U.S. patent application number 11/389434 was filed with the patent office on 2007-09-27 for polyanhydride polymers and their uses in biomedical devices.
Invention is credited to Olexander Hnojewyj, Patrick Rivelli, Sunil K. Varshney, Jianxin Zhang.
Application Number | 20070225472 11/389434 |
Document ID | / |
Family ID | 38309995 |
Filed Date | 2007-09-27 |
United States Patent
Application |
20070225472 |
Kind Code |
A1 |
Varshney; Sunil K. ; et
al. |
September 27, 2007 |
Polyanhydride polymers and their uses in biomedical devices
Abstract
A biocompatible, bioerodable polyanhydride polymer having a
Young's modulus between about 1.5 and 3 and a selected rate of
surface degradation, and methods of forming and using the polymer,
are disclosed. The polymer is formed of a polyester prepolymer
having a preferred molecular weight of greater than 5 and less than
7.5 Kdaltons, and a selected number of anhydride linkages between 5
and about 30.
Inventors: |
Varshney; Sunil K.;
(Montreal, CA) ; Hnojewyj; Olexander; (Emerald
Hills, CA) ; Zhang; Jianxin; (Dorval, CA) ;
Rivelli; Patrick; (Palo Alto, CA) |
Correspondence
Address: |
PERKINS COIE LLP
P.O. BOX 2168
MENLO PARK
CA
94026
US
|
Family ID: |
38309995 |
Appl. No.: |
11/389434 |
Filed: |
March 23, 2006 |
Current U.S.
Class: |
528/272 |
Current CPC
Class: |
C08G 67/04 20130101;
C08L 73/02 20130101 |
Class at
Publication: |
528/272 |
International
Class: |
C08G 63/02 20060101
C08G063/02 |
Claims
1. A polyanhydride polymer having the structure: ##STR4## wherein,
##STR5## where E is a para ester or an meta or para ether linkage,
and the pre-polymer is an .alpha.-.omega.,-dihydroxy terminated
polyester or polyether polymer having a molecular weight in a
selected range between 1 to 10 Kdaltons; x=80% to 98% by weight,
y=20% to 2% by weight, n=2 to 4, m=2 to 10; and the average total
number of anhydride linkages is a selected number in the range
between 5-30.
2. The polymer of claim 1, the linked phenoxy structure in the
polymer is 1,3-bis(p-carboxyphenoxy)propane anhydride, and is
present in the polymer in at least 2% by weight.
3. The polymer of claim 1, wherein the pre-polymer has an average
molecular weight greater than 5 Kdaltons and less than 10 Kdaltons,
and the polymer has an average total number of anhydride linkages
between 8 and 12.
4. The polymer of claim 1, wherein the pre-polymer is an
.alpha.-.omega.,-dihydroxy terminated polylactide,
poly.epsilon.-caprolactone or polyglycolide polymer.
5. The polymer of claim 4, wherein the pre-polymer includes a
polyethylene glycol group.
6. The polymer of claim 1, which is joined at one of its ends to a
branched alcohol, forming a branched polyanhydride polymer.
7. A method of producing a biodegradable, polyanhydride polymer
having a selected Young's modulus between 1.5-3 GPa, comprising (i)
selecting a polylactide, polycaprolactone or polyglycolide
.alpha.-.omega.,-dihydroxy polymer whose polymer chains having an
average polymer-chain molecular weight greater than 5 Kdaltons and
less than 10 Kdaltons, where lower Young's modulus values are
attained by selecting an average polymer-chain molecular weight
greater than 5 Kdaltons and less than about 10 Kdaltons, (ii)
converting the selected polymer chains to
.alpha.-.omega.,-dianhydride chains, and (iii) polymerizing the
.alpha.-.omega.,-dianhydride chains under time and temperature
conditions effective to produce a polylactide-based polyanhydride
polymer having a selected average number of anhydride linkages in
the range between 5 and 25, where lower Young's modulus values are
attained with a lower average total number of anhydride
linkages.
8. The method of claim 7, wherein the .alpha.-.omega.,-dihydroxy
polymer chains selected in step (i) are polylactide,
poly.epsilon.-caprolactone, or polyglycolide chains having an
average molecular weight greater than 5 and less than 7.5 Kdaltons,
and the total number of anhydride linkages is between 8-12.
9. The method of claim 7, for use in producing a biodegradable,
polyanhydride polymer having a rate of surface degradation that is
effective to fully erode a bar of the polymer having dimensions of
50 microns.times.50 microns.times.2 mm, when incubated in phosphate
buffered saline at 37.degree. C., within a selected period of 5-180
days, wherein the .alpha.-.omega.,-dianhydride chains are
polymerized in step (iii) under conditions effective to produce a
selected rate of surface degradation, where a higher rate of
surface degradation is achieved with a greater average total number
of anhydride linkages.
10. The method of claim 7, wherein step (ii) includes reacting the
.alpha.-.omega.,-dihydroxy chains with succinic or glutaric
anhydride under conditions effective to convert the
.alpha.-.omega.,-dianhydride chains to
.alpha.-.omega.,-dicarboxylic acid chains, removing unreacted
anhydride, and reacting the .alpha.-.omega.,-dicarboxylic acid
chains with acetic anhydride under conditions effective to achieve
the selected average number of anhydride linkages in the anhydride
polymer.
11. The method of claim 9, wherein step (iii) is carried out in the
presence of a dicarboxy phenoxy alkyl dianhydride compound of the
form: ##STR6## and the polyanhydride polymer formed has the
structure: ##STR7## where E is a para ester linkage or a para or
meta ether linkage, and the pre-polymer is an
.alpha.-.omega.,-dihydroxy terminated polyester or polyether
polymer having a molecular weight in a selected range between 1 to
10 Kdaltons; x=80% to 98% by weight, y=20% to 2% by weight, n=2 to
4, m=2 to 10; and the average total number of anhydride linkages is
a selected number in the range between 5-25.
12. A biodegradable polyester-based polyanhydride polymer having,
as a repeating polymer unit, a polylactide, polycaprolactone or
polyglycolide .alpha.-.omega.,-dianhydride chain having an average
molecular weight greater than 5 and less than 10 Kdaltons, and
between 8-12 anhydride linkages, and characterized by: (i) a
Young's modulus between 1.5-3 GPa, and (ii) a rate of surface
degradation that is effective to fully erode a bar of the polymer
having dimensions of 50 microns.times.50 microns.times.2 mm, when
incubated in phosphate buffered saline at 37.degree. C., within a
selected period of 5-365 days.
13. The polymer of claim 12, wherein the rate of surface
degradation is effective to fully erode a bar of the polymer having
dimensions of 50 microns.times.50 microns.times.2 mm, when
incubated in phosphate buffered saline at 37.degree. C., within a
selected period of 5-180 days.
14. The polymer of claim 13, formed as an expandable, biodegradable
intravascular stent.
15. The polymer of claim 14, having a drug embedded within the
polymer, for release therefrom, as the polymer is bioeroded.
16. An expandable, biodegradable stent comprising a biodegradable,
polyanhydride polymer having, as a repeating polymer unit, the
dianhydride of a polylactide, polycaprolactone or polyglycolide
.alpha.-.omega.,-dihydroxy polymer having an average molecular
weight greater than 5 and less than 10 Kdaltons, a selected Young's
modulus between 1.5 and 3, and a selected average number of
anhydride linkages in the range between 5 and 30.
17. The stent of claim 16, wherein the polyanhydride polymer forms
a biodegradable stent core, and the core is coated, on its exterior
surface(s), with a polymer coating composed of a second
biodegradable polyanhydride having a Young's modulus greater than
3, and a drug embedded therein.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to improved biodegradable
polyanhydride polymers, and to polyanhydride polymers having
elasticity characteristics suitable for a variety of implantation
uses, such as biodegradable stents.
BACKGROUND OF THE INVENTION
[0002] Biodegradable polymers are being used for many applications
in medicine, including as a carrier for controlled release drug
delivery systems, and in biodegradable bone pins, screws, and
scaffolds for cells in tissue engineering. A principal advantage of
the materials based on biodegradable polymers over existing
non-biodegradable polymers or metal-based material is that the
products are removed over time by bioerosion, avoiding the need for
surgical removal.
[0003] Despite the growing need in medical applications, only few
synthetic biodegradable polymers are currently used routinely in
humans as carriers for drug delivery: ester copolymers of lactide,
lactone and glycolide (PLA family) and anhydride copolymers of
sebacic acid (SA) and 1,3-bis-carboxyphenoxy)propane (CPP). PLA is
the most widely used due to its history of safe use as surgical
sutures and in current drug delivery products like the Lupron Depot
19. While the development of PLA remains among the most important
advances in medical biomaterials, there are some limitations that
significantly curtail its use, in particular:
[0004] 1. PLA polymers typically take a few weeks to several months
to completely degrade in the body, but the device is typically
depleted of drug more rapidly.
[0005] 2. PLA devices undergo bulk erosion, which leads to a
variety of undesirable outcomes, including exposure of unreleased
drug to a highly acidic environment.
[0006] 3. It is difficult to release drugs in a continuous manner
from PLA particles owing to the polymers' bulk-erosion
mechanism.
[0007] 4. The particularly fine PLA particles needed for
intravenous injection or inhalation can agglomerate significantly,
making resuspension for injection or aerosolization for inhalation
difficult.
[0008] Polyanhydrides, because of their more labile polymer bond,
show a more rapid degradation rate and also tend to exhibit
surface, rather than bulk degradation. Because of these advantages,
polyanhydrides polymers may be preferred in biological applications
where it is critical to achieve a high degradation rate and/or a
better controlled rate of erosion from the polymer surface.
[0009] More recently, mixed polester/polyanhydride polymers that
combine the release characteristics of both polyester and
polyanhydride polymers have been proposed. See, for example,
Storey, R. et al., J. Macromol Sci., Pure Appl. Chem., A34(2) pp
265-280 (1997),. U.S. Pat. No. 5,756,652, and Korhonen, H. et al.,
Macromol Chem. Phys., 205, pp 937-945 (2004). These polymers may be
thought of as containing a selected proportion of ester and
anhydride linkages along the polymer backbone chains. Increasing
the proportion of anhydride linkages in the mixed polymers leads to
enhanced rate of surface erosion. In certain types of mixed
polyester/polyanhydride polymers, at least, the rate of erosion was
found to be biphasic, evidencing a relatively rapid release of
polyester components and a slower breakdown of the released
polyester moieties.
[0010] One limitation of polyanhydride polymers, however, is their
relatively high stiffness, or Young's modulus of elasticity,
typically in the range of 3-5 GPa, making these polymers unsuitable
for applications in which polymer expansion or bending is required.
One important area where an expandable polymer would be useful is
intravascular stents, which are carried on balloon catheters and
deployed at a site of vascular injury by radial expansion,
requiring the ability to expand significantly, and once expanded to
hold their shape within a vessel. These physical requirements have
limited stent construction heretofore largely to metal-lattice
construction.
