U.S. patent application number 11/724555 was filed with the patent office on 2007-09-20 for biodegradable hydrophobic polysaccharide-based coatings.
This patent application is currently assigned to SurModics, Inc.. Invention is credited to Stephen J. Chudzik, Jeffrey J. Missling.
Application Number | 20070218102 11/724555 |
Document ID | / |
Family ID | 38461027 |
Filed Date | 2007-09-20 |
United States Patent
Application |
20070218102 |
Kind Code |
A1 |
Chudzik; Stephen J. ; et
al. |
September 20, 2007 |
Biodegradable hydrophobic polysaccharide-based coatings
Abstract
Implantable medical articles having a coating formed of
hydrophobic derivatives of natural biodegradable polysaccharides
are described. The coatings can include a bioactive agent, and
demonstrate desirable bioactive agent release profiles and can be
prepared to have high drug loading. The coated implantable medical
articles can be used to treat medical conditions, such as those
requiring prolonged administration of the bioactive agent at a
target location in the body.
Inventors: |
Chudzik; Stephen J.; (St.
Paul, MN) ; Missling; Jeffrey J.; (Eden Prairie,
MN) |
Correspondence
Address: |
KAGAN BINDER, PLLC
SUITE 200, MAPLE ISLAND BUILDING, 221 MAIN STREET NORTH
STILLWATER
MN
55082
US
|
Assignee: |
SurModics, Inc.
|
Family ID: |
38461027 |
Appl. No.: |
11/724555 |
Filed: |
March 15, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60782957 |
Mar 15, 2006 |
|
|
|
60900853 |
Feb 10, 2007 |
|
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Current U.S.
Class: |
424/426 ;
424/422; 424/428 |
Current CPC
Class: |
C08L 3/02 20130101; A61L
27/54 20130101; A61L 2300/41 20130101; A61L 2300/222 20130101; C08B
30/18 20130101; A61K 9/0024 20130101; A61L 31/10 20130101; A61L
31/16 20130101; A61L 31/148 20130101; A61F 9/0017 20130101; A61L
2300/604 20130101; A61F 2/14 20130101; A61K 9/0051 20130101; A61L
27/20 20130101; A61L 2300/606 20130101; A61L 27/20 20130101; C08L
5/16 20130101; A61L 31/10 20130101; C08L 5/16 20130101 |
Class at
Publication: |
424/426 ;
424/422; 424/428 |
International
Class: |
A61F 2/06 20060101
A61F002/06 |
Claims
1. An implantable medical article comprising a biodegradable
bioactive-agent releasing coating, the coating comprising a matrix
of hydrophobic derivatives of natural biodegradable polysaccharides
and bioactive-agent within the matrix, wherein the coating is
capable of releasing bioactive agent following placement of the
medical article in a subject.
2. The implantable medical article of claim 1 wherein the matrix
comprises hydrophobic derivatives having an average molecular
weight of 100,000 Da or less.
3. The implantable medical article of claim 2 wherein the matrix
comprises hydrophobic derivatives having an average molecular
weight of 50,000 Da or less.
4. The implantable medical article of claim 3 wherein the matrix
comprises hydrophobic derivatives having an average molecular
weight of 25,000 Da or less.
5. The implantable medical article of claim 4 wherein the matrix
comprises hydrophobic derivatives having an average molecular
weight in the range of 2000 Da to 20,000 Da.
6. The implantable medical article of claim 5 wherein the matrix
comprises hydrophobic derivatives having an average molecular
weight in the range of 4000 Da to 10,000 Da.
7. The implantable medical article of claim 1 wherein the
hydrophobic derivatives comprise a
poly-.alpha.(1.fwdarw.4)glucopyranose backbone.
8. The implantable medical article of claim 1 wherein the
hydrophobic derivatives comprise a plurality of groups pendent from
a polysaccharide backbone, the groups comprising a hydrocarbon
segment selected from the group consisting of linear, branched, and
cyclic C.sub.2-C.sub.18 groups.
9. The implantable medical article of claim 8 wherein the
hydrocarbon segment is selected from the group consisting of
linear, branched, and cyclic C.sub.4-C.sub.10 groups.
10. The implantable medical article of claim 9 wherein the
hydrocarbon segment is selected from the group consisting of
linear, branched, or cyclic C.sub.5-C.sub.7 groups.
11. The implantable medical article of claim 10 wherein the
plurality of groups pendent from the polysaccharide backbone
provide a degree of substitution in the range of 2-3.
12. The implantable medical article of claim 11 wherein the
hydrocarbon segment is a C.sub.6 aromatic group.
13. The implantable medical article of claim 9 wherein the
hydrocarbon segment is selected from the group consisting of
branched C.sub.4-C.sub.10 alkyl groups.
14. The implantable medical article of claim 13 wherein the
plurality of groups pendent from the polysaccharide backbone
provide a degree of substitution in the range of 0.5-1.5.
15. The implantable medical article of claim 1 wherein the
hydrophobic derivatives have a Tg of 35.degree. C. or greater.
16. The implantable medical article of claim 15 wherein the
hydrophobic derivatives have a Tg in the range of 40.degree. C. to
90.degree. C.
17. The implantable medical article of claim 1 wherein the
hydrophobic derivatives are present in the coating in an amount in
the range of 35 wt % to 90 wt %.
18. The implantable medical article of claim 17 wherein the
hydrophobic derivatives are present in the coating in an amount in
the range of 35 wt % to 60 wt %.
19. The implantable medical article of claim 1 wherein the
bioactive agent is present in the coating in an amount in the range
of 10 wt % to 65 wt %.
20. The implantable medical article of claim 1 wherein the coating
is formed on the surface of an implantable ocular device.
21. The implantable medical article of claim 1 wherein the coating
is formed on the surface of an implantable intravascular
device.
22. The implantable medical article of claim 1 wherein the
bioactive agent is coupled to a polysaccharide backbone of the
hydrophobic derivatives via a hydrolyzable ester bond.
23. The implantable medical article of claim 1 wherein the coating
further comprises a biocompatible hydrophilic polymer.
24. The implantable medical article of claim 23 wherein the
biocompatible hydrophilic polymer is selected from the group
consisting of group consisting of poly(ethylene glycol),
hydrophilic polysaccharides, polyvinyl pyrrolidones, polyvinyl
alcohols, low molecular weight methyl cellulose, hydroxypropyl
methyl cellulose (HPMC).
25. A method for delivering a bioactive agent to a subject
comprising steps of: implanting at a target site in a subject an
implantable medical article comprising a biodegradable
bioactive-agent releasing coating, the coating comprising a matrix
of hydrophobic derivatives of natural biodegradable polysaccharides
and bioactive agent within the matrix, and allowing the bioactive
agent to be released from the coating in the subject following the
step of implanting.
26. The method of claim 25 wherein the step of implanting comprises
delivering the article to a portion of the eye.
27. The method of claim 25 wherein the step of allowing, the
bioactive agent released comprises a carboxylate group.
28. The method of claim 25 wherein the bioactive agent is coupled
to a polysaccharide backbone of the hydrophobic derivatives via a
hydrolyzable ester bond.
29. A method for preparing a biodegradable bioactive-agent
releasing coating on a medical article comprising steps of:
preparing a coating composition comprising hydrophobic derivatives
of natural biodegradable polysaccharides and bioactive-agent; and
applying the coating composition on a surface of a medical article
to form a coating, wherein the bioactive-agent is capable of being
released from the coating following implantation of the medical
article in a subject.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present non-provisional Application claims the benefit
of commonly owned provisional Application having Ser. No.
60/782,957, filed on Mar. 15, 2006, and entitled HYDROPHOBIC
DERIVATIVES OF NATURAL BIODEGRADABLE POLYSACCHARIDES; and commonly
owned provisional Application having Ser. No. 60/900,853, filed on
Feb. 10, 2007, and entitled BIODEGRADABLE HYDROPHOBIC
POLYSACCHARIDE-BASED DRUG DELIVERY IMPLANTS; which Applications are
incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to biodegradable coatings for
implantable medical articles. The method also relates to methods
for treating medical conditions by releasing a bioactive agent from
the coatings to a subject.
BACKGROUND
[0003] Coatings formed on the surface of medical devices have been
shown to be beneficial as they can improve the properties of the
device in one or more ways. As examples, coatings can provide the
surface of implantable medical devices, such as catheters and
stents, with lubricious, non-thrombogenic, biocompatible, and
drug-delivery properties. Coatings providing one or more of these
features can improve the function of the implanted device in the
body.
[0004] Site-specific drug delivery can be accomplished by injection
and/or implantation of an article or device that releases the drug
to the treatment site. Injection of drugs can have limitations, for
example, by requiring multiple administrations, increasing risk of
complications (such as infection), and patient discomfort.
Implantation of a coated article or device that delivers drug to
the treatment site via the coating has therefore gained much
interest in recent years.
[0005] For example, stents have been prepared with
non-biodegradable coatings that include anti-proliferative
compounds. These compounds can be released from the stents surface
and minimizes the accumulation of smooth muscle cells on the stent
surface, thereby providing an anti-restenotic effect.
[0006] Generally speaking, a bioactive agent can be coupled to the
surface of a medical device by surface modification, embedded, and
released from within polymeric materials (matrix-type), or
surrounded by and released through a carrier (reservoir-type). The
polymeric materials in such applications should optimally act as a
biologically inert barrier and not induce further inflammation
within the body. However, the molecular weight, porosity of the
polymer, a greater percentage of coating exposed on the medical
device, and the thickness of the polymer coating can contribute to
adverse reactions to the medical device.
[0007] Drug-releasing biodegradable coatings formed from polylactic
acid have been used to coat medical device surfaces (see, for
example, U.S. Pat. No. 6,258,121). As the coating degrades, the
bioactive agent is released from the surface of the device. These
types of biodegradable materials, however, have the potential to
degrade into products that cause unwanted side effects in the body
by virtue of their presence or concentration in vivo. These
unwanted side effects can include immune reactions, toxic buildup
of the degradation products in the body, or the initiation or
provocation of other adverse effects on cells or tissue in the
body. If materials that are used to prepare the implant promote an
adverse tissue response in the body, the effectiveness of the
implant can be reduced.
[0008] Several other challenges confront the use of medical devices
or articles that release bioactive agents into a patient's body.
For example, treatment may require release of the bioactive
agent(s) over an extended period of time (for example, weeks,
months, or even years), and it can be difficult to sustain the
desired release rate of the bioactive agent(s) over such long
periods of time.
[0009] While advances in site-specific implantable drug delivery
systems have been made, many systems do not release drug in a
desired manner following implantation in a patient. For example, in
many systems the majority of the drug present in the article is
released from the device in an initial burst, resulting in
premature depletion of the drug. Following this depletion, the drug
may be delivered to the subject in sub-optimal amounts.
[0010] In other systems, such as those based on polylactide-type
biodegradable polymers, the majority of drug may be released at
later points during the administration period due to bulk erosion
of the drug containing biodegradable matrices.
[0011] If drug is prematurely released from the implant, or not
released until later, the duration of treatment or the rate of
release may not be as long as desired. This can cause the implant
to be therapeutically less effective.
[0012] In addition, many drug delivery systems may demonstrate a
great variation in the rate of drug release over the period of
implantation. In these cases, an optimal rate of drug release may
be seen only during a very small window over the period of
implantation.
SUMMARY OF THE INVENTION
[0013] Generally, the present invention relates to implantable
medical articles that include a biodegradable coating. The coating
comprises a matrix of hydrophobic derivatives of natural
biodegradable polysaccharides (also referred to herein as
"hydrophobic polysaccharides").
[0014] In some aspects, the coating includes a bioactive agent,
which can be released from the coating after the implantable
medical article is placed within a subject. The present invention
also relates to treating medical conditions using medical articles
having biodegradable coatings formed of the hydrophobic
polysaccharides.
[0015] Coating compositions including hydrophobic polysaccharides
adhere well to the surface of medical articles to which they are
applied, and form coatings with properties that are desirable for
use in the body. The biodegradable coatings of the invention are
shown herein to demonstrate one more of the following properties,
such as compliance, conformability, and/or durability, which
provide(s) benefits for in vivo use. These properties can prevent
or minimize cracking, delamination, and/or abrasion of the coating
when the coated medical article is manipulated during steps in
involving placement of the coated article in the body.
[0016] The hydrophobic polysaccharides can be used in combination
with various coating solvents, allowing the preparation of
compositions that can be suitably mixed with a variety of
excipients or bioactive agents. The coating compositions can also
be prepared having a high concentration of solids, allowing the
formation of, in some embodiments, a coating having a high content
of bioactive agent. The coating materials can also be readily
applied to surfaces of implantable medical articles using
conventional coating methods, such as spray coating and dip
coating.
[0017] The matrix of hydrophobic polysaccharides that form the
coating can be degraded into natural materials, which in turn
improve the compatibility of the device. Degradation of the coating
can result in the release of, for example, naturally occurring
mono- or disaccharides, such as glucose, which are common serum
components. This provides an advantage over coatings formed from
polyglycolide-type molecules, which can degrade into products that
cause unwanted side effects in the body by virtue of their presence
or concentration in vivo.
[0018] In some aspects, the invention provides an implantable
medical article comprising a biodegradable bioactive-agent
releasing coating. The coating comprises a matrix of hydrophobic
derivatives of natural biodegradable polysaccharides and
bioactive-agent within the matrix, and the coating is capable of
releasing bioactive agent following placement of the medical
article in a subject.
[0019] Preferably, the coatings of the present invention include
hydrophobic derivatives of lower molecular weight natural
biodegradable polysaccharides, wherein the hydrophobic derivatives
have a molecular weight of about 500,000 Da or less. Even more
preferably hydrophobic derivatives having a molecular weight of
about 100,000 Da or less, 50,000 Da or less, 25,000 Da or less, or
in the range of 2000 Da to about 20,000 Da, or in the range of 4000
to 10,000 Da, are used to form the coating.
[0020] In some aspects, the coatings are formed from low molecular
weight hydrophobic derivatives of .alpha.-1,4 glucopyranose
polymers. For example, the implants can be formed from a polymer
selected from hydrophobic derivatives of maltodextrin, polyalditol,
amylose, and cyclodextrin polymers. In some aspects the hydrophobic
derivative is a non-cyclic glucopyranose polymer. In some aspects
the hydrophobic derivative is a linear glucopyranose polymer.
[0021] A hydrophobic derivative can include a hydrophobic portion
comprising a plurality of groups pendent from a polysaccharide
backbone, the groups comprising a hydrocarbon segment. In some
aspects, the hydrocarbon segment selected from linear, branched,
and cyclic. C.sub.2-C.sub.18 groups. In more specific aspects, the
hydrocarbon segment is selected from, linear, branched, and cyclic
C.sub.4-C.sub.8 groups, and even more specific aspects, from
linear, branched, or cyclic C.sub.5-C.sub.7 groups.
[0022] The hydrocarbon segment can be saturated or unsaturated, and
can include linear, branched, and cyclic alkyl groups, or aromatic
groups.
[0023] In many aspects the degree of substitution of the groups on
the hydrophobic derivative is about 1 or greater, or in the range
of about 2 to 3.
[0024] In many aspects the groups are cleavable from the
polysaccharide backbone. For example, the groups that include the
hydrocarbon segment are coupled to the polysaccharide backbone of
the hydrophobic derivatives via a hydrolyzable ester bond.
Following implantation, the groups that include the hydrocarbon
segment can be cleaved from the polysaccharide backbone. As a
result, the surface of the coating can be come more hydrophilic and
result in loss of the coating material by solubilization and/or
enzymatic degradation due to the loss of repulsion of fluids.
[0025] In yet other aspects the hydrocarbon segment is a short
chain branched alkyl group. It has been found that very compliant
and durable hydrophobic coatings can be formed from hydrophobic
derivatives having short chain branched alkyl groups pendent from
the polysaccharide backbone, at relatively low degrees of
substitution. This is advantageous for the preparation of coatings
that have a relatively fast rate of degradation. Given the low
degree of substitution, loss of the short chain branched alkyl
group causes an abrupt change in property of the hydrophobic
polysaccharide to hydrophilic, and promotes loss and degradation of
portions of the coating at a relatively rapid rate. Exemplary short
chain branched alkyl group are branched C.sub.4-C.sub.10 groups. In
many aspects the degree of substitution of the short chain branched
alkyl group on the hydrophobic derivative is in the range of
0.5-1.5.
