U.S. patent application number 14/168806 was filed with the patent office on 2014-05-29 for biologically absorbable coating for implantable devices based on copolymers having ester bonds and methods of fabricating the same.
This patent application is currently assigned to Abbott Cardiovascular Systems Inc.. The applicant listed for this patent is Abbott Cardiovascular Systems Inc.. Invention is credited to Stephen D. Pacetti.
Application Number | 20140147686 14/168806 |
Document ID | / |
Family ID | 34965777 |
Filed Date | 2014-05-29 |
United States Patent
Application |
20140147686 |
Kind Code |
A1 |
Pacetti; Stephen D. |
May 29, 2014 |
BIOLOGICALLY ABSORBABLE COATING FOR IMPLANTABLE DEVICES BASED ON
COPOLYMERS HAVING ESTER BONDS AND METHODS OF FABRICATING THE
SAME
Abstract
Coatings for an implantable medical device and a method of
fabricating thereof are disclosed, and the coatings comprise
biologically absorbable poly(ester amides).
Inventors: |
Pacetti; Stephen D.; (San
Jose, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Abbott Cardiovascular Systems Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Abbott Cardiovascular Systems
Inc.
Santa Clara
CA
|
Family ID: |
34965777 |
Appl. No.: |
14/168806 |
Filed: |
January 30, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10805036 |
Mar 16, 2004 |
8685431 |
|
|
14168806 |
|
|
|
|
Current U.S.
Class: |
428/474.4 |
Current CPC
Class: |
A61L 31/06 20130101;
Y10T 428/31725 20150401; C08L 77/12 20130101; A61L 31/06 20130101;
A61L 31/10 20130101 |
Class at
Publication: |
428/474.4 |
International
Class: |
A61L 31/10 20060101
A61L031/10 |
Claims
1. A medical article comprising an implantable substrate having a
coating, the coating including a polymeric product of a reaction
between a first reagent, a second reagent, and a third reagent,
wherein: (a) the first reagent is selected from a group consisting
of compounds having formulae (1), (2), (3), and (4): ##STR00062##
(b) the second reagent is selected from a group consisting of
compounds having formulae (5), (6), (7), and (8): ##STR00063## (c)
the third reagent is a dicarboxylic acid having the formula (9):
##STR00064## wherein: R.sub.1 is hydrogen, methyl, iso-propyl,
sec-butyl; iso-butyl, or benzyl group; R.sub.2 is methylene,
methylmethylene, n-propylene, iso-propylene, ethylmethylene,
n-butylene, iso-butylene, sec-butylene, or n-amylene group; R.sub.3
is a straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is an integer between 2 and 12; R.sub.4
is a moiety derived from a compound selected from a group
consisting of poly(propylene glycol), random poly(ethylene
glycol-co-propylene glycol), poly(ethylene
glycol)-block-poly(propylene glycol), hyaluronic acid,
poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate),
poly(vinyl pyrrolidone), and cellulosics; X is a straight chained
or branched aliphatic alkylene group C.sub.nH.sub.2n, wherein n is
an integer between 2 and 12; and Y is a straight chained or
branched aliphatic alkylene group C.sub.nH.sub.2n, wherein n is 1,
2, or 5.
2. The medical article of claim 1, wherein the implantable
substrate is a stent.
3. The medical article of claim 1, wherein the compound of formula
(1) is a diol-diamine, the diol-diamine is a product of
condensation of an amino acid and a diol.
4. The medical article of claim 3, wherein the amino acid has the
formula (10): H.sub.2N--CHR.sub.1--COOH. (10)
5. The medical article of claim 3, wherein the amino acid is
selected from a group consisting of glycine, alanine, valine,
isoleucine, leucine, and phenyl alanine.
6. The medical article of claim 3, wherein a diol is selected from
a group consisting of ethylene glycol, 1,3-propanediol, 1,4-butane
diol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol,
1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol,
and 1,12-dodecanediol.
7. The medical article of claim 1, wherein the compound of formula
(2) is an amidediol, the amidediol is a product of condensation of
a hydroxy acid and a diamine.
8. The medical article of claim 7, wherein the hydroxy acid has the
formula (11): HO--R.sub.2--COOH. (11)
9. The medical article of claim 7, wherein the hydroxy acid is
selected from a group consisting of glycolic acid, lactic acid,
.beta.-hydroxybutyric acid, .alpha.-hydroxyvaleric acid, and
.epsilon.-hydroxycaproic acid.
10. The medical article of claim 7, wherein the diamine is selected
from a group consisting of putrescine, 1,2-ethanediamine, and
cadavarene.
11. The medical article of claim 1, wherein the compound of formula
(3) is selected from a group consisting of ethylene glycol,
1,3-propanediol, 1,4-butane diol, 1,5-pentanediol, 1,6-hexanediol,
1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol,
1,11-undecanediol, and 1,12-dodecanediol.
12. The medical article of claim 1, wherein the compound of formula
(4) is selected from a group consisting of putrescine,
1,2-ethanediamine, and cadavarene.
13-18. (canceled)
19. A medical article comprising an implantable substrate having a
coating, the coating including a copolymer having a general formula
(12) or (13): -[M-P].sub.m-[M-Q].sub.n- (12) -[M.sub.1-P].sub.p-
(13) wherein: M is a moiety represented by the structure having the
formula (14) ##STR00065## P is a moiety selected from a group
consisting of structures having the formulae (15), (16), (17), and
(18): ##STR00066## Q is a moiety selected from a group consisting
of structures having the formulae (19), (20), and (21) ##STR00067##
M.sub.1 is a moiety represented by the structure having the formula
(22): ##STR00068## R.sub.1 is hydrogen, methyl, iso-propyl,
sec-butyl; iso-butyl, or benzyl group; R.sub.2 is methylene,
methylmethylene, n-propylene, iso-propylene, ethylmethylene,
n-butylene, iso-butylene, sec-butylene, or n-amylene group; R.sub.3
is a straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is an integer between 2 and 12; X is a
straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is an integer between 2 and 12; Y is a
straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is 1, 2, or 5; Z is a moiety derived
from a compound selected from a group consisting of poly(propylene
glycol), random poly(ethylene glycol-co-propylene glycol),
poly(ethylene glycol)-block-poly(propylene glycol), hyaluronic
acid, poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate),
poly(vinyl pyrrolidone, and cellulosics; and m, n, and p are
integers where the value of m is between 5 and 1,800, the value of
n is between 1 and 800 and the value of p is between 4 and
1,500.
20. (canceled)
21. A method for fabricating a medical article, the method
including synthesizing a copolymer and forming a coating based on
the copolymer on at least a portion of an implantable substrate,
the synthesizing of the copolymer including reacting a first
reagent with a second reagent and with a third reagent, wherein:
(a) the first reagent is selected from a group consisting of
compounds having formulae (1), (2), (3), and (4): ##STR00069## (b)
the second reagent is selected from a group consisting of compounds
having formulae (5), (6), (7), and (8): ##STR00070## (c) the third
reagent is a dicarboxylic acid having the formula (9): ##STR00071##
wherein: R.sub.1 is hydrogen, methyl, iso-propyl, sec-butyl;
iso-butyl, or benzyl group; R.sub.2 is methylene, methylmethylene,
n-propylene, iso-propylene, ethylmethylene, n-butylene,
iso-butylene, sec-butylene, or n-amylene group; R.sub.3 is a
straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is an integer between 2 and 12; R.sub.4
is a moiety derived from a compound selected from a group
consisting of poly(propylene glycol), random poly(ethylene
glycol-co-propylene glycol), poly(ethylene
glycol)-block-poly(propylene glycol), hyaluronic acid,
poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate),
poly(vinyl pyrrolidone), and cellulosics; X is a straight chained
or branched aliphatic alkylene group C.sub.nH.sub.2n, wherein n is
an integer between 2 and 12; Y is a straight chained or branched
aliphatic alkylene group C.sub.nH.sub.2n, wherein n is 1, 2, or
5.
22. The method of claim 21, wherein the implantable substrate is a
stent.
23. The method of claim 21, wherein the molar ratio between the
first reagent, the second reagent, and the third reagent is about
1:1:2.
24. The method of claim 21, wherein the compound of formula (1) is
a diol-diamine, the diol-diamine is a product of condensation of an
amino acid and a diol.
25. The method of claim 24, wherein the amino acid has the formula
(10): H.sub.2N--CHR.sub.1--COOH. (10)
26. The method of claim 24, wherein the amino acid is selected from
a group consisting of glycine, alanine, valine, isoleucine,
leucine, and phenyl alanine.
27. The method of claim 24, wherein a diol is selected from a group
consisting of ethylene glycol, 1,3-propanediol, 1,4-butane diol,
1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol,
1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, and
1,12-dodecanediol.
28. The method of claim 21, wherein the compound of formula (2) is
an amidediol, the amidediol is a product of condensation of a
hydroxy acid and a diamine.
29. The method of claim 28, wherein the hydroxy acid has the
formula (11): HO--R.sub.2--COOH. (11)
30. The method of claim 28, wherein the hydroxy acid is selected
from a group consisting of glycolic acid, lactic acid,
.beta.-hydroxybutyric acid, .alpha.-hydroxyvaleric acid, and
.epsilon.-hydroxycaproic acid.
31. The method of claim 28, wherein the diamine is selected from a
group consisting of putrescine, 1,2-ethanediamine, and
cadavarene.
32. The method of claim 21, wherein the compound of formula (3) is
selected from a group consisting of ethylene glycol,
1,3-propanediol, 1,4-butane diol, 1,5-pentanediol, 1,6-hexanediol,
1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol,
1,11-undecanediol, and 1,12-dodecanediol.
33. The method of claim 21, wherein the compound of formula (4) is
selected from a group consisting of putrescine, 1,2-ethanediamine,
and cadavarene.
34-39. (canceled)
40. A method for fabricating a medical article, the method
including synthesizing a copolymer and forming a coating based on
the copolymer on at least a portion of an implantable substrate,
wherein the copolymer has a general formula (12) or (13):
-[M-P].sub.m-[M-Q].sub.n- (12) -[M.sub.1-P].sub.p- (13) wherein: M
is a moiety represented by the structure having the formula (14)
##STR00072## P is a moiety selected from a group consisting of
structures having the formulae (15), (16), (17), and (18):
##STR00073## Q is a moiety selected from a group consisting of
structures having the formulae (19), (20), and (21) ##STR00074##
M.sub.1 is a moiety represented by the structure having the formula
(22): ##STR00075## R.sub.1 is hydrogen, methyl, iso-propyl,
sec-butyl; iso-butyl, or benzyl group; R.sub.2 is methylene,
methylmethylene, n-propylene, iso-propylene, ethylmethylene,
n-butylene, iso-butylene, sec-butylene, or n-amylene group; R.sub.3
is a straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is an integer between 2 and 12; X is a
straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is an integer between 2 and 12; Y is a
straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is 1, 2, or 5; and Z is a moiety derived
from a compound selected from a group consisting of poly(propylene
glycol), random poly(ethylene glycol-co-propylene glycol),
poly(ethylene glycol)-block-polypropylene glycol), hyaluronic acid,
poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate),
poly(vinyl pyrrolidone, and cellulosics; and m, n, and p are
integers where the value of m is between 5 and 1,800, the value of
n is between 1 and 800 and the value of p is between 4 and
1,500.
