U.S. patent application number 11/724553 was filed with the patent office on 2007-11-08 for hydrophobic derivatives of natural biodegradable polysaccharides and uses thereof.
This patent application is currently assigned to SurModics, Inc.. Invention is credited to Stephen J. Chudzik.
Application Number | 20070260054 11/724553 |
Document ID | / |
Family ID | 38461027 |
Filed Date | 2007-11-08 |
United States Patent
Application |
20070260054 |
Kind Code |
A1 |
Chudzik; Stephen J. |
November 8, 2007 |
Hydrophobic derivatives of natural biodegradable polysaccharides
and uses thereof
Abstract
Low molecular weight hydrophobic derivatives of non-cyclic
.alpha.(1.fwdarw.4)glucopyranose polymers and non-reducing
polysaccharides are described. The derivates can be used to form
matrices in various forms, including body members of implantable
articles, coatings, and consumer items, which have desirable
properties.
Inventors: |
Chudzik; Stephen J.; (St.
Paul, 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.: |
11/724553 |
Filed: |
March 15, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60782957 |
Mar 15, 2006 |
|
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60900853 |
Feb 10, 2007 |
|
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Current U.S.
Class: |
536/123.12 ;
536/123.13 |
Current CPC
Class: |
A61L 2300/604 20130101;
A61L 2300/41 20130101; A61L 27/20 20130101; A61F 9/0017 20130101;
A61L 2300/606 20130101; A61L 27/54 20130101; C08L 3/02 20130101;
A61L 2300/222 20130101; A61L 31/148 20130101; C08B 30/18 20130101;
A61L 31/16 20130101; A61K 9/0051 20130101; A61K 9/0024 20130101;
A61L 31/10 20130101; A61F 2/14 20130101; A61L 27/20 20130101; C08L
5/16 20130101; A61L 31/10 20130101; C08L 5/16 20130101 |
Class at
Publication: |
536/123.12 ;
536/123.13 |
International
Class: |
C07H 1/00 20060101
C07H001/00 |
Claims
1. A hydrophobic derivative of a natural biodegradable
polysaccharide comprising: a non-cyclic
poly-.alpha.(1.fwdarw.4)glucopyranose backbone; and a plurality of
groups pendent from the poly-.alpha.(1.fwdarw.4)glucopyranose
backbone, the groups comprising a hydrocarbon segment comprising
two or more carbon atoms; wherein the hydrophobic derivative has a
molecular weight of 100,000 Da or less.
2. The hydrophobic derivative of claim 1 having a molecular weight
50,000 Da or less.
3. The hydrophobic derivative of claim 2 wherein the hydrophobic
derivative has a molecular weight of 25,000 Da or less.
4. The hydrophobic derivative of claim 3 wherein the hydrophobic
derivative has a molecular weight in the range of 2000 Da to 20,000
Da.
5. The hydrophobic derivative of claim 4 wherein the hydrophobic
derivative has a molecular weight in the range of 4000 Da to 10,000
Da.
6. The hydrophobic derivative of claim 1 wherein the hydrocarbon
segment is selected from the group consisting of linear, branched,
and cyclic C.sub.2-C.sub.18 groups.
7. The hydrophobic derivative of claim 6 wherein the hydrocarbon
segment is selected from the group consisting of linear, branched,
and cyclic C.sub.4-C.sub.10 groups.
8. The hydrophobic derivative of claim 7 wherein the plurality of
groups pendent from the poly-.alpha.(1.fwdarw.4)glucopyranose
backbone provide a degree of substitution in the range of 2-3.
9. The hydrophobic derivative of claim 7 wherein the hydrocarbon
segment is selected from the group consisting of linear, branched,
and cyclic C.sub.5-C.sub.7 groups.
10. The hydrophobic derivative of claim 7 wherein the hydrocarbon
segment is selected from the group consisting of branched
C.sub.4-C.sub.8 alkyl groups.
11. The hydrophobic derivative of claim 10 wherein the plurality of
groups pendent from the poly-.alpha.(1.fwdarw.4)glucopyranose
backbone provide a degree of substitution in the range of
0.5-1.5.
12. The hydrophobic derivative of claim 7 wherein the hydrocarbon
segment is an aromatic C.sub.6 group.