[0011] It would thus be desirable to provide a biocompatible,
biodegradable polymer having improved biodegradation and
drug-release properties. It would also be desirable to provide a
biocompatible, biodegradable stent having the requisite
deformability and shape-retention, but also capable of biodegrading
over a desired"stenting" period and exhibiting surface rather than
bulk erosion.
SUMMARY OF THE INVENTION
[0012] The invention includes, in one aspect, polyanhydride polymer
having the structure: ##STR1##
[0013] where E is a para ester linkage or an ortho or para ether
linkage, the pre-polymer is an .alpha.-.omega.,-dihydroxy
terminated polyester or polyether polymer having a molecular weight
in a selected range between 1 to 10 Kdaltons; x=80% to 98% by
weight, y=20% to 2% by weight, n=2 to 4, m=2 to 10; and the average
total number of anhydride linkages is a selected number in the
range between 5-30. The linked phenoxy structure in the polymer may
be 1,3-bis(p-carboxyphenoxy)propane anhydride, present in the
polymer in at least 2% by weight. The prepolymer may be an
.alpha.-.omega.,-dihydroxy terminated polylactide,
poly.epsilon.-caprolactone or polyglycolide polymer, and may
include an internal polyethylene glycol group.
[0014] In one exemplary embodiment, the pre-polymer has an average
molecular weight greater than 5 Kdaltons and less than 7.5
Kdaltons, and the polymer has an average total number of anhydride
linkages between 8 and 12.
[0015] The polymer may be joined at one of its ends to a branched
alcohol, forming a branched polyanhydride polymer.
[0016] In another aspect, the invention includes a method of
producing a biodegradable, polyanhydride polymer having a selected
Young's modulus between 1.5-3 GPa. In practicing the method, a
polylactide, polycaprolactone or polyglycolide
.alpha.-.omega.,-dihydroxy polymer whose polymer chains having an
average polymer-chain molecular weight greater than 5 Kdaltons and
less than 10 Kdaltons is selected, where lower Young's modulus
values are attained by selecting an average polymer-chain molecular
weight greater than 5 Kdaltons and less than about 7.5 Kdaltons.
The .alpha.-.omega.,-dihydroxy polymer is converted to
.alpha.-.omega.,-dianhydride chains, and polymerized under time and
temperature conditions effective to produce a polylactide-based
polyanhydride polymer having a selected average number of anhydride
linkages in the range between 5 and 30, where lower Young's modulus
values are attained with a lower average total number of anhydride
linkages.
[0017] The .alpha.-.omega.,-dihydroxy polymer chains selected in
may be polylactide, poly.gamma.-caprolactone, or polyglycolide
chains having an average molecular weight greater than 5 and less
than about 7.5 Kdaltons, and the total number of anhydride linkages
produced in the polymerization step are between 8-12.
[0018] For use in producing a biodegradable, polyanhydride polymer
having a rate of surface degradation that is effective to fully
erode a bar of the polymer having dimensions of 50 microns.times.50
microns.times.2 mm, when incubated in phosphate buffered saline at
37.degree. C., within a selected period of 5-180 days, wherein the
.alpha.-.omega.,-dianhydride chains are polymerized in step (iii)
under conditions effective to produce a selected rate of surface
degradation, where a higher rate of surface degradation is achieved
with a greater average total number of anhydride linkages.
[0019] The step of converting the .alpha.-.omega.,-dihydroxy
polymer to .alpha.-.omega.,-dianhydride chains may include reacting
the .alpha.-.omega.,-dihydroxy chains with succinic or glutaric
anhydride under conditions effective to convert the
.alpha.-.omega.,-dianhydride chains to
.alpha.-.omega.,-dicarboxylic acid chains, removing unreacted
anhydride, and reacting the .alpha.-.omega.,-dicarboxylic acid
chains with acetic anhydride under conditions effective to achieve
the selected average number of anhydride linkages in the anhydride
polymer.
[0020] The polymerization step may be carried out in the presence
of a dicarboxy phenoxy alkyl dianhydride compound of the form:
##STR2##
[0021] where the polyanhydride polymer formed has the structure:
##STR3##
[0022] where E is a para ester linkage or an ortho or para ether
linkage, the pre-polymer is an .alpha.-.omega.,-dihydroxy
terminated polyester or polyether polymer having a molecular weight
in a selected range between 1 to 10 Kdaltons;
[0023] x=80% to 98% by weight, y=20% to 2% by weight, n=2 to 4, m=2
to 10; and the average total number of anhydride linkages is a
selected number in the range between 5-30, preferably 5-25.
[0024] In still another aspect, there is disclosed a biodegradable
polyester-based polyanhydride polymer having, as a repeating
polymer unit, a polylactide, polycaprolactone or polyglycolide
.alpha.-.omega.,-dianhydride chain having an average molecular
weight greater than 5 and less than 10 Kdaltons, and between 8-12
anhydride linkages. The polymer is characterized by: (i) a Young's
modulus between 1.5-3 GPa, and (ii) a rate of surface degradation
that is effective to fully erode a bar of the polymer having
dimensions of 50 microns.times.50 microns.times.2 mm, when
incubated in phosphate buffered saline at 37.degree. C., within a
selected period of 5-365 days. Rates of full erosion may be, for
example, 5-30 days, 5-90 days, 5-180 days and 50-365 days.
[0025] The polymer may be used, for example, as the core or base of
an expandable, intravascular stent, and/or may be used as a
polymeric carrier of a drug-eluting coating in an expandable
stent.
[0026] In a related embodiment, the invention includes an
expandable, biodegradable stent comprising a biodegradable,
polyanhydride polymer having, as a repeating polymer unit, the
dianhydride of a polylactide, polycaprolactone or polyglycolide
.alpha.-.omega.,-dihydroxy polymer having an average molecular
weight greater than 5 and less than 10 Kdaltons, a selected Young's
modulus between 1.5 and 3, and a selected average number of
anhydride linkages in the range between 5 and 25.
[0027] In one embodiment, the polyanhydride polymer forms a
biodegradable stent core, and the core is coated, on its exterior
surface(s), with a polymer coating composed of a second
biodegradable polyanhydride having a Young's modulus greater than
3, and a drug embedded therein.
[0028] These and other objects and features of the present
invention will become more fully apparent when the following
detailed description is read in conjunction with the accompanying
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 illustrates steps in the synthesis of an
.alpha.-.omega.,-dihydroxy polylactide prepolymer having a
diethylene glycol core, and the conversion of the dihydroxy
prepolymer to a dicarboxylic acid prepolymer;
[0030] FIG. 2 illustrates steps in the conversion of the
dicarboxylic acid prepolymer of FIG. 1 to an
.alpha.-.omega.,-dianhydride polylactide prepolymer, and its
polymerization to yield a polyanhydride polymer;
[0031] FIG. 3 illustrates steps in the synthesis of a
polyethyleneglycol-based polyanhydride;
[0032] FIG. 4 illustrates steps in the synthesis of a
1,3-bis(p-carboxyphenoxy)propane subunit;
[0033] FIG. 5 illustrates steps in the synthesis of a polyanhydride
copolymer of polylactide and the 1,3-bis(p-carboxyphenoxy)propane
subunit of FIG. 4; and
[0034] FIGS. 6A and 6B illustrate in perspective (6A) and
cross-section (6B) a stent constructed in accordance with the
invention;
[0035] FIG. 7 is a plot showing the rates of degradation of (i) a
PLA polymer, (ii) a PLA polyanhydride polymer constructed in
accordance with the invention; and (iii) a conventional
polyanhydride polymer.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0036] Unless indicated otherwise, the terms below have the
following definitions:
[0037] A "polyanhydride polymer" is a polymer having at least some
anhydride linkages between subunits of the polymer chain. More
particularly, a polyanhydride polymer as defined herein, includes
polyester or polyether subunits or blocks joined by anhydride
linkages, and this polymer is also identified herein as a mixed
polyester/polyanhydride or polyether/polyanhydride polymer. This
polyanhydride polymer may also contain other polymer subunits or
blocks, forming block copolymers whose blocks are linked by
anhydride linkages. The composition of such polyanhydride
co-polymers may be expressed in terms of relative weight percent of
the two polymer blocks making up the block co-polymer.
[0038] A "prepolymer" refers to a polyester or polyether polymer
chain which, when converted to a suitable
.alpha.-.omega.,-dicarboxylic acid terminated polymer, forms the
polymer subunits of one of the polymer subunits in a polyanhydride
polymer. The dicarboxylic acid form of the prepolymer may also be
referred to as a prepolymer.
[0039] A polymer subunit or block refers to a chain of two or
subunits of the same polymer, such as a polyester subunit or a
diphenoxy subunit, where the polymer subunit can itself contain
additional components, such as a polyethylene glycol core joining
polyester moieties.
[0040] The "average number of anhydride linkages" in an anhydride
polymer is the average total number of anhydride linkages present
connected the one or more polymer subunits in the polyanhydride
chains, and may be determined, for example, by determining the
average molecular weight of the anhydride polymer, knowing the
relative amounts and sizes of the individual polymer blocks making
up the polyanhydride polymer.
[0041] The "average molecular weight of polymer chains" in a
polymer composition is the average molecular weight of the chains
determined with respect to polylactide standard (from Polymer
source Inc.) by size exclusion chromatography, according to
standards methods (Ref: A. Kowalski, et. al., Macromolecules 1998,
31, 2114). Average molecular weight of the poly lactide anhydrides
also be measured by other means, including laser-desorption
ionization time-of-flight mass spectrometry, as described Zhu, H.
et al, Journal of the American Society for Mass Spectrometry,
Volume 9, Number 4, April 1998, pp. 275-281(7). Viscosity average
molecular weight of the polylacdide anhydride can be determined by
solution viscosity measured in chroloform at 35 C using Ubbelohde
viscometer size 4 (obtained from Cannon Instrument Co. USA).
Intrinsic viscosity is defined as the viscosity of polymer solution
in unlimited dilute concentration. It is independent on the
concentration by virtue of extrapolation to zero concentration. In
practice, when the polymer solution is enough dilute to separate
the chain each other by solvent, the relative viscosity (.eta.r)
and specific viscosity (.eta.sp) will follow the equations:
.eta.sp/c=[.eta.]+k'[.eta.].sup.2c ln
.eta.r/c=[.eta.]+k''[.eta.].sup.2c where:
[0042] .eta.r=.eta. solution/.eta. solvent
[0043] .eta.sp=(.eta. solution/.eta. solvent)-1
[0044] Within the dilute concentration range, intrinsic viscosity
can be obtained by plotting .eta.sp/c vs. c and ln .eta.r/c vs c to
extrapolate the line to c=0.
[0045] The relationship between intrinsic viscosity and molecular
weight can be found in Mark-Houwink equation:
[.eta.]=.kappa.M.sup..alpha. where .kappa. and .alpha. are
parameters related to type of polymer, solvent and temperature. The
molecular weight can be calculated from intrinsic viscosity if the
parameters are known. In the present case, for example, the poly
(D/L-lactide) based polyanhydride can be considered as pure
poly(D/L-lactide) with several anhydride linkages instead of ester
linkages. The parameters of poly(D/L-lactide) can be used to
estimate the molecular weight of polyanhydride. The estimate
anhydride linkage per chain of the polymer can be estimated from
the molecular weight of the polyanhydride divided by the molecular
weight of the pre polymer. The average number of anhydride linkage
can also be determined from Light Scattering detectors attached on
line with size exclusion chromatography. The size of macromolecule
is large enough to emitting the light scattering, which can be used
to calculate the molecular weight. Combining size exclusion
chromatography (SEC) and light scattering on-line detector gives a
rapid, efficient way to determine molecular weight and molecular
weight distribution. Unlike pure polylactide, polylactide anhydride
cannot be eluted properly through the column packing materials.
This might be due to strong adsorption of the polyanhydride chains
with the packing material of our columns.
[0046] In the determination of the molecular weights of the
polyanhydride, the SEC columns are disconnected and a known
concentration of polyanhydride is directly injected to the Viscotek
T60A dual detector (Visco-LS) and the Varian 9040 RI detector with
a guard column between the sample injector and the detectors.
Chloroform (dried on CaH2) or THF (dried over benzophenone/Na
complex) is used as the eluent at a flow rate of 1 ml/min. dn/dc of
the polymer was calculated in CHCl3 and in THF. Molecular weight,
intrinsic viscosity and radius of gyration were than analyzed by
the Viscotek TriSEC software.
[0047] "Young's modulus" or "Young's modulus of elasticty" is a
measure of the stiffness of a given material. It is defined as the
limit for small strains of the rate of change of stress with
strain. This can be experimentally determined from the slope of a
stress-strain curve created during tensile tests conducted on a
sample of the material, and is usually expressed in GPa, i.e.,
10.sup.12 N/m.sup.2. Relatively stiff polymers, such as
conventional polyanhydrides, polystyrene, and polyimides, have
Young's modulus values in the range 3-5. Soft or highly flexible
polymer, such as polyethylene, or rubber, can have Young's modulus
values below 1. Young's modulus measurements can be made, for
example, as described in L. A. Carlsson et al., Experimental
Characterization of Advanced Composite Materials, Chapter 3 and 4,
and ASTM Standard #E111-4 method, as detailed, for example, in the
ACTIVE STANDARD: E111-04 Standard Test Method for Young's Modulus,
Tangent Modulus, and Chord Modulus, available form ASTM
international [0048]
(http://www.astm.org/cgi-bin/SoftCart.exe/DATABASE.CART/REDLINE
PAGES/E111.htm?E+mystore) II. Synthesis of Polyester/polyanhydride
Polymers
[0049] The synthesis of the polymers of the invention generally
proceeds in three steps. First, one of more prepolymer blocks or
block subunits are provided, e.g., by synthesis. As will be seen
further below, one of the prepolymers, and typically the dominant
polymer subunit in the polyanhydride polymer, is preferably a
polyester prepolymer having a molecular weight in the range 1-10
Kdaltons. Where the invention is practiced to produce a
polyanhydride polymer having a desired Young's modular of
elasticity in the range 1.5-3, the prepolymer has a molecular
weight greater than 5 Kdaltons and preferably less than about 10
Kdaltons, preferably about 6-7 Kdaltons.
[0050] The polyester prepolymer may include a non-polyester core,
for example, a dihydric alcohol core, such as a diethylene glycol
core, as seen below in Examples 1 and 2 with respect to FIGS. 1 and
2. Preferred polyester polymers are biocompatible, bioerodable
polyester polymers, such as polydactyl acid (PLA, or polylactide),
polyglycolic acid (PGA), and poly.epsilon.-caprolactone, each
preferably containing a dihydric alcohol core. Methods for
synthesizing such polyester or polyether or mixed
polyether/polyester polymers are well-known in the art, and one
exemplary method is described in Example 1 below with reference to
FIG. 1.
[0051] In addition to a polyester (and/or polyether) prepolymer
component(s), the polyanhydride polymer of the invention may
contain other block components, such as diphenoxy subunits, such as
the 1,3 bis carboxy phenoxy propane subunit whose synthesis is
described in Example 4 with respect to FIG. 4. In an anhydride
polymer whose subunits include both polyester and at least one
other block, e.g., a diphenoxy subunit, the polyester is preferably
present in an amount 80%-98 percent by weight of the final polymer,
with the other component(s) being present in an amount 2-20% by
weight of the final polymer.
[0052] In the second step in forming the polyanhydride of the
invention, the prepolymer component(s) from above are converted to
terminal-group dicarboxylic acids, e.g., from
.alpha.-.omega.,-dihydroxy terminated polyester prepolymers, to
corresponding .alpha.-.omega.,-dicarboxylic acid terminated
prepolymers. This conversion is typically carried out by reaction
of the prepolymer with succinic anhydride. More generally, reaction
of reaction of .alpha.-.omega.,-dihydroxy terminated polyester (or
polyether) polymers with cyclic anhydride produce
.alpha.-.omega.,-dicarboxylic acid terminated polyester (or
polyether) prepolymers, according to known methods. Methods for
converting polyester or polyether or mixed polyether/polyester
polymers to corresponding dicarboxylic acids are well-known in the
art. Exemplary methods are described in Example 2 below with
respect to reference to FIG. 2.
[0053] In the final polymerization step, prepolymer components of
the polymer are polymerized under conditions effective to link the
prepolymer components by anhydride linkages. This is done, in one
exemplary method, by first reacting the dicarboxylic acid
prepolymer or block components with acetic anhydride, to convert
the terminal acid groups to corresponding anhydrides. The
prepolymer dianhydrides are then dried to remove unreacted acetic
anhydride. In the final polymerization step, the dianhydride block
or prepolymer components are mixed in a desired weight proportion,
as noted above, and reacted under conditions effective to produce a
polyanhydride polymer having a selected number of polyanhydride
linkages, e.g., 3-30 anhydride linkages.
[0054] One exemplary polymerization method that is the one method
described in Example 2 below with reference to FIG. 2. Briefly, in
this method, the dianhydride component(s) are added to a metal
oxide, such as calcium oxide, and heated under an inert atmosphere
until melting, with continued heating under vacuum to remove excess
acetic anhydride, with additional heating, e.g., at a temperature
between 180.degree. C. to 220.degree. C., until a desired degree of
polymerization has occurred. The degree of polymerization, that is,
the number of anhydride linkages in the final polymer can be
determined readily from intrinsic viscosity of the polymer and by
light scattering measurement from Viscotek detectors, as described
above, to determine polyanhydride molecular weight, then dividing
by the known molecular weight of the pre polymer. As will be seen
below, the desired extent of polymerization will be dictated by
elasticity properties and rates of degradation that are desired.
For example, in accordance with one embodiment of the invention, it
has been discovered that greatest polyanhydride elasticity (lowest
Young's modulus) can be achieved in a polyester prepolymer having
an average molecular weight of about 6 Kdaltons, and between 8-12
anhydride linkages. Above, 8-12 linkages, the polymer will show a
greater rate of surface degradation, and also a greater Young's
modulus. Thus, in accordance with this embodiment of the invention,
biocompatible, biodegradable polymers having a desired elasticity
and surface degradation rate can be achieved by certain reaction
variables that are readily selected, including:
[0055] 1. The molecular weight of the polyester (or polyether)
prepolymer. As noted above, and seen from the data in Section III
below, greatest polymer flexibility (lowest Young's modulus) can be
achieved at a polyester prepolymer molecular weight of greater than
5 Kdaltons and less than about 7-10 Kdaltons;
[0056] 2. The extent of polymerization as measured by the average
number of anhydride linkages in the final polymer, which will
effect both elasticity and rate of surface degradation;
[0057] 3. The presence of block components other polyester
prepolymers. For example, including the polyanhydride includes the
1,3,-bis carboxyphenoxypropane component described in Example 4 has
the effect of improving the bioerosion characteristics of the
polymer, for example, to favor bioerosion over bulk erosion.
III. Applications
[0058] A. Polymer Characteristics
[0059] As noted above, the present invention provides a method for
producing a biodegradable, polyanhydride polymer having a selected
Young's modulus between 1.5-3 GPa, and optionally, a polymer having
both a selected Young's modulus and selected rate of surface
degradation.
[0060] Young's modulus of the polyanhydridepolymer may be
determined by standard methods, such as by the ASTM Standard
#E111-4 method, as described above. Young's modulus measurements
carried out on various polyanhydrides of the invention showed
increasing elasticity (lower Young's modulus values) with greater
polyester lengths (a polyester prepolymer with a diethyleneglycol
core) with increasing prepolymer molecular weight in the molecular
weight range 1-6 Kdaltons, and decreasing elasticity as the
prepolymer molecular weight was increased beyond about 6-7.5
Kdaltons, at a fixed number of about 10 anhydride linkages. In
general, the method of the invention will be effective in achieving
Young's modulus values in the range 1.5-3, as opposed to the higher
values (e.g., greater than 3 and up to 5, seen with conventional
anhydride polymers.
[0061] The second variable in the polymer method is number of
anhydride linkages, which will affect both elasticity and rate of
polymer degradation. In carrying out the method of the invention,
once an optimal prepolymer length is identified, for purposes of
obtaining desired elasticity properties in the polymer, the
polymerization conditions can be varied to achieve a selected
number of anhydride linkages, typically selected to strike a
balance between achieving desired elasticity properties and surface
degradation properties. The selected average number of anhydride
linkages is preferably between 5-30, where polyanhydride polymers
having a greater number of such linkages showing more rapid surface
degradation rates.
[0062] To illustrate, at a polyester prepolymer molecular weight of
between 6-7.5 Kdaltons, optimal flexibility is achieved under
polymerization conditions that yield an average of about 8-12, and
more specifically, about 10 anhydride linkages. However, if a
greater surface degradation rate is desired, polymerization
conditions yielding a greater number of anhydride linkages, e.g.,
up to 30, would be employed. As can be seen from Example 2,
increasing numbers of anhydride linkages is achieved by carrying
out the polymerization reaction for longer periods, e.g., up to
6-12 hours, and optionally, at somewhat higher temperatures, e.g.,
170.degree. C. preferably at 180.degree. C.
[0063] The degradation properties of the novel polyanhydrides of
the invention can be seen from the degradation plots shown in FIG.
7. The graph compares the rate of degradation of a conventional PLA
polymer, a conventional polyanhydride, and a polyanhydride of the
invention having a prepolymer molecular weight of between 6-7.5
Kdaltons, and an average of about (8-12 anhydride linkages.
Degradation rates were measured using a polymer bar having bar
dimensions of 50 microns.times.50 microns.times.2 mm, incubated in
phosphate-buffered saline (PBS) at 37.degree. C. for periods of up
to 100 days. At periodic test intervals, the bar was weighed to
determine loss of material, and also inspected microscopically to
determine whether degradation was largely occurring at the surface,
as evidenced by a relatively smooth-surfaced bar, or by bulk
degradation, as evidenced by the presence of pits or cavities
within the bar.
[0064] As seen from FIG. 7, PLA polymer showed little degradation
after 80 days. With longer degradation times, the PLA bar showed
signs of bulk degradation. The polyanhydride polymer, by contrast,
was about 90% degraded after one day and completely degraded within
10 days. At all times, the bar had a smooth surface indicative of
surface degradation. The polyester-based polyanhydride showed a
relatively linear degradation rate that was intermediate between
the other two polymers, losing about 40% of its weight after about
50 days. Extrapolating these times points, complete degradation
would occur over a period of about 150 days. Further, inspection of
the degrading polymer showed that degradation was occurring by
surface, rather than bulk loss.
[0065] B. Biodegradable Stents
[0066] The polyester- or polyether-based polyanhydrides of the
invention have a number of biomedical applications that take
advantage of the improved elasticity and/or degradation properties
of the polymers. For example, the block-copolymers described with
respect to FIG. 5 may be advantageous for drug-delivery because of
improved bioerodability. In this application, the block co-polymers
would be formed in the presence of a selected drug, at a
drug/polymer ratio in the range 1:50 to 1:1, and formed into
desired drug-delivery devices of particles, e.g., injectable
particles having sizes in the 5 to 50 micron size range.
[0067] An important application of the high-flexibility
polyanhydride described above is in a biocompatible, biodegradable
intravascular stent. Currently stents for use at intravascular
sites of injury are deployed by radial expansion over a balloon
catheter, and thus require the ability to expand significantly and
to hold their expanded shape when deployed, properties that led to
the widespread use of metals, such as stainless steel, in stent
construction. The present invention provides an expandable,
shape-retaining bioerodable stent material, allowing the advantages
of physical stenting, but in a device that will ultimately
biodegrade by surface erosion over a selected stenting period.
[0068] FIG. 6A shows a stent 10 constructed in accordance with a
conventional stent architecture, but formed from a biocompatible,
biodegradable polyanhydride material in accordance with the
invention. As seen best in FIG. 6B, the stent includes a core 14
formed of a lattice of interconnected struts, such as struts 16,
according to known stent architecture. This core, which is formed
of an expandable, controlled-degradation polyanhydride of the
invention, may be made conventionally, e.g., by forming the polymer
into a cylindrical sleeve, and laser cutting the struts. Typically,
the polyanhydride forming the core will have a degradation rate for
complete bioerosion over a 180-360 day period.
[0069] The stent's core may be coated with a biodegradable
drug-eluting coating, designed to release an anti-restensosis drug,
such as taxol or rapamycin, embedded in the coating, over a
selected time period. Typically, drug-elution is designed to occur
over a relatively short period, e.g., 3 days to two weeks post
implantation, and therefore the coating can be formed
advantageously from a conventional polyanhydride with rapid surface
erosion characteristics. Such a drug-containing polymer may be
prepared by known methods, and applied to the stent core by
conventional means, such as by dipping or spraying. The coating has
a typical thickness between 3-50 microns and thus can be expanded,
along with the stent core, even though the coating has a Young's
modulus in the range greater than 3 GPa.
[0070] This aspect of the invention thus includes an expandable,
biodegradable stent comprising a biodegradable, polyanhydride
polymer having, as a repeating polymer unit, the dianhydride of a
polylactide, polycaprolactone or polyglycolide
.alpha.-.omega.,-dihydroxy polymer having an average molecular
weight greater than 5 and less than 10 Kdaltons, a selected Young's
modulus between 1.5 and 3, and a selected average number of
anhydride linkages in the range between 5 and 25. In the embodiment
just described, the polyanhydride polymer forms a biodegradable
stent core which is coated, on its exterior surface(s), with a
polymer coating composed of a second biodegradable polyanhydride
having a Young's modulus greater than 3, and a drug embedded
therein.
[0071] The following examples will illustrate various methods for
synthesizing and characterizing polyanhydride polymers, in
accordance with the present invention, but are in no way intended
to limit the scope of the invention.
EXAMPLE 1
Synthesis of .alpha.-.omega.,-di Carboxylic Acid Poly Lactide
Prepolymer
Prepolymer of D/L-lactide
[0072] The steps in this example are described with reference to
FIG. 1. Diethylene glycol distilled over CaH.sub.2 before use.
D/L-lactide was sublimed under vacuum. All the solvents were
purified by distillation over proper dehydrating reagent to remove
the moisture. Under argon protection, to a 1000 ml flask add 0.0238
mole of diethylene glycol, D/L-lactide (120 g) were charge. The
mixture was heated to 135.degree. C. Once the lactide monomer was
melted down than catalyst of Tin(II) 2-ethylhexanoate (100 mg-1 ml
of toluene) was added by glass syringe. The mixture was heated to
135.degree. C. for 25 minutes. In 25 minutes the monomer conversion
reaches to about 90% an equilibration of polymerization with the
un-reacted monomer. The reaction was stopped by cooling down the
reaction flask in cold water. The solidified polymer was dissolved
in acetone and the polymer was precipitated in ethanol/hexane 2:8
v/v mixture. This procedure of precipitation was repeated three
times to remove the unreacted lactide monomer.
[0073] The presence of lactide monomer in the form polymer was
checked by FTIR by the disappearance of a characteristic absorbance
at 1250 cm.sup.-1 from the cylic structure of the monomer. The
yield of the polymer was 109 g. The SEC and NMR analysis show that
the polymer has the required molecular weight (Mn 6500, Mw/Mn 1.08)
as expected and bears two-hydroxyl termini on the chain ends. After
drying the hydroxyl terminated poly(D/L-lactide) under vacuum and
azeotrope distillation over toluene (to ensure the moisture free
prepolymer), 8 g of succinic anhydride (sublimed under vacuum) was
mixed with polymer and the mixture was heated to 130.degree. C. for
8 hours.
[0074] The polymer was dissolved in dichloromethane when it is
cold. 500 ml of water was introduced and the solution was stirred
for 1 hour. The water was separated by a separatory-globes shape
funnel. The washing of the polymer solution was carried out three
times to remove the unreacted succinic anhydride (the disappearance
of the anhydride peak (1820 cm.sup.-1) on the FTIR spectrum). The
polymer was recovered from precipitation into cold diethyl ether.
The yield of the polymer was 105 g.
EXAMPLE 2
Synthesis of .alpha.-.omega.,-di Anhydride Poly Lactide Prepolymer
and its Polymerization to Yield Polyanhydride Based on Poly
Lactide
[0075] The steps in this example are described with reference to
FIG. 2. .alpha.-.omega.,-dicarboxylic acid poly lactide
(D/L-lactide) from example 1 (105 g)was heated with 600 ml acetic
anhydride (chemical purity+99%) to 100.degree. C. for 8 hours, then
the mixture was applied vacuum to remove the excess of acetic
anhydride. Once all the unreacted acetic anhydride was removed
under vacuum, the obtained polymer was added 10 mg of calcium
oxide, under Argon protection, the mixture was cooked at
165.degree. C. until melting. The temperature was increased to
180.degree. C. for 4 hours with vacuum removal of acetic anhydride.
Finally, the temperature will reach to 180.degree. C. for 8 hours
to extend the molecular weight to a maximum. The resulting
polyanhydride is pure enough for our applications. The molecular
weight was estimated from viscosity about 40,000 to 80,000. The
polymer has the molecular weight higher enough to draw the flexible
fibers.
[0076] Additional anhydrides were similarly prepared using (i) the
.alpha.-.omega.,-di carboxylic acid of a poly lactide pre-polymer
having molecular weight 500; (ii) the .alpha.-.omega.,-di
carboxylic acid of a poly lactide prepolymer having molecular
weight of 1000.
EXAMPLE 3
Synthesis of a Poly(ethylene glycol) Based Polyanhydride
[0077] The steps in this example are described with reference to
FIG. 3. Poly(ethylene glycol), Sample lot # P4790-EG20H with
Mn=3400, 120 g was dissolved in 300 ml dry toluene at 45.degree. C.
Azeotropic distillation of toluene was applied to remove the
moisture in the sample. After almost all toluene removed, 14 g of
succinic anhydride was added and the mixture was heated up to
120.degree. C. under argon protection. The reaction completed after
4 hours at this temperature. The polymer was dissolved in
dichloromethane when it is cold. 500 ml of water was introduced and
the solution was stirred for 1 hour. The water was separated by a
separatory-globes shape funnel. The washing of the polymer solution
was carried out three times to remove the unreacted succinic
anhydride (the disappearance of the anhydride peak (1820 cm.sup.-1)
on the FTIR spectrum). The polymer was recovered from precipitation
into cold diethyl ether. The yield of the polymer was 110 g.
[0078] Dry .alpha.-.omega.,-di carboxy terminated PEG was mixed
with acetic anhydride (chemical purity+99%), and the solution was
reflux for 8 hours. Then, the vacuum was applied to remove the
excess of acetic anhydride. The highly viscous mass material was
added with 50 mg of calcium oxide, under Argon protection, the
mixture was cooked at 165.degree. C. until melting. The temperature
was increased to 180.degree. C. for 4 hours with vacuum removal of
acetic anhydride. Finally, the temperature will reach 195.degree.
C. for 8 hours to extend the molecular weight to maximum. The
resulting polyanhydride is pure enough for our applications. The
molecular weight was estimated from viscosity about 30,000 to
50,000.
EXAMPLE 4
Synthesis of a Polyanhydride Copolymer Containing Polylactide and
Bis 1,3-bis-carboxyphenoyxypropane Block Component
[0079] The steps in this example are described with reference to
FIGS. 4 and 5. A known quantity of dicarboxy phenoxy alkyl
dianhydride compound was mixed with poly lactide dianhydride
prepolymer by weight and the mixture was heated under argon in the
presence of CaO as catalyst. The polymerization temperature was
kept 150.degree. C. for 2 h under continuous argon atmosphere to
remove the liberated acetic anhydride side product. Finally the
vacuum was applied to the mixture and the temperature increased to
180.degree. C. for 2 h. and the temperature raised to 190.degree.
C. for 3 h. The polymerization was stopped by cooling down. The
product was isolated in the form of light brown color chunk
pieces.
[0080] Although the invention has been described with respect to
certain methods and applications, it will be appreciated that a
variety of changes and modification may be made without departing
from the invention as claimed.
* * * * *
References