41. (canceled)
42. The medical article of claim 19, wherein the copolymer is of
formula (41): ##STR00076##
43. The method of claim 40, wherein the copolymer is of formula
(41): ##STR00077##
44. A medical article comprising an implantable substrate having a
coating, the coating including a copolymer having the formula:
##STR00078##
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional application of U.S.
application Ser. No. 10/805,036 filed on Mar. 16, 2004, the
teaching of which is incorporated by reference in its entirety
herein.
BACKGROUND
[0002] 1. Field of the Invention
[0003] This invention is directed to coatings for drug delivery
devices, such as drug eluting vascular stents, and methods for
producing the same.
[0004] 2. Description of the State of the Art
[0005] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. A catheter assembly having a
balloon portion is introduced percutaneously into the
cardiovascular system of a patient via the brachial or femoral
artery. The catheter assembly is advanced through the coronary
vasculature until the balloon portion is positioned across the
occlusive lesion. Once in position across the lesion, the balloon
is inflated to a predetermined size to radially compress against
the atherosclerotic plaque of the lesion to remodel the lumen wall.
The balloon is then deflated to a smaller profile to allow the
catheter to be withdrawn from the patient's vasculature.
[0006] A problem associated with the above procedure includes
formation of intimal flaps or torn arterial linings which can
collapse and occlude the conduit after the balloon is deflated.
Moreover, thrombosis and restenosis of the artery may develop over
several months after the procedure, which may require another
angioplasty procedure or a surgical by-pass operation. To reduce
the partial or total occlusion of the artery by the collapse of
arterial lining and to reduce the chance of the development of
thrombosis and restenosis, a stent is implanted in the lumen to
maintain the vascular patency.
[0007] Stents are used not only as a mechanical intervention but
also as a vehicle for providing biological therapy. As a mechanical
intervention, stents act as scaffoldings, functioning to physically
hold open and, if desired, to expand the wall of the passageway.
Typically, stents are capable of being compressed, so that they can
be inserted through small vessels via catheters, and then expanded
to a larger diameter once they are at the desired location.
Examples in patent literature disclosing stents which have been
applied in PTCA procedures include stents illustrated in U.S. Pat.
No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to
Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor.
[0008] Biological therapy can be achieved by medicating the stents.
Medicated stents provide for the local administration of a
therapeutic substance at the diseased site. In order to provide an
efficacious concentration to the treated site, systemic
administration of such medication often produces adverse or toxic
side effects for the patient. Local delivery is a preferred method
of treatment in that smaller total levels of medication are
administered in comparison to systemic dosages, but are
concentrated at a specific site. Local delivery thus produces fewer
side effects and achieves more favorable results. One proposed
method for medicating stents involves the use of a polymeric
carrier coated onto the surface of a stent. A solution which
includes a solvent, a polymer dissolved in the solvent, and a
therapeutic substance dispersed in the blend is applied to the
stent. The solvent is allowed to evaporate, leaving on the stent
surface a coating of the polymer and the therapeutic substance
impregnated in the polymer.
[0009] One polymer that can be used for making stent coatings for
local drug delivery can be selected from a group of poly(ester
amides) described in U.S. Pat. No. 6,503,538 to Chu et al. However,
some mechanical properties, such as hardness of the poly(ester
amides) taught by Chu et al. may be insufficiently good for stent
applications. Accordingly, there is a need to have poly(ester
amides) with better properties to allow the poly(ester amides) to
be used to make stent coatings for local drug delivery.
SUMMARY
[0010] According to one aspect of the present invention, a medical
article is provided, the article comprises an implantable substrate
having a coating, the coating includes a polymeric product of a
reaction between a first reagent, a second reagent, and a third
reagent, wherein: (a) the first reagent can be one of the compounds
having formulae (1), (2), (3), and (4);
##STR00001##
(b) the second reagent can be one of the compounds having formulae
(5), (6), (7), and (8);
##STR00002##
and, (c) the third reagent can be a dicarboxylic acid having the
formula (9):
##STR00003##
[0011] In formulae (1)-(9), R.sub.1 can be hydrogen, methyl,
iso-propyl, sec-butyl; iso-butyl, or benzyl group; R.sub.2 can be
methylene, methylmethylene, n-propylene, iso-propylene,
ethylmethylene, n-butylene, iso-butylene, sec-butylene, or
n-amylene group; R.sub.3 can be a straight chained or branched
aliphatic alkylene group C.sub.nH.sub.2n, wherein n is an integer
between 2 and 12; R.sub.4 can be a moiety derived from a compound
selected from a group consisting of poly(ethylene glycol),
polypropylene glycol), random poly(ethylene glycol-co-propylene
glycol), poly(ethylene glycol)-block-polypropylene glycol),
hyaluronic acid, poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate),
poly(vinyl pyrrolidone), and cellulosics; X can be a straight
chained or branched aliphatic alkylene group C.sub.nH.sub.2n,
wherein n is an integer between 2 and 12; and Y can be a straight
chained or branched aliphatic alkylene group C.sub.nH.sub.2n,
wherein n is 1, 2, or 5.
[0012] According to another aspect of the present invention, a
medical article is provided. The article comprises an implantable
substrate having a coating, and the coating includes a copolymer
having a general formula (10) or (11):
-[M-P].sub.m-[M-Q].sub.n- (10)
-[M.sub.1-P].sub.p- (11)
wherein, M can be a moiety represented by the structure having the
formula (12);
##STR00004##
P can be one of the moieties having the formulae (13), (14), (15),
and (16);
##STR00005##
Q can be one of the moieties having the formulae (17), (18), and
(19);
##STR00006##
and M.sub.1 can be a moiety represented by the formula (20);
##STR00007##
[0013] In formulae (10)-(20), R.sub.1 can be hydrogen, methyl,
iso-propyl, sec-butyl; iso-butyl, or benzyl group; R.sub.2 can be
methylene, methylmethylene, n-propylene, iso-propylene,
ethylmethylene, n-butylene, iso-butylene, sec-butylene, or
n-amylene group; R.sub.3 can be a straight chained or branched
aliphatic alkylene group C.sub.nH.sub.2n, wherein n is an integer
between 2 and 12; X can be a straight chained or branched aliphatic
alkylene group C.sub.nH.sub.2n, wherein n is an integer between 2
and 12; Y can be a straight chained or branched aliphatic alkylene
group C.sub.nH.sub.2n, wherein n is 1, 2, or 5; Z can be a moiety
derived from a compound selected from a group consisting of
poly(ethylene glycol), poly(propylene glycol), random poly(ethylene
glycol-co-propylene glycol), poly(ethylene
glycol)-block-poly(propylene glycol), hyaluronic acid,
poly(2-hydroxyethyl methacrylate),
poly(3-hydroxypropylmethacrylamide), poly(styrene sulfonate),
poly(vinyl pyrrolidone), and cellulosics; and m, n, and p can be
integers where the value of m is between 5 and 1,800, the value of
n is between 1 and 800 and the value of p is between 4 and
1,500.
[0014] According to yet another aspect of the current invention, a
method for fabricating a medical article is provided, the method
includes synthesizing a copolymer and forming a coating based on
the copolymer on at least a portion of an implantable substrate,
the synthesizing of the copolymer including reacting a first
reagent with a second reagent and with a third reagent, wherein:
(a) the first reagent can be one of the compounds having formulae
(1), (2), (3), and (4); (b) the second reagent can be one of the
compounds having formulae (5), (6), (7), and (8); and (c) the third
reagent is a dicarboxylic acid having the formula (9), where the
formulae (1)-(9) are provided above.
[0015] According to yet another aspect of the current invention, a
method for fabricating a medical article is provided, the method
including synthesizing a copolymer and forming a coating based on
the copolymer on at least a portion of an implantable substrate,
wherein the copolymer has a general formula (10) or (11), where the
formulae (10) and (11) are provided above.
DETAILED DESCRIPTION
1. Terms and Definitions
[0016] The following definitions apply:
[0017] The term "biologically absorbable" coatings and/or polymers
is defined as coatings and/or polymers that are capable of being
completely degraded and/or eroded when exposed to bodily fluids
such as blood and are gradually resorbed, absorbed and/or
eliminated by the body. The processes of breaking down and eventual
absorption and elimination of the coating and/or polymer can be
caused, for example, by hydrolysis, metabolic processes, bulk or
surface erosion, and the like.
[0018] Whenever the reference is made to "biologically absorbable"
stent coatings and/or polymers forming such stent coatings, it is
understood that after the process of degradation, erosion,
absorption, and/or resorption has been completed, no coating, in
excess of possibly insignificant trace amount, will remain on the
stent. In other words, stent coatings and/or polymers forming such
stent coatings are considered "biologically absorbable" if the
coatings and/or polymers are substantially broken down by the in
vivo environment, or by the in vitro environment, such as one
having physical, chemical, and/or biological characteristics
substantially similar to those of the in vivo environment. An
amount of time needed to break down the coatings and/or polymers
can be between about 1 day and several years, or between about 1
day and about 24 months; alternatively, between about 2 months and
about 18 months; alternatively, between about 3 month and about 12
months.
[0019] For purposes of the present invention, "substantially broken
down" means that a substantial reduction of the molecular weight of
a polymer occurs as a result of the exposure of the polymer to the
in vivo environment or to a simulated in vivo environment. The
simulated in vivo environment can be the in vitro environment
having physical, chemical, and/or biological characteristics that
are identical or substantially similar to those of the in vivo
environment. Standard analytical techniques normally used by those
having ordinary skill in the art can be used to monitor the change
of the molecular weight of the polymer. One analytical technique
that can be used includes immersing the polymer in a simulated in
vivo environment and measuring the loss of the molecular weight of
the polymer over time. A number of methods can be used for
measuring the molecular weight, for example, gel permeation
chromatography (GPC). In some embodiments, if the polymer has lost
more than about 10% of its original molecular weight over a 3-month
period, then it can be classified as biodegradable.