13. The hydrophobic derivative of claim 1 wherein the groups
pendent from the poly-.alpha.(1.fwdarw.4)glucopyranose backbone are
coupled to the backbone via hydrolyzable covalent bonds.
14. The hydrophobic derivative of claim 1 wherein the groups
pendent from the poly-.alpha.(1 .fwdarw.4)glucopyranose backbone
are coupled to the backbone via hydrolyzable ester bonds.
15. A hydrophobic derivative of a natural biodegradable
polysaccharide comprising: a non-cyclic
poly-.alpha.(1.fwdarw.4)glucopyranose backbone; and a plurality of
groups pendent from the poly-.alpha.(1.fwdarw.4)glucopyranose
backbone, wherein the hydrophobic derivative has a molecular weight
of 100,000 Da or less and a Tg of 35.degree. C. or greater.
16. The hydrophobic derivative of claim 15 having a Tg in the range
of 40.degree. C. to 65.degree. C.
17. A hydrophobic derivative of a natural biodegradable
polysaccharide comprising: a hydrophilic portion comprising a
non-cyclic poly-.alpha.(1.fwdarw.4)glucopyranose backbone; and a
hydrophobic portion comprising a plurality of groups pendent from
the poly-.alpha.(1.fwdarw.4)glucopyranose backbone, wherein the
weight ratio between the hydrophilic portion and the hydrophobic
portion in the range of 5:1 to 1:1.25, and wherein the hydrophobic
derivative has a molecular weight of 100,000 Da or less.
18. The hydrophobic derivative of claim 17 wherein the weight ratio
between the hydrophilic portion and the hydrophobic portion in the
range of 2:1 to 1:1.25
19. The hydrophobic derivative of claim 18 wherein the weight ratio
between the hydrophilic portion and the hydrophobic portion in the
range of 1:0.75 to 1:1.25
20. The hydrophobic derivative of claim 19 wherein the weight ratio
between the hydrophilic portion and the hydrophobic portion in the
range of 1:1 to 1:1.25
21. A hydrophobic derivative of a natural biodegradable
polysaccharide comprising: a non-cyclic
poly-.alpha.(1.fwdarw.4)glucopyranose backbone; and a plurality of
groups pendent from the poly-.alpha.(1.fwdarw.4)glucopyranose
backbone, the groups comprising a hydrocarbon segment, wherein at
least a portion of the groups comprise a bioactive agent that is
cleavable from the poly-.alpha.(1.fwdarw.4)glucopyranose backbone,
wherein the hydrophobic derivative has a molecular weight of
100,000 Da or less.
22. The hydrophobic derivative of claim 21 wherein the bioactive
agent is an anti-inflammatory agent.
23. The hydrophobic derivative of claim 21 wherein the bioactive
agent is an antiproliferative.
24. The hydrophobic derivative of claim 21 wherein the bioactive
agent is a steroid.
25. The hydrophobic derivative of claim 21 wherein the bioactive
agent comprises a carboxylate group.
26. A hydrophobic derivative of a natural biodegradable
polysaccharide comprising: a polymeric backbone comprising
non-reducing disaccharides; and a plurality of groups pendent from
the polymeric backbone, wherein the hydrophobic derivative has a
molecular weight of 100,000 Da or less.
27. The hydrophobic derivative of claim 26 wherein the polymeric
backbone is selected from the group consisting of polytrehalose,
polysucrose, and polyalditol.
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 hydrophobic derivatives of
natural biodegradable polysaccharides, and articles including these
derivatives.
BACKGROUND
[0003] Polylactide (PLA) is a synthetic biodegradable thermoplastic
derived from lactic acid that has been used extensively in the
preparation of a wide variety of items. In particular, PLA has been
used to construct biodegradable articles such as bags, containers,
diapers and packaging materials. PLA has also been used for in the
fabrication of biodegradable medical devices such as sutures that
can dissolve in physiological conditions.
[0004] Similar to other thermoplastics, PLA can be processed into
fibers and films, thermoformed, or injection molded. While PLA
provides desirable processing and degradation properties, it
suffers from brittleness, hardness, inflexibility, and low melt
tension. In order to overcome these undesirable characteristics,
PLA is often blended with secondary agents, such as plasticizers,
to improve its properties. Many commonly used secondary agents such
as plasticizers, however, are not degradable. This presents
obstacles for the preparation of PLA-based articles that are
intended to be completely degradable.
SUMMARY OF THE INVENTION
[0005] Generally, the present invention relates to hydrophobic
derivatives of a natural biodegradable polysaccharide ("hydrophobic
polysaccharides"), articles that include these hydrophobic
polysaccharides, and methods utilizing these articles.
[0006] Generally, the hydrophobic polysaccharides comprise a
poly-.alpha.(1.fwdarw.4)glucopyranose backbone and have a low
molecular weight and a plurality of groups pendent from the
backbone that provide the hydrophobic portion. These hydrophobic
polysaccharides have been found to be amenable to use in various
fabrication processes and also can be used to form articles with
desirable properties, such as properties desirable for use in
association with implantable medical articles. For example,
matrices formed using hydrophobic polysaccharides of the invention
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 matrix during use.
The coating compositions can also be prepared having a high
concentration of solids, allowing the formation of a matrix having
a high content of a secondary compound, such as a bioactive agent.
Coatings for implantable medical articles as well as the body
members of implantable medical articles exemplify hydrophobic
polysaccharide matrices.
[0007] The hydrophobic polysaccharides can be degraded into natural
materials, which provide advantages for compatibility of
implantable articles. Degradation of the matrix 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 matrices 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.
[0008] In one aspect, the invention provides a hydrophobic
derivative of a natural biodegradable polysaccharide comprising a
non-cyclic poly-.alpha.(1.fwdarw.4)glucopyranose backbone and a
plurality of groups pendent from the
poly-.alpha.(1.fwdarw.4)glucopyranose backbone, the groups
comprising a hydrocarbon segment having two or more carbon atoms,
wherein the hydrophobic derivative has a molecular weight of about
100,000 Da or less.
[0009] In another aspect, the invention provides a hydrophobic
derivative of a natural biodegradable polysaccharide comprising a
non-cyclic poly-.alpha.(1.fwdarw.4)glucopyranose backbone; and a
plurality of groups pendent from the
poly-.alpha.(1.fwdarw.4)glucopyranose backbone, wherein the
hydrophobic derivative has a molecular weight of about 100,000 Da
or less, and a glass transition temperature of 35.degree. C. or
greater.
[0010] In another aspect, the invention provides a hydrophobic
derivative of a natural biodegradable polysaccharide comprising a
hydrophilic portion comprising a non-cyclic
poly-.alpha.(1.fwdarw.4)glucopyranose backbone; a hydrophobic
portion comprising a plurality of groups pendent from the
poly-.alpha.(1.fwdarw.4)glucopyranose backbone, wherein the weight
ratio between the hydrophilic portion and the hydrophobic portion
in the range of 5:1 to 1:1.25, and wherein the hydrophobic
derivative has a molecular weight of about 100,000 Da or less.
[0011] In another aspect, the invention provides a hydrophobic
derivative of a natural biodegradable polysaccharide comprising a
non-cyclic poly-.alpha.(1.fwdarw.4)glucopyranose backbone; and a
plurality of groups pendent from the
poly-.alpha.(1.fwdarw.4)glucopyranose backbone, the groups
comprising a hydrocarbon segment, wherein at least a portion of the
groups comprise a bioactive agent that is cleavable from the
poly-.alpha.(1.fwdarw.4)glucopyranose backbone, and wherein the
hydrophobic derivative has a molecular weight of about 100,000 Da
or less.
[0012] In another aspect, the invention provides a hydrophobic
derivative of a natural biodegradable polysaccharide comprising a
polymeric backbone comprising non-reducing disaccharides and a
plurality of groups pendent from the polymeric backbone, wherein
the hydrophobic derivative has a molecular weight of about 100,000
Da or less. The polymeric backbone can be selected from the group
consisting of polytrehalose, polysucrose, and polyalditol.
[0013] In another aspect, the invention provides a disposable
article formed of a hydrophobic polysaccharide of the
invention.
[0014] In another aspect, the invention provides coating for an
implantable medical article, wherein the coating is formed of a
hydrophobic polysaccharide of the invention.
[0015] In another aspect, the invention provides an implantable
medical article having a body member that is formed of a
hydrophobic polysaccharide of the invention.
[0016] In another aspect, the invention provides a method for
delivering a bioactive agent to a subject comprising the steps of:
implanting in a subject at a target location an implantable medical
article formed of a hydrophobic polysaccharide of the invention;
and allowing the bioactive agent to be released from the
implantable medical article to provide a therapeutic effect to the
subject.
[0017] In another aspect, the invention provides a method for
delivering a bioactive agent to a subject comprising the steps of:
implanting in a subject at a target location an implantable medical
article comprising a coating formed of a hydrophobic
polysaccharides of the invention and a bioactive agent; and
allowing the bioactive agent to be released from the coating to
provide a therapeutic effect to the subject.
BRIEF DESCRIPTION OF THE DRAWING
[0018] FIG. 1 is a graph illustrating elution profiles of stents
coated with lidocaine and hydrophobic polysaccharides.
DETAILED DESCRIPTION
[0019] 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.
[0020] 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.
[0021] The invention is generally directed to the hydrophobic
derivatives of non-cyclic .alpha.(1.fwdarw.4)glucopyranose
polymers, articles that are formed using these hydrophobic
polysaccharides, and uses of articles formed from these hydrophobic
polysaccharides. The invention is also directed to hydrophobic
derivatives of polysaccharides formed of non-reducing sugars, such
as polyalditol. The hydrophobic polysaccharides have a low
molecular weight and are useful for the preparation of polymeric
matrices, which can be in a variety of forms, such as coatings or
body members of articles.
[0022] As used herein, a "hydrophobic derivative" of a non-cyclic
.alpha.(1.fwdarw.4)glucopyranose polymer refers to a non-cyclic
.alpha.(1.fwdarw.4)glucopyranose polymer with a hydrophobic
portion, wherein the hydrophobic derivative is not soluble in
water. In many cases the hydrophobic portion includes a plurality
of groups that are pendent from poly
.alpha.(1.fwdarw.4)glucopyranose backbone and that, together,
provide the polymer with the hydrophobic property. The plurality of
pendent groups is 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.
[0023] The non-cyclic .alpha.(1.fwdarw.4)glucopyranose polymer
portion includes repeating glucopyranose monomeric units having
.alpha.(1.fwdarw.4) linkages and is capable of being enzymatically
degraded. Exemplary non-cyclic .alpha.(1.fwdarw.4)glucopyranose
polymer portions include maltodextrin and amylose.
[0024] 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.
[0025] 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 a hydrophobic portion. In other aspects, as
starting material, amylose can be used in a mixture that includes
other polysaccharides.
[0026] 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.
[0027] 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.
[0028] Steps may be performed before, during, and/or after the
process of derivatizing the amylose polymer to provide for a
hydrophobic derivative, to enrich the amount of amylose, or to
purify the amylose.
[0029] Amylose of particular molecular weights can be obtained
commercially or can be prepared. For example, synthetic amyloses
with an average molecular mass of 70 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 polysaccharide, and the presence of other optional
components in the composition, such as bioactive agents.
[0030] 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
polysaccharide.
[0031] Maltodextrin is typically generated by hydrolyzing a starch
slurry with heat-stable .alpha.-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.
[0032] 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.).
[0033] In another aspect, the hydrophobic polysaccharide has a
polymeric backbone formed of non-reducing disaccharides (natural
biodegradable non-reducing polysaccharides). 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. A
non-reducing polysaccharide can provide an inert matrix thereby
improving the stability of sensitive bioactive agents, such as
proteins and enzymes.
[0034] To facilitate discussion of the invention, the hydrophobic
derivatives of the non-cyclic .alpha.(1.fwdarw.4)glucopyranose
polymers and non-reducing polysaccharides are generally referred to
herein as "hydrophobic polysaccharides."
[0035] In many aspects the polysaccharide portion and the
hydrophobic portion comprise the predominant portion of the
hydrophobic polysaccharide. In one aspect, the wherein the weight
ratio between the hydrophilic portion and the hydrophobic portion
in the range of 5:1 to 1:1.25. For example, based on a weight
percentage, the polysaccharide portion can be about 25% wt of the
hydrophobic polysaccharide 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 polysaccharide, the
hydrophobic portion can be about 25% wt of the hydrophobic
polysaccharide 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 polysaccharide has approximately 50% of its weight
attributable to the polysaccharide portion, and approximately 50%
of its weight attributable to its hydrophobic portion.
[0036] The hydrophobic polysaccharide 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.).
[0037] A hydrophobic polysaccharide can be prepared by coupling one
or more hydrophobic compound(s) to a natural biodegradable
polysaccharide polymer. Methods for preparing hydrophobic
polysaccharides are described herein.
[0038] The hydrophobic polysaccharides have a molecular weight of
100,000 Da or less. Use of these lower molecular weight derivatives
provides matrices having desirable physical properties. In some
aspects the hydrophobic polysaccharides have a molecular weight of
about 50,000 Da or less, or 25,000 Da or less. Particularly
preferred size ranges for the hydrophobic 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.
[0039] 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), such as preparations of hydrophobic polysaccharides.
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 = i N i M i 2 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.i 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
ultracentrifugation. 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] In forming the hydrophobic polysaccharide, and as an
example, a compound having a hydrocarbon segment can be covalently
coupled to one or more portions of the polysaccharide.
[0044] 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:
[M]-[L]-[H]
[0045] 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.
[0046] 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]
[0047] 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.
[0048] 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).
[0049] 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 polysaccharide will include chemical linkages that are
both enzymatically cleavable (the polymer backbone) and
non-enzymatically hydrolytically cleavable (the linkage between
pendent group and the polymer backbone).
[0050] Other cleavable chemical linkages that can be used to bond
the pendent groups to the polysaccharide include peroxyester
groups, disulfide groups, and hydrazone groups.
[0051] 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 polysaccharide includes chemical linkages that are
enzymatically cleavable (the polymer backbone).
[0052] 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.
[0053] Various factors can be taken into consideration in the
synthesis of the hydrophobic polysaccharide. These factors include
the physical and chemical properties of the 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.
[0054] In preparing the hydrophobic 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.
[0055] 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.
[0056] To exemplify these levels of derivation, very low molecular
weight (less than 10,000 Da) glucopyranose polymers were 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) was dissolved
in a suitable solvent, such as tetrahydrofuran. Next, a solution
having butyric anhydride in an amount of 18 g (0.11 mols) was added
to the maltodextrin solution. The reaction was allowed to proceed,
effectively forming pendent butyrate groups on the pyranose rings
of the maltodextrin polymer. This level of derivation resulted in a
degree of substitution (DS) of butyrate group of the hydroxyl
groups on the maltodextrin of about 1.
[0057] 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 DS1. 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 the
group having the hydrocarbon segment.
[0058] 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.
[0059] In some modes of practice, the invention provides a
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.
[0060] In some modes of practice, the invention provides a
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
[0061] The degree of substitution can influence the hydrophobic
character of the polysaccharide. In turn, coatings formed from
hydrophobic polysaccharides 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.
[0062] 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
hydrophobic polysaccharide has 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 of 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.
[0063] Even at these low degrees of substitution the MD-val can
form forms matrices 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 matrix that
can quickly degrade in vivo.
[0064] Various synthetic schemes can be used for the preparation of
a hydrophobic 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.
[0065] 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 backbone
via a hydrolyzable bond or a non-hydrolyzable bond.
[0066] 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.
[0067] 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 backbone via an ester group.
[0068] 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.
[0069] Generally, if compounds having large hydrocarbon segments
are used for the synthesis of the hydrophobic polysaccharide, 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 polysaccharide with a DS of 1, a compound having a
hydrocarbon segment with an alkyl chain length of C.sub.(x X 2) is
reacted in an amount to provide a hydrophobic polysaccharide with a
DS of 0.5.
[0070] The hydrophobic polysaccharide can also be synthesized
having combinations of pendent groups with two or more different
hydrocarbon segments, respectively. For example, the hydrophobic
polysaccharide 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 polysaccharide.
[0071] In other cases the hydrophobic polysaccharide is synthesized
having a non-hydrolyzable bond linking the hydrocarbon segment to
the polysaccharide backbone. Exemplary non-hydrolyzable bonds
include urethane bonds.
[0072] The hydrophobic 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 polysaccharide is prepared
by reacting a mixture of butyric acid anhydride and butyl
isocyanate with maltodextrin. This yields a hydrophobic
polysaccharide 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 polysaccharide 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
polysaccharide can maintain a desired degree of hydrophobicity,
prior to enzymatic degradation of the polysaccharide backbone.
[0073] 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 hydrophobic polysaccharide and
released from the matrix to provide a therapeutic effect in a
subject. 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.
[0074] Other illustrative compounds comprising hydrocarbon segments
include valproic acid and retinoic acid. These compounds can be
coupled to a polysaccharide backbone, and then cleaved from the
polysaccharide backbone 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).
[0075] 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 polysaccharide, such as maltodextrin or
polyalditol, resulting in pendent triamcinolone groups coupled via
ester bonds to the polysaccharide.
[0076] The hydrophobic 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 a subject. An
example of such a hydrophobic polysaccharide is
maltodextrin-caproate-triamcinolone. This hydrophobic
polysaccharide 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.
[0077] 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.
[0078] It has been discovered that these hydrophobic
polysaccharides can be used to form articles that are wholly or
partially degradable. A partially degradable article can be an
article that has a biostable portion, such as a biostable body
member, and a biodegradable portion, such as a biodegradable
coating. The articles of the invention have desirable and
beneficial physical properties. For example, the hydrophobic
polysaccharides can be used to form biodegradable coatings that
demonstrate excellent durability, compliance, and rate of
degradation. Furthermore, these coatings offer advantages for the
controlled release of bioactive agents, if included in the coating.
Advantageously, these articles can be formed without requiring the
covalent crosslinking of the polysaccharide polymers.
[0079] The hydrophobic polysaccharides of the invention can be used
in many applications, including systems and methods wherein the
hydrophobic polysaccharide is contacted with a carbohydrase.
Interestingly, it has also been discovered some of the hydrophobic
polysaccharides can be formed into coatings or articles that have a
substantially slow rate of degradation. This is desirable in a
variety of applications where it desired that the article (or
coating) maintain its integrity for a protracted period of time,
such as a period of months to years, but that it eventually
degrades. Given this, the hydrophobic polysaccharides have utility
in a broad range of applications. Such applications include medical
applications, including implantable medical articles and coatings
for implantable medical articles for the long-term treatment of
various conditions. These hydrophobic polysaccharides can also be
used in the preparation of disposable consumer items. In these
applications the structural integrity of the item is maintained for
a period of use. However, following disposal, the item loses its
structural integrity as the hydrophobic polysaccharide
degrades.
[0080] Generally, the hydrophobic polysaccharide is used to form an
article, or a portion of an article, that can be degraded. In some
aspects, the article is a disposable consumer item. A disposable
consumer item broadly refers to any sort of article that is
utilized by an individual and then disposed of after use. Following
disposal, the article can be degraded in an appropriate waste
environment. For example, the article can be disposed of in a
landfill wherein the article is exposed to conditions that promote
its degradation. For example, the article is exposed to
carbohydrases present in the soil or water. These carbohydrases can
be produced from environmental microorganisms and promote the
degradation of the article over a period of time.
[0081] Examples of disposable consumer items include packaging
materials, paper products, tissues, towels, wipes, food containers,
beverage containers, utensils, plates, cups, boxes, food wrap, food
bags, garbage bags, personal care items, feminine hygiene products,
restroom supplies, seat covers, child and infant care products.
[0082] In some aspects, the hydrophobic polysaccharide is used to
form the body member, or a portion of a body member, of an
implantable medical article. In these aspects, a degradable body
member, or portion thereof, can provide mechanical properties at
the implantation site and can maintain these mechanical properties
until they are no longer needed. After a period of time has
elapsed, the body member is degraded to an extent that the
mechanical properties are no longer provided, and the degraded
components of the article are processed by the body.
[0083] In some embodiments, the body member of the medical article
slowly degrades and transfers stress at the appropriate rate to
surrounding tissues as these tissues heal and can accommodate the
stress once borne by the body member of the medical article. The
medical article can optionally include a coating or a bioactive
agent to provide one or more additional functional features,
however, these are not required in order for the article to be of
use at the treatment site.
[0084] A biodegradable stent structure formed from the hydrophobic
polysaccharide is an example of a body member of an implantable
device. Other body members are exemplified herein.
[0085] The article can also comprise fibers, such as microfibers
and/or nanofibers that are formed from the hydrophobic
polysaccharide. The fibers can be included in or associated with
various articles including implantable medical articles and cell
culture articles.
[0086] In another aspect of the invention, the hydrophobic
polysaccharide is used to form a coating on the surface of a
medical article. The hydrophobic polysaccharide can be present in
one or more coated layers all or a portion of the surface of the
device. 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, such as
hydrophobic amylose or maltodextrin. 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.
[0087] Bioactive agents can also be included in the coating. The
bioactive agent 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.
[0088] The following list of medical articles is provided to
illustrate various medical articles that can be fabricated from the
hydrophobic polysaccharide to form the body member of the medical
articles. This list of various medical articles also exemplifies
various body members that can be provided with a coating that
includes the hydrophobic polysaccharide.
[0089] 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.
[0090] 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;
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.
[0091] In some aspects the hydrophobic polysaccharide is utilized
in an ophthalmic article. Compositions including the hydrophobic
polysaccharide can be used for the formation of a coating on the
surface of an ophthalmic article, in the construction of the body
member of the ophthalmic article, or both. The ophthalmic article
can be configured for placement at an external or internal site of
the eye. In some aspects, the articles can be utilized to deliver a
bioactive agent to an anterior segment of the eye (in front of the
lens), and/or a posterior segment of the eye (behind the lens).
Suitable ophthalmic devices can also be utilized to provide
bioactive agent to tissues in proximity to the eye, when
desired.
[0092] Suitable external articles can be configured for topical
administration of bioactive agent. Such external devices can reside
on an external surface of the eye, such as the cornea (for example,
contact lenses) or bulbar conjunctiva. In some embodiments,
suitable external devices can reside in proximity to an external
surface of the eye.
[0093] 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 ("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.), 2004/0133155 A1
("Devices for Intraocular Drug Delivery," Varner et al.),
2005/0059956 A1 ("Devices for Intraocular Drug Delivery," Varner et
al.), and U.S. application Ser. Nos. 11/204,195 (filed Aug. 15,
2005, Anderson et al.), Ser. No. 11/204,271 (filed Aug. 15, 2005,
Anderson et al.), Ser. No. 11/203,981 (filed Aug. 15, 2005,
Anderson et al.), Ser. No. 11/203,879 (filed Aug. 15, 2005,
Anderson et al.), Ser. No. 11/203,931 (filed Aug. 15, 2005,
Anderson et al.); and related applications.
[0094] In some aspects of the invention, a coating including the
hydrophobic polysaccharide is formed on a non-linear intraocular
device.
[0095] In some aspects, the ophthalmic article can be configured
for placement, or can be formed, at a subretinal area within the
eye. Illustrative ophthalmic devices for subretinal application
include, but are not limited to, those described in U.S. Patent
Publication No. 2005/0143363 ("Method for Subretinal Administration
of Therapeutics Including Steroids; Method for Localizing
Pharmacodynamic Action at the Choroid and the Retina; and Related
Methods for Treatment and/or Prevention of Retinal Diseases," de
Juan et al.); U.S. application Ser. No. 11/175,850 ("Methods and
Devices for the Treatment of Ocular Conditions," de Juan et al.);
and related applications.
[0096] Ophthalmic articles can also be configured for placement
within any desired tissues of the eye. For example, ophthalmic
devices can be configured for placement at a subconjunctival area
of the eye, such as devices positioned extrasclerally but under the
conjunctiva, such as glaucoma drainage devices and the like.
[0097] A coating that includes the hydrophobic polysaccharide can
be formed on the body member of a medical article, including those
listed herein, wherein the medical article is formed of a
non-biodegradable material. For example, a coating can be formed on
a body member of a medical article that is partially or entirely
fabricated from a plastic polymer. 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.
[0098] Other suitable polymers that can be used to construct the
body member include polyamides, polyimides, polyolefins,
polystyrenes, polyesters, polycarbonates, polyketones, polyureas,
acrylonitrile butadiene, butadiene rubber, chlorinated and
chloro-sulfonated polyethylene, chloroprene, EPM, EPDM, PE-EPDM,
PP-EPDM, EVOH, epichlorihydrin, isobutylene isoprene, isoprene,
polysulfides, silicones, NBR/PVC, styrene butadienes, and vinyl
acetate ethylenes, and combinations thereof.
[0099] In some cases the coating of the invention is formed on an
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.
[0100] 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.
[0101] Blends of these polymers with other biodegradable polymers
can also be used.
[0102] Coatings that include the hydrophobic polysaccharide can
also be formed on medical devices that are 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.
[0103] Commonly used metals 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 a coating composition
that includes the hydrophobic polysaccharide.
[0104] 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.
[0105] 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.
[0106] Other surfaces that can be 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.
[0107] The hydrophobic polysaccharide can be formed into, or can be
present in a coated layer on, an article having a porous structure.
In many cases the porous structure of the article is a fabric or
has fabric-like qualities. The porous structure can be formed from
textiles, which include woven materials, knitted materials, and
braided materials. Particularly useful textile materials are woven
materials which can be formed using any suitable weave pattern
known in the art.
[0108] The porous structure can be that of a graft, sheath, cover,
patch, sleeve, wrap, casing, and the like, including many of the
medical articles described herein. These types of articles can
function as the medical article itself or be used in conjunction
with another part of a medical article.
[0109] Other particular contemplated porous structures include
grafts, particularly grafts having textured exterior portions.
Examples of textured grafts include those that have velour-textured
exteriors, with textured or smooth interiors. Grafts constructed
from woven textile products are well known in the art and have been
described in numerous documents, for example, U.S. Pat. No.
4,047,252; U.S. Pat. No. 5,178,630; U.S. Pat. No. 5,282,848; and
U.S. Pat. No. 5,800,514.
[0110] A medical article having a biodegradable coating including
the hydrophobic polysaccharide, or a medical article that is formed
using the hydrophobic polysaccharide can be prepared by assembling
an article having two or more "parts." These parts can be pieces of
a medical article that can be put together to form the article. All
or a portion of the part of the medical article can include the
hydrophobic polysaccharide. In this regard, the invention also
contemplates parts of medical article (for example, not the fully
assembled article) that include the hydrophobic polysaccharide.
[0111] In one aspect, the invention provides coatings that include
a coated layer comprising the hydrophobic polysaccharide, wherein
the coating is also capable of releasing one or more bioactive
agents.
[0112] In one aspect of the invention, a bioactive agent is present
in association with a hydrophobic coated layer that includes the
hydrophobic polysaccharide. In these aspects, the bioactive agent
generally has poor or no solubility in water. Depending on the
properties of the hydrophobic layer and the bioactive agent
associated with the hydrophobic layer, the coating can demonstrate
a particular release mechanism.
[0113] In one aspect, the bioactive agent may be released from the
coated layer with little or no degradation of the hydrophobic
polysaccharide. For example, a coated layer that includes
maltodextrin-butyrate having a high degree of substitution (such as
in the range of DS 2-DS 3) and a hydrophobic bioactive agent that
is not covalently bonded to the maltodextrin-butyrate may release
the bioactive agent with little or no degradation of the coating.
That is, release of the bioactive agent is primarily driven by
diffusion of the bioactive agent from the coated layer.
[0114] In other aspect, degradation of the coated layer containing
the hydrophobic polysaccharide contributes to release of the
bioactive agent. In these aspects, the coated layer is weaker and
more susceptible to degradation. For example, the coated layer can
be formed from a maltodextrin-butyrate having a lower degree of
substitution (such as about DS 1) and that includes a bioactive
agent. Degradation of the coated layer can proceed by hydrolysis of
the butyrate group and enzymatic degradation of the maltodextrin.
Depending on the properties of the bioactive agent, release can
occur by degradation of the coated layer; however, diffusion of the
bioactive agent from the coated layer may also occur.
[0115] The bioactive agent may be covalently bonded to the natural
biodegradable polysaccharide. In some aspects the bioactive agent
is a group pendent from the hydrophobic polysaccharide, such as a
butyrate group. Preferably, if the bioactive agent is covalently
bonded, it is cleavable from the polysaccharide. Cleavable chemical
linkages that can be used to bond the bioactive agent to the
polysaccharide include ester group, peroxyester groups, disulfide
groups, and hydrazone groups. Alternatively, the cleavable linking
group can be enzymatically cleaved, for example, by proteases or by
carbohydrases.
[0116] Another aspect relates to the ability of the hydrophobic
polysaccharide to control release of a bioactive agent from another
portion of the coating. In these aspects the coating includes more
than one coated layer of material, wherein a bioactive agent is
present in a first coated layer, and second coated layer of
material that includes the hydrophobic polysaccharide. The second
coated layer is able to control the release of the bioactive agent
from the coating.
[0117] For example, a first coated layer that includes a polymeric
material and a bioactive agent can be formed between the device
surface and a second coated layer that includes the hydrophobic
polysaccharide. The bioactive agent diffