunits with pendent carboxylic acid groups are
processible by compression molding and extrusion. As a general
rule, copolymers with less than 20 molar percent of monomeric
repeating subunits with pendent carboxylic acid groups are not
soluble in water.
[0069] For copolymers having more than 20 mole percent of monomeric
subunits with pendent carboxylic acid groups, some thermal
degradation has been observed during conventional compression
molding and extrusion at elevated temperatures. Copolymers having
more than 20 mole percent of monomeric subunits with pendent
carboxylic acid groups tend to exhibit increased swelling (due to
imbibition of water) during exposure to aqueous media and when more
than about 50 mole percent of monomeric subunits carry free
carboxylic acid groups, the copolymer tend to become water soluble
and their behavior will be similar to the behavior of the
corresponding homopolymers, which dissolve in pH 7.4 phosphate
buffer to the extent of about 2 mg/mL.
[0070] Irrespective of the amount of carboxylic acid groups, all
copolymers of the present invention are good film-forming
materials. Copolymers having less than about 70 mole percent of
monomeric subunits with pendent carboxylic acid groups can be
processed into porous foams by salt leaching techniques as
described in Freed et al., J. Biomed. Mater. Res., 27, 11-23
(1993), or by phase separation techniques, as described in Schugens
et al., J. Biomed. Meter. Res., 30, 449-462 (1996). The disclosure
of these publications is incorporated herein by reference.
Copolymers having more than about 70 mole percent of monomeric
subunits with pendent carboxylic acid groups tend to be water
soluble and must be processed into porous foams as described for
the corresponding homopolymers.
[0071] It has now been found that the free carboxylic acid groups
have a profound effect on the degradation and resorption rates of
the polymers of the present invention. This makes it possible to
fine-tune the degradation/resorption of the polymers of the present
invention by controlling the molar fraction of free carboxylic acid
groups (as defined with respect to Formula VIII). This is a
significant advantage over the polycarbonates and polyarylates of
the prior art which do not have pendent free carboxylic acid groups
and whose degradation/resorption rate could not be readily varied
by small changes in the polymer structure. The effect of the free
carboxylic acid groups on degradation/resorption can be very
dramatic as shown by the example of a polycarbonate: Poly (DTE
carbonate) is a polymer defined by Formula VIII where x=1, f=0, and
R.sub.12 is defined by Formula V where c=2, d=1 and R.sub.1,
.dbd.CH.sub.2--CH.sub.3. It has been found previously, that this
polymer will not lose any mass when stored in phosphate buffered
solution under physiological conditions for over 18 months.
However, if about 20 mole percent of the R.sub.1, groups are
replaced by free carboxylic acid groups, thin films of the
corresponding copolymer will exhibit significant mass loss after as
little as 20 weeks under identical storage conditions. If about 50
percent of the R.sub.1, groups are replaced by free carboxylic acid
groups, thin films of the corresponding copolymer will completely
degrade/dissolve within about one week.
[0072] The composition of the polymers of the present invention can
also be used to influence the interactions with cells. When the
polycarbonates or polyarylates of the present invention do not
contain polyalkylene oxide (f=0 in Formula VE), they can be more
adhesive growth substrates for cell cultures compared to the
ester-protected polymers of the prior art. The negative charge from
the free carboxylic acid groups present on the surface of the
polymers has been discovered to improve the attachment and growth
of rat lung fibroblasts and may facilitate specific interactions
with proteins, peptides and cells. The polymers are thus useful as
scaffolding implants for tissue reconstruction. The polymer
surfaces may also be modified by simple chemical protocols to
attach specific peptides, in particular, the important peptides
containing variations of the "RGD" integrin binding sequence known
to affect cellular attachment in a profound way. Thus, the ability
to immobilize peptides and proteins via the free carboxylic acid
groups onto the polymer surface to elicit selective cellular
responses will be of major importance in tissue engineering
applications and in implant design. The necessary chemical
techniques to attach ligands to polymer-bound carboxylic acid
groups are well known in the art and have, among others, been
described by Nathan et al., Bioconj. Chem., 4, 54-62 (1993). The
disclosure of this publication is incorporated herein by
reference.