[0020] The term "poly(ester amide)" or "PEA" is defined as a
polymer having both at least one ester bond (I) and at least one
amide bond (II):
##STR00008##
2. Embodiments of the Invention
[0021] A coating for an implantable medical device, such as a
stent, according to embodiments of the present invention, can be a
multi-layer structure that can include the following three
layers:
[0022] (a) a drug-polymer layer (also referred to as "reservoir" or
"reservoir layer"), comprising a polymer and a drug, or
alternatively a polymer free drug layer;
[0023] (b) an optional primer layer; and/or
[0024] (c) an optional topcoat layer.
[0025] Each layer of the stent coating can be formed on the stent
by dissolving a polymer or a blend of polymers in a solvent, or a
mixture of solvents, and applying the resulting polymer solution on
the stent by spraying or immersing the stent in the solution. After
the solution has been applied onto the stent, the coating is dried
by allowing the solvent to evaporate. The process of drying can be
accelerated if the drying is conducted at an elevated
temperature.
[0026] To incorporate a drug into the reservoir layer, the drug can
be combined with the polymer solution that is applied onto the
stent as described above. Alternatively, to fabricate a
polymer-free drug layer, the drug can be dissolved in a suitable
solvent or mixture of solvents, and the resulting drug solution can
be applied on the stent by spraying or immersing the stent in the
drug solution.
[0027] Instead of introducing the drug as a solution, the drug can
be introduced as a colloid system, such as a suspension in an
appropriate solvent phase. To make the suspension, the drug can be
dispersed in the solvent phase using conventional techniques used
in colloid chemistry. Depending on a variety of factors, e.g., the
nature of the drug, those having ordinary skill in the art can
select the solvent to form the solvent phase of the suspension, as
well as the quantity of the drug to be dispersed in the solvent
phase. The suspension can be mixed with a polymer solution and the
mixture can be applied on the stent as described above.
Alternatively, the drug suspension can be applied on the stent
without being mixed with the polymer solution.
[0028] The drug-polymer layer can be applied directly onto at least
a part of the stent surface to serve as a reservoir for at least
one active agent or a drug which is incorporated into the reservoir
layer. The optional primer layer can be applied between the stent
and the reservoir to improve the adhesion of the drug-polymer layer
to the stent. The optional topcoat layer can be applied over at
least a portion of the reservoir layer and to serve as a rate
limiting membrane which helps to control the rate of release of the
drug. The topcoat layer can be essentially free from any active
agents or drugs.
[0029] In one embodiment, any or all of the layers of the stent
coating, can be made of a polymer that is both biologically
beneficial and biologically degradable, erodable, absorbable,
and/or resorbable. In another embodiment, just the outermost layer
of the coating can be limited to such a polymer.
[0030] To illustrate in more detail, in the stent coating having
all three layers described above (i.e., the primer, the reservoir
layer, and the topcoat layer), the outermost layer is the topcoat
layer, which is made of a biologically absorbable block copolymer.
In this case, optionally, the remaining layers (i.e., the primer
and the reservoir layer) can be also fabricated of a biologically
absorbable block copolymer; the block copolymer can be the same or
different in each layer. If the topcoat layer is not used, the
stent coating can have only two layers: the optional primer and the
reservoir. The reservoir in this case is the outermost layer of the
stent coating and is made of a biologically absorbable block
copolymer. Optionally, the primer can be also fabricated of a
biologically absorbable block copolymer, which can be the same or
different in the reservoir and in the primer. In one embodiment,
the biologically absorbable copolymers that can be used for making
any of the stent coating layers include poly(ester amides) (PEA).
Optionally, in some other embodiments, condensation copolymers,
such as poly(esters) having no amide bonds, can be used instead of
PEAs.
[0031] The synthetic techniques that can be used for obtaining both
the PEAs and the poly(esters) are described below in the
application. Generally, the PEAs are products of reaction between
at least one reagent from group A, at least one reagent from group
B and a reagent C.sub.1 from group C. The poly(esters) are products
of reaction between at least one reagent from group A and a reagent
C.sub.2 from group C. The precursor-reagents from groups A, B, and
C that can be used are characterized as follows.
[0032] A. Group A Reagents.
[0033] The group A precursor-reagents (hereinafter, "reagents")
that can be used for synthesizing the biologically absorbable
copolymers according to embodiments of the present invention are
summarized in Table 1. The definition used to describe a chemical
family to which each of the group A reagents belongs is also
provided in Table 1.
TABLE-US-00001 TABLE 1 Group A Reagents No. Code Reagent General
Formula Reagent Definition 1 A.sub.1 ##STR00009## Diol-diamine 2
A.sub.2 ##STR00010## Amidediol 3 A.sub.3 HO--X--OH Diol 4 A.sub.4
H.sub.2N--Y--NH.sub.2 Diamine
[0034] In the general formulae of compounds A.sub.1, A.sub.2,
A.sub.3, and A.sub.4 presented in Table 1, the substitutents
R.sub.1, R.sub.2, X, and Y can be as follows:
R.sub.1--(a) hydrogen;
[0035] (b) methyl (--CH.sub.3);
[0036] (c) iso-propyl (-i-C.sub.3H.sub.7);
[0037] (d) sec-butyl (-sec-C.sub.4H.sub.9);
[0038] (e) iso-butyl (-i-C.sub.4H.sub.9); or
[0039] (f) benzyl (--C.sub.6H.sub.5);
R.sub.2--(a) methylene (--CH.sub.2--);
[0040] (b) ethylene (--CH.sub.2CH.sub.2--);
[0041] (c) methylmethylene [--CH(CH.sub.3)--];
[0042] (d) straight chained or branched propylene, such as: [0043]
(d1) n-propylene (--CH.sub.2CH.sub.2CH.sub.2--); [0044] (d2)
iso-propylene [--CH.sub.2CH(CH.sub.3)--]; or [0045] (d3)
ethylmethylene [--CH(CH.sub.2CH.sub.3)--];
[0046] (e) straight chained or branched butylene, such as: [0047]
(e1) n-butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), [0048] (e2)
iso-butylene [--CH.sub.2CH(CH.sub.3)CH.sub.2--], or [0049] (e3)
sec-butylene [--CH(CH.sub.2CH.sub.3)CH.sub.2--];
[0050] (f) straight chained or branched pentylene, such as: [0051]
(f1) n-pentylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--),
[0052] (f2) iso-pentylene [--C(CH.sub.3).sub.2CH.sub.2CH.sub.2--],
[0053] (f3) neopentylene {--CH[C(CH.sub.3).sub.3]--}, [0054] (f4)
2-methyl-1-butylene [--C(CH.sub.3)(CH.sub.2CH.sub.3)CH.sub.2--],
[0055] (f5) sec-iso-pentylene [--C(CH.sub.3).sub.2CH(CH.sub.3)--],
or [0056] (f6) methylpropylmethylene
[--C(CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)--]; or
[0057] (g) groups that are present in some amino acids, such as:
[0058] (g1) methyleneamide (present in asparagine)
[--CH.sub.2(CONH.sub.2)--]; [0059] (g2) ethyleneamide (present in
glutamine) [--CH.sub.2CH.sub.2(CONH.sub.2)--]; [0060] (g3)
methylmercaptomethylmethylene (present in methionine)
[--CH.sub.2(CH.sub.2SCH.sub.3)--]; or [0061] (g4) n-propyleneamino
group (--CH.sub.2CH.sub.2CH.sub.2NH--) which is derived from
2-pyrrolidine group present (present in proline);
[0062] X--straight chained or branched aliphatic alkylene group
C.sub.nH.sub.2n, wherein n is an integer between 2 and 16, e.g.,
methylene, ethylene, propylene, butylene, amylene (pentylene),
hexylene, heptylene, octylene, nonylene, decylene, undecylene, or
dodecylene group; and
[0063] Y--straight chained or branched aliphatic alkylene group
C.sub.2H.sub.4 (ethylene), C.sub.3H.sub.6 (propylene),
C.sub.4H.sub.8 (butylene), or C.sub.5H.sub.10 (pentylene also known
as amylene).
[0064] The reagent A.sub.1 is a diol-diamine that can be
synthesized by condensation of two molar equivalents of an amino
acid and one molar equivalent of a diol. The synthesis can be
carried under the conditions favoring esterification of the amino
acid via the amino acid's carboxyl group. The reaction can be
conducted under dehydrating conditions which include anhydrous
environment and an elevated temperature, for example, about
50.degree. C., and can be catalyzed by a strong acid or base, e.g.,
p-toluenesulfonic acid.
[0065] The diol that can be used to make the reagent A.sub.1 has
the formula HO--X--OH, where X is as defined above. Representative
examples of diols that can be used include ethylene glycol,
1,3-propanediol, 1,4-butane diol, 1,5-pentanediol, 1,6-hexanediol,
1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol,
1,11-undecanediol, and 1,12-dodecanediol. The amino acid that can
be used to make the reagent A.sub.1 has the formula
H.sub.2N--CHR.sub.1--COOH, where R.sub.1 is as defined above. Some
amino acids that can be used are summarized in Table 2.
TABLE-US-00002 TABLE 2 Amino Acids That Can Be Used for Making the
Reagent A.sub.1 Amino Acid (H.sub.2N--CHR.sub.1--COOH) No. R.sub.1
Formula Name 1 --H H.sub.2N--CH.sub.2--COOH glycine 2 --CH.sub.3
##STR00011## alanine 3 --i-C.sub.3H.sub.7 ##STR00012## valine 4
--sec-C.sub.4H.sub.9 ##STR00013## isoleucine 5 --i-C.sub.4H.sub.9
##STR00014## leucine 6 C.sub.6H.sub.5CH.sub.2-- ##STR00015## phenyl
alanine 7 --CH.sub.2).sub.2--S--CH.sub.3 ##STR00016## methionine
(.alpha.-amino-.gamma.- methylmercaptobutyric acid) 8
--CH.sub.2--C(O)--NH.sub.2 ##STR00017## asparagine (.alpha.-amino-
succinamic acid) 9 --(CH.sub.2).sub.2--C(O)--NH.sub.2 ##STR00018##
glutamine (2-amino- glutaramic acid)
[0066] In addition to amino acids listed in Table 2, alternatively
other amino acids can be used. One example of such alternative
amino acids is proline (2-pyrrolidine carboxylic acid). Other
alternative amino acids that can be used include some amino acids
having free hydroxyl groups or second carboxyl groups if the free
hydroxyl groups or the second carboxyl groups are protected first.
The protection is needed so as to avoid interference when reagent
A.sub.1 is subsequently reacted with reagents of groups B and C, as
discussed above. Examples of the amino acids that can be used after
the free hydroxyl or second carboxyl groups are protected include
tyrosine, serine, or glutamic acid.
[0067] The reagent A.sub.2 is an amidediol that can be synthesized
by condensation of two molar equivalents of a hydroxy acid and one
molar equivalent of a diamine. The synthesis can be carried under
the conditions favoring formation of an amide bond. The reaction
can be conducted under dehydrating conditions, which include
anhydrous environment and can be catalyzed by a strong base. Simple
heating of the neat starting materials with the simultaneous
removal of generated water by distillation can also be used.