[0026] The coating can be formed using hydrophobic polysaccharides
having a desired glass transition temperature (Tg). In some
aspects, the coating is formed from hydrophobic derivatives having
a Tg of 35.degree. C. or greater, about 40.degree. C. or greater,
such as in the range of about 40.degree. C. to about 90.degree.
C.
[0027] In some aspects, the coating includes a hydrophilic
biocompatible polymer. A hydrophilic biocompatible polymer can
increase the rate of release of bioactive agent from the coating.
In some aspects, the hydrophilic polymer is selected from the group
consisting of poly(ethylene glycol), hydrophilic polysaccharides,
polyvinyl pyrrolidones, polyvinyl alcohols, low molecular weight
methyl cellulose, hydroxypropyl methyl cellulose (HPMC), and the
like. In some aspects, the coating comprises up to about 10% wt of
the hydrophilic biocompatible polymer.
[0028] The coatings of the invention can be formed on a surface of
any medical device hat is introduced temporarily or permanently
into a subject for the prophylaxis or treatment of a medical
condition. These devices include any that are introduced
subcutaneously, percutaneously or surgically to rest within an
organ, tissue, or lumen of an organ, such as arteries, veins,
ventricles or atria of the heart, or in a portion of the eye. The
device can be a biostable device, a partially degradable device, or
a completely degradable device. For example, stents fabricated from
degradable or erodable metalic or polymeric materials can be coated
with the hydrophobic polysaccharides of the invention.
[0029] According to the materials and methods described herein,
stents having coatings that were formed from hydrophobic
polysaccharides were prepared and tested for degradation and
bioactive agent release both in vitro and in vivo.
[0030] Results of the experimental studies of the present invention
showed that bioactive agent was released from the coating on the
stents during the period of implantation in vivo. Ex situ analysis
showed loss of the coating formed of the hydrophobic natural
biodegradable polysaccharides after the implantation period. It was
shown in a porcine model that approximately 50% of the coating
comprising the hydrophobic natural biodegradable polysaccharide and
a drug was remaining after 28 days of implantation. In view of
this, the coatings of the invention can be formed on the surface of
an implantable medical article and used for the site-specific
treatment of any one of a variety of medical conditions.
[0031] Results also showed the coatings of the invention provided a
moderate or minimal initial burst of bioactive agent, and no late
stage burst. This is beneficial, as depletion of substantial
amounts of bioactive agent from the coating at an early stage
following implantation can be avoided.
[0032] The coatings were also prepared having a high bioactive
agent load, but were still able to release the bioactive agent at a
steady, therapeutically effective rate. This allows the coated
implantable articles to be useful for the prolonged release of
bioactive agents to treat medical conditions.
[0033] Various types of bioactive agents can be delivered from the
coating. Exemplary bioactive agents include, anti-proliferative
agents, anti-inflammatory agents, angiogenesis inhibitors,
neuroprotective agents, beta adrenergic agents, prostaglandins, or
combinations thereof.
[0034] In some aspects, bioactive agent is present in an amount up
to about 65 wt % of the implant, such as in the range of about 10
wt % to about 65 wt %, up to about 55% wt, such as in the range of
about 25 wt % to about 55 wt %, or about 40 wt % to about 50 wt
%.
[0035] In some aspects the bioactive agent is coupled to and
cleavable from the polysaccharide backbone. Like the groups that
include the hydrocarbon segment, a bioactive agent can be coupled
to the polysaccharide backbone via a hydrolyzable ester bond. In
some aspect, the bioactive agent can include a hydrocarbon segment,
which can contribute the hydrophobic properties of the hydrophobic
polysaccharide.
[0036] For example, in some cases the coatings can be formed to
release the bioactive agent in a therapeutically useful amount for
a period of time greater than one month, three months, six months,
a year, and even to about two years. Given the prolonged release of
bioactive agent, the need for periodic administration of the
bioactive agent is not required. This is beneficial as it
eliminates or significantly reduces need for patient
compliance.
[0037] In addition, it was found that changes to the biodegradable
polysaccharide chemistry and/or coating composition could be made
to alter the release rate of the bioactive agent within
therapeutically useful ranges. This "tunability" of bioactive
release represents an advantage for implantable medical articles,
as specific daily doses of bioactive agent can be provided to a
subject.
[0038] The invention also provides a method for delivering a
bioactive agent to a subject. The method comprises a step of
implanting at a target site in a subject an implantable medical
article comprising a biodegradable bioactive-agent releasing
coating, the coating comprising a matrix of hydrophobic derivatives
of natural biodegradable polysaccharides and bioactive agent within
the matrix. The method also comprises a step of allowing the
bioactive agent to be released from the coating in the subject
following the step of implanting.
[0039] The coatings of the invention can release bioactive agent in
a therapeutically effective range, such as an amount of nanograms
per day, up to about tens of micrograms per day. In some aspects,
the bioactive agent is released from the coating in an amount in
the range of about 0.01 microgram per day to about 10 micrograms
per day.
[0040] In some specific aspects, the method for delivering a
bioactive agent to a subject is performed for the treatment of an
ocular condition or indication. In the step of implanting, an
ocular article having a coating in implanted at a location in the
eye. The ocular article is maintained in the eye for a period of
time sufficient for the treatment of the ocular condition of
indication.
[0041] The invention also provides methods for forming a coating on
implantable medical articles. The method comprises a step of
preparing a coating composition comprising hydrophobic derivatives
of natural biodegradable polysaccharides and bioactive-agent.
[0042] A step of applying the coating composition on a surface of a
medical article to form a coating is then performed. Given the
properties of the hydrophobic polysaccharide, a coating composition
having bioactive at a high concentration can be prepared in a
suitable solvent. The composition can then be applied by a
technique such as spray coating or dip coating.
[0043] In another aspect of the invention, the coating can be
formed on a surface of the device without a bioactive agent. The
coating can be used as a degradable barrier that temporarily
prevents contact of body fluids or tissues with the structural
material of the implantable medical article. In some cases this can
improve the biocompatibility of the article by shielding its
surface.
[0044] In other cases the coating is formed on the surface of an
implantable medical article that is formed from a material that
erodes or degrades in the body. The coating of the invention
therefore functions to slow the erosion or degradation of the
structural portion of the implantable medical article, and lengthen
its in vivo lifetime. The coated article can be completely erodable
or degradable in vivo, and therefore not require removal after
implantation and a period of treatment. In some aspects the
coatings of the invention are formed on the surface of an erodable
or degradable stent formed of a metal, such as magnesium, or formed
of a polymer.
[0045] Therefore, in another aspect, the invention provides an
implantable medical article comprising a biodegradable coating. The
coating comprises a matrix of hydrophobic derivatives of natural
biodegradable polysaccharides, wherein the coating is capable of
temporarily shielding the structural portion of the implantable
medical article following implantation. In some aspects the
implantable medical article is erodable or degradable.
[0046] Therefore, in another aspect, the invention provides an
implantable medical article comprising a biodegradable coating. The
coating comprises a matrix of hydrophobic derivatives of natural
biodegradable polysaccharides, wherein the coating is capable of
temporarily shielding the structural portion of the implantable
medical article following implantation. In some aspects the
implantable medical article is erodable or degradable.
[0047] In another aspect, the invention provides a method for
prolonging the in vivo lifetime of an implantable medical article
that is formed from an erodable or degradable material. The method
comprises a step of forming a coating on the surface of an
implantable medical article that is formed from an erodable or
degradable material, the coating comprising a matrix of hydrophobic
derivatives of natural biodegradable polysaccharides. The method
also comprises a step of implanting at a target site in a subject
the implantable medical article having the coating. Following
implantation, the coated article has an in vivo lifetime that is
longer than an in vivo lifetime of an implantable medical article
without the coating.
[0048] In another aspect, the invention provides a method for
treating a cardiovascular disease or a cardiovascular condition.
The method comprises step of implanting at an intravascular site in
a subject an implantable prosthesis comprising a biodegradable
coating, the coating comprising a matrix of hydrophobic derivatives
of natural biodegradable polysaccharides. The method also comprises
a step of maintaining the prosthesis at the site for a period of
time to treat the cardiovascular disease or a cardiovascular
condition. In some aspects the implantable prosthesis is a stent.
In some aspects the coating comprises a bioactive agent which is
released to the subject during the step of maintaining.
BRIEF DESCRIPTION OF THE DRAWINGS
[0049] FIG. 1 is a graph illustrating elution profiles of stents
coated with lidocaine and hydrophobic derivatives of natural
biodegradable polysaccharides.
DETAILED DESCRIPTION
[0050] The embodiments of the present invention described herein
are not intended to be exhaustive or to limit the invention to the
precise forms disclosed in the following detailed description.
Rather, the embodiments are chosen and described so that others
skilled in the art can appreciate and understand the principles and
practices of the present invention.
[0051] All publications and patents mentioned herein are hereby
incorporated by reference. The publications and patents disclosed
herein are provided solely for their disclosure. Nothing herein is
to be construed as an admission that the inventors are not entitled
to antedate any publication and/or patent, including any
publication and/or patent cited herein.
[0052] The invention is generally directed to coatings formed of a
matrix comprising hydrophobic derivatives of natural biodegradable
polysaccharides. The coatings can be formed on all or a portion of
the surface of an implantable medical article. In some aspects,
bioactive agent can be included within the coating, and releasable
from the coating following implantation of the article in a
patient. In related aspects, the invention is also directed to
methods for delivering bioactive agents to a subject from the
coatings on the implantable medical articles. The invention is also
related to coatings formed of the hydrophobic polysaccharides that
are used as a temporary barrier on the surface of implantable
medical devices. The invention is also directed to methods for
preparing the medical implants of the invention.
[0053] The hydrophobic polysaccharide can be present in one or more
coated layers, on all or a portion of the surface of the
implantable medical article. A "coating" as used herein can include
one or more "coated layers", each coated layer including one or
more coating materials. In some cases, the coating can be formed of
a single layer of material that includes the hydrophobic
polysaccharide. In other cases, the coating includes more than one
coated layer, at least one of the coated layers including the
hydrophobic polysaccharide. If more than one layer is present in
the coating, the layers can be composed of the same or different
materials.
[0054] If a bioactive agent is included in the coating it can be in
the same coated layer as the hydrophobic polysaccharide, or in a
different coated layer. The bioactive agent can be released from
the coating upon degradation of the coated layer that includes the
hydrophobic polysaccharide. Alternatively, or additionally, the
coated layer that includes the hydrophobic polysaccharide can
modulate bioactive agent release. In this aspect some or no
degradation of the coated layer that includes the hydrophobic
polysaccharide may occur.
[0055] The following list of medical articles is provided to
illustrate surfaces on which the hydrophobic polysaccharide can be
applied to form a coating.
[0056] These types of articles are typically introduced temporarily
or permanently into a mammal for the prophylaxis or treatment of a
medical condition. For example, these articles can be introduced
subcutaneously, percutaneously or surgically to rest within an
organ, tissue, or lumen of an organ, such as arteries, veins,
ventricles, or atria of the heart.
[0057] Exemplary medical articles include vascular implants and
grafts, grafts, surgical devices; synthetic prostheses; vascular
prosthesis including endoprosthesis, stent-graft, and
endovascular-stent combinations; small diameter grafts, abdominal
aortic aneurysm grafts; wound dressings and wound management
device; hemostatic barriers; mesh and hernia plugs; patches,
including uterine bleeding patches, atrial septic defect (ASD)
patches, patent foramen ovale (PFO) patches, ventricular septal
defect (VSD) patches, and other generic cardiac patches; ASD, PFO,
and VSD closures; percutaneous closure devices, mitral valve repair
devices; left atrial appendage filters; valve annuloplasty devices,
catheters; central venous access catheters, vascular access
catheters, abscess drainage catheters, drug infusion catheters,
parenteral feeding catheters, intravenous catheters (e.g., treated
with antithrombotic agents), stroke therapy catheters, blood
pressure and stent graft catheters; anastomosis devices and
anastomotic closures; aneurysm exclusion devices; biosensors
including glucose sensors; cardiac sensors; birth control devices;
breast implants; infection control devices; membranes; tissue
scaffolds; tissue-related materials; shunts including cerebral
spinal fluid (CSF) shunts, glaucoma drain shunts; dental devices
and dental implants; ear devices such as ear drainage tubes,
tympanostomy vent tubes; ophthalmic devices; cuffs and cuff
portions of devices including drainage tube cuffs, implanted drug
infusion tube cuffs, catheter cuff, sewing cuff; spinal and
neurological devices; nerve regeneration conduits; neurological
catheters; neuropatches; orthopedic devices such as orthopedic
joint implants, bone repair/augmentation devices, cartilage repair
devices; urological devices and urethral devices such as urological
implants, bladder devices, renal devices and hemodialysis devices,
colostomy bag attachment devices; biliary drainage products.
[0058] In some aspects, the biodegradable coating is formed on an
ophthalmic article. The ophthalmic article can be configured for
placement at an external or internal site of the eye. Suitable
ophthalmic devices can also be utilized to provide bioactive agent
to tissues in proximity to the eye, when desired.
[0059] Implantable articles configured for placement at an internal
site of the eye can reside within any desired area of the eye. In
some aspects, the ophthalmic article can be configured for
placement at an intraocular site, such as the vitreous.
Illustrative intraocular devices include, but are not limited to,
those described in U.S. Pat. No. 6,719,750 B2, which describes a
non-linear intraocular device ("Devices for Intraocular Drug
Delivery," Varner et al.) and U.S. Pat. No. 5,466,233 ("Tack for
Intraocular Drug Delivery and Method for Inserting and Removing
Same," Weiner et al.); U.S. Publication Nos. 2005/0019371 A1
("Controlled Release Bioactive Agent Delivery Device," Anderson et
al.), and 2004/0133155 A1 ("Devices for Intraocular Drug Delivery,"
Varner et al.) and related applications.
[0060] In some aspects, the biodegradable coating is formed on a
stent. Stents include vascular stents such as self-expanding stents
and balloon expandable stents. "Expandable" means the stent can be
expandable from a reduced diameter configuration utilizing an
expansion member, such as a balloon. The particular configuration
of the stent body is not critical to the invention described
herein, and the inventive biodegradable materials and methods can
be applied to virtually any stent configuration.
[0061] It can be desirable to fabricate the stent such that the
material is nonsolid. In other words, desirable to include pores or
other passages through the material that can enable endothelial
cells at the implantation site to grow into and over the stent so
that biodegradation will occur within the vessel wall rather than
in the lumen of the vessel, which could lead to embolization of the
dissolved material.
[0062] In some cases the implantable medical article is partially
or entirely fabricated from a plastic polymer. In this regard, the
biodegradable coating can be formed on a plastic surface. Plastic
polymers include those formed of synthetic polymers, including
oligomers, homopolymers, and copolymers resulting from either
addition or condensation polymerizations. Examples of suitable
addition polymers include, but are not limited to, acrylics such as
those polymerized from methyl acrylate, methyl methacrylate,
hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid,
methacrylic acid, glyceryl acrylate, glyceryl methacrylate,
methacrylamide, and acrylamide; vinyls such as ethylene, propylene,
vinyl chloride, vinyl acetate, vinyl pyrrolidone, vinylidene
difluoride, and styrene. Examples of condensation polymers include,
but are not limited to, nylons such as polycaprolactam, polylauryl
lactam, polyhexamethylene adipamide, and polyhexamethylene
dodecanediamide, and also polyurethanes, polycarbonates,
polyamides, polysulfones, poly(ethylene terephthalate),
polydimethylsiloxanes, and polyetherketone.
[0063] Other suitable polymers for the substrate material include
polyamides, polyimides, polyolefins, polystyrenes, polyesters,
polycarbonates, polyketones, polyureas, acrylonitrile butadiene
copolymers, butadiene rubber, chlorinated and chloro-sulfonated
polyethylene, polychloroprene, ethylene propylene (EPM) copolymers,
ethylene propylene diene (EPDM) copolymers, polyethylene-ethylene
propylene diene PE-EPDM copolymers, polypropylene-ethylene
propylene diene (PP-EPDM) copolymers, ethylene-vinyl alcohol
copolymer (EVOH), polyepichlorihydrin, isobutylene isoprene
copolymer, polyisoprene, polysulfides, silicones polymers, nitrile
butadiene copolymer/polyvinylchloride blends (NBR/PVC), styrene
butadiene copolymers, and vinyl acetate ethylene copolymers, and
combinations thereof.
[0064] In some cases the implantable medical article is partially
or entirely fabricated from a degradable polymer. The article can
degrade in an aqueous environment, such as by simple hydrolysis, or
can be enzymatically degraded.