[0073] On the other hand, the incorporation of polyalkylene oxide
blocks decreases the adhesiveness of the polymeric surfaces.
Polymers for which f is greater than 5 mole percent according to
Formula Vin are resistant to cell attachment and may be useful as
non-thrombogenic coatings on surfaces in contact with blood. These
polymers also resist bacterial adhesion.
[0074] The polymers of the present invention having pendent
carboxylic acid groups may be prepared by the palladium-catalyzed
hydrogenolysis of corresponding polymers having pendent benzyl
carboxylate groups. Essentially any palladium-based hydrogenolysis
catalyst is suitable for use with the present invention. Palladium
on barium sulfate is preferred because it has been found to be the
easiest to separate from the polymer. This not only provides a
polymer of high purity, it also permits the efficient recycling of
this expensive catalyst.
[0075] A level of palladium on barium sulfate between about 5 and
about 10 percent by weight is preferred. Lower levels either extend
reaction time or reduce yield and higher levels represent an
unnecessary expense.
[0076] The use of dimethylformamide as the reaction solvent is
critical. The polymer starting material having pendent benzyl
carboxylate groups should be dissolved in dimethylformamide at a
solution concentration (w/v %) between about 5 and about 50
percent, and preferably between about 10 and about 20 percent.
[0077] The polymer is stirred until a clear solution is obtained.
The palladium catalyst is then added, after which the hydrogen
source is supplied to the reaction mixture.
[0078] The amount of palladium catalyst to be employed is that
amount that is effective to catalyze the hydrogenolysis reaction.
The absolute mass ratio of elemental palladium to the polymer is
not as important as the surface activity of the elemental
palladium. The amount of a catalyst preparation to be used will
depend upon the specific catalytic activity of the preparation, and
this can be readily determined by one of ordinary skill in the art
without undue experimentation.
[0079] For a preparation containing about 5 percent by weight of
palladium on barium sulfate, between about 15 and about 30 weight
percent, and preferably about 25 weight percent, of the preparation
should be used relative to the polymeric starting material. If the
catalyst preparation is being recycled, higher levels of the
preparation will be needed, because as the catalyst is reused, the
palladium is slowly deactivated, and the amount used must be
adjusted to maintain the stated catalytic activity. However, the
increases in catalyst levels needed to adjust for the loss of
catalytic activity can also be determined by one of ordinary skill
in the art without undue experimentation.
[0080] Essentially any hydrogen source for palladium-catalyzed
hydrogenolysis is suitable for use with the present invention. For
example, the reaction mixture may be supplied with a hydrogen gas
blanket. Alternatively, a transfer hydrogenolysis reagent, such as
1,4-cyclohexadiene may be used. The use of a transfer
hydrogenolysis reagent in combination with hydrogen gas blanketing
is preferred. The reaction rate was found to accelerate
dramatically when the two hydrogen sources were used together.
[0081] When the transfer hydrogenolysis reagent is employed as a
hydrogen source, a stoichiometric excess relative to the polymeric
starting material should be employed. With 1,4-cyclohexadiene, this
represents an excess up to about 50 weight percent, and preferably
about a 10 weight percent excess, relative to the polymeric
starting material.
[0082] The hydrogenolysis reaction can also be performed under
pressure of hydrogen gas in a PARR hydrogenolysis apparatus. Under
these conditions, the removal of benzyl ester pendent chains is
particularly fast and no transfer hydrogenolysis reagent needs to
be added. Irrespective of the exact mode of conducting the
reaction, it is important to maintain strictly anhydrous
conditions.
[0083] The progress of the reaction can be measured by monitoring
the removal of the benzyl ester from the polymeric starting
material in reaction aliquots by NMR spectroscopy. When the
reaction has come to completion (about 24 to 48 hours), the polymer
is isolated by filtering off the solid palladium catalyst and the
filtrate is added into water to precipitate the polymer. The
polymer can then be purified by dissolving in 9:1 methylene
chloride-methanol (about 10 percent to about 20 percent w/w) and
reprecipitating in ether. The polymeric product may then be dried
to constant weight under high vacuum.
[0084] The polymers of the present invention having pendent
carboxylic acid groups are not limited to those polymers prepared
by hydrogenolysis. Any other method that allows for the selective
removal of a pendent carboxylate ester group is suitable for use in
the preparation of the polymers of the present invention. For
example, iodotrimethylsilane may be used to selectively remove
methyl ester pendent chains in the presence of ethyl ester pendent
chains. However, the hydrogenolysis method of the present invention
is preferred because it produces a higher reaction yield.
[0085] The polymers of the present invention can find application
in areas where both solid materials and solvent-soluble materials
are commonly employed. Such applications include polymeric
scaffolds in tissue engineering applications and medical implant
applications, including the use of the polycarbonates and
polyarylates of the present invention to form shaped articles such
as vascular grafts and stents, bone plates, sutures, implantable
sensors, barriers for surgical adhesion prevention, implantable
drug delivery devices, scaffolds for tissue regeneration, and other
therapeutic agent articles that decompose harmlessly within a known
period of time.
[0086] Controlled drug delivery systems may be prepared, in which a
biologically or pharmaceutically active agent is physically
embedded or dispersed within a polymeric matrix or physically
admixed with a polycarbonate or polyarylate of the present
invention. Because the polymers of the present invention have a pH
dependent dissolution rate, they are useful as drug coatings for
gastrointestinal release to protect some drugs from degrading in
the acidic environment of the stomach because the polymers are
stable and non-water soluble in acidic environments but dissolve
and degrade rapidly when exposed to neutral or basic
environments.
[0087] The following non-limiting examples set forth hereinbelow
illustrate certain aspects of the invention. All parts and
percentages are by mole percent unless otherwise noted and all
temperatures are in degrees Celsius. Poly(DTBn-DTE carbonates) were
prepared using the method disclosed by U.S. Pat. No. 5,099,060. The
5 percent palladium on barium sulfate catalyst, 1,4-cyclohexadiene,
and thionyl chloride were obtained from Acros Organics, a division
of Fisher Scientific Company. Poly (ethylene glycol) 2000 (PEG
2000) was obtained from Aldrich Chemical Company. Tyrosine benzyl
ester as its p-toluenesulfonic acid salt was obtained from Sigma
Chemical Company. All solvents were HPLC grade. All other reagents
were of analytical grade and were used as received.
EXAMPLES
[0088] Examples use the following product characterization
procedures.
Spectroscopy
[0089] 1H NMR spectra and .sup.13C NMR spectra were recorded
respectively at 199.98 MHz and 49.99 MHz on a Varian Gemini 200 in
5 mm tubes at 10 percent (w/v) in deuterated solvents. Chemical
shifts are reported in ppm.
Molecular Weights
[0090] Molecular weights were determined by GPC on a
chromatographic system consisting of a Perkin-Elmer Model 410 pump,
a Waters Model 410 Refractive Index Detector and a Perkin-Elmer
Model 2600 computerized data station. Two PL-gel GPC columns (105
and 103 Angstrom pore size, 30 cm length) were operated in series
at a flow rate of 1 mL/min tetrahydrofuran (THF). Polymer solutions
(5 mg/mL) were prepared, filtered (0.45 micron membrane filter) and
allowed to equilibrate for 30 minutes prior to injection. The
injection volume was 25 microliters. Molecular weights were
calculated relative to polystyrene standards (PolymerLaboratories,
Inc.) without further corrections.
Thermal Analysis
[0091] Determination of product purity was based on melting point
depression measured with a TA Instruments 910 Differential Scanning
Calorimeter (DSC) calibrated with indium. For determination of the
melting temperature, a 2.0 mg sample was subjected to a single run
at a heating rate of 1 C/min. over a 60 C range.
Atomic Absorption
[0092] Residual levels of the catalyst preparation were measured by
atomic absorption by Quantitative Technologies Inc.
[0093] The following table defines the abbreviations adopted for
the diphenols illustrated by the examples below:
TABLE-US-00001 Desaminotyrosyl tyrosine free acid DT
Desaminotyrosyl tyrosine ethyl ester DTE Desaminotyrosyl tyrosine
benzyl ester DTBn
Example 1
Hydrogenolysis of Poly(DTBn5o-DTEsO Carbonate) Preparation
[0094] In a 500 mL round-bottomed flask was placed 15 g of poly
(DTBn-DTE carbonate) which contained DTBn and DTE in a 1:1 ratio.
To the flask was then added 150 mL of dry DMF and the mixture was
stirred until a clear solution was obtained. To this solution were
added 3.5 g of 5 percent Pd on BaSO.sub.4 catalyst and 7 mL of
1,4-cyclohexadiene (hydrogen donor). The mixture was stirred at
room temperature. A rubber balloon filled with hydrogen gas was
attached to the mouth of the flask using a gas inlet adapter. The
balloon was replenished with hydrogen as needed. After about 40 h
of stirring a 0.5 mL sample was withdrawn, centrifuged, and then
precipitated by adding to water with stirring. The precipitate was
dried and analyzed by .sup.1H NMR, which showed complete conversion
of the benzyl groups to free acid. The reaction was stopped and the
reaction mixture was centrifuged. The supernatant was filtered
using 0.45 tM syringe filter in several portions. (A celite bed on
a fritted glass funnel can also be used for the filtration.) A
clear light yellow filtrate was obtained. The filtrate was added to
1.5 L of deionized water with agitation using a mechanical stirrer.
(A high speed blender can also be used for the precipitation to
obtain finely divided particles.) The precipitated product was
isolated by filtration and washed with 750 mL of water in a high
speed blender. The product was dried in a nitrogen stream for 16 h
and then dried in a vacuum oven at room temperature for two days.
For further purification, the product was dissolved in 150 mL of
9:1 methylene chloride-methanol and precipitated with 1.5 L of
ether and then dried as above.
[0095] The hydrogenation can also be carried out in a PARR
hydrogenator at high hydrogen pressures (60 psi). When a
hydrogenator is used at high hydrogen pressures, the transfer
hydrogen donor, 1,4-cyclohexadiene is not necessary.
Structure Proof
[0096] The .sup.1H NMR spectrum of the product in DMSO-d.sub.6
showed the following resonances (8, ppm relative to TMS): 8.40 (br
s, 1H, NH of DTE), 8.25 (br s, 1H, NH of DT), 7.15-7.35 (m, 8H,
aromatic H's), 4.50 (m, 1H, CH of tyrosine), 4.03 (q 1H, CH.sub.2,
--CH.sub.3), 2.20-3.20 (M, 6H, CH.sub.2's of DAT and Tyrosine),
1.11 (t., 1.5H, CH.sub.2, --CH.sub.3). Also a multiplet that is
found in poly(DTBn-DTE carbonate) at 5.1 ppm for benzyl H's was
completely absent indicating complete removal of the benzyl
protecting group. The equal intensity of the two NH peaks indicate
that the DT and DTE are in equal concentration. The ratio of H's of
tyrosine CH to the H's of CH.sub.2, --CH.sub.3 show that there is
one ethyl ester group for every two monomer subunits. These
spectral data indicate that the polymer contains DT and DTE in 1:1
ratio and the benzyl protecting group is completely removed.
Characterization
[0097] The molecular weight of the product was determined by GPC
using the THF as the mobile phase. A M.sub.w of 74 Kda and M.sub.n
47 Kda were obtained. The T.sub.g of the polymer was found to be
114.degree. C. by DSC and the decomposition temperature (for 10
percent decomposition) was 309.degree. C. Atomic absorption
measurements showed a Pd concentration of 39 ppm and a barium
concentration less than the detection limit (10 ppm).
Example 2
Hydrogenolysis of Poly(DTBn.sub.0.05-DTE.sub.0.95 Carbonate)
Preparation
[0098] The hydrogenolysis of a 15 gram sample of poly (DTBn-DTE
carbonate), which contained DTBn and DTE in a 1:19 ratio and had a
M.sub.w of 286 Kda and M.sub.n of 116 Kda was performed as in
Example 1.
Structure Proof
[0099] The .sup.1H NMR spectrum of the product in DMSO-d.sub.6
showed the following resonances (.delta., ppm relative to TMS):
8.40 (br s, 0.95H, NH of DTE), 8.25 (br s, 0.05H, NH of DT),
7.15-7.35 (m, 8H, aromatic H's), 4.71 (m, 1H, CH of tyrosine), 4.03
(q, 1.9H, CH.sub.2--CH.sub.3), 2.1-3.3 (m, 6H, CH.sub.2's of DAT
and Tyrosine), 1.11 (t, 2.85H, CH.sub.2--CH.sub.3). Also a
multiplet that is found in poly (DTBn-DTE carbonate) at 5.1 ppm due
to benzyl H's was completely absent indicating complete removal of
the benzyl protecting groups. The 1:19 ratio of the DT-NH peak to
the DTE-NH peak indicates that the polymer is made of 5% DT and 95%
DTE. The ratio of CH group to the ethyl ester group shows that
there are nineteen ethyl ester groups for every twenty monomer
subunits. These spectral data indicate that the polymer contains DT
and DTE in 1:19 ratio and the benzyl protecting group is completely
removed.
Characterization
[0100] The molecular weight of the product was determined by GPC
using THF as the mobile phase. A M.sub.w of 125 Kda and M.sub.n 55
Kda were obtained. The T.sub.g of the polymer was found to be 96 C
by DSC and the decomposition temperature (for 10% decomposition)
was 334 C.
Example 3
Hydrogenolysis of Poly(DTBn.sub.0.025-DTE.sub.0.90 Carbonate)
Preparation
[0101] Hydrogenolysis of a 15 g sample of poly (DTBn-DTE carbonate)
which contained DTBn and DTE in a 1:9 ratio and had a M.sub.w of
183 Kda and M.sub.n of 84 Kda was performed as in Example 1.
Structure Proof
[0102] The .sup.1H NMR spectrum of the product in DMSO-d.sub.6
showed the following resonances (.delta., ppm relative to TMS):
8.40 (br s, 0.9H, NH of DTE), 8.25 (br, s, 0.1H, NH of DT),
7.15-7.35 (m, 8H, aromatic H's), 4.50 (m, 1H, CH of tyrosine), 4.03
(q, 1.8H, CH.sub.2, CH.sub.3), 2.1-3.3 (m, 6H, CH.sub.2's of DAT
and Tyrosine), 1.11 (t, 2.7H, CH.sub.2, --CH.sub.3). Also a
multiplet that is found in poly (DTBn-DTE carbonate) at 5.1 ppm due
to benzyl H's was completely absent indicating complete removal of
the benzyl protecting groups. The 1:9 ratio of the DT-NH peak to
the DTE-NH peak ester group shows that there are nine ethyl ester
groups for every ten monomer subunits. These spectral data indicate
that the polymer contains DT and DTE in 1:9 ratio and the benzyl
protecting group is completely removed.
Characterization
[0103] The molecular weight of the product was determined by GPC
using THF as the mobile phase. A M.sub.w of 100 Kda and M.sub.n 46
Kda were obtained. The T.sub.g of the polymer was found to be 98 C
by DSC and the decomposition temperature (for 10% decomposition)
was 330 C.
Example 4
Hydrogenolysis of Poly(DTBn.sub.0.25-DTE.sub.0.75 Carbonate)
Preparation
[0104] Hydrogenolysis of a 15 g sample of poly (DTBn-DTE carbonate)
which contained DTBn and DTE in a 1:3 ratio and had a M.sub.w of
197 Kda and M.sub.n of 90 Kda was performed as in Example 1.
Structure Proof
[0105] The .sup.1H NMR spectrum of the product in DMSO-d.sub.6
showed the following resonances (5, ppm relative to TMS): 8.40 (br
s, 0.75H, NH of DTE), 8.25 (br s, 0.25H, NH of DT), 7.15-7.35 (m,
8H, aromatic H's), 4.50 (m, 1H, CH of tyrosine), 4.03 (q, 1.5H,
CH.sub.2--CH.sub.3), 2.1-3.3 (m, 6H, CH.sub.2's of DAT and
Tyrosine), 1.11 (t, 2.25H, CH.sub.2--CH.sub.3). Also a multiplet
that is found in poly (DTBn-DTE carbonate) at 5.1 ppm due to benzyl
H's was completely absent indicating complete removal of the benzyl
protecting groups. The 1:3 ratio of the DT-NH peak to the DTE-NH
peak indicates that the polymer is made of 25% DT and 75% DTE. The
ratio of CH group to the ethyl ester group shows that there are
three ethyl ester groups for every four monomer subunits. These
spectral data indicate that the polymer contains DT and DTE in 1:3
ratio and the benzyl protecting group is completely removed.
Characterization
[0106] The molecular weight of the product was determined by GPC
using THF as the mobile phase. A M.sub.w of 115 Kda and M.sub.n 57
Kda were obtained. The T.sub.g of the polymer was found to be
106.degree. C. by DSC and the decomposition temperature (for 10%
decomposition) was 309.degree. C.
Example 5
[0107] Poly(DT-DTE carbonate) copolymers with DT contents of 20
percent, 40 percent, 60 percent and 100 percent were also prepared.
Solvent casting films were made and pH-dependent dissolution and
degradation studies were performed. Poly(100% DT carbonate) was
found to be stable and insoluble in pH<5 acidic buffer solution.
However, 25 to 30 mg polymer film dissolved in 10 mL of PBS of pH
7.4 at 37.degree. C. in several hours. Degradation of the dissolved
polymer was followed by aqueous GPC using a UV detector at 220 nm.
It was observed that the polymer dissolved without significant
degradation. When the polymer solution in buffer was incubated at
37.degree. C. the polymer degraded rapidly.
[0108] Dissolution and degradation rates of the copolymers
decreased with decreasing DT content. The copolymer with 60 percent
DT content dissolved in pH 7.4 PBS in one day. The copolymer with
40 percent DT content dissolved in pH 7.4 PBA in two days. The
copolymer with 20 percent DT content was not soluble in pH 7.4 PBS
at 37.degree. C.
Example 6
Hydrogenolysis of Poly(DTBn-Adipate)
Preparation
[0109] In a 500 mL pressure bottle was placed 21 g of poly
(DTBn-adipate) having a M.sub.w of 76.8 Kda and M.sub.n of 43.7
Kda. To the bottle was then added 200 mL of DMF and the mixture was
stirred until a clear solution was obtained. To this solution were
added 4 g of 5% Pd on BaSO.sub.4 catalyst. The pressure bottle was
attached to the Parr hydrogenator and the air inside the bottle was
displaced with hydrogen by alternatively pressurizing with hydrogen
and then pressurizing. The bottle was maintained at a hydrogen
pressure of 60 psi and then subjected to shaking for 24 h. An
aliquot was withdrawn and after suitable treatment examine by
.sup.1H NMR which showed complete removal of the benzyl group. The
reaction was stopped and the reaction mixture was centrifuged. The
supernatant was filtered using a celite bed on a sintered
glassfunnel. The filtrate was added to 2.0 L of cooled deionized
water in a high speed blender. The precipitated product was
isolated by filtration and washed with 2.0 L of water. The product
was dried in a stream of nitrogen for 16 h and then dried in vacuum
oven at room temperature for 2 days.
Structure Proof
[0110] The .sup.1H NMR spectrum of the product in DMSO-d.sub.6
showed the following resonances (8, ppm relative to TMS): 8.26 (br
s, 0.95H, NH), 7.00-7.09 (m, 8H, aromatic H's), 4.71 (m, 1H, CH of
tyrosine), 2.2-3.3 (m, 10H, CH.sub.2's of DAT, Tyrosine and
CH.sub.2--CO--), 1.74 (t, 4H, CH.sub.2--CH.sub.2 of adipate). Also,
a multiplet that is found in poly (DTBn-adipate) ai 5.1 due to
benzyl H's was completely absent, indicating complete removal of
the benzyl protecting groups. Also, the amide NH peaks had shifted
from 8.45 ppm in poly (DTBn-adipate) to 8.26 ppm. The phenyl
resonance of the benzyl group at 7.35 ppm was also absent in the
product. No other significant changes in the spectrum were
observed.
Characterization
[0111] The molecular weight of the product was determined by GPC
using THF as the mobile phase. A M.sub.w of 36.2 Kda and M.sub.n
25.4 Kda were obtained. The T.sub.g of the polymer was found to be
106.degree. C. by DSC and the decomposition temperature (for 10%
decomposition) was 334.degree. C.
Example 7
The Unexpected Acceleration of Polymer Degradation Due to the
Presence of Free Carboxylic Acid Groups
[0112] Poly (DTE carbonate) is a solid, extremely hydrophobic
polymer that absorbs less than 3% (by weight) of water and that
exhibits no detectable mass loss due to resorption under
physiological conditions. Upon incorporation of monomer units with
free carboxylic acid groups, these material properties change to an
unexpected extent. FIG. 1 illustrates that when x=0.5, f=0, and
A=C.dbd.O (as defined in Formula VIII), the copolymer will
completely resorb (dissolve) within 100 hours at physiological
conditions in vitro (phosphate buffered solution, pH 7.4, 37 C),
and when x=0, f=0, and A=C.dbd.O (as defined in Formula VIII), the
free acid homopolycarbonate will completely resorb (dissolve)
within about 7 hours at physiological conditions in vitro.
[0113] The polymers with free carboxylic acid groups can be cast
into films either by compression molding or by solvent casting and
can be fabricated into sponges by salt leaching techniques or by
phase separation techniques. The homopolymers (x=0, f=0, and
A=C.dbd.O as defined in Formula VIII) dissolve in phosphate buffer
of pH 7.4 to the extent of 2 mg/mL. When examined by aqueous GPC
using UV detection at 200 nm it was found that the polymer
dissolved without significant backbone degradation. However, once
in solution, backbone degradation to low molecular weight oligomers
and eventually to monomer occurred. After 70 h of incubation the
peak molecular weight decreased from 40,000 g/mole to about 4,000
g/mole and about 10% of the sample weight consisted of monomer.
With poly (DT.sub.0.5-DTE.sub.0.5 carbonate) the solubility is
considerably reduced to 0.2 mg/mL. However, a sample of this
polymer also resorbed mostly by dissolution without significant
backbone degradation. For copolycarbonates with a DT content of 25
mole percent and lower (x>0.75, f=0, and A=C.dbd.O, as defined
in Formula VUE), no solubility was observed by HPLC.
[0114] The present invention thus provides new free-acid versions
of prior art polymers with increased rates of degradation that are
prepared by a highly selective palladium-catalyzed hydrogenolysis
process. The new polymers satisfy heretofore unmet needs for
tissue-compatible implantable biomaterials with reduced, as well as
increased, rates of degradation.
[0115] 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.
* * * * *