[0068] The diamine that can be used to make the reagent A.sub.2 has
the formula H.sub.2N--Y--NH.sub.2,
[0069] where Y is as defined above. Accordingly, examples of
diamines that can be used include 1,4-butanediamine (putrescine)
(Y.dbd.CH.sub.2CH.sub.2CH.sub.2CH.sub.2). Alternatively, other
diamines, such as 1,2-ethanediamine (Y.dbd.CH.sub.2CH.sub.2) or
1,5-pentanediamine (cadavarene)
(Y.dbd.CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2) can be used. The
hydroxy acid that can be used to make the reagent A.sub.2 has the
formula HO--R.sub.2--COOH, where R.sub.2 is as defined above. Some
hydroxy acids that can be used are summarized in Table 3.
TABLE-US-00003 TABLE 3 Hydroxy Acids That Can Be Used For Making
The Reagent A.sub.2 Hydroxy Acid (HO--R.sub.2--COOH) No. R.sub.2
Formula Name 1 --CH.sub.2-- HO--CH.sub.2--COOH glycolic
(hydroxyacetic) acid 2 --CH.sub.2--CH.sub.2--
HO--CH.sub.2--CH.sub.2--COOH .beta.-hydroxypropionic acid 3
##STR00019## ##STR00020## lactic (.alpha.- hydroxypropionic) acid 4
##STR00021## ##STR00022## .beta.-hydroxybutyric acid 5 ##STR00023##
##STR00024## .alpha.-hydroxyvaleric acid 6 ##STR00025##
##STR00026## .beta.-hydroxyvaleric acid 7 --(CH.sub.2).sub.5--
HO--(CH.sub.2).sub.5--COOH .epsilon.-hydroxycaproic acid 8
##STR00027## ##STR00028## .alpha.-hydroxycaproic acid 8
##STR00029## ##STR00030## .beta.-hydroxycaproic acid 9 ##STR00031##
##STR00032## .delta.-hydroxycaproic aid
[0070] The reagent A.sub.3 is a common simple diol having the
formula HO--X--OH, where X is as defined above; and the reagent
A.sub.4 is a common simple diamine having the formula
H.sub.2N--Y--NH.sub.2, where Y is as defined above.
[0071] B. Group B Reagents.
[0072] The group B reagents that can be used for synthesizing the
biologically absorbable copolymers according to embodiments of the
present invention are summarized in Table 4. Exemplary definitions
used to describe a chemical family to which each of the group B
reagents belongs is also provided in Table 4.
TABLE-US-00004 TABLE 4 Group B Reagents Exemplary Reagent No. Code
Reagent General Formula Definition (R.sub.4 = PEG) 1 B.sub.1
##STR00033## PEG-diester-diamine 2 B.sub.2 ##STR00034##
PEG-amidediol 3 B.sub.3 HO--R.sub.4--OH PEG-diol 4 B.sub.4
H.sub.2N--R.sub.4--NH.sub.2 PEG-diamine
[0073] In general formulae of compounds B.sub.1, B.sub.2, B.sub.3,
and B.sub.4 presented in Table 4, the substitutents R.sub.1 and
R.sub.2 are as defined above. One example of the R.sub.4 moiety
that can be used is a moiety derived from poly(ethylene glycol)
(PEG). Alternatively, other biologically beneficial moieties can be
used as R.sub.4, for example, moieties derived from poly(propylene
glycol) (PPG), random or block copolymers of PEG and PPG,
hyaluronic acid, poly(2-hydroxyethylmethacrylate),
poly(3-hydroxypropylmethacrylamide), or cellulosics.
[0074] The reagent B.sub.1 can be a PEG-diester-diamine moiety
(i.e., when R.sub.4=PEG) that can be synthesized by condensation of
two molar equivalents of an amino acid and one molar equivalent of
PEG. The synthesis can be carried under the conditions favoring
esterification of the amino acid via the carboxyl group. The
reaction can be conducted under dehydrating conditions which
include anhydrous environment and an elevated temperature, for
example, about 50.degree. C., and can be catalyzed by a strong acid
or base, e.g., p-toluenesulfonic acid. To make the reagent B.sub.1,
PEG having molecular weight between about 100 and 4,000 Daltons,
for example, about 300 Daltons, can be used. Any amino acid listed
in Table 2 can be used. Alternatively, other amino acids can be
used, for example, tyrosine, serine, or glutamic acid, if free
hydroxyl groups of tyrosine and serine or the second carboxyl group
of glutamic acid are protected so as not to interfere when reagent
B.sub.1 is subsequently reacted with reagents of groups A and C, as
discussed above.
[0075] The reagent B.sub.2 can be a PEG-amidediol that can be
synthesized by condensation of two molar equivalents of a hydroxy
acid and one molar equivalent of a PEG-diamine. The synthesis can
be carried under the conditions favoring formation of an amide
bond. The reaction can be conducted under dehydrating conditions
which include anhydrous environment, and can be catalyzed by a
strong base, or prepared from neat reagents by heating at high
temperature with the simultaneous removal of generated water, e.g.,
the removal of water by distillation. Any hydroxy acid listed in
Table 3 can be used. PEG terminated with amino groups on both ends
(PEG-diamine reagent B.sub.4) can be obtained from Huntsman
Chemical Co. of Houston, Tex. under the trade name JEFFAMINE.
[0076] C. Group C Reagents.
[0077] The group C reagents that can be used for synthesizing the
biologically absorbable copolymers according to embodiments of the
present invention are summarized in Table 5. The definition used to
describe a chemical family to which each of the group C reagents
belongs is also provided in Table 5.
TABLE-US-00005 TABLE 5 Group C Reagents No. Code Reagent General
Formula Reagent Definition 1 C.sub.1 ##STR00035## Dicarboxylic acid
2 C.sub.2 ##STR00036## PEG-dicarboxylic acid
[0078] In general formula of compound C.sub.1 presented in Table 5,
the substituent R.sub.3 is simply a covalent bond, or a straight
chained or branched aliphatic alkylene group C.sub.nH.sub.2n,
wherein n is an integer having a value between 0 and 12, e.g. a
single bond (n=0), methylene, ethylene, propylene, butylene,
amylene (pentylene), hexylene, heptylene, octylene, nonylene,
decylene, undecylene, or dodecylene group, or an aromatic group,
e.g., phenyl or para-phenylene. Some examples of dicarboxylic acids
that can be used as the reagent C.sub.1 are summarized in Table
6.
TABLE-US-00006 TABLE 6 Dicarboxylic Acids That Can Be Used As The
Reagent C.sub.1 Dicarboxylic Acid (HOOC--R.sub.3--COOH) No. R.sub.3
Formula Name 1 --(CH.sub.2).sub.2-- HOOC--(CH.sub.2).sub.2--COOH
succinic (butanedioic) acid 2 --(CH.sub.2).sub.4--
HOOC--(CH.sub.2).sub.4--COOH adipic (hexanedioic) acid 3
--(CH.sub.2).sub.8-- HOOC--(CH.sub.2).sub.8--COOH sebacic
(decanedioic) acid 4 (p)-C.sub.6H.sub.4--
HOOC-(p)C.sub.6H.sub.4--COOH terephthalic (1,4- benzene
dicarboxylic) acid
[0079] In addition to the dicarboxylic acids listed in Table 6,
examples of other dicarboxylic acids that can be also used include
oxalic acid, malonic acid, glutaric acid, pimelic acid, suberic
acid, or azelaic acid. As mentioned above, to synthesize the PEAs,
at least one reagent of group A can be reacted with at least one
reagent of group B and reagent C.sub.1. To make the poly(esters),
at least one reagent of group A can be reacted with reagent
C.sub.2.
[0080] One of several routes can be utilized to synthesize the
polymers of this invention. Those having ordinary skill in the art
can appreciate that the reagents of groups A, B, and C may
themselves contain hydrolysable bonds, i.e. ester or amide bonds.
These reagents can be then polymerized, the polymerization creating
additional bonds that may be both ester and amide bonds, only amide
bonds, or only ester bonds. Given that the reagents can be obtained
separately, the types of polymers formed during the polymerization
can belong to one of the following four categories (A), (B), (C),
or (D):
[0081] (A) Polymers in which amide bonds are formed between
reagents which themselves contain ester bonds. Using the reagent
codes defined earlier, these polymers can be described as products
of reaction between: [0082] (1) A.sub.1, B.sub.1 and C.sub.1
(A.sub.1-B.sub.1-C.sub.1); [0083] (2) A.sub.1, B.sub.4 and C.sub.1
(A.sub.1-B.sub.4-C.sub.1); [0084] (3) A.sub.4, B.sub.1 and C.sub.1
(A.sub.4-B.sub.1-C.sub.1); and [0085] (4) A.sub.1 and C.sub.2
(A.sub.1-C.sub.2).
[0086] (B) Polymers in which amide bonds are formed between
reagents which themselves contain neither ester nor amide bonds.
Using the reagent codes defined earlier, these polymers can be
described as products of reaction between: [0087] (1) A.sub.4,
B.sub.4 and C.sub.1 (A.sub.4-B.sub.4-C.sub.1); and [0088] (2)
A.sub.4 and C.sub.2 (A.sub.4-C.sub.2).
[0089] (C) Polymers in which both ester and amide bonds are formed
between the reagents. The subunits themselves may contain ester and
amide bonds, only ester bonds, only amide bonds, or neither ester
nor amide bonds. Using the reagent codes defined earlier, these
polymers can be described as products of reaction between: [0090]
(1) A.sub.1, B.sub.2 and C.sub.1 (A.sub.1-B.sub.2-C.sub.1); [0091]
(2) A.sub.1, B.sub.3 and C.sub.1 (A.sub.1-B.sub.3-C.sub.1); [0092]
(3) A.sub.2, B.sub.1 and C.sub.1 (A.sub.2-B.sub.1-C.sub.1); [0093]
(4) A.sub.2, B.sub.4 and C.sub.1 (A.sub.2-B.sub.4-C.sub.1); [0094]
(5) A.sub.3, B.sub.1 and C.sub.1 (A.sub.3-B.sub.1-C.sub.1); [0095]
(6) A.sub.3, B.sub.4 and C.sub.1 (A.sub.3-B.sub.4-C.sub.1); [0096]
(7) A.sub.4, B.sub.2 and C.sub.1 (A.sub.4-B.sub.2-C.sub.1); and
[0097] (8) A.sub.4, B.sub.3 and C.sub.1
(A.sub.4-B.sub.3-C.sub.1).
[0098] (D) Polymers in which ester bonds are formed between
reagents which themselves may contain amide bonds, or neither amide
nor ester bonds. Using the reagent codes defined earlier, these
polymers can be described as products of reaction between: [0099]
(1) A.sub.2, B.sub.2 and C.sub.1 (A.sub.2-B.sub.2-C.sub.1); [0100]
(2) A.sub.2, B.sub.3 and C.sub.1 (A.sub.2-B.sub.3-C.sub.1); [0101]
(3) A.sub.2 and C.sub.2 (A.sub.2-C.sub.2); [0102] (4) A.sub.3,
B.sub.2 and C.sub.1 (A.sub.3-B.sub.2-C.sub.1); [0103] (5) A.sub.3,
B.sub.3 and C.sub.1 (A.sub.3-B.sub.3-C.sub.1); and [0104] (6)
A.sub.3 and C.sub.2 (A.sub.3-C.sub.2).
[0105] Due to the types of bonds being formed, and the types of
bonds present, those having ordinary skill in the art will
understand that the polymerization scheme need be adjusted for each
category in order to form the desired polymer while not hydrolyzing
or degrading the existing bonds in the reagents, or creating
uncontrolled, mixed species. Some examples of the synthesis of
particular polymers are provided below in the "Examples" section of
the present application.
[0106] As a result of the synthesis, biologically absorbable PEAs
having a general formula (A) or poly(esters) having a general
formula (B) can be obtained:
-[M-P].sub.m-[M-Q].sub.n- (A)
-[M.sub.1-P].sub.p- (B)
wherein:
[0107] M is a moiety represented by the structure
##STR00037##
[0108] P is a moiety including
##STR00038##
[0109] Q is a moiety selected from a group consisting of
##STR00039##
[0110] M.sub.1 is a moiety represented by the structure
##STR00040##
[0111] R.sub.1, R.sub.2, R.sub.3, X and Y are substitutents and
moieties as defined above;
[0112] Z is a moiety that can be derived from a compound selected
from a group consisting of poly(ethylene glycol)(PEG),
polypropylene glycol) (PPG), random or block copolymers of PEG and
PPG, hyaluronic acid, poly(2-hydroxyethylmethacrylate),
poly(3-hydroxypropyl methacrylamide), poly(styrene sulfonate),
poly(vinyl pyrrolidone), and cellulosics; and
[0113] m, n, and p are integers where the value of m can be between
5 and 1,800, the value of n can be between 1 and 800 and the value
of p can be between 4 and 1,500.
[0114] Any layer of the stent coating can contain any amount of the
biologically absorbable copolymers described above, or a blend of
more than one of such copolymers. If less than 100% of the layer is
made of the biologically absorbable copolymers, or blends thereof,
described above, alternative polymers can comprise the balance.
Examples of the alternative polymers that can be used include
polyacrylates, such as poly(butyl methacrylate), poly(ethyl
methacrylate), and poly(ethyl methacrylate-co-butyl methacrylate),
and fluorinated polymers and/or copolymers, such as poly(vinylidene
fluoride) and poly(vinylidene fluoride-co-hexafluoropropene),
poly(N-vinyl pyrrolidone), poly(hydroxyvalerate), poly(L-lactic
acid), polycaprolactone, poly(lactide-co-glycolide),
poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),
polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid),
poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene
carbonate), polyphosphoester, polyphosphoester urethane, poly(amino
acids), cyanoacrylates, poly(trimethylene carbonate),
poly(iminocarbonate), co-poly(ether-esters), polyalkylene oxalates,
polyphosphazenes, biomolecules (such as fibrin, fibrinogen,
cellulose, starch, collagen and hyaluronic acid), polyurethanes,
silicones, polyesters, polyolefins, polyisobutylene and
ethylene-alphaolefin copolymers, vinyl halide polymers and
copolymers (such as polyvinyl chloride), polyvinyl ethers (such as
polyvinyl methyl ether), polyvinylidene chloride,
polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as
polystyrene), polyvinyl esters (such as polyvinyl acetate),
copolymers of vinyl monomers with each other and olefins, e.g.,
poly(ethylene-co-vinyl alcohol) (EVAL), ethylene-methyl
methacrylate copolymers, acrylonitrile-styrene copolymers, ABS
resins, and ethylene-vinyl acetate copolymers; polyamides (such as
Nylon 66 and polycaprolactam), alkyd resins, polycarbonates,
polyoxymethylenes, polyimides, polyethers, epoxy resins,
polyurethanes, rayon, rayon-triacetate, cellulose, cellulose
acetate, cellulose butyrate, cellulose acetate butyrate,
cellophane, cellulose nitrate, cellulose propionate, cellulose
ethers, and carboxymethyl cellulose.
[0115] Representative examples of some solvents suitable for making
the stent coatings include N,N-dimethylacetamide (DMAC),
N,N-dimethylformamide (DMF), tethrahydrofurane (THF),
cyclohexanone, xylene, toluene, acetone, i-propanol, methyl ethyl
ketone, propylene glycol monomethyl ether, methyl butyl ketone,
ethyl acetate, n-butyl acetate, and dioxane. Some solvent mixtures
can be used as well. Representative examples of the mixtures
include:
[0116] (1) DMAC and methanol (e.g., a 50:50 by mass mixture);
[0117] (2) water, i-propanol, and DMAC (e.g., a 10:3:87 by mass
mixture);
[0118] (3) i-propanol, and DMAC (e.g., 80:20, 50:50, or 20:80 by
mass mixtures);
[0119] (4) acetone and cyclohexanone (e.g., 80:20, 50:50, or 20:80
by mass mixtures);
[0120] (5) acetone and xylene (e.g. a 50:50 by mass mixture);
[0121] (6) acetone, FLUX REMOVER AMS, and xylene (e.g., a 10:50:40
by mass mixture); and
[0122] (7) 1,1,2-trichloroethane and chloroform (e.g., a 80:20 by
mass mixture).
[0123] FLUX REMOVER AMS is trade name of a solvent manufactured by
Tech Spray, Inc. of Amarillo, Tex. comprising about 93.7% of a
mixture of 3,3-dichloro-1,1,1,2,2-pentafluoropropane and
1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance of
methanol, with trace amounts of nitromethane. Those having ordinary
skill in the art will select the solvent or a mixture of solvents
suitable for a particular polymer being dissolved.
[0124] The therapeutic substance which can be used in the reservoir
layer can include any substance capable of exerting a therapeutic
or prophylactic effect for a patient. The therapeutic substance may
include small molecule substances, peptides, proteins,
oligonucleotides, and the like. The therapeutic substance could be
designed, for example, to inhibit the activity of vascular smooth
muscle cells. It can be directed at inhibiting abnormal or
inappropriate migration and/or proliferation of smooth muscle cells
to inhibit restenosis.
[0125] Examples of therapeutic substances that can be used include
antiproliferative substances such as actinomycin D, or derivatives
and analogs thereof (manufactured by Sigma-Aldrich of Milwaukee,
Wis., or COSMEGEN available from Merck). Synonyms of actinomycin D
include dactinomycin, actinomycin IV, actinomycin I.sub.1,
actinomycin X.sub.1, and actinomycin C.sub.1. The active agent can
also fall under the genus of antineoplastic, anti-inflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,
antibiotic, antiallergic and antioxidant substances. Examples of
such antineoplastics and/or antimitotics include paclitaxel (e.g.
TAXOL.RTM. by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel
(e.g. Taxotere.RTM., from Aventis S.A., Frankfurt, Germany)
methotrexate, azathioprine, vincristine, vinblastine, fluorouracil,
doxorubicin hydrochloride (e.g. Adriamycin.RTM. from Pharmacia
& Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin.RTM.
from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such
antiplatelets, anticoagulants, antifibrin, and antithrombins
include sodium heparin, low molecular weight heparins, heparinoids,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist antibody, recombinant
hirudin, and thrombin inhibitors such as ANGIOMAX (Biogen, Inc.,
Cambridge, Mass.). Examples of such cytostatic or antiproliferative
agents include angiopeptin, angiotensin converting enzyme
inhibitors such as captopril (e.g. Capoten.RTM. and Capozide.RTM.
from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or
lisinopril (e.g. Prinivil.RTM. and Prinzide.RTM. from Merck &
Co., Inc., Whitehouse Station, N.J.); calcium channel blockers
(such as nifedipine), colchicine, fibroblast growth factor (FGF)
antagonists, fish oil (omega 3-fatty acid), histamine antagonists,
lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol
lowering drug, brand name Mevacor.RTM. from Merck & Co., Inc.,
Whitehouse Station, N.J.), monoclonal antibodies (such as those
specific for Platelet-Derived Growth Factor (PDGF) receptors),
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitors, suramin, serotonin blockers, steroids, thioprotease
inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric
oxide. An example of an antiallergic agent is permirolast
potassium. Other therapeutic substances or agents which may be
appropriate include alpha-interferon, genetically engineered
epithelial cells, tacrolimus, dexamethasone, and rapamycin and
structural derivatives or functional analogs thereof, such as
40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of
EVEROLIMUS available from Novartis),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin.
[0126] The coatings and methods of the present invention have been
described with reference to a stent, e.g., a balloon expandable or
self-expandable stent. The use of the coating is not limited to
stents, and the coating can also be used with a variety of other
medical devices, such as implantable medical devices. Examples of
the implantable medical device that can be used in conjunction with
the embodiments of this invention include stent-grafts, grafts
(e.g., aortic grafts), catheters, guidewires, artificial heart
valves, cerebrospinal fluid shunts, pacemaker electrodes, axius
coronary shunts and endocardial leads (e.g., FINELINE and ENDOTAK,
available from Guidant Corporation). The underlying structure of
the device can be of virtually any design. The device can be made
of a metallic material or an alloy such as, but not limited to,
cobalt-chromium alloys (e.g., ELGILOY), stainless steel (316L),
"MP35N," "MP20N," ELASTINITE (Nitinol), tantalum, tantalum-based
alloys, nickel-titanium alloy, platinum, platinum-based alloys such
as, e.g., platinum-iridium alloy, iridium, gold, magnesium,
titanium, titanium-based alloys, zirconium-based alloys, or
combinations thereof. Devices made from bioabsorbable or biostable
polymers can also be used with the embodiments of the present
invention. "MP35N" and "MP20N" are trade names for alloys of
cobalt, nickel, chromium and molybdenum available from Standard
Press Steel Co. of Jenkintown, Pa. "MP35N" consists of 35% cobalt,
35% nickel, 20% chromium, and 10% molybdenum. "MP20N" consists of
50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
[0127] Medical devices can be also made from the materials of the
invention. Moreover, the polymers can be used for a variety of
medical applications, including particles for drug delivery to
embolize blood vessels. The polymers of the present invention can
have a variety of medical applications, including the treatment of
stenosis, restenosis, and cancer.
3. Examples
[0128] The following examples are provided to further illustrate
embodiments of the present invention.
Example 1
[0129] A copolymer having formula (III) can be synthesized and used
in practice of the invention.
##STR00041##
[0130] The copolymer (III) is a product of copolymerization of
reagents A.sub.1, B.sub.1, and C.sub.1. A.sub.1 can be a
diol-diamine shown in Table 1 where R.sub.1 is i-C.sub.4H.sub.9 and
X is (CH.sub.2).sub.6. In other words, A.sub.1 can be synthesized
by condensation of leucine with 1,6-hexanediol. B.sub.1 can be a
PEG-diester-diamine shown in Table 4 where R.sub.1 is
i-C.sub.4H.sub.9 and PEG.sub.300 symbolizes a moiety derived from
poly(ethylene glycol) having molecular weight of about 300 Daltons.
In other words, B.sub.1 can be synthesized by condensation of
leucine with poly(ethylene glycol) having molecular weight of about
300 Daltons. C.sub.1 can be a dicarboxylic acid shown in Table 5
where R.sub.3 is (CH.sub.2).sub.8 (sebacic acid, which is also
shown in Table 6).
[0131] To synthesize copolymer (III), about 30.8 ml dry
triethylamine (about 0.22 mole) in about 55 ml dry solvent
N,N'-dimethylacetamide at room temperature can be added to a
mixture of:
[0132] (a) about 36.37 g (about 0.053 mole) di-para-toluenesulfonic
acid salt of bis-(L-leucine)-1,6-hexylene diester;
[0133] (b) about 39.3 g (about 0.047 mole) di-para-toluenesulphonic
acid salt of bis-(L-leucine)-PEG300 diester; and
[0134] (c) about 44.4 g (about 0.1 mole) di-para-nitrophenyl
sebacinate.
[0135] The mixture can be stirred until full dissolution and then
the temperature can be raised to about 80.degree. C. After stirring
for about 24 hours, the viscous mixture can be cooled to room
temperature, diluted with about 100 ml ethanol, and precipitated
into an excess of water. The separated polymer can be thoroughly
washed with water, spread thinly onto a TEFLON pan, and dried at
room temperature under vacuum (about 70 mm Hg) for about 24
hours.
Example 2
[0136] A copolymer having formula (IV) can be synthesized and used
in practice of the invention.
##STR00042##
[0137] The copolymer (IV) is a product of copolymerization of
reagents A.sub.1, B.sub.1, and C.sub.1. A.sub.1 can be a
diol-diamine shown in Table 1, where R.sub.1 is CH.sub.3 and X is
(CH.sub.2).sub.4. In other words, A.sub.1 can be synthesized by
condensation of alanine with 1,4-butanediol. B.sub.1 can be a
PEG-diester-diamine shown in Table 4 where R.sub.1 is
i-C.sub.4H.sub.9 and PEG.sub.300 symbolizes a moiety derived from
poly(ethylene glycol) having molecular weight of about 300 Daltons.
In other words, B.sub.1 can be synthesized by condensation of
alanine with poly(ethylene glycol) having molecular weight of about
300 Daltons. C.sub.1 can be a dicarboxylic acid shown in Table 5
where R.sub.3 is (CH.sub.2).sub.2 (succinic acid, which is also
shown in Table 6).
[0138] To synthesize copolymer (IV), about 30.8 ml dry
triethylamine (about 0.22 mole), in about 55 ml dry solvent
N,N'-dimethylacetamide, at room temperature, can be added to a
mixture of:
[0139] (a) about 30.43 g (about 0.053 mole) di-para-toluenesulfonic
acid salt of bis-(L-alanine)-1,4-butylene diester;
[0140] (b) about 36.86 g (about 0.047 mole) di-para-toluenesulfonic
acid salt of bis-(L-alanine)-PEG300 diester; and
[0141] (c) about 36.0 g (about 0.1 mole) di-para-nitrophenyl
succinate.
[0142] The mixture can be stirred until full dissolution and then
the temperature can be raised to about 80.degree. C. After stirring
for about 24 hours, the viscous mixture can be cooled to room
temperature, diluted with about 100 ml ethanol, and precipitated
into an excess of water. The separated polymer is thoroughly washed
with water, spread thinly into a TEFLON pan, and dried at room
temperature under vacuum (about 70 mm Hg) for about 24 hours.
Example 3
[0143] A copolymer having formula (V) can be synthesized and used
in practice of the invention.
##STR00043##
[0144] The copolymer (V) is a product of copolymerization of
reagents A.sub.1, B.sub.1, and C.sub.1. A.sub.1 can be a
diol-diamine shown in Table 1 where R.sub.1 is i-C.sub.4H.sub.9 and
X is (CH.sub.2).sub.4. In other words, A.sub.1 can be synthesized
by condensation of leucine with 1,4-butanediol. B.sub.1 can be a
PEG-diester-diamine shown in Table 4 where R.sub.1 is
i-C.sub.4H.sub.9 and PEG.sub.300 symbolizes a moiety derived from
poly(ethylene glycol) having molecular weight of about 300 Daltons.
In other words, B.sub.1 can be synthesized by condensation of
leucine with poly(ethylene glycol) having molecular weight of about
300 Daltons. C.sub.1 can be a dicarboxylic acid shown in Table 5
where R.sub.3 is para-C.sub.6H.sub.4 (terephthalic acid, which is
also shown in Table 6).
[0145] The copolymer (V) can be obtained using the same synthetic
technique as described in Example 2 for copolymer (IV), except
di-para-nitrophenyl terephthalate can be used to make the copolymer
(V), instead of di-para-nitrophenyl succinate. In copolymer (V),
the value of n can be between about 64 and about 97 and the value
of m can be between about 3 and about 36, where m+n=100.
Example 4
[0146] A copolymer having formula (VI) can be synthesized and used
in practice of the invention.
##STR00044##
[0147] The copolymer (VI) is a product of copolymerization of
reagents A.sub.1, B.sub.2, and C.sub.1. A.sub.1 can be a
diol-diamine shown in Table 1 where R.sub.1 is i-C.sub.4H.sub.9 and
X is (CH.sub.2).sub.6. In other words, A.sub.1 can be synthesized
by condensation of leucine with 1,6-hexanediol. B.sub.2 can be a
PEG-amidediol shown in Table 4 where R.sub.2 is methylmethylene
CH(CH.sub.3).
[0148] In other words, B.sub.2 can be synthesized by condensation
of lactic acid with PEG-diamine shown as reagent B.sub.4 in Table
4. PEG-diamine can be based on poly(ethylene glycol) having
molecular weight of about 600 Daltons, which is symbolized by the
abbreviation PEG.sub.600.
[0149] For example, JEFFAMINE ED-600 available from Huntsman Corp.
can be used. JEFFAMINE ED-600 is a trade name of
O,O'-bis-[(2-aminopropyl) poly(propylene
glycol)-block-poly(ethylene glycol)-block-poly(propylene glycol)],
which is a polyether diamine with a polyalkylene oxide backbone.
The molecular weight of JEFFAMINE ED-600 is about 600 Daltons.
[0150] C.sub.1 can be a dicarboxylic acid shown in Table 5 where
R.sub.3 is (CH.sub.2).sub.8 (sebacic acid, which is also shown in
Table 6). In copolymer (VI), the value of n can be between about 60
and about 93 and the value of m can be between about 7 and about
40, where m+n=100.
Example 5
[0151] A copolymer having formula (VII) can be synthesized and used
in practice of the invention.
##STR00045##
[0152] The copolymer (VII) can be synthesized in same way as the
copolymer (VI) of Example 4, except instead of a reagent B.sub.2
(e.g., PEG-amidediol), reagent B.sub.4 (e.g., PEG-diamine) shown in
Table 4 can be used. In copolymer (VII), the value of n can be
between about 59 and about 96 and the value of m can be between
about 4 and about 41, where m+n=100.
Example 6
[0153] A copolymer having formula (VIII) can be synthesized and
used in practice of the invention.
##STR00046##
[0154] The copolymer (VIII) is a product of copolymerization of
reagents A.sub.2, B.sub.1, and C.sub.1. A.sub.2 can be an amidediol
shown in Table 1 where R.sub.2 is methylmethylene CH(CH.sub.3) and
Y is (CH.sub.2).sub.4. In other words, A.sub.2 can be synthesized
by condensation of lactic acid with the 1,4-diamino butane
(putrescine).
[0155] B.sub.1 can be a PEG-diester-diamine shown in Table 4 where
R.sub.1 is i-C.sub.4H.sub.9. In other words, B.sub.1 can be
synthesized by condensation of leucine with poly(ethylene glycol)
having molecular weight of about 2,000 Daltons, which is symbolized
by the abbreviation PEG.sub.2000.
[0156] C.sub.1 can be a dicarboxylic acid shown in Table 5 where
R.sub.3 is (CH.sub.2).sub.8 (sebacic acid, which is also shown in
Table 6). In copolymer (VIII), the value of n can be between about
86 and about 99 and the value of m can be between about 1 and about
14, where m+n=100.
Example 7
[0157] A copolymer having formula (IX) can be synthesized and used
in practice of the invention.
##STR00047##
[0158] The copolymer (IX) can be synthesized in same way as the
copolymer (VIII) of Example 6, except instead of a reagent B.sub.1
(PEG-diester-diamine), reagent B.sub.2 (PEG-amidediol) shown in
Table 4 can be used, where R.sub.2 is methylmethylene CH(CH.sub.3).
In other words, B.sub.2 can be synthesized by condensation of
lactic acid with PEG-diamine shown as reagent B.sub.4 in Table 4.
PEG-diamine can be based on poly(ethylene glycol) having molecular
weight of about 600 Daltons, which is symbolized by the
abbreviation PEG.sub.600. In copolymer (IX), the integer value of n
can be between about 69 and about 98 and the value of m can be
between about 2 and about 31, where m+n=100.
Example 8
[0159] A copolymer having formula (X) can be synthesized and used
in practice of the invention.
##STR00048##
[0160] The copolymer (X) can be synthesized in same way as the
copolymer (IX) of Example 7, except that a reagent B.sub.3 shown in
Table 4, (HO--R.sub.4--OH), for example, PEG-diol, can be used
instead of a reagent B.sub.2 (e.g., PEG-amidediol). PEG-diol can be
based on poly(ethylene glycol) having molecular weight of about 300
Daltons, which is symbolized by the abbreviation PEG.sub.300.
[0161] A.sub.2 and B.sub.3 reagents can be combined and reacted
first to form an A.sub.2-B.sub.3 moiety, followed by adding a
C.sub.1 reagent and completing polycondensation. The conditions for
the synthesis can be determined by those having ordinary skill in
the art. For example, the final step of the reaction (reacting
C.sub.1 with the A.sub.2-B.sub.3 moiety) can be conducted in the
presence of a coupling agent such as carbodiimide.
[0162] Optionally, instead of a C.sub.1 diacid, a dichloride of the
diacid can be used, for instance, sebacyl dichloride. In copolymer
(X), the value of n can be between about 54 and about 96 and the
value of m can be between about 4 and about 46, where m+n=100.
[0163] Alternative versions of the copolymer (X) can be also
synthesized to make the copolymer (X) harder. For example, an amino
acid with shorter R.sub.2 group or a shorter chain diamine (e.g.,
ethanediamine instead of 1,4-butanediamine) can be used for
preparing the reagent A.sub.2.
[0164] Other possible methods of increasing the hardness of the
copolymer (X) include using a shorter dicarboxylic acid C.sub.1
(e.g., adipic acid instead of sebacic acid), or using PEG with
lower molecular weight, or reducing the proportion of the
PEG-containing units in the overall copolymer (X).
Example 9
[0165] A copolymer having formula (XI) can be synthesized and used
in practice of the invention.
##STR00049##
[0166] The copolymer (XI) can be synthesized in same way as the
copolymer (X) of Example 9, except that a reagent B.sub.4 (such as
PEG-diamine) shown in Table 4 can be used instead of a reagent
B.sub.3 (e.g., PEG-diol). PEG-diamine can be based on poly(ethylene
glycol) having molecular weight of about 600 Daltons, which is
symbolized by the abbreviation PEG.sub.600. In copolymer (XI), the
value of n can be between about 3 and about 35, and the value of m
can be between about 97 and about 65, where m+n=100.
Example 10
[0167] A copolymer having formula (XII) can be synthesized and used
in practice of the invention.
##STR00050##
[0168] The copolymer (XII) can be synthesized in same way as the
copolymer (VIII) of Example 6, except that a reagent A.sub.3 (diol)
shown in Table 1 can be used instead of a reagent A.sub.2
(amidediol), where X is (CH.sub.2).sub.6. In other words,
1,6-hexanediol can be used as the reagent A.sub.3. A poly(ethylene
glycol) moiety having molecular weight of about 300 Daltons can
comprise a part of copolymer (XII), which is symbolized by the
abbreviation PEG.sub.300. In copolymer (XII), the value of n can be
between about 98 and about 71 and the value of m can be between
about 2 and about 29, where m+n=100.
Example 11
[0169] A copolymer having formula (XIII) can be synthesized and
used in practice of the invention.
##STR00051##
[0170] The copolymer (XIII) can be synthesized in same way as the
copolymer (XII) of Example 10, except that a reagent B.sub.2 (e.g.,
PEG-amidediol) shown in Table 4 can be used instead of a reagent
B.sub.1 (such as PEG-diester-diamine), where R.sub.2 is
methylmethylene CH(CH.sub.3). In other words, B.sub.2 can be
synthesized by condensation of lactic acid with PEG-diamine shown
as reagent B.sub.4 in Table 4. PEG-diamine can be based on
poly(ethylene glycol) having molecular weight of about 600 Daltons,
which is symbolized by the abbreviation PEG.sub.600.
[0171] In copolymer (XIII), the value of n can be between about 98
and about 76 and the value of m can be between about 2 and about
24, where m+n=100.
Example 12
[0172] A copolymer having formula (XIV) can be synthesized and used
in practice of the invention.
##STR00052##
[0173] The copolymer (XIV) can be synthesized in same way as the
copolymer (XIII) of Example 11, except that a reagent B.sub.4
(e.g., PEG-diamine) as shown in Table 4 can be used instead of a
reagent B.sub.2 (such as PEG-amidediol). PEG-diamine can be based
on poly(ethylene glycol) having molecular weight between about 300
and about 2,400 Daltons, for example, about 600 Daltons, which is
symbolized by the abbreviation PEG.sub.600. Reagent A.sub.3
(1,6-hexanediol) and reagent C.sub.1 (sebacic acid) can be combined
and reacted first to form an A.sub.3-C.sub.1 moiety, followed by
adding reagent B.sub.4 and completing polycondensation. To
facilitate the formation of the A.sub.3-C.sub.1 moiety, sebacyl
dichloride can be used as the C.sub.1 reagent instead of sebacic
acid. The conditions for the synthesis can be determined by those
having ordinary skill in the art.
[0174] In copolymer (XIV), the value of n can be between about 98
and about 73 and the value of m can be between about 2 and about
27, where m+n=100.
Example 13
[0175] A copolymer having formula (XV) can be synthesized and used
in practice of the invention.
##STR00053##
[0176] The copolymer (XV) can be synthesized in same way as the
copolymer (VIII) of Example 6, except that a reagent A.sub.4
(diamine) shown in Table 1 can be used instead of a reagent A.sub.2
(amidediol), where Y is (CH.sub.2).sub.4.
[0177] In other words, putrescine can be used as the reagent
A.sub.4. A poly(ethylene glycol) moiety having molecular weight
between about 300 Daltons and about 4,000 Daltons, for example,
about 300 Daltons, can comprise a part of copolymer (XV), which is
symbolized by the abbreviation PEG.sub.3oo.
[0178] In copolymer (XV), the value of n can be between about 98
and about 73 and the value of m can be between about 2 and about
27, where m+n=100.
Example 14
[0179] A copolymer having formula (XVI) can be synthesized and used
in practice of the invention.
##STR00054##
[0180] The copolymer (XVI) can be synthesized in same way as the
copolymer (IX) of Example 7, except that a reagent A.sub.4
(diamine) shown in Table 1 can be used instead of a reagent A.sub.2
(amidediol), where Y is (CH.sub.2).sub.4. In other words,
putrescine can be used as the reagent A.sub.4.
[0181] A poly(ethylene glycol) moiety having molecular weight
between about 300 Daltons and about 4,000 Daltons, for example,
about 600 Daltons, can comprise a part of copolymer (XVI), which is
symbolized by the abbreviation PEG.sub.600.
[0182] In copolymer (XVI), the value of n can be between about 98
and about 77, and the value of m can be between about 2 and about
23, where m+n=100.
Example 15
[0183] A copolymer having formula (XVII) can be synthesized and
used in practice of the invention.
##STR00055##
[0184] The copolymer (XVII) can be synthesized in same way as the
copolymer (X) of Example 8, except that a reagent A.sub.4 (diamine)
shown in Table 1 can be used instead of a reagent A.sub.2
(amidediol), where Y is (CH.sub.2).sub.4. In other words,
putrescine can be used as the reagent A.sub.4.
[0185] A poly(ethylene glycol) moiety having molecular weight
between about 300 Daltons and about 4,000 Daltons, for example,
about 2,000 Daltons can comprise a part of copolymer (XVII), which
is symbolized by the abbreviation PEG.sub.2000.
[0186] In copolymer (XVII), the value of n can be between about 995
about 910 the value of m can be between about 5 and about 90, where
m+n=1000.
Example 16
[0187] A copolymer having formula (XVIII) can be synthesized and
used in practice of the invention.
##STR00056##
[0188] To synthesize the copolymer (XVIII), reagents A.sub.1 and
C.sub.2, can be combined in the molar ratio of about 1:1 and
copolymerized. The conditions for the synthesis can be determined
by those having ordinary skill in the art. A.sub.1 can be a
diol-diamine shown in Table 1, where R.sub.1 is i-C.sub.4H.sub.9
and X is (CH.sub.2).sub.6. In other words, A.sub.1 can be
synthesized by condensation of leucine with 1,6-hexanediol. C.sub.2
can be a PEG-dicarboxylic acid shown in Table 5, derived from
poly(ethylene glycol) having molecular weight of about 1,000
Daltons, which is symbolized by the abbreviation PEG.sub.1000. A
total molecular weight of the copolymer (XVIII) can be between
about 20,000 Daltons and about 50,000 Daltons. The value of the
integer p can be between about 14 and about 360.
Example 17
[0189] A copolymer having formula (XIX) can be synthesized and used
in practice of the invention.
##STR00057##
[0190] The copolymer (XIX) can be synthesized in same way as the
copolymer (XVIII) of Example 16, except that a reagent A.sub.2
(amidediol) shown in Table 1 can be used instead of a reagent
A.sub.1 (diol-diamine), where R.sub.2 is methylmethylene
CH(CH.sub.3), and Y is (CH.sub.2).sub.4. In other words, A.sub.2
can be synthesized by condensation of lactic acid with putrescine.
C.sub.2 can be a PEG-dicarboxylic acid shown in Table 5 derived
from poly(ethylene glycol) having molecular weight of about 1,000
Daltons, which is symbolized by the abbreviation PEG.sub.1000.
[0191] A total molecular weight of the copolymer (XIX) can be
between about 20,000 Daltons and about 50,000 Daltons. The value of
the integer p can be between about 15 and about 390.
Example 18
[0192] Co-poly-{[N,N'-adipoyl-bis-(L-alanine)-1,4-butylene
diester].sub.37-[N,N'-adipoyl-bis-(L-alanine)-PEG300
diester].sub.67} having formula (XX) can be synthesized and used in
practice of the invention. This copolymer belongs to category (A),
type A.sub.1-B.sub.1-C.sub.1, described above.
##STR00058##
[0193] To synthesize the copolymer (XX), about 41 ml (about 0.293
mole) dry triethylamine in about 75 ml dry solvent
N,N'-dimethylacetamide, at room temperature, can be added to a
mixture of:
[0194] (a) about 28.64 g (about 0.0497 mole)
di-para-toluenesulfonic acid salt of bis-(L-alanine)-1,4-butylene
diester;
[0195] (b) about 65.57 g (about 0.0834 mole)
di-para-toluenesulphonic acid salt of bis-(L-alanine)-PEG300
diester; and
[0196] (c) about 51.62 g (about 0.1331 mole) di-para-nitrophenyl
adipate.
[0197] The mixture can be stirred until full dissolution and then
the temperature can be raised to about 80.degree. C. After stirring
for about 24 hours, the viscous mixture can be cooled to room
temperature, diluted with about 100 ml ethanol, and precipitated
into an excess of water. The separated polymer can be thoroughly
washed with water, spread thinly onto a TEFLON pan, and dried at
room temperature under vacuum (about 70 mm Hg) for about 24
hours.
[0198] As amide bonds are formed in the presence of existing ester
bonds, mild conditions need to be used, and this will be understood
by those having ordinary skill in the art. For example,
polymerization techniques using good leaving groups such as
para-nitrophenol or carboxyl groups activated by carbodiimides can
be used. In this invention, the range of stoichiometries can be
determined by the desired mass content of PEG.
[0199] For example, the final polymer can contain between about 5
mass % and about 50 mass % of PEG. For copolymer (XX), this
corresponds to molar ratios of the two blocks of
(alanine/butanediol-adipic acid) (A.sub.1-C.sub.1 blocks) and
(alanine/PEG-adipic acid) (B.sub.1-C.sub.1 blocks) between about
94:6 and about 12:88.