[0065] Examples of classes of synthetic polymers that can be used
to form the structure of the article include polyesters,
polyamides, polyurethanes, polyorthoesters, polycaprolactone (PCL),
polyiminocarbonates, aliphatic carbonates, polyphosphazenes,
polyanhydrides, and copolymers thereof. Specific examples of
biodegradable materials that can be used in connection with the
device of the invention include polylactide, polygylcolide,
polydioxanone, poly(lactide-co-glycolide),
poly(glycolide-co-polydioxanone), polyanhydrides,
poly(glycolide-co-trimethylene carbonate), and
poly(glycolide-co-caprolactone). As an example, the hydrophobic
polysaccharide can provide a barrier coating to articles fabricated
from PLA or copolymers thereof. The coating can shield the article
during a portion or all of a desired period of treatment. The
coating article can still be fully degradable.
[0066] Blends of these polymers with other biodegradable polymers
can also be used.
[0067] In other cases, the coating can be formed on a medical
device that is partially or entirely fabricated from a metal.
Although many devices or articles are constructed from
substantially all metal materials, such as alloys, some may be
constructed from both non-metal and metal materials, where at least
a portion of the surface of the device is metal. The metal surface
may also be a thin surface layer. Such surfaces can be formed by
any method including sputter coating metal onto all or portions of
the surface of the device.
[0068] Metals that can be used in medical articles include
platinum, gold, or tungsten, as well as other metals such as
rhenium, palladium, rhodium, ruthenium, titanium, nickel, and
alloys of these metals, such as stainless steel, titanium/nickel,
nitinol alloys, cobalt chrome alloys, non-ferrous alloys, and
platinum/iridium alloys. One exemplary alloy is MP35. These metals,
including other alloys or combinations, can be suitable substrates
for disposing a coating composition containing the hydrophobic
polysaccharides of the invention.
[0069] The surface of metal-containing medical devices can be
pretreated (for example, with a Parylene.TM.-containing coating
composition) in order to alter the surface properties of the
biomaterial, when desired. Metal surfaces can also be treated with
silane reagents, such as hydroxy- or chloro-silanes.
[0070] In some aspects the biodegradable coating is formed on the
surface of an erodable implantable medical device formed from of a
metal. For example, the biodegradable coating can be formed on a
magnesium alloy stent that can be corroded following placement in a
subject (see, for example, De Mario, C. et al. (2004) J. Interv.
Cardiol., 17(6):391-395, and Heublein, B., et al. (2003) Heart;
89:651-656). The erodable implantable medical device can also
include a bioactive agent, if desired.
[0071] In aspects where the structure of the implantable medical
article is fabricated from a material that is erodable or
degradable, an in vivo lifetime of the article can be determined.
The biodegradable coatings of the present invention can be applied
to the surface of these erodable or degradable articles to prolong
their in vivo lifetime. The in vivo lifetime is a period of time
starting upon placement of the coated article at a target location,
and ending when the coated article is completely degraded at the
target location.
[0072] Other surfaces that can be optionally coated include those
that include human tissue such as bone, cartilage, skin and teeth;
or other organic materials such as wood, cellulose, compressed
carbon, and rubber. Other contemplated biomaterials include
ceramics including, but not limited to, silicon nitride, silicon
carbide, zirconia, and alumina, as well as glass, silica, and
sapphire. Combinations of ceramics and metals can also be
coated.
[0073] In some aspects, a bioactive agent can be released from the
coated article during the entire in vivo lifetime, or during a
portion of the coated article's in vivo lifetime. The bioactive
agent can be present in the coating, within the structure of the
article itself, or in both.
[0074] The period of time in which the bioactive agent is released
from the coated article is referred to as the "bioactive agent
release period." If the bioactive agent release period is less than
the in vivo lifetime of the coating, the bioactive agent is
generally released from the coating at a rate faster than loss
and/or degradation of the hydrophobic polysaccharide from the
coating. In this case, release of the bioactive agent out of the
coating, such as by diffusion, may cause the bioactive agent
release period to be less than the in vivo lifetime of the
coating.
[0075] A "subject" refers to an organism in which the coated
medical article is placed and which the bioactive agent becomes
available in following implantation. The subject can be a patient
having a medical condition, wherein the condition is treatable
using a bioactive agent that is released from the medical implants
of the invention. The subject can be a human, another mammal, or a
non-mammalian organism. For example, the subject can be a
domesticated mammal such as a dog, cat, horse, cow, sheep, rabbit,
etc. The subject can also be a bird, fish, or reptile.
[0076] The coating includes a matrix of hydrophobic derivatives of
natural biodegradable polysaccharides. The matrix is formed via
hydrophobic interactions of the hydrophobic portion of the
polysaccharide. Bioactive agent, if included in the coating, can be
held within the matrix. The bioactive agent is released to the
subject after the coated article is delivered to a target location
in the body.
[0077] As used herein, a "hydrophobic derivative" of a natural
biodegradable polysaccharide refers to a natural biodegradable
polysaccharide having one or more pendent groups attached to the
polysaccharide. In many cases the hydrophobic derivative includes a
plurality of groups comprising hydrocarbon segments attached to the
polysaccharide. When a plurality of groups comprising hydrocarbon
segments is attached they are collectively referred to as the
"hydrophobic portion" of the hydrophobic derivative. The
hydrophobic derivatives of the invention therefore include a
hydrophobic portion and a polysaccharide portion.
[0078] The coating of the present invention is described as being
formed from a "matrix" of hydrophobic derivative of a natural
biodegradable polysaccharide. Generally, the matrix provides the
structural framework of the coating, which is established by
association of the groups comprising the hydrocarbon segments that
are pendent from the polysaccharide backbone. The structural
integrity of the coating can therefore be in part based on the
hydrophobic interactions in the matrix. Optionally, the matrix can
optionally include other types of non-hydrophobic associations
between polysaccharides, such as covalent or non-covalent
crosslinks which may be formed by groups pendent from the
polysaccharide or groups independent of the polysaccharide.
[0079] The polysaccharide portion comprises a "natural
biodegradable polysaccharide," which refers to a non-synthetic
polysaccharide that is capable of being enzymatically degraded.
Natural biodegradable polysaccharides include polysaccharide and/or
polysaccharide derivatives that are obtained from natural sources,
such as plants or animals. Natural biodegradable polysaccharides
include any polysaccharide that has been processed or modified from
a natural biodegradable polysaccharide (for example, maltodextrin
is a natural biodegradable polysaccharide that is processed from
starch). Exemplary natural biodegradable polysaccharides include
maltodextrin, amylose, cyclodextrin, polyalditol, hyaluronic acid,
dextran, heparin, chondroitin sulfate, dermatan sulfate, heparan
sulfate, keratan sulfate, dextran, dextran sulfate, pentosan
polysulfate, and chitosan. Preferred polysaccharides are low
molecular weight polymers that have little or no branching, such as
those that are derived from and/or found in starch preparations,
for example, maltodextrin, amylose, and cyclodextrin. Therefore,
the natural biodegradable polysaccharide can be a substantially
non-branched or completely non-branched poly(glucopyranose)
polymer.
[0080] As used herein, "amylose" or "amylose polymer" refers to a
linear polymer having repeating glucopyranose units that are joined
by .alpha.-1,4 linkages. Some amylose polymers can have a very
small amount of branching via .alpha.-1,6 linkages (about less than
0.5% of the linkages) but still demonstrate the same physical
properties as linear (unbranched) amylose polymers do. Generally
amylose polymers derived from plant sources have molecular weights
of about 1.times.10.sup.6 Da or less. Amylopectin, comparatively,
is a branched polymer having repeating glucopyranose units that are
joined by .alpha.-1,4 linkages to form linear portions and the
linear portions are linked together via .alpha.-1,6 linkages. The
branch point linkages are generally greater than 1% of the total
linkages and typically 4%-5% of the total linkages. Generally
amylopectin derived from plant sources have molecular weights of
1.times.10.sup.7 Da or greater.
[0081] Amylose can be obtained from, or is present in, a variety of
sources. Typically, amylose is obtained from non-animal sources,
such as plant sources. In some aspects, a purified preparation of
amylose is used as starting material for the preparation of the
amylose polymer having pendent groups comprising pendent groups
that include hydrocarbon segments. In other aspects, as starting
material, amylose can be used in a mixture that includes other
polysaccharides.
[0082] For example, in some aspects, starch preparations having a
high amylose content, purified amylose, synthetically prepared
amylose, or enriched amylose preparations can be used in the
preparation of a hydrophobic derivative of amylose. In starch
sources, amylose is typically present along with amylopectin, which
is a branched polysaccharide. If a mixture of amylose and a higher
molecular weight precursor is used (such as amylopectin), it is
preferred that amylose is present in the composition in an amount
greater than the higher molecular weight precursor. For example, in
some aspects, starch preparations having high amylose content,
purified amylose, synthetically prepared amylose, or enriched
amylose preparations can be used in the preparation of a
hydrophobic derivative of amylose polymer. In some embodiments the
composition includes a mixture of polysaccharides including amylose
wherein the amylose content in the mixture of polysaccharides is
50% or greater, 60% or greater, 70% or greater, 80% or greater, or
85% or greater by weight. In other embodiments the composition
includes a mixture of polysaccharides including amylose and
amylopectin and wherein the amylopectin content in the mixture of
polysaccharides is 30% or less, or 15% or less.
[0083] The amount of amylopectin present in a starch may also be
reduced by treating the starch with amylopectinase, which cleaves
.alpha.-1,6 linkages resulting in the debranching of amylopectin
into amylose.
[0084] Steps may be performed before, during, and/or after the
process of derivatizing the amylose polymer with a pendent group
comprising a hydrocarbon segment to enrich the amount of amylose,
or purify the amylose.
[0085] Amylose of particular molecular weights can be obtained
commercially or can be prepared. For example, synthetic amyloses
with average molecular masses of 70 kDa, 110 kDa, and 320 kDa, can
be obtained from Nakano Vinegar Co., Ltd. (Aichi, Japan). The
decision of using amylose of a particular size range may depend on
factors such as the physical characteristics of the composition
(e.g., viscosity), the desired rate of degradation of the coating
formed from the hydrophobic derivative, and the presence of other
optional components in the composition, such as bioactive
agents.
[0086] Purified or enriched amylose preparations can be obtained
commercially or can be prepared using standard biochemical
techniques such as chromatography. In some aspects, high-amylose
cornstarch can be used to prepare the hydrophobic derivative.
[0087] Maltodextrin is typically generated by hydrolyzing a starch
slurry with heat-stable a-amylase at temperatures at 85-90.degree.
C. until the desired degree of hydrolysis is reached and then
inactivating the .alpha.-amylase by a second heat treatment. The
maltodextrin can be purified by filtration and then spray dried to
a final product. Maltodextrins are typically characterized by their
dextrose equivalent (DE) value, which is related to the degree of
hydrolysis defined as: DE=MW dextrose/number-averaged MW starch
hydrolysate X 100. Generally, maltodextrins are considered to have
molecular weights that are less than amylose molecules.
[0088] A starch preparation that has been totally hydrolyzed to
dextrose (glucose) has a DE of 100, whereas starch has a DE of
about zero. A DE of greater than 0 but less than 100 characterizes
the mean-average molecular weight of a starch hydrolysate, and
maltodextrins are considered to have a DE of less than 20.
Maltodextrins of various molecular weights, for example, in the
range of about 500 Da to 5000 Da are commercially available (for
example, from CarboMer, San Diego, Calif.).
[0089] Another contemplated class of natural biodegradable
polysaccharides is natural biodegradable non-reducing
polysaccharides. A non-reducing polysaccharide can provide an inert
matrix thereby improving the stability of sensitive bioactive
agents, such as proteins and enzymes. A non-reducing polysaccharide
refers to a polymer of non-reducing disaccharides (two
monosaccharides linked through their anomeric centers) such as
trehalose (.alpha.-D-glucopyranosyl .alpha.-D-glucopyranoside) and
sucrose (.beta.-D-fructofuranosyl .alpha.-D-glucopyranoside). An
exemplary non-reducing polysaccharide comprises polyalditol which
is available from GPC (Muscatine, Iowa). In another aspect, the
polysaccharide is a glucopyranosyl polymer, such as a polymer that
includes repeating (1.fwdarw.3)O-.beta.-D-glucopyranosyl units.
[0090] Dextran is an .alpha.-D-1,6-glucose-linked glucan with
side-chains 1-3 linked to the backbone units of the dextran
biopolymer. Dextran includes hydroxyl groups at the 2, 3, and 4
postions on the glucopyranose monomeric units. Dextran can be
obtained from fermentation of sucrose-containing media by
Leuconostoc mesenteroides B512F.
[0091] Dextran can be obtained in low molecular weight
preparations. Enzymes (dextranases) from molds such as Penicillium
and Verticillium have been shown to degrade dextran. Similarly many
bacteria produce extracellular dextranases that split dextran into
low molecular weight sugars.
[0092] Chondroitin sulfate includes the repeating disaccharide
units of D-galactosamine and D-glucuronic acid, and typically
contains between 15 to 150 of these repeating units. Chondroitinase
AC cleaves chondroitin sulfates A and C, and chondroitin.
[0093] Hyaluronic acid (HA) is a naturally derived linear polymer
that includes alternating .beta.1,4-glucuronic acid and
.beta.1,3-N-acetyl-D-glucosamine units. HA is the principal
glycosaminoglycan in connective tissue fluids. HA can be fragmented
in the presence of hyaluronidase.
[0094] In many aspects the polysaccharide portion and the
hydrophobic portion comprise the predominant portion of the
hydrophobic derivative of the natural biodegradable polysaccharide.
Based on a weight percentage, the polysaccharide portion can be
about 25% wt of the hydrophobic derivative or greater, in the range
of about 25% to about 75%, in the range of about 30% to about 70%,
in the range of about 35% to about 65%, in the range of about 40%
to about 60%, or in the range of about 45% to about 55%. Likewise,
based on a weight percentage of the overall hydrophobic derivative,
the hydrophobic portion can be about 25% wt of the hydrophobic
derivative or greater, in the range of about 25% to about 75%, in
the range of about 30% to about 70%, in the range of about 35% to
about 65%, in the range of about 40% to about 60%, or in the range
of about 45% to about 55%. In exemplary aspects, the hydrophobic
derivative has approximately 50% of its weight attributable to the
polysaccharide portion, and approximately 50% of its weight
attributable to its hydrophobic portion.
[0095] The hydrophobic derivative has the properties of being
insoluble in water. The term for insolubility is a standard term
used in the art, and meaning 1 part solute per 10,000 parts or
greater solvent. (see, for example, Remington: The Science and
Practice of Pharmacy, 20th ed. (2000), Lippincott Williams &
Wilkins, Baltimore Md.).
[0096] A hydrophobic derivative can be prepared by associating one
or more hydrophobic compound(s) with a natural biodegradable
polysaccharide polymer. Methods for preparing hydrophobic
derivatives of natural biodegradable polysaccharides are described
herein.
[0097] The hydrophobic derivatives of the natural biodegradable
polysaccharides preferably have a molecular weight of 500,000 Da or
less. Use of these lower molecular weight derivatives provides
implants with desirable physical and drug-releasing properties. In
some aspects the hydrophobic derivatives have a molecular weight of
about 250,000 Da or less, about 100,000 Da or less, about 50,000 Da
or less, or 25,000 Da or less. Particularly preferred size ranges
for the natural biodegradable polysaccharides are in the range of
about 2,000 Da to about 20,000 Da, or about 4,000 Da to about
10,000 Da.
[0098] The molecular weight of the polymer is more precisely
defined as "weight average molecular weight" or M.sub.w. M.sub.w is
an absolute method of measuring molecular weight and is
particularly useful for measuring the molecular weight of a polymer
(preparation). Polymer preparations typically include polymers that
individually have minor variations in molecular weight. Polymers
are molecules that have a relatively high molecular weight and such
minor variations within the polymer preparation do not affect the
overall properties of the polymer preparation. The weight average
molecular weight (M.sub.w) can be defined by the following
formula:
M w = .SIGMA. i N i M i 2 .SIGMA. i N i M i ##EQU00001##
wherein N represents the number of moles of a polymer in the sample
with a mass of M, and .SIGMA..sub.s is the sum of all
N.sub.iM.sub.i (species) in a preparation. The M.sub.w can be
measured using common techniques, such as light scattering or
ultracentrifilgation. Discussion of M.sub.w and other terms used to
define the molecular weight of polymer preparations can be found
in, for example, Allcock, H. R. and Lampe, F. W. (1990)
Contemporary Polymer Chemistry; pg 271.
[0099] The addition of hydrophobic portion will generally cause an
increase in molecular weight of the polysaccharide from its
underivitized, starting molecular weight. The amount increase in
molecular weight can depend on one or more factors, including the
type of polysaccharide derivatized, the level of derivation, and,
for example, the type or types of groups attached to the
polysaccharide to provide the hydrophobic portion.
[0100] In some aspects, the addition of hydrophobic portion causes
an increase in molecular weight of the polysaccharide of about 20%
or greater, about 50% or greater, about 75% or greater, about 100%
or greater, or about 125%, the increase in relation to the
underivitized form of the polysaccharide.
[0101] As an example, a maltodextrin having a starting weight of
about 3000 Da is derivitized to provide pendent hexanoate groups
that are coupled to the polysaccharide via ester linkages to
provide a degree of substitution (DS) of about 2.5. This provides a
hydrophobic polysaccharide having a theoretical molecular weight of
about 6000 Da.
[0102] In forming the hydrophobic derivative of the natural
biodegradable polysaccharide and as an example, a compound having a
hydrocarbon segment can be covalently coupled to one or more
portions of the polysaccharide. For example, the compound can be
coupled to monomeric units along the length of the polysaccharide.
This provides a polysaccharide derivative with one or more pendent
groups. Each chemical group comprises a hydrocarbon segment. The
hydrocarbon segment can constitute all of the pendent chemical
group, or the hydrocarbon segment can constitute a portion of the
pendent chemical group. For example, a portion of the hydrophobic
polysaccharide can have the following structure, wherein M is a
monomeric unit of the polysaccharide, and in the pendent chemical
group ([L]-[H]), H is the hydrocarbon segment, and L is a chemical
group linking the hydrocarbon segment to the monomeric unit of the
polysaccharide:
[M]-[L]-[H]
[0103] The pendent group can also include an additional portion
that is not a hydrocarbon segment [N] as represented by the
following structure:
[M]-[L]-[H]--[N]
[0104] A "hydrocarbon segment" herein refers to a group of
covalently bonded carbon atoms having the formula (CH.sub.n).sub.m,
wherein m is 2 or greater, and n is independently 2 or 1. A
hydrocarbon segment can include saturated hydrocarbon groups or
unsaturated hydrocarbon groups, and examples thereof include alkyl,
alkenyl, alkynyl, cyclic alkyl, cyclic alkenyl, aromatic
hydrocarbon and aralkyl groups.
[0105] The monomeric units of the hydrophobic polysaccharides
described herein typically include monomeric units having ring
structures with one or more reactive groups. These reactive groups
are exemplified by hydroxyl groups, such as the ones that are
present on glucopyranose-based monomeric units of amylose and
maltodextrin. These hydroxyl groups can be reacted with a compound
that includes a hydrocarbon segment and a group that is reactive
with the hydroxyl group (a hydroxyl-reactive group).
[0106] Examples of hydroxyl reactive groups include acetal,
carboxyl, anhydride, acid halide, and the like. These groups can be
used to form a hydrolytically cleavable covalent bond between the
hydrocarbon segment and the polysaccharide backbone. For example,
the method can provide a pendent group having a hydrocarbon
segment, the pendent group linked to the polysaccharide backbone
with a cleavable ester bond. In these aspects, the synthesized
hydrophobic derivative of the natural biodegradable polysaccharide
will include chemical linkages that are both enzymatically
cleavable (the polymer backbone) and non-enzymatically
hydrolytically cleavable (the linkage between the pendent group and
the polymer backbone).
[0107] Other cleavable chemical linkages that can be used to bond
the pendent groups to the polysaccharide include peroxyester
groups, disulfide groups, and hydrazone groups.
[0108] In some cases the hydroxyl reactive groups include those
such as isocyanate and epoxy. These groups can be used to form a
non-cleavable covalent bond between the pendent group and the
polysaccharide backbone. In these aspects, the synthesized
hydrophobic derivative of the natural biodegradable polysaccharide
includes chemical linkages that are enzymatically cleavable (the
polymer backbone).
[0109] Other reactive groups, such as carboxyl groups, acetyl
groups, or sulphate groups, are present on the ring structure of
monomeric units of other natural biodegradable polysaccharides,
such as chondrotin or hyaluronic acid. These groups can also be
targeted for reaction with a compound having a hydrocarbon segment
to be bonded to the polysaccharide backbone.
[0110] Various factors can be taken into consideration in the
synthesis of the hydrophobic derivative of the natural
biodegradable polysaccharide. These factors include the physical
and chemical properties of the natural biodegradable
polysaccharide, including its size, and the number and presence of
reactive groups on the polysaccharide and solubility, the physical
and chemical properties of the compound that includes the
hydrocarbon segment, including its the size and solubility, and the
reactivity of the compound with the polysaccharide.
[0111] In preparing the hydrophobic derivative of the natural
biodegradable polysaccharide any suitable synthesis procedure can
be performed. Synthesis can be carried out to provide a desired
number of groups with hydrocarbon segments pendent from the
polysaccharide backbone. The number and/or density of the pendent
groups can be controlled, for example, by controlling the relative
concentration of the compound that includes the hydrocarbon segment
to the available reactive groups (e.g., hydroxyl groups) on the
polysaccharide.
[0112] The type and amount of groups having the hydrocarbon segment
pendent from the polysaccharide is sufficient for the hydrophobic
polysaccharide to be insoluble in water. In order to achieve this,
as a general approach, a hydrophobic polysaccharide is obtained or
prepared wherein the groups having the hydrocarbon segment pendent
from the polysaccharide backbone in an amount in the range of 0.25
(pendent group): 1 (polysaccharide monomer) by weight.
[0113] To exemplify these levels of derivation, very low molecular
weight (less than 10,000 Da) glucopyranose polymers are reacted
with compounds having the hydrocarbon segment to provide low
molecular weight hydrophobic glucopyranose polymers. In one mode of
practice, the natural biodegradable polysaccharide maltodextrin in
an amount of 10 g (MW 3000-5000 Da; .about.3 mmols) is dissolved in
a suitable solvent, such as tetrahydrofuran. Next, a solution
having butyric anhydride in an amount of 18 g (0.11 mols) is added
to the maltodextrin solution. The reaction is allowed to proceed,
effectively forming pendent butyrate groups on the pyranose rings
of the maltodextrin polymer. This level of derivation results in a
degree of substitution (DS) of butyrate group of the hydroxyl
groups on the maltodextrin of about 1.
[0114] For maltodextrin and other polysaccharides that include
three hydroxyl groups per monomeric unit, on average, one of the
three hydroxyl groups per glycopyranose monomeric unit becomes
substituted with a butyrate group. A maltodextrin polymer having
this level of substitution is referred to herein as
maltodextrin-butyrate DS 1. As described herein, the DS refers to
the average number of reactive groups (including hydroxyl and other
reactive groups) per monomeric unit that are substituted with
pendent groups comprising hydrocarbon segments.
[0115] An increase in the DS can be achieved by incrementally
increasing the amount of compound that provides the hydrocarbon
segment to the polysaccharide. As another example, butyrylated
maltodextrin having a DS of 2.5 is prepared by reacting 10 g of
maltodextrin (MW 3000-5000 Da; .about.3 mmols) with 0.32 mols
butyric anhydride.
[0116] In some modes of practice, the invention provides an coating
comprising hydrophobic glucopyranose polymer comprising a DS in the
range of about 2-3, comprising pendent linear, branched, or cyclic
a C.sub.4-C.sub.10 groups, and the polymer has a MW in the range of
about 2000 to about 20000 Da.
[0117] In some modes of practice, the invention provides an coating
comprising hydrophobic glucopyranose polymer comprising a DS in the
range of about 2-3, comprising pendent linear, branched, or cyclic
C.sub.5-C.sub.7 groups, and the polymer has a MW in the range of
about 2000 to about 20000 Da.
[0118] The degree of substitution can influence the hydrophobic
character of the polysaccharide. In turn, coatings formed from
hydrophobic derivatives having a substantial amount of groups
having the hydrocarbon segments bonded to the polysaccharide
backbone (as exemplified by a high DS) are generally more
hydrophobic and can be more resistant to degradation. For example,
a matrix formed from maltodextrin-butyrate DS1 has a rate of
degradation that is faster than a matrix formed from
maltodextrin-butyrate DS2.
[0119] The type of hydrocarbon segment present in the groups
pendent from the polysaccharide backbone can also influence the
hydrophobic properties of the polymer. In one aspect, the coating
is formed using a hydrophobic polysaccharide having pendent groups
with hydrocarbon segments being short chain branched alkyl group.
Exemplary short chain branched alkyl group are branched
C.sub.4-C.sub.10 groups. The preparation of a hydrophobic polymer
with these types of pendent groups is exemplified by the reaction o
maltodextrin with valproic acid/anhydride with maltodextrin
(MD-val). The reaction can be carried out to provide a relatively
lower degree of substitution of the hydroxyl groups, such as is in
the range of 0.5-1.5. Although these polysaccharides have a lower
degree of substitution, the short chain branched alkyl group
imparts considerable hydrophobic properties to the
polysaccharide.
[0120] Even at these low degrees of substitution the MD-val forms
coatings that are very compliant and durable. Because of the low
degrees of substitution, the pendent groups with the branched
C.sub.8 segment can be hydrolyzed from the polysaccharide backbone
at a relatively fast rate, thereby providing a biodegradable
coatings that have a relatively fast rate of degradation.
[0121] For polysaccharides having hydrolytically cleavable pendent
groups comprising hydrocarbon segments, penetration by an aqueous
solution can promote hydrolysis and loss of groups pendent from the
polysaccharide backbone. This can alter the properties of the
implant, and can result in greater access to enzymes that promote
the degradation of the natural biodegradable polysaccharide, and/or
can result in the loss of the polysaccharides from the coating as
they become solubilized.
[0122] Various synthetic schemes can be used for the preparation of
a hydrophobic derivative of a natural biodegradable polysaccharide.
In some modes of preparation, pendent polysaccharide hydroxyl
groups are reacted with a compound that includes a hydrocarbon
segment and a group that is reactive with the hydroxyl groups. This
reaction can provide polysaccharide with pendent groups comprising
hydrocarbon segments.
[0123] Any suitable chemical group can be coupled to the
polysaccharide backbone and provide the polysaccharide with
hydrophobic properties, wherein the polysaccharide becomes
insoluble in water. Preferably, the pendent group includes one or
more atoms selected from C, H, O, N, and S.
[0124] In some aspects, the pendent group comprises a hydrocarbon
segment that is a linear, branched, or cyclic C.sub.2-C.sub.18
group. More preferably the hydrocarbon segment comprises a
C.sub.2-C.sub.10, or a C.sub.4-C.sub.8, linear, branched, or cyclic
group. The hydrocarbon segment can be saturated or unsaturated, and
can comprise alkyl groups or aromatic groups, respectively. The
hydrocarbon segment can be linked to the polysaccharide chain via a
hydrolyzable bond or a non-hydrolyzable bond.
[0125] In some aspects the compound having a hydrocarbon segment
that is reacted with the polysaccharide backbone is derived from a
natural compound. Natural compounds with hydrocarbon segments
include fatty acids, fats, oils, waxes, phospholipids,
prostaglandins, thromboxanes, leukotrienes, terpenes, steroids, and
lipid soluble vitamins.
[0126] Exemplary natural compounds with hydrocarbon segments
include fatty acids and derivatives thereof, such as fatty acid
anhydrides and fatty acid halides. Exemplary fatty acids and
anhydrides include acetic, propionic, butyric, isobutyric, valeric,
caproic, caprylic, capric, and lauric acids and anhydrides,
respectively. The hydroxyl group of a polysaccharide can be reacted
with a fatty acid or anhydride to bond the hydrocarbon segment of
the compound to the polysaccharide via an ester group.
[0127] The hydroxyl group of a polysaccharide can also cause the
ring opening of lactones to provide pendent open-chain hydroxy
esters. Exemplary lactones that can be reacted with the
polysaccharide include caprolactone and glycolides.
[0128] Generally, if compounds having large hydrocarbon segments
are used for the synthesis of the hydrophobic derivative, a smaller
amount of the compound may be needed for its synthesis. For
example, as a general rule, if a compound having a hydrocarbon
segments with an alkyl chain length of C.sub.x is used to prepare a
hydrophobic derivative with a DS of 1, a compound having a
hydrocarbon segment with an alkyl chain length of C.sub.(x.times.2)
is reacted in an amount to provide a hydrophobic derivative with a
DS of 0.5.
[0129] The hydrophobic derivative of the natural biodegradable
polysaccharide can also be synthesized having combinations of
pendent groups with two or more different hydrocarbon segments,
respectively. For example, the hydrophobic derivative can be
synthesized using compounds having hydrocarbon segments with
different alkyl chain lengths. In one mode of practice, a
polysaccharide is reacted with a mixture of two or more fatty acids
(or derivatives thereof) selected from the group of acetic acid,
propionic acid, butyric acid, isobutyric acid, valeric acid,
caproic acid, caprylic acid, capric acid, and lauric acid to
generate the hydrophobic derivative.
[0130] In other cases the hydrophobic derivative is synthesized
having a non-hydrolyzable bond linking the hydrocarbon segment to
the polysaccharide backbone. Exemplary non-hydrolyzable bonds
include urethane bonds.
[0131] The hydrophobic derivative of the natural biodegradable
polysaccharide can also be synthesized so that hydrocarbon segments
are individually linked to the polysaccharide backbone via both
hydrolyzable and non-hydrolyzable bonds. As another example, a
hydrophobic derivative is prepared by reacting a mixture of butyric
acid anhydride and butyl isocyanate with maltodextrin. This yields
a hydrophobic derivative of maltodextrin with pendent butyric acid
groups that are individually covalently bonded to the maltodextrin
backbone with hydrolyzable ester linkages and non-hydrolyzable
urethane linkages. The degradation of a coating having this type of
hydrophobic derivative can occur by loss of the butyrate groups
from hydrolysis of the ester linkages. However, a portion of the
butyrate groups (the ones that are bonded via the urethane groups)
are not removed from the polysaccharide backbone and therefore the
natural biodegradable polysaccharide can maintain a desired degree
of hydrophobicity, prior to enzymatic degradation of the
polysaccharide backbone.
[0132] In some aspects, the group that is pendent from the
polysaccharide backbone has properties of a bioactive agent. In
this regard, the coating comprises polysaccharide-coupled bioactive
agent. In some aspects, a bioactive agent which has a hydrocarbon
segment can be hydrolyzed from the natural biodegradable polymer
and released from the matrix to provide a therapeutic effect. One
example of a therapeutically useful compound having a hydrocarbon
segments is butyric acid, which has been shown to elicit tumor cell
differentiation and apoptosis, and is thought to be useful for the
treatment of cancer and other blood diseases.
[0133] Other illustrative compounds comprising hydrocarbon segments
include valproic acid and retinoic acid. These compounds can be
coupled to a polysaccharide backbone to provide a pendent group,
and then cleaved from the polysaccharide backbone following
implantation of the coated article in a subject. Retinoic acid is
known to possess antiproliferative effects and is thought to be
useful for treatment of proliferative vitreoretinopathy (PVR). The
pendent group that provides a therapeutic effect can also be a
natural compound (such as butyric acid, valproic acid, and retinoic
acid).
[0134] Other illustrative compound that can be coupled to the
polysaccharide backbone is a corticosteroid. An exemplary
corticosteroid is triamcinolone. One method of coupling
triamcinolone to a natural biodegradable polymer is by employing a
modification of the method described in Cayanis, E. et al.,
Generation of an Auto-anti-idiotypic Antibody that Binds to
Glucocorticoid Receptor, The Journal of Biol. Chem., 261(11):
5094-5103 (1986). Triamcinolone hexanoic acid is prepared by
reaction of triamcinolone with ketohexanoic acid; an acid chloride
of the resulting triamcinolone hexanoic acid can be formed and then
reacted with the natural biodegradable polymer, such as
maltodextrin or polyalditol, resulting in pendent triamcinolone
groups coupled via ester bonds to the natural biodegradable
polymer.
[0135] The hydrophobic derivative of the natural biodegradable
polysaccharide can also be synthesized having two or more different
pendent groups, wherein at least one of the pendent groups
comprises a bioactive agent. The hydrophobic polysaccharide can be
synthesized with an amount of a pendent groups comprising a
bioactive agent, that when released from the polysaccharide,
provides a therapeutic effect to the subject. An example of such a
hydrophobic derivative is maltodextrin-caproate-triamcinolone. This
hydrophobic derivative can be prepared by reacting a mixture
including triamcinolone hexanoic acid and an excess of caproic
anhydride (n-hexanoic anhydride) with maltodextrin to provide a
derivative with a DS of 2.5.
[0136] In some aspects, the group that is pendent from the
polysaccharide includes a hydrocarbon segment that is an aromatic
group, such as a phenyl group. As one example, o-acetylsalicylic
acid is reacted with a polysaccharide such as maltodextrin to
provide pendent chemical group having a hydrocarbon segment that is
a phenyl group, and a non-hydrocarbon segment that is an acetate
group wherein the pendent group is linked to the polysaccharide via
an ester bond.
[0137] The term "bioactive agent," refers to an inorganic or
organic molecule, which can be synthetic or natural, that causes a
biological effect when administered in vivo to a subject. The
invention contemplates coatings having bioactive agent within the
matrix, but not coupled to the hydrophobic polysaccharide,
bioactive agent coupled to the hydrophobic polysaccharide, and
combinations thereof. The invention also contemplates coated
medical articles wherein the bioactive agent is present in the
article (such as within the body member of a biodegradable
stent).
[0138] A partial list of bioactive agents is provided below.
According to embodiments of the present invention, one may choose
one or more of the bioactive agents to be included in a coating
formed of the hydrophobic derivative of the natural biodegradable
polysaccharide and/or coated medical article. A comprehensive
listing of bioactive agents, in addition to information of the
water solubility of the bioactive agents, can be found in The Merck
Index Thirteenth Edition, Merck & Co. (2001).
[0139] Coatings and/or coated medical articles prepared according
to the invention can be used to release bioactive agents falling
within one or more of the following classes include, but are not
limited to: ACE inhibitors, actin inhibitors, analgesics,
anesthetics, anti-hypertensives, anti polymerases, antisecretory
agents, anti-AIDS substances, antibiotics, anti-cancer substances,
anti-cholinergics, anti-coagulants, anti-convulsants,
anti-depressants, anti-emetics, antifungals, anti-glaucoma solutes,
antihistamines, antihypertensive agents, anti-inflammatory agents
(such as NSAIDs), anti metabolites, antimitotics, antioxidizing
agents, anti-parasite and/or anti-Parkinson substances,
antiproliferatives (including antiangiogenesis agents),
anti-protozoal solutes, anti-psychotic substances, anti-pyretics,
antiseptics, anti-spasmodics, antiviral agents, calcium channel
blockers, cell response modifiers, chelators, chemotherapeutic
agents, dopamine agonists, extracellular matrix components,
fibrinolytic agents, free radical scavengers, growth hormone
antagonists, hypnotics, immunosuppressive agents, immunotoxins,
inhibitors of surface glycoprotein receptors, microtubule
inhibitors, miotics, muscle contractants, muscle relaxants,
neurotoxins, neurotransmitters, polynucleotides and derivatives
thereof, opioids, photodynamic therapy agents, prostaglandins,
remodeling inhibitors, statins, steroids, thrombolytic agents,
tranquilizers, vasodilators, and vasospasm inhibitors.
[0140] Antibiotics are art recognized and are substances that
inhibit the growth of or kill microorganisms. Examples of
antibiotics include penicillin, tetracycline, chloramphenicol,
minocycline, doxycycline, vancomycin, bacitracin, kanamycin,
neomycin, gentamycin, erythromycin, cephalosporins, geldanamycin,
and analogs thereof. Examples of cephalosporins include
cephalothin, cephapirin, cefazolin, cephalexin, cephradine,
cefadroxil, cefamandole, cefoxitin, cefaclor, cefuroxime,
cefonicid, ceforanide, cefotaxime, moxalactam, ceftizoxime,
ceftriaxone, and cefoperazone.
[0141] Antiseptics are recognized as substances that prevent or
arrest the growth or action of microorganisms, generally in a
nonspecific fashion, e.g., by inhibiting their activity or
destroying them. Examples of antiseptics include silver
sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium
hypochlorite, phenols, phenolic compounds, iodophor compounds,
quaternary ammonium compounds, and chlorine compounds.
[0142] Anti-viral agents are substances capable of destroying or
suppressing the replication of viruses. Examples of anti-viral
agents include .alpha.-methyl-P-adamantane methylamine,
hydroxy-ethoxymethylguanine, adamantanamine,
5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, and adenine
arabinoside.
[0143] Enzyme inhibitors are substances that inhibit an enzymatic
reaction. Examples of enzyme inhibitors include edrophonium
chloride, N-methylphysostigmine, neostigmine bromide, physostigmine
sulfate, tacrine HCl, tacrine, 1-hydroxymaleate, iodotubercidin,
p-bromotetramisole,
10-(.alpha.-diethylaminopropionyl)-phenothiazine hydrochloride,
calmidazolium chloride, hemicholinium-3,3,5-dinitrocatechol,
diacylglycerol kinase inhibitor I, diacylglycerol kinase inhibitor
II, 3-phenylpropargylamine, N-monomethyl-L-arginine acetate,
carbidopa, 3-hydroxybenzylhydrazine HCl, hydralazine HCl,
clorgyline HCl, deprenyl HCl, L(-), deprenyl HCl, D(+),
hydroxylamine HCl, iproniazid phosphate,
6-MeO-tetrahydro-9H-pyrido-indole, nialamide, pargyline HCl,
quinacrine HCl, semicarbazide HCl, tranylcypromine HCl,
N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride,
3-isobutyl-1-methylxanthine, papaverine HCl, indomethacin,
2-cyclooctyl-2-hydroxyethylamine hydrochloride,
2,3-dichloro-.alpha.-methylbenzylamine (DCMB),
8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride,
p-aminoglutethimide, p-aminoglutethimide tartrate, R(+),
p-aminoglutethimide tartrate, S(-), 3-iodotyrosine,
alpha-methyltyrosine, L(-)alpha-methyltyrosine, D L(-),
cetazolamide, dichlorphenamide,
6-hydroxy-2-benzothiazolesulfonamide, and allopurinol.
[0144] Anti-pyretics are substances capable of relieving or
reducing fever. Anti-inflammatory agents are substances capable of
counteracting or suppressing inflammation. Examples of such agents
include aspirin (salicylic acid), indomethacin, sodium indomethacin
trihydrate, salicylamide, naproxen, colchicine, fenoprofen,
sulindac, diflunisal, diclofenac, indoprofen and sodium
salicylamide. Local anesthetics are substances that have an
anesthetic effect in a localized region. Examples of such
anesthetics include procaine, lidocaine, tetracaine and
dibucaine.
[0145] Examples of statins include lovastatin, pravastatin,
simvastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin,
and superstatin.
[0146] Examples of steroids include glucocorticoids such as
cortisone, hydrocortisone, dexamethasone, betamethasone,
prednisone, prednisolone, methylprednisolone, triamcinolone,
beclomethasone, fludrocortisone, and aldosterone; sex steroids such
as testostersone, dihydrotestosterone, estradiol,
diethylstilbestrol, progesterone, and progestins.
[0147] The bioactive agent can be an immunosuppressive agent, for
example, rapamycin, ABT-578, cyclosporine, everolimus, mycophenolic
acid, sirolimus, tacrolimus, and the like.
[0148] In some cases a coating composition, such as one for a spray
coating process, can be prepared having the hydrophobic
polysaccharide at a concentration in the range of about 5 mg/mL to
about 500 mg/mL in the composition. In one modes of practice the
hydrophobic polysaccharide is present in the composition at about
50 mg/mL and the composition is used for coating a surface.
[0149] The coatings of the present invention can be formed by first
preparing a coating composition that includes the hydrophobic
derivative of a natural biodegradable polysaccharide. In some
aspects, one or more bioactive agent(s) can be included in the
coating composition. In the coating composition, the bioactive
agent can be in mixture with the hydrophobic derivative (but not
coupled to the hydrophobic derivative), coupled to the hydrophobic
derivative, or both. The bioactive agent can be present in the
composition at a concentration that allows formation of a coating
or an article with therapeutically useful properties. The amount
and type of bioactive agent may be chosen based on the type of
hydrophobic derivative present in the composition.
[0150] To illustrate one method of preparing a coating, a
composition is prepared by the combining a bioactive agent with a
hydrophobic polysaccharide in a suitable solvent. Examples of
solvents that can be used include aromatic compounds such as
toluene and xylene, and ethers such as tetrahydrofuran. Other
suitable solvents include halogenated alkanes such as methylene
chloride and chloroform; and amides such as dimethylformamide
(DMF). Combinations of one or more of these or other solvents can
also be used. The type of solvent system used can be chosen
according to the hydrophobic polysaccharide, the bioactive agent,
and any other optional component present in the composition.
[0151] In cases where formation of a coating with a high bioactive
agent is desired, the natural biodegradable polysaccharide and the
bioactive agent can, in combination, comprise about 90% or greater
by weight, 95% or greater by weight, 97.5% or greater by weight, or
99% or greater by weight, of the total solids of the coating
composition. In turn, when applied to the surface of an article to
be coated, the coating can include these same percentages
solids.
[0152] More specifically, in some aspects, bioactive agent is
present in an amount in the range of about 10 wt % to about 65 wt %
of the solids in the coating or coating composition, and the
hydrophobic polysaccharide is present in the range of about 90 wt %
to about 35 wt %. In more specific aspects, bioactive agent is
present in an amount in the range of about 25 wt % to about 55 wt %
of the solids in the coating or coating composition, and the
hydrophobic polysaccharide is present in the range of about 75 wt %
to about 45 wt %. In even more specific aspects, bioactive agent is
present in an amount in the range of about 40 wt % to about 50 wt %
of the solids in the coating or coating composition, and the
hydrophobic polysaccharide is present in the range of about 60 wt %
to about 50 wt %.
[0153] The hydrophobic polysaccharide can optionally be blended
with one or more other hydrophobic compounds in a composition for
preparation of the coating. The other hydrophobic compounds can be
biodegradable polymers. For example, the coating can be prepared
using a blend of two or more different hydrophobic polysaccharides.
The hydrophobic polysaccharide can differ with regards to one or
more of the following aspects: molecular weight, type of pendent
group (e.g., type of hydrocarbon segment), and amount of groups
pendent from the polysaccharide.
[0154] The hydrophobic polysaccharide can also be blended with
different types of biodegradable polymers. Examples include
polyesters such as poly(lactic acid) (poly(lactide)), poly(glycolic
acid) (poly(glycolide)) poly(lactide-co-glycolide),
poly(dioxanone); polylactones such as poly(caprolactone) and
poly(valerolactone), copolymers such as
poly(glycolide-co-polydioxanone), poly(glycolide-co-trimethylene
carbonate), and poly(glycolide-co-caprolactone);
poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(tartronic
acid), poly(.beta.-malonic acid), poly(propylene fumarate);
degradable polyesteramides; degradable polyanhydrides and
polyalkeneanhydrides (such as poly(sebacic acid),
poly(1,6-bis(carboxyphenoxy)hexane,
poly(1,3-bis(carboxyphenoxy)propane); degradable polycarbonates and
aliphatic carbonates; degradable polyiminocarbonates; degradable
polyarylates; degradable polyorthoesters; degradable polyurethanes;
degradable polyphosphazenes; degradable polyhydroxyalkanoates;
degradable polyamides; degradable polypeptides; and copolymers
thereof.
[0155] Compositions of the invention that include the hydrophobic
polysaccharide in an organic solvent can be used to coat the
surface of a variety of implantable medical devices. The coating
composition (with or without bioactive agent) can be applied to a
medical device using standard techniques to cover the entire
surface of the device, or a portion of the device surface. If more
than one coated layer is applied to a surface, it is typically
applied successively. For example, a hydrophobic polysaccharide
coated layer can be formed by, for example, dipping, spraying,
bushing, or swabbing the coating material on the article to form a
layer, and then drying the coated layer. The process can be
repeated to provide a coating having multiple coated layers,
wherein at least one layer includes the natural biodegradable
polysaccharide. The compositions of the present invention are
particularly suitable for use in spray coating processes.
[0156] An exemplary spray coating process and apparatus that can be
used for coating implantable medical articles using the
compositions of the present invention is described in U.S. Patent
Publication No. 2004-0062875-A1 (filed Sep. 27, 2002).
[0157] A composition that includes the hydrophobic polysaccharide
can be spray coated directly onto the surface of a body member of a
medical article, or can be spray coated onto a surface that
includes one or more coated layers of material previously formed on
the body member. The composition may be spray coated onto a coated
layer of material that includes a bioactive agent.
[0158] Other coated layers can include polymers such as
methacrylate, acrylate, alkylacrylate, acrylamide,
vinylpyrrolidinone, vinylacetamide, or vinyl formamide polymers.
These polymers can also include latent reactive groups, such as
photoreactive groups.
[0159] In some cases the coated layer that includes the hydrophobic
derivative is formed on a base layer. The base layer can serve one
or more functions, for example, it can provide an improved surface
for the formation of a coated layer that includes the hydrophobic
derivative.
[0160] Components of the biodegradable coating can be applied to
the medical device using standard techniques to cover the entire
surface of the device, or a portion of the device surface. As
indicated, the components can be applied to the medical device
independently or together, for example, in a composition. The
coating formed on the device can be a single layer coating, or a
multiple layer coating.
[0161] In some aspects the coating comprises a biocompatible
hydrophilic polymer. The biocompatible hydrophilic polymer can
increase the rate of release of the bioactive agent from the
coating, as compared to an equivalent coating that does not include
the biocompatible hydrophilic polymer. The biocompatible
hydrophilic polymer can be biodegradable or non-biodegradable.
Exemplary biocompatible hydrophilic polymers include poly(ethylene
glycol), hydrophilic polysaccharides, polyvinyl pyrrolidones,
polyvinyl alcohols, low molecular weight methyl cellulose,
hydroxypropyl methyl cellulose (HPMC), and the like.
[0162] The biodegradable hydrophilic polymer is thought to create
hydrophilic domains in the coating. These hydrophilic domains are
thought to drive fluid into the coating after the coated
implantable article has been placed within a subject. In one
proposed mechanism, release of the bioactive agent is thought to be
promoted by an increase in osmotic pressure with the coating, which
forces bioactive agent out of the coating. In another proposed
mechanism, release of the bioactive agent is thought to be promoted
by the hydrolysis of pendent groups linked via hydrolytically
cleavable ester groups. This decreases the hydrophobicity of the
coating, and increases the rate of release of the bioactive
agent.
[0163] For example, in some aspects, bioactive agent is present in
an amount in the range of about 10 wt % to about 65 wt % of the
solids in the coating or coating composition, and the hydrophobic
derivative of the natural biodegradable polysaccharide is present
in the range of about 70 % to about 35 wt % of the solids in the
coating or coating composition, and the biodegradable hydrophilic
polymer is present in an amount in the range of about 1 % to about
20 % of the solids in the coating or coating composition In more
specific aspects, bioactive agent is present in an amount in the
range of about 25 wt % to about 55 wt % of the solids in the
coating or coating composition, the hydrophobic derivative is
present in the range of about 60 wt % to about 40 wt % of the
solids in the coating or coating composition, and the biodegradable
hydrophilic polymer is present in an amount in the range of about 5
% to about 15 % of the solids in the coating or coating
composition.
[0164] In even more specific aspects, bioactive agent is present in
an amount in the range of about 40 wt % to about 50 wt % of the
solids in the coating or coating composition, the hydrophobic
derivative is present in the range of about 50 wt % to about 40 wt
% of the solids in the coating or coating composition, and the
biodegradable hydrophilic polymer is present in an amount in the
range of about 7.5 % to about 12.5 % of the solids in the coating
or coating composition.
[0165] Other optional components can be included in the coating.
These components can be included in amounts less than the amounts
of hydrophobic polysaccharide or bioactive agent in the coating.
These optional components can change or improve the properties of
the coating.
[0166] Components that can facilitate the detection of the
implanted medical article include colorants, radiopacifying agents,
and radioisotopes. The presence of one or more of these components
can facilitate detection of the location of article following
implantation.
[0167] Another class of optional components is excipients.
Excipients can improve the stability of the bioactive agent that is
associated with the coating and/or act as a plasticizing agent to
change the physical property of the coating. Exemplary excipients
include glycerol, diethylene glycol, sorbitol, sorbitol esters,
maltitol, sucrose, fructose, invert sugars, corn syrup, and
mixtures thereof. The amount and type of excipient(s) can be based
on known standards and techniques. Antioxidants can be added to the
coating to maintain coating properties, including the stability of
the bioactive agent.
[0168] Optional components can also be used to change the
elasticity, flexibility, wettability, or adherent properties, (or
combinations thereof) of the coating.
[0169] Implantable medical articles that include a biodegradable
coating can be treated to sterilize one or more parts of the
article, or the entire article. Sterilization can take place prior
to using the coated article and/or, in some cases, during
implantation of the medical article. For example, a stent with a
biodegradable coating can be sterilized before insertion into the
body. In some aspects the coated article can be contacted with an
aqueous sterilization solution.
[0170] According to some aspects of the invention, bioactive agent
is made available to a subject using a method that involves the
following steps. One step is implanting at a target site in a
subject a medical article having a coating comprising a
biodegradable coating comprising a matrix of hydrophobic natural
biodegradable polysaccharides and bioactive-agent within the
matrix. Another step is allowing the bioactive agent to be released
from the coating in the subject following the step of
implanting.
[0171] While the step of implanting can be performed to place the
coated medical article at a desired location anywhere in the body,
an exemplary process involves the placement of a stent having a
biodegradable coating in the vasculature.
[0172] Stents with the biodegradable coating as described herein
have particular application in the field of coronary angioplasty.
As used herein, the terms "stent" and "prosthesis" are used
interchangeably to some extent in describing the invention, insofar
as the methods, apparatus, and structures of the invention can be
utilized not only in connection with an expandable intraluminal
vascular graft for expanding partially occluded segments of a
vessel, duct, or body passageways, such as within an organ, but can
also be utilized for many other purposes as an expandable
prosthesis for many other types of body passageways. For example,
expandable prostheses can also be used for such purposes as (1)
supportive graft placement within blocked arteries opened by
transluminal recanalization, but which are likely to collapse in
the absence of internal support; (2) similar use following catheter
passage through mediastinal and other veins occluded by inoperable
cancers; (3) reinforcement of catheter created intrahepatic
communications between portal and hepatic veins in patients
suffering from portal hypertension; (4) supportive graft placement
of narrowing of the esophagus, the intestine, the ureters, the
urethra, and the like; (5) intraluminally bypassing a defect such
as an aneurysm or blockage within a vessel or organ; and (6)
supportive graft reinforcement of reopened and previously
obstructed bile ducts. Accordingly, use of the term "prosthesis"
encompasses the foregoing usages within various types of body
passageways, and the use of the term "intraluminal graft"
encompasses use for expanding the lumen of a body passageway.
Further, the term "body passageway" encompasses any lumen or duct
within the body, such as those previously described, as well as any
vein, artery, or blood vessel within the vascular system.
[0173] Coated stents can be adapted for deployment and implantation
using conventional methods known in the art and employing
percutaneous transluminal catheter devices. Coated stents can be
designed for deployment by any of a variety of in situ expansion
means, such as an inflatable balloon or a polymeric plug that
expands upon application of pressure. For example, the tubular body
of the stent can be positioned to surround a portion of an
inflatable balloon catheter. The stent, with the balloon catheter
inside is configured at a first, collapsed diameter. The stent and
the inflatable balloon are percutaneously introduced into a body
lumen, following a previously positioned guidewire in an
over-the-wire angioplasty catheter system, and tracked by suitable
means (such as fluoroscopy) until the balloon portion and
associated stent are positioned within the body passageway at the
implantation site. Thereafter, the balloon is inflated and the
stent is expanded by the balloon portion from the collapsed
diameter to a second expanded diameter. After the stent has been
expanded to the desired final expanded diameter, the balloon is
deflated and the catheter is withdrawn, leaving the stent in place.
During placement, the stent can optionally be covered by a
removable sheath or other means to protect both the stent and the
vessels.
[0174] For self-expanding stents, the following procedure can be
applicable. In order to deliver a stent to the site of a stenotic
lesion (implantation site), the external diameter of the stent is
reduced so that the stent can easily traverse the blood vessels
leading to the implantation site. The stent is disposed within the
reduced diameter portion of the vessel. Thus, the stent is reduced
by, for example, elongating the stent, allowing for a corresponding
reduction in diameter, and maintained in such a reduced diameter or
collapsed configuration during the delivery process. Once at the
implantation site, the forces tending to reduce the diameter of the
stent are released whereby the stent can support and/or dilate the
stenotic portion of the vessel.
[0175] In some aspects, the stent can be delivered to an
implantation site by placing the reduced diameter stent within a
delivery sheath that is in turn fed through a guide catheter
through the vasculature to the implantation site. The stent
carrying sheath is then advanced from the distal end of the guide
catheter over a guide wire into the targeted vessel and to the
implantation site (site of a stenotic lesion).
[0176] A second sheath can be provided proximally of the collapsed
stent and used to facilitate removal of the stent from the outer
sheath. For example, once the sheath has been disposed at the
implantation site of a vessel, the inner, proximal sheath is held
in place while the outer sheath is retracted or pulled proximally
with respect to the stent. Removal of the outer sheath removes the
forces that retain the stent in its collapsed configuration and
thus allow the stent to self-expand within the stenotic portion of
the vessel to support and dilate the vessel walls. The inner sheath
prevents the stent from moving proximally with the outer sheath.
The inner and outer sheaths as well as the guide wire and guide
catheter can then be removed from the vascular system.
Alternatively, the inner and outer sheaths can be removed and a
balloon catheter fed through the guide catheter over the guide wire
and into the expanded stent. The balloon can then be inflated
within the stent so as to urge the stent into firm engagement with
the walls of the vessel and/or to augment the dilation of the
artery effected by the stent alone.
[0177] In some aspects, the stent can be delivered to the
implantation site on a balloon catheter. Such balloon catheters are
well known and will not be described in more detail here.
[0178] Another exemplary process involves the placement of an
ocular article having a biodegradable coating in a portion of the
eye.
[0179] An ocular article having a coating formed of hydrophobic
derivatives of natural biodegradable polysaccharides can be
implanted into a portion of the eye using any suitable method.
Typically, the ocular article is delivered using an insertion
instrument to provide the coated medical article to the targeted
site within the eye. The term "implantation site" refers to the
site within a patient's body at which the coated medical article is
located during a treatment course according to the invention.
[0180] The ocular article can be placed at an implantation site
within the eye tissues. Suitable ocular implants can perform a
function and/or provide bioactive agent to any desired area of the
eye. For example, an implantation site can be chosen to provide
bioactive agent primarily to an anterior segment of the eye (in
front of the lens), or to a posterior segment of the eye (behind
the lens). Suitable ocular implants can also be utilized to provide
bioactive agent to tissues in proximity to the eye, when desired.
In some aspects, the ophthalmic article can be configured for
placement at an intraocular site, such as the vitreous.
[0181] The vitreous chamber is the largest chamber of the eye and
contains the vitreous humor or vitreous. Generally speaking, the
vitreous is bound interiorly by the lens, posterior lens zonules
and ciliary body, and posteriorly by the retinal cup. The vitreous
is a transparent, viscoelastic gel that is 98% water and has a
viscosity of about 2-4 times that of water. The main constituents
of the vitreous are hyaluronic acid (HA) molecules and type II
collagen fibers, which entrap the HA molecules. The viscosity is
typically dependent on the concentration of HA within the vitreous.
The vitreous is traditionally regarded as consisting of two
portions: a cortical zone, characterized by more densely arranged
collagen fibrils, and a more liquid central vitreous.
[0182] Therefore, in some aspects, the invention provides methods
for placing an ocular article at a site within the body, the site
comprising a gel-like material, such as viscoelastic gel.
[0183] In many aspects of the invention, the ocular article is
placed in the vitreous. In some aspects, the ocular article can be
delivered through the scleral tissue (trans-scleral injection).
[0184] The ocular article can be used for the treatment of diabetic
retinopathy, which is characterized by angiogenesis in the retinal
tissue.
[0185] Diabetic retinopathy has four stages. While the ocular
article can be delivered to a subject diagnosed with diabetic
retinopathy during any of these four stages, it is common to treat
the condition at a later stage.
[0186] The first stage is mild nonproliferative retinopathy which
is characterized by the appearance of microaneurysms in retinal
blood vessels. The second stage is moderate nonproliferative
retinopathy which is characterized by blockage of the retinal blood
vessels. The third stage is severe nonproliferative retinopathy
which is characterized by a more extensive blockage of the retinal
blood vessels, which deprive several areas of the retina with their
blood supply and results in the formation of new blood vessels in
the retina (angiogenesis) in response to this deprivation. The
fourth stage is proliferative retinopathy which is characterized by
active formation of new blood vessels, which have an abnormal
morphology. These abnormally-formed vessels grow along the retinal
and vitreal surface and are prone to leak blood, which can result
in severe vision loss.
[0187] The treatment of diabetic retinopathy can be accomplished by
delivering the ocular article to a target location so that one or
more anti-angiogenic factors is released from the ocular article
and affects sub-retinal tissue. In some aspects the bioactive agent
is an inhibitor of angiogenesis such as anecortave acetate, or a
receptor tyrosine kinase antagonist.
[0188] Compounds and methods for treating diabetic retinopathy with
a receptor tyrosine kinase antagonist have been described in U.S.
Pat. No. 5,919,813. In some aspects, the coated medical article of
the present invention comprises a compound of formula I:
##STR00001##
wherein V, W and X are selected from the group consisting of hydro,
hydroxyl, alkoxy, halo, an ester, an ether, a carboxylic acid
group, a pharmaceutically acceptable salt of a carboxylic acid
group, and ----SR, in which R is hydrogen or an alkyl group, and Y
is selected from the group consisting of oxygen, sulfur, C(OH), and
C.dbd.O, and Z is selected from the group consisting of hydro and
C(O)OR.sub.1, wherein R.sub.1 is an alkyl. In some aspects, the
alkoxy is a C.sub.1-C.sub.6 alkoxy. In some aspects, the halo is
fluorine, chlorine or bromine. In some aspects, the ester is a
C.sub.1-C.sub.6 ester. In some aspects, the ether is a
C.sub.1-C.sub.6 ether. Pharmaceutically acceptable salts of the
carboxylic acid group include sodium and potassium salts. In some
aspects, the alkyl groups are C.sub.1-C.sub.6 alkyl groups. In some
aspects, the protein tyrosine kinase pathway inhibitor is
genistein.
[0189] Exemplary dosage ranges using a compound of formula I are
from about 1 mg/kg/day to about 100 mg/kg/day, or more specifically
from about 15 mg/kg/day to about 50 mg/kg/day.
[0190] Combination drug delivery strategies can also be carried out
for the treatment of diabetic retinopathy. For example, retinal
tissue can be treated with one or more neurotrophic factors.
Exemplary neurotrophic factors include ciliary neurotrophic factor
(CNTF) and glial cell-derived neurotrophic factor (GDNF). In
addition neuroprotective agents such as coenzyme Q10, creatine, and
minocycline can be delivered from the implant. As an example,
minocycline is thought to be a neuroprotective agent (in addition
to its role as an antibiotic with anti-inflammatory effects) as it
may also prevent the cascade of events leading to programmed cell
death (apoptosis).
[0191] The treatment of diabetic retinopathy can be performed by
administration of the coated medical article alone, or can be
performed with other procedures such as laser surgery and/or
vitrectomy.
[0192] The coated medical article can be used for the treatment of
uveitis, which is characterized by inflammation of the uvea. The
uvea is the layer of the eye between the sclera and the retina and
includes the iris, ciliary body, and choroid. The uvea provides
most of the blood supply to the retina.
[0193] Forms of uveitis include anterior uveitis, which typically
involves inflammation that is limited to the iris (iritis). Another
form of uveitis involves inflammation of the pars plana (between
the iris and the choroid). Another form of uveitis is posterior
uveitis affects primarily the choroid (choroiditis). The ocular
article of the present invention can be delivered to a target site
in the eye for the treatment of any of these particular
conditions.
[0194] The present invention contemplates treating uveitis by
delivering one or more anti-inflammatory factors in the sub-retinal
space.
[0195] In a more particular aspect of the present invention,
steroids, including anti-inflammatory steroids and corticosteroids,
are delivered to the sub-retinal space. Exemplary anti-inflammatory
steroids and corticosteroids include hydrocortisone, hydrocortisone
acetate, dexamethasone 21-phosphate, fluocinolone, medrysone,
methylprednisolone, prednisolone 21-phosphate, prednisolone
acetate, fluoromethalone, betamethasone, and triamcinolone, or
triamcinolone acetonide.
[0196] In an exemplary embodiment, the dosage of the steroid is
between about 10 .mu.g and about 500 .mu.g over a period of time in
the range of about three to about twelve months. This dosage range
is applicable to each of the three following stages of macular
degeneration, namely: early onset macular degeneration, atrophic
macular degeneration (AMD) and neovascular macular degeneration
(NMD).
[0197] The ocular article can also be used for the treatment of
retinitis pigmentosa, which is characterized by retinal
degeneration. For example, the present invention contemplates
treating retinitis pigmentosa by delivering one or more
neurotrophic factors in the sub-retinal space.
[0198] The ocular article can also be used for the treatment of
age-related macular degeneration (AMD). AMD is characterized by
both angiogenesis and retinal degeneration. Specific forms of AMD
include, but are not limited to, dry age-related macular
degeneration, exudative age-related macular degeneration, and
myopic degeneration. The ocular article of the present invention
can be delivered to a target site in the eye for the treatment of
any of these forms of AMD. As an example, the coated medical
article can be used to deliver one or more of the following drugs
for the treatment of AMD: anti-VEGF (vascular endothelial growth
factor) compounds, neurotrophic factors, and/or anti-angiogenic
factors. In some specific aspects, the ocular article is used to
release a corticosteriod for the treatment of sub-retinal
tissue.
[0199] The ocular article can also be used for the treatment of
glaucoma, which is characterized by increased ocular pressure and
loss of retinal ganglion cells. The ocular article of the present
invention can be delivered to a target site in the eye for the
treatment of glaucoma contemplated for the release of one or more
neuroprotective agents that protect cells from excitotoxic damage.
Such agents include N-methyl-D-aspartate (NMDA) antagonists,
cytokines, and neurotrophic factors.
[0200] An ocular article condition can also be treated by
delivering the coated medical article to a target location in the
eye to release an antiproliferative agent, such as 13-cis retinoic
acid, retinoic acid derivatives, 5-fluorouracil, taxol, rapamycin,
analogues of rapamycin, tacrolimus, ABT-578, everolimus,
paclitaxel, taxane, or vinorelbine.
[0201] An ocular condition can also be treated by delivering the
ocular article to a target location in the eye to release a beta
adrenergic agent such as isoproterenol, epinephrine, norepinephrine
(agonists) and propranolol (antagonist).
[0202] An ocular condition can also be treated by delivering the
ocular article to a target location in the eye to release a
prostaglandin such as PGE.sub.2 or PGF.sub.2.
[0203] The ocular article of the present invention can also be used
for the prophylactic treatment of a subject. In other words, the
coated medical article may be provided to a subject even if there
has not been a diagnosed existence of a disorder or disease. For
example, in more than 50% of cases where AMD occurs in one eye, it
will subsequently occur in the unaffected eye within a year. In
such cases, prophylactic administration of a therapeutic medium
such as a steroid into the unaffected eye may prove to be useful in
minimizing the risk of, or preventing, AMD in the unaffected
eye.
[0204] The bioactive agent can be released for a period of time and
in an amount sufficient to treat a medical condition in a subject,
such as one suffering from a cardiovascular disease or compilation.
One distinct advantage of the present invention are that bioactive
agents can be released from the coating at a steady rate, meaning
that there is not substantial variation in amount of bioactive
agent released per day over the bioactive agent release period of
the coating. Given this, the coatings of the invention allow for
drug delivery that is close to a zero-order release rate. The
bioactive agent can also be released in therapeutically effective
amounts for treatment of medical conditions.
[0205] In some aspects, the bioactive agent is released at an
average rate in the range of 10 ng/day to 10 .mu.g/day. In more
specific aspects, the bioactive agent is released at an average
rate in the range of 100 ng/day to 7.5 .mu.g/day. In yet more
specific aspects, the bioactive agent is released at an average
rate in the range of 500 ng/day to 5 .mu.g/day. In yet more
specific aspects, the bioactive agent is released at an average
rate in the range of 750 ng/day to 2.5 .mu.g/day. In yet more
specific aspects, the bioactive agent is released at an average
rate of approximately 1 .mu.g/day.
[0206] Another distinct advantage is that the coatings can be
prepared having a particularly long bioactive agent release period,
in which therapeutically effective amounts of bioactive agent are
able to be released at later points during this period. With regard
to bioactive agent release, the coating can have a "half-life,"
which is the period of time at which half of the total amount of
bioactive agent that is present in the coating is released during
the bioactive agent release period.
[0207] For example, in one aspect, 50% of the amount of bioactive
agent present in the coating is released from the coating after a
period of 100 days. In this regard, the coating can be used for the
treatment of medical conditions wherein bioactive agent is to be
released for a period of time of about 3 months or greater, a
period of time of about 6 months or greater, a period of time of
about 9 months or greater, a period of time of about 12 months or
greater, a period of time in the range of about 3 to about 6
months, a period of time in the range of about 3 to about 9 months,
a period of time in the range of about 3 to about 12 months, or a
period of time in the range of about 3 to about 24 months.
[0208] In some aspects, depending on the properties of the implant,
a carbohydrase can promote the degradation of the coating. For
example, the groups pendent from the polysaccharide backbone can be
released by hydrolytic cleavage, and a portion of the coating can
become accessible to a carbohydrase, which can enzymatically digest
the polysaccharide and degrade the coating.
[0209] In these aspects, hydrolysis of the ester bond, which can
occur non-enzymatically, and enzymatic hydrolysis of the linkages
between the monomeric (or dimeric) units of the polysaccharide
portion can contribute to degradation of the coating. For example,
non-enzymatic hydrolysis can lead to cleavage and loss of the
pendent group comprising the hydrocarbon segment from the coating.
This loss may lead to a portion of the article becoming more
hydrophilic, and subject to attack by a carbohydrase resulting in
biodegradation of the polysaccharide, and/or further decomposition
of the coating by loss of the polysaccharide from the surface.
[0210] Degradation by a carbohydrase may occur before, during,
or/and after the release of the bioactive agent. Examples of
carbohydrases that can specifically degrade natural biodegradable
polysaccharide coatings include .alpha.-amylases, such as salivary
and pancreatic .alpha.-amylases; disaccharidases, such as maltase,
lactase and sucrase; trisaccharidases; and glucoamylase
(amyloglucosidase).
[0211] Serum concentrations for amylase are estimated to be in the
range of about 50-100 U per liter, and vitreal concentrations also
fall within this range (Varela, R. A., and Bossart, G. D. (2005) J
Am Vet Med Assoc 226:88-92).
[0212] In some aspects, a carbohydrase can be administered to a
subject to increase its concentration in the body fluid or tissue
surrounding the coated article, so that the carbohydrase may
promote the degradation of the implant. Exemplary routes for
introducing a carbohydrase include local injection, intravenous
(IV) routes, and the like. Alternatively, degradation can be
promoted by indirectly increasing the concentration of a
carbohydrase in the vicinity of the coated article, for example, by
a dietary process, or by ingesting or administering a compound that
increases the systemic levels of a carbohydrase.
[0213] In other cases, the carbohydrase can be provided on a
portion of the article that is coated. For example the carbohydrase
may be released from a portion of the article to promote its own
degradation.
[0214] The coating can also be eroded by liberatation of
polysaccharides from the surface of the implant. For example, after
pendent groups are released from the polysaccharide by hydrolytic
cleavage, the polysaccharide can loose its hydrophobic association
with the remaining portion of the implant, and be partially or
wholly released into fluid or tissue surrounding the implant.
Degradation of the liberated polysaccharide by a carbohydrase can
take place during or after liberation of the polysaccharide.
[0215] Degradation of the hydrophobic derivatives of the
biodegradable polysaccharides of the present invention can result
in the release of naturally occurring mono- or disaccharides, such
as glucose. These naturally occurring mono- or disaccharides which
are common serum components and present little or no immunogenic or
toxic risk to the individual.
[0216] Optionally, a lipase can be used in association with the
article to accelerate degradation of the bond between the pendent
group and the polysaccharide (e.g., ester bond).
[0217] The invention will be further described with reference to
the following non-limiting Examples. It will be apparent to those
skilled in the art that many changes can be made in the embodiments
described without departing from the scope of the present
invention. Thus the scope of the present invention should not be
limited to the embodiments described in this application, but only
by embodiments described by the language of the claims and the
equivalents of those embodiments. Unless otherwise indicated, all
percentages are by weight.
EXAMPLE 1
[0218] 11 g of dried maltodextrin (GPC, Grain Processing
Corporation, Muscatine, Iowa) was dissolved in 100 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 20 g
(0.244 moles, 19.32 mls, Sigma-Aldrich) of 1-methylimidizole
followed by 50 g (0.32 moles, 52 mls, Sigma-Aldrich, Milwaukee,
Wis.) of butyric anhydride were added with stirring at room
temperature. The reaction solution was stirred for one hour and was
then quenched with deionized water. The taffy-like material that
precipitated from the quenched reaction mixture was placed in 1,000
MWCO dialysis tubing and dialyzed vs. continuous flow deionized
water for three days. After this time the solid product was
lyophilized. 23.169 g of a white powdery solid was obtained. The
theoretical degree of substitution (DS) was 2.5.
EXAMPLE 2
[0219] 10 g of dried MD was dissolved in 100 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 23.7 g
(0.29 moles, 22.9 mls) of 1-methylimidizole followed by 29.34 g
(0.29 moles, 27.16 mls) of acetic anhydride (Sigma-Aldrich,
Milwaukee, Wis.) were added with stirring at room temperature. The
reaction solution was stirred for one hour and was then slowly add
to 750 mls of deionized water in a Waring blender. The precipitated
solid was collected via filtration, re-suspended in 1 L of
deionized water and stirred for one hour. The solid was collected
via filtration and dried in vacuo. 15.92 g of a yellow powdery
solid was obtained. The theoretical DS was 2.5
EXAMPLE 3
[0220] 10 g of dried MD was dissolved in 100 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 9.49 g
(0.11 moles, 9.17 mls) of 1-methylimidizole followed by 18.19 g
(0.11 moles, 18.81 mls) of butyric anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid was collected via filtration and dried in
vacuo. 16.11 g of a white powdery solid was obtained. The
theoretical DS was 1.
EXAMPLE 4
[0221] 10 g of dried MD was dissolved in 100 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 14.24 g
(0.17 moles, 13.76 mls) of 1-methylimidizole followed by 27.32 g
(0.17 moles, 28.25 mls) of butyric anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid was collected via filtration and dried in
vacuo. 18.95 g of a white powdery solid was obtained. The
theoretical DS was 1.5.
EXAMPLE 5
[0222] 10 g of dried MD was dissolved in 100 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 18.97 g
(0.23 moles, 18.33 mls) of 1-methylimidizole followed by 36.39 g
(0.23 moles, 37.63 mls) of butyric anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid was collected via filtration and dried in
vacuo. 19.78 g of a white powdery solid was obtained. The
theoretical DS was 2.
EXAMPLE 6
[0223] 10 g of dried polyalditol (GPC, Grain Processing
Corporation, Muscatine, Iowa) was dissolved in 100 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 28.46 g
(0.35 moles, 27.5 mls) of 1-methylimidizole followed by 54.58 g
(0.35 moles, 56.44 mls) of butyric anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then quenched with deionized water. The reaction
mixture was placed in 1,000 MWCO dialysis tubing and dialyzed vs.
continuous flow deionized water for three days. After this time the
solution was lyophilized. 11.55 g of a white powdery solid was
obtained. The theoretical DS was 2.
EXAMPLE 7
[0224] 1 g of dried .beta.-cyclodextrin (Sigma-Aldrich, Milwaukee,
Wis.) was dissolved in 10 mls of dimethyl sulfoxide with stirring.
When the solution was complete, 5.02 g (0.061 moles, 4.85 mis) of
1-methylimidizole followed by 9.62 g (0.061 moles, 9.95 mls) of
butyric anhydride were added with stirring at room temperature. The
reaction solution was stirred for one hour and was then quenched
with deionized water. The reaction mixture was placed in 1,000 MWCO
dialysis tubing and dialyzed vs. continuous flow deionized water
for three days. After this time the solution was lyophilized. 234
mg of a white powdery solid was obtained. The theoretical DS was
2.
EXAMPLE 8
[0225] 10 g of dried MD was dissolved in 100 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 23.7 g
(0.29 moles, 22.9 mls) of 1-methylimidizole followed by 37.38 g
(0.29 moles, 36.8 mls) of propionoic anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid was collected via filtration and dried in
vacuo. 18.49 g of a white powdery solid was obtained. The
theoretical DS was 2.5.
EXAMPLE 9
[0226] 10 g of dried MD was dissolved in 100 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 9.48 g
(0.12 moles, 9.16 mls) of 1-methylimidizole followed by 14.95 g
(0.12 moles, 14.73 mls) of propionoic anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid was collected via filtration and dried in
vacuo. 14.32 g of a white powdery solid was obtained. The
theoretical DS was 1.
EXAMPLE 10
[0227] 4 g of dried MD was dissolved in 40 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 9.48 g
(0.12 moles, 9.16 mls) of 1-methylimidizole followed by 24.63 g
(0.12 moles, 26.6 mls) of caproic anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid obtained was taffy-like and collected via
filtration and dried in vacuo. 7.18 g of a white solid was
obtained. The theoretical DS was 2.5.
EXAMPLE 11
[0228] 4 g of dried MD was dissolved in 40 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 3.79 g
(0.046 moles, 3.7 mls) of 1-methylimidizole followed by 9.85 g
(0.046 moles, 10.64 mls) of caproic anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid was collected via filtration and dried in
vacuo. 9.02 g of a white powdery solid was obtained. The
theoretical DS was 1.
EXAMPLE 12
[0229] 2.0 g of dried MD was dissolved in 10 mls of dimethyl
sulfoxide with stirring. 0.751 g (2.3 mmole) decanoic anhydride was
dissolved in 3 ml of chloroform. When the solutions were complete
0.188 g (2.3 mmoles, 0.183 mls) of 1-methylimidizole was added to
the DMSO/MD solution followed by the addition of the
chloroform/anhydride solution and 7.0 ml DMSO. The reaction was
stirred for 1 hour at room temperature. The reaction mixture was
placed in 1,000 MWCO dialysis tubing and dialyzed vs. continuous
flow deionized water for three days. The dialysis tube and contents
were placed in 1 liter of acetone/methanol-50/50 (volume) three
times for more than 1 hour for each solvent change. The dialysis
tube and contents were then placed in 4 liters of
acetone/methanol-50/50 (volume) three times for 1 day for each
solvent change. The solid from the dialysis tube was dried in
vacuo. 1.69 g of a white solid was obtained. The theoretical DS was
0.1.
EXAMPLE 13
[0230] 5.0 g of dried MD was dissolved in 10 mls of dimethyl
sulfoxide with stirring. 3.15 g (5.75 mmole) stearic anhydride was
dissolved in 3 ml of chloroform. When the solutions were complete
0.472 g (5.75 mmoles, 0.458 mls) of 1-methylimidizole was added to
the DMSO/MD solution followed by the addition of the
chloroform/anhydride solution and 7.0 ml DMSO. The reaction was
stirred for 1 hour at room temperature. The reaction mixture was
placed in 1,000 MWCO dialysis tubing and dialyzed vs. continuous
flow deionized water for three days. The dialysis tube and contents
were placed in 1 liter of acetone/methanol-50/50 (volume) three
times for more than 1 hour for each solvent change. The dialysis
tube and contents were then placed in 4 liters of
acetone/methanol-50/50 (volume) three times for 1 day for each
solvent change. The solid from the dialysis tube was dried in
vacuo. 6.58 g of a white powdery solid was obtained. The
theoretical DS was 0.1.
EXAMPLE 14
[0231] 4 g of dried MD was dissolved in 40 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 9.48 g
(0.12 moles, 9.16 mls) of 1-methylimidizole followed by 24.63 g
(0.12 moles, 26.6 mls) of caproic anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid obtained was taffy-like and collected via
filtration and dried in vacuo. 7.18 g of a white solid was
obtained. The theoretical DS was 2.5.
EXAMPLE 15
[0232] 4 g of dried MD was dissolved in 40 mls of dimethyl
sulfoxide with stirring. When the solution was complete, 9.48 g
(0.12 moles, 9.16 mls) of 1-methylimidizole followed by 24.63 g
(0.12 moles, 26.6 mls) of heptanoic anhydride were added with
stirring at room temperature. The reaction solution was stirred for
one hour and was then slowly add to 750 mls of deionized water in a
Waring blender. The precipitated solid was collected via
filtration, re-suspended in 1 L of deionized water and stirred for
one hour. The solid obtained was taffy-like and collected via
filtration and dried in vacuo. 7.18 g of a white solid was
obtained. The theoretical DS was 2.5.
EXAMPLE 16
[0233] Vacuum oven-dried Polyalditol PD60 (4.10 g),
N-hydroxysuccinimide (0.38 g), 4-di(methylamino)pyridine (0.39 g),
and 2-propylpentanoic acid (9.01 g; valproic acid) were weighed
into a 120 mL amber vial. Anhydrous dimethyl sulfoxide, DMSO, (50
mL) was poured into the vial, purged with nitrogen, and placed on a
rotary shaker to dissolve. N,N'-diisopropylcarbodiimide, DIC, (9.47
g) was weighed into a 30 mL amber vial and dissolved with 10 mL of
anhydrous DMSO. The DIC solution was poured into the 120 mL amber
vial and purged with nitrogen gas. A Teflon stir bar was inserted
into the 120 mL vial before being capped and placed on a stir plate
to stir overnight at room temperature. After overnight stirring, no
visible product was seen and the reaction was placed in a
55.degree. C. oven to stir overnight. The reaction formed two
layers after heating overnight and was precipitated into 2 L
deionized water while stirring. The yellowish/white solid was
vacuum-filtered using a water aspirator and rinsed three times with
deionized water (100 mL). The solid precipitate was collected and
dried in a vacuum oven at 40.degree. C. overnight. The dried solid
was organic soluble (tetrahydrofuran, methylene chloride). A 50
mg/mL solution in THF was prepared and tested by dip coating onto a
clean Pebax rod giving a uniform, off-white coating.
EXAMPLE 17
[0234] Vacuum oven-dried Polyalditol PD60 (4.10 g),
N-hydroxysuccinimide (0.38 g), 4-di(methylamino)pyridine (0.39 g),
and o-acetylsalicylic acid, ASA, (11.26 g) were weighed into a 120
mL amber vial. Anhydrous dimethyl sulfoxide (50 mL) was poured into
the vial, purged with nitrogen, and placed on a rotary shaker to
dissolve. N,N'-diisopropylcarbodiimide, DIC, (9.47 g) was weighed
into a 30 mL amber vial and dissolved with 10 mL of anhydrous DMSO.
The DIC solution was poured into the 120 mL amber vial and purged
with nitrogen gas. A Teflon stir bar was inserted into the 120 mL
vial before being capped and placed on a stir plate to stir
overnight at room temperature. After overnight stirring, no visible
product was seen and the reaction was placed in a 55.degree. C.
oven to stir overnight. The reaction formed a viscous, orange
material after heating overnight and was precipitated into 2 L
deionized water while stirring. The orange solid was
vacuum-filtered using a water aspirator and rinsed once with
acetone (25 mL) followed by three times with deionized water (100
mL). The solid precipitate was collected and dried in a vacuum oven
at 40.degree. C. overnight. The dried solid was organic soluble
(tetrahydrofuran, methylene chloride).
[0235] Stainless steel stents were coated with the polyalditol-ASA
polymer. Half of the coated stents were balloon expanded. Expanded
and unexpanded coated stents were evaluated by SEM. No evidence of
cracking or delamination was observed.
EXAMPLE 18
Release of Lidocaine from Stainless Steel Stents
[0236] A solution was prepared in 15 mls of THF containing 200 mgs
of poly(butylmethacrylate) (PBMA) with an approximate weight
average molecular weight of 337 kD, 200 mgs poly (ethylene-co-vinyl
acetate) (PEVA) with a vinyl acetate content of 33% (w/w), and 200
mgs lidocaine.
[0237] Stainless steel stents were prepared for coating as follows.
The stents were cleaned by soaking in a 6% (by volume) solution of
ENPREP-160SE (Cat. #2108-100, Enthone-OMI, Inc., West Haven, Conn.)
in deionized water for 1 hour. After soaking, the parts were then
rinsed several times with deionized water. After rinsing, the
stents were soaked for 1 hour at room temperature in 0.5% (by
volume) methacryloxypropyltrimethoxy silane (Cat.# M6514, Sigma
Aldrich, St. Louis, Mo.) made in a 50% (by volume) solution of
deionized water and isopropyl alcohol. The stainless steel wires
were allowed to drain and air dry. The dried stents were then
placed in a 100.degree. C. oven for 1 hour.
[0238] After oven-drying, the stents were placed in a parylene
coating reactor (PDS 2010 LABCOTER.TM. 2, Specialty Coating
Systems, Indianapolis, Ind.) and coated with 2 g of Parylene C
(Specialty Coating Systems, Indianapolis, Ind.) by following the
operating instructions for the LABCOTER.TM. system. The resulting
Parylene C coating was approximately 1-2 .mu.m thickness.
[0239] Solutions for coatings were sprayed onto the Parylene C
treated stents using an IVEK sprayer (IVEK Dispenser 2000, IVEK
Corp., North Springfield, Vt.) mounting a nozzle with a 1.0 mm
(0.04 inch) diameter orifice and pressurized at 421.84 g/cm.sup.2
(6 psi). The distance from the nozzle to the stent surface during
coating application was 5 to 5.5 cm. A coating application
consisted of spraying 40 .mu.L of the coating solution back and
forth on the stent for 7 seconds. The spraying process of the
coating was repeated until the amount of lidocaine on the stent was
estimated to be around 200 micrograms. The coating compositions on
the stents were dried by evaporation of solvent, approximately 8-10
hours, at room temperature (approximately 20.degree. C. to
22.degree. C.). After drying, the coated stents were re-weighed.
From this weight, the mass of the coating was calculated, which in
turn permitted the mass of the coated polymer(s) and lidocaine to
be determined.
[0240] Three solutions were prepared in THF; each solution was
prepared at 50 mg/mL. The three solutions were comprised of
maltodextrin-propionate (MD-Prop) (from Example 8),
maltodextrin-acetate (MD-Ace) (from Example 2), and
maltodextrin-caproate (MD-Cap) (from Example 10). Each of these
solutions was coated onto PBMA/PEVA/lidocaine coated stents as
described above. The spraying process was repeated until the amount
of MD polymer was estimated to be around 500 micrograms.
[0241] The Elution Assay utilized herein was as follows. Phosphate
buffered saline (PBS, 10 mM phosphate, 150 mM NaCl, pH 7.4, aqueous
solution) was pipetted in an amount of 3 mL to 10 mL into an amber
vial with a Teflon.TM. lined cap. A wire or coil treated with the
coating composition was immersed into the PBS. A stir bar was
placed into the vial and the cap was screwed tightly onto the vial.
The PBS was stirred with the use of a stir plate, and the
temperature of the PBS was maintained at 37.degree. C. with the use
of a water bath. The sampling times were chosen based upon the
expected or desired elution rate. At the sampling time point, the
stent was removed from the vial and placed into a new vial
containing fresh PBS. A UV/VIS spectrophotometer was used to
determine the concentration of the drug in the PBS solution that
previously contained the stent treated with the coating
composition. The cumulative amount of drug eluted versus time was
plotted to obtain an elution profile. The elution profiles are
illustrated graphically in FIG. 1.
EXAMPLE 19
Barrier Coating on Degradable Magnesium Alloy Coupon
[0242] 1 cm.times.0.75 cm strips were cut from a sheet of magnesium
alloy (96% magnesium, 3% aluminum, 1% zinc; Goodfellow Cambridge
Lmtd., Huntington, England). 1000 mg of MD-Cap DS 2.5 (from Example
10) was dissolved in THF at 5 room temperature. Half of the
magnesium alloy strips were coated with MD-Cap DS 2.5 by dipping
the bottom half of each strip into the polymer solution, removing
the strip, allowing the strip to dry, dipping the top half of the
strip into the polymer solution, removing the strip and allowing
the strip to dry. This procedure was repeated 4 times. Both the
coated and uncoated strips were subsequently weighed. Coated and
uncoated 10 strips are placed individually into vials and 2 mls of
phosphate buffered saline (PBS) pH 7.4 is added to each vial. The
vials were sealed and placed in a 37.degree. C. environmental
chamber. At various time points the vials were removed from the
chamber and the strips visually observed; approximate estimates of
the amount of each strip remaining were made and are shown in Table
1.
TABLE-US-00001 TABLE 1 Time Strip Observations 0 uncoated 100%
remaining 0 coated 100% remaining 8 hrs uncoated Slight pitting of
surface 8 hrs coated Nothing discernable 24 hrs uncoated Clear
pitting of surface 24 hrs coated Nothing discernable 48 Hrs
uncoated Heavy pitting, edges dissolving 48 hrs coated Slight
pitting of surface 5 days uncoated Approx. 30% dissolved 5 days
coated Clear pitting of surface 6 days uncoated Approx. 40%
dissolved 6 days coated Edges dissolving 7 days uncoated Approx.
80% dissolved 7 days coated Approx 5% dissolved 8 days uncoated
Approx. 90% dissolved 8 days coated Approx 10% dissolved 9 days
uncoated 100% dissolved 9 days coated Approx 35% dissolved
On day 9 the coated strips were removed from their vials and
weighed; they had retained an average of 63.0% of their original
mass.
EXAMPLE 20
Rapamycin Eluting Stents in a Pig Model
Stent Preparation
[0243] Stainless steel stents were prepared for coating as follows.
The stents were cleaned by soaking in a 6% (by volume) solution of
ENPREP-160SE (Cat. #2108-100, Enthone-OMI, Inc., West Haven, Conn.)
in deionized water for 1 hour. After soaking, the parts were then
rinsed several times with deionized water. Stents were coated with
MD-caproate from Example 10 (Hex 2.5 MD lot 2795-159) with and
without rapamycin. The polymer was stored room temperature before
use.
[0244] Coating solutions were prepared in THF by mixing
freshly-prepared stock solutions of polymer and rapamycin.
Polymer-only coating solutions contained 50 mg/mL of the polymer.
Polymer/drug coating solutions contained a total solid load of 50
mg/mL, of which 50 wt % was rapamycin (i.e., 25 mg/mL polymer+25
mg/mL rapamycin). All coating solutions were passed through a 10
.mu.m filter before being used for coating.
[0245] Coating was performed with an ultrasonic spray system (Gen
III) in a Class 10,000 clean room. Coated parts were dried under a
flow of N2 at room temperature overnight. Each of the solutions
atomized well and produced acceptable coatings on the stents.
[0246] Coated stents (50% rapamycin) were crimped onto balloon
catheters. Stents were crimped at ambient temperature and humidity.
No sleeve was present during crimping; the stent coatings were in
direct contact with the Delrin crimping head. An effort was made to
prevent strut-to-strut contact during the crimping process. After
crimping, the stent/catheter assemblies were packaged, labeled,
sterilized via EtO. Following sterilization, the assemblies were
placed under vacuum overnight at room temperature to remove
residual EtO.
[0247] The crimped stents were immersed in PBS at 37.degree. C. for
5 minutes. The balloon was then inflated to a pressure of 9 atm,
held for 5 s, and the pressure was released. The catheter and
expanded stent were removed from the PBS and rinsed with DI water.
Stents that did not easily fall off the balloons were removed with
a tweezers. Stents were dried under a flow of nitrogen at room
temperature. Dried stents were examined with optical microscopy and
imaged with SEM to assess the mechanical properties of the
coatings. Balloons were examined with optical microscopy to
determine whether any coating material remained on the balloon. In
general, coatings with and without rapamycin exhibited good
mechanical properties
In vitro Drug Release and Coating Studies
[0248] Elution measurements were conducted in 2 different
solutions: PBS and PBS supplemented with a physiologic
concentration of amylase at 37.degree. C. Each stent was placed in
a conical glass vial to which 4 mL of the appropriate solution was
added. The vials were placed in a shaking incubator during elution.
At determined intervals, the eluent was completely removed from the
vial and sampled for rapamycin content. 4 mL of fresh solution was
then placed in the vial. A robotic system assisted in the
collection of samples and replacement of solution. Samples for drug
content were placed into a 96-well UV plate and rapamycin was
detected by UV absorbance at 279 nm. Each polymer coating was run
in triplicate. Stent weights were taken concurrently to determine
the rate of coating degradation.
[0249] Rapamycin eluted from the stents with a first order release
rate over 40 days. Approximately 50% of the coating remained on the
stents after 40 days. Stent coatings containing drug and coated
stents placed in enzyme solution lost coating weight at a faster
rate than those without drug and those placed in buffer only.
Porcine System
[0250] The purpose of this study was to use the porcine coronary
and peripheral artery model to assess the biological affects of the
MD-caproate degradable polymer, with and without rapamycin.
Angiographic, histomorphometric and histopathologic variables were
evaluated at predetermined time intervals.
[0251] Excessive neointimal growth has been identified as a major
cause of late failure of the percutaneous transluminal coronary
angioplasty (PTCA) procedure. Rapamycin, a potent anti-neoplastic,
promotes the assembly of microtubules and inhibits the tubulin
disassembly process to prevent cell proliferation. Rapamycin
delivered from coronary stents (drug eluting stent) has been shown
to inhibit neointimal growth in studies conducted in both animal
models and in humans. Concern has been expressed about the
long-term effects of durable drug eluting polymers that have been
coated on stents.
[0252] Both male and female domestic Yorkshire crossbred swine were
used in this study. All animals were acclimated, fasted, underwent
a physical examination and received pre-procedure medications prior
to stent implantation.
Experimental Design
[0253] Animals underwent the swine stent injury model described by
Schwartz, et al. (2002) Circulation 218:669-696. Following a
preliminary angiogram, stents were implanted in each of the 3 main
coronary arteries (right coronary artery (RCA), left anterior
descending (LAD), or left circumflex (LCX), based on angiographic
assessment of the artery diameter and length (one stent per
vessel). Vessel section were limited to reference size of 2.6 mm to
3.4 mm based on visual estimation and online QCA at the time of
implant.
[0254] The artery segment was selected based on the ability of the
vessel to accommodate the diameter and length of the stent. The
implantation pressure was varied according to the balloon
compliance curve, included in the packaging, to achieve a target
stent/vessel ratio of 1.10:1 with a range of 1.05-1.20:1
[0255] Prior to implantation, the animal was designated for a
specific cohort (1 month or 3 months). At the predetermined time
point, stents were harvested.
[0256] After animal preparation was completed, the femoral artery
was accessed using a percutaneous approach. A 7F introducer
arterial sheath was placed and advanced into the artery. After a
baseline ACT was recorded, an initial bolus of heparin (100 IU/kg
IV) was given. Additional doses of heparin were administered to
maintain an ACT of .gtoreq.250 seconds. Doses given were based on
the ACT levels. ACT was tested approximately every 15-30
minutes.
Implant Procedures
[0257] Under fluoroscopic guidance, a 6F or appropriate guide
catheter was inserted through the sheath and advanced to the
appropriate location. After placement of the guide catheter,
angiographic images of vessels were obtained with contrast media to
identify the proper location for the deployment site. Quantitative
angiography was performed to determine the appropriate vessel size
for implantation.
[0258] The stents were implanted in each of the three major
branches of the coronary arteries (RCA, LAD, and LCX). An effort
was made to evenly distribute the experimental group and controls
to the different vessels.
[0259] After visualization of the arterial anatomy, a target
segment ranging from 2.6 mm to 3.4 mm mid-segment diameter was
chosen, and a 0.014'' guidewire was inserted into the chosen
artery. QCA was then performed to accurately document the reference
diameter for stent placement.
[0260] Each stent delivery system was prepared by applying vacuum
to the balloon port; contrast/flush solution (50:50) was introduced
by releasing the vacuum. The stent was introduced into the
appropriate artery by advancing the stented balloon catheter
through the guide catheter and over the guidewire to the deployment
site. The balloon was inflated at a steady rate to a pressure
sufficient to target a balloon:artery ratio of 1.10:1 with a range
of 1.05-1.20:1 and held for approximately 20 seconds. A contrast
injection was performed during full inflation to demonstrate
occlusion with the balloon. After the target balloon:artery ratio
had been achieved for approximately 20 seconds, vacuum was applied
to the inflation device in order to deflate the balloon. Complete
balloon deflation was verified with fluoroscopy. The delivery
system was then slowly removed.
Explant Procedures
[0261] At the designated endpoint, the animals were weighed,
sedated, and anesthetized. An arterial sheath was introduced in the
femoral vessels and heparin was administered as previously
described. A guiding catheter was placed and advanced under
fluoroscopic guidance into the coronary arteries. After placement
of the guide catheter into the appropriate coronary ostium,
angiographic images of the vessel were taken to evaluate the
stented sites. At the end of the terminal angiography procedure,
the animals were euthanized.
[0262] Following gross assessment, a trained technician performed
excision of the whole heart. Dissection of the implanted coronary
arterial bed with subsequent removal of the stent and neointima was
performed prior to perfusion fixation when stents were explanted
for surface characterization. The neointima was weighed then frozen
and held at -70 C. Hearts were perfused with saline or Lactated
Ringers solution until the fluid ran clear and pressure
perfusion-fixed with 10% buffered formalin until there was a color
change in the tissue. Whole hearts and any additional tissues were
shipped to the study pathologist for complete histopathological
analysis. A group of stents was retrieved for surface analysis.
Histopathological Analyses of 28-Day Explants
Coated Stents without Drug
[0263] The stents are well expanded against the arterial wall and
lumens are patent with no evidence of thrombus formation,
aneurysms, or malapposition. The neointima growth consists
primarily of smooth muscle cells and proteoglycan/collagen matrix
with organized layers near the lumen. In the majority of stents,
injury to the arterial wall is minimal, except for the mid section
from CV17805 (896, LCx), which shows 5 struts penetrating into the
medial wall with extensive macrophage infiltration and the LCx
stent from CV17802 (animal No. 887), which shows extensive
granulomas. Organized layers of smooth muscle cells are found more
towards the lumen while more disorganized clusters of smooth muscle
cells are found near struts. Fibrin accumulation around stent
struts is generally absent. Giant cells around stent struts are
minimal. Re-endothelialization of luminal surfaces is near complete
with very rare adherent inflammatory cells. Inflammation around
stent struts was absent or minimal except for stents with
granulomas to include all sections from CV17802 (887, LCx), which
showed severe granulomatous reactions in all sections consisting of
eosinophils, macrophages and giant cells. Hemorrhage around stent
stuts is generally mild. The non-stented proximal and distal
segments generally showed balloon overstretch injury evidenced by
accumulated proteoglycan matrix (bluish-green staining on Movat) in
the medial wall and mild neointimal growth.
Coated Stents with Drug
[0264] The stents are well expanded against the arterial wall and
lumens are patent with no evidence of thrombus formation,
aneurysms, or malapposition. The neointimal growth is mild
consisting primarily of smooth muscle cells and
proteoglycan/collagen matrix with organized layers near the lumen.
Injury to the arterial wall is minimal. Organized layers of smooth
muscle cells are found more towards the lumen while more
disorganized clusters of smooth muscle cells are found near struts.
Fibrin accumulation around stent struts is generally mild to
moderate, which in a few struts was extensive. There are occasional
giant cells near stent struts. Re-endothelialization of luminal
surfaces is near complete with very rare adherent inflammatory
cells. Inflammation around stent struts was generally minimal.
Hemorrhage around stent stuts is present and generally mild. The
non-stented proximal and distal segments generally showed balloon
overstretch injury evidenced by accumulated proteoglycan matrix
(bluish-green staining on Movat) in the medial wall and mild
neointimal growth.
Uncoated Stents
[0265] The stents are well expanded against the arterial wall and
lumens are patent with no evidence of thrombus formation, aneurysms
or malapposition. The struts are generally covered by mild to
moderate neointimal growth consisting of organized layers of smooth
muscle cells towards the lumen while more disorganized clusters of
smooth muscle cells are found near struts together with
proteoglycan matrix. There is little fibrin accumulation around
stent struts with minimal giant cell infiltration and overall
inflammation is minimal. Re-endothelialization of luminal surfaces
is near complete with rare adherent inflammatory cells. The
non-stented proximal and distal segments generally showed balloon
overstretch injury evidenced by accumulated proteoglycan matrix
(bluish-green staining) in the medial wall and mild neointimal
growth.
Surface Analysis of Explanted Stents
[0266] Explanted stents were examined using SEM. The coated
explanted stents showed an adherent polymer covering approximately
30-50% of the stent surface. Coated stents with rapamycin generally
showed more polymer degradation than coated stents without
rapamycin.
* * * * *