Example 19
[0200] Co-poly-{[N,N'-sebacyl-1,4-butylene
diamide].sub.86-[N,N'-sebacyl-(ED-600) diamide].sub.14} having
formula (XXI) can be synthesized and used in practice of the
invention. This copolymer belongs to category (B), type
(A.sub.4-B.sub.4-C.sub.1), described above.
##STR00059##
[0201] In formula (XXI), "ED-600" is an abbreviation symbolizing
JEFFAMINE ED-600 polymer described above (see Example 4).
[0202] To synthesize the copolymer (XXI), about 104 ml (about 0.744
mole) dry triethylamine in about 65 ml dry solvent
N,N'-dimethylacetamide, at room temperature, can be added to a
mixture of:
[0203] (a) about 23.38 g (about 0.266 mole) dry 1,4-diaminobutane;
and
[0204] (b) about 25 g (about 0.0417 mole) dry ED-600.
[0205] The mixture can be stirred, under a nitrogen atmosphere at
room temperature, until full dissolution. The mixture can be cooled
in ice water and about 80.75 g (about 0.338 mole) sebacoyl chloride
can be added dropwise with stirring. The solution can be allowed to
come to ambient temperature with stirring stirred continued
overnight. The viscous mixture can then be precipitated into an
excess of water. The separated polymer can be thoroughly washed
with water, spread thinly into a TEFLON pan, and dried at room
temperature under vacuum (about 70 mm Hg) for about 24 hours.
[0206] As only amide bonds are present, without any other
hydrolysable groups, harsher synthetic conditions can be used for
this category as understood by those having ordinary skill in the
art. For example, acid chlorides can be used. The mass contents of
PEG in the final copolymer (XXI) can be between about 5 mass % and
about 50 mass %. For copolymer (XXI), this corresponds to molar
ratios of the two blocks of diamine-sebacic acid (A.sub.4-C.sub.1
blocks) and ED-600-sebacic acid (B.sub.4-C.sub.1 blocks) of between
about 97:3 and about 57:43.
Example 20
[0207] Co-poly-{[N,N'-succinyl-bis-(L-leucine)-1,3-propylene
diester].sub.82-[succinyl-PEG.sub.600 diester].sub.18} having
formula (XXII) can be synthesized and used in practice of the
invention. This copolymer belongs to category (C), type
(A.sub.1-B.sub.3-C.sub.1), described above.
##STR00060##
[0208] To synthesize the copolymer (XXII), about 26.8 g (about
0.227 mole) succinic acid, and about 52.3 g (about 0.454 mole)
N-hydroxysuccinimide can be added to about 100 ml dry
N,N'-dimethylformamide at room temperature under nitrogen and
dissolved with stirring. About 93.67 g (about 0.454 mole)
dicyclohexylcarbodiimide (DCC) can be to the mixture added, and the
mixture can be allowed to stir for about 16 hours at room
temperature.
[0209] The reaction mixture can be filtered through filter paper to
remove the urea byproduct, and the solution can be placed into a
reaction flask. The following compounds can then be added to the
reaction mixture with continued stirring:
[0210] (a) about 55.9 g (about 0.185 mole) the free base of
bis-(L-leucine)-1,3-propylene diester; and
[0211] (b) about 25 g (about 0.0417 mole) poly(ethylene glycol)
having molecular weight of about 600 Daltons (PEG600).
[0212] The mixture can be stirred at room temperature for about 2
hours and then the temperature can be increased to about 60.degree.
C. and stirred for about two more hours. The polymer can
precipitated by adding the reaction solution dropwise to about 2
liters of ethyl acetate with stirring. The precipitated polymer can
be placed as a thin layer into a TEFLON pan and dried at room
temperature under vacuum (about 70 mm Hg) for about 24 hours.
[0213] In this category, both amide and ester bonds are present in
the copolymer. Accordingly, mild conditions need to be used, as
understood by those having ordinary skill in the art. For example,
carboxylate groups activated by carbodiimides can be used or good
leaving groups such as para-nitro-phenol can be used. The mass
contents of PEG in the final copolymer (XXII) can be between about
5 mass % and about 50 mass %. For copolymer (XXII), this
corresponds to molar ratios of the two blocks of
leucine/propanediol-succinic acid (A.sub.1-C.sub.1 blocks) and
PEG-diol-succinic acid (B.sub.3-C.sub.1 blocks) between about 94:6
and about 12:88.
Example 21
[0214] Co-poly-{[terephthalyl-bis-(D,L-lactate)-1,4-butylene
diamide].sub.81-[terphthalyl-bis-(glycolate)-ED600 diamide].sub.19}
having formula (XXIII) can be synthesized and used in practice of
the invention. This copolymer belongs to category (D), type
(A.sub.2-B.sub.2-C.sub.1), described above.
##STR00061##
[0215] To synthesize the copolymer (XXIII), the following compounds
can be combined in a reaction flask equipped with nitrogen
atmosphere, vacuum port, and heating mantle:
[0216] (a) about 0.12 g (about 3.5.times.10.sup.-4 moles) titanium
tetrabutoxide;
[0217] (b) about 41.2 g (about 0.178 mole)
bis-(D,L-lactate)-1,4-butylene diamide;
[0218] (c) about 29.83 g (about 0.0417 mole) bis-(glycolate)-ED600
diamide, where (ED-600 is as described above; and
[0219] (d) about 42.6 g (about 0.219 mole) dimethyl
terephthalate.
[0220] The flask can be sealed and heated to about 180.degree. C.
for about 2 hours. After about 2 hours, the pressure can be reduced
to about 0.1 Torr, and the solution can be maintained at about
180.degree. C. for about two more hours.
[0221] In this category, only ester bonds present in the copolymer.
Amide bonds may, or may not, be present in the reagents.
Accordingly, transesterification reactions, under dehydrating
conditions, in the presence of the Lewis or Bronsted acid catalysts
can be used. Use of acid chlorides is also a viable synthetic
technique, because the only hydrolysable bonds that may be present
in the reagents are stable amide bonds. The mass contents of PEG in
the final copolymer (XXIII) can be between about 5 mass % and about
50 mass %. For copolymer (XXIII), this corresponds to molar ratios
of the two blocks of (A.sub.2-C.sub.1 blocks) (B.sub.2-C.sub.1
blocks) between about 97:3 and about 49:51.
Example 22
[0222] A first composition can be prepared, the composition
including:
[0223] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass %
co-poly-{[N,N'-sebacoyl-bis-(L-leucine)-1,6-hexylene
diester].sub.75-[N,N'-sebacoyl-L-lysine benzyl ester].sub.25};
[0224] (b) between about 0.1 mass % and about 2.0 mass %, for
example, about 0.5 mass % paclitaxel; and
[0225] (c) the balance, a solvent blend of ethanol and
1,1,2-trichloroethane, where the mass ratio between ethanol and
1,1,2-trichloroethane can be about 1:1.
[0226] The first composition can be applied onto the surface of
bare 12 mm VISION stent (available from Guidant Corporation).
Coating can be sprayed and dried to form a drug-polymer layer. A
spray coater can be used having a 0.014 round nozzle maintained at
ambient temperature with a feed pressure of about 2.5 psi (0.17
atm) and an atomization pressure of about 15 psi (1.02 atm).
Coating can be applied at about 20 .mu.g per pass. Between the
passes the stent can be dried for about 10 seconds in a flowing air
stream at about 50.degree. C. About 270 .mu.g of wet coating can be
applied. The stent can be baked at about 50.degree. C. for about
one hour, yielding a drug-polymer layer containing about 250 .mu.g
of dry coating.
[0227] A second composition can be prepared by mixing the following
components:
[0228] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % copolymer (XX) described in Example 18;
and
[0229] (b) the balance, a solvent blend of ethanol and
1,1,2-trichloroethane, where the mass ratio between ethanol and
1,1,2-trichloroethane can be about 1:1.
[0230] The second composition can be applied onto the dry
drug-polymer layer to form the topcoat layer. The same spraying
technique and equipment can be used for the applying the topcoat
layer as described for the drug-polymer layer. About 120 .mu.g of
wet coating can be applied, followed by drying, e.g., baking at
about 50.degree. C. for about one hour, yielding about 100 .mu.g of
a biocompatible topcoat layer.
Example 23
[0231] A first composition can be prepared by mixing the following
components:
[0232] (a) between about 1.0 mass % and about 15 mass %, for
example, about 2.0 mass % copolymer
co-poly-{[N,N'-sebacoyl-bis-(L-leucine)-1,6-hexylene
diester].sub.75-[N,N'-sebacoyl-L-lysine-4-amino-TEMPO
amide].sub.25}; and
[0233] (b) the balance, 100% ethanol.
[0234] The first composition can be applied onto the surface of
bare 12 mm VISION stent using equipment and coating technique
described in Example 22. About 120 .mu.g of wet coating can be
applied. The stents can be baked at about 50.degree. C. for about
one hour, yielding about 100 .mu.g of a dry primer layer. The
copolymer forming the primer layer includes 4-amino-TEMPO
(4-amino-2,2',6,6'-tetramethylpiperidine-1-oxy) moiety attached to
lysine via an amide linkage.
[0235] A second composition can be prepared by mixing the following
components:
[0236] (a) between about 0.1 mass % and about 3.0 mass %, for
example, about 2.0 mass % EVEROLIMUS; and
[0237] (b) the balance, 100% ethanol.
[0238] The second composition can be applied onto the dry primer
layer, to form the pure drug layer. The same spraying technique and
equipment can be used for the applying the drug layer as described
above. Coating can be applied at about 20 .mu.g per pass. Between
the passes the stent can be dried for about 10 seconds in a flowing
air stream at about 50.degree. C. About 110 .mu.g of neat drug
coating can be applied. The stent can be baked at about 50.degree.
C. for about one hour, yielding a pure dry drug-layer containing
about 100 .mu.g of dry coating.
[0239] A third composition can be prepared by mixing the following
components:
[0240] (a) between about 0.5 mass % and about 10 mass %, for
example, about 1.0 mass copolymer (XX) described in Example 18;
[0241] (b) between about 0.5 mass % and about 10 mass %, for
example, about 1.0 mass %
co-poly-{[N,N'-sebacoyl-bis-(L-leucine)-1,6-hexylene
diester].sub.75-[N,N'-sebacoyl-L-lysine benzyl ester].sub.25}
described in Example 22; and
[0242] (c) the balance, 100% ethanol.
[0243] The third composition can be applied onto the dry pure drug
layer to form the topcoat layer. The same spraying technique and
equipment can be used for the applying the topcoat layer as
described above. About 440 .mu.g of wet coating can be applied,
followed by drying, e.g., baking at about 50.degree. C. for about
one hour, yielding about 400 .mu.g of a biocompatible topcoat
layer, which can also control the release of the drug.
[0244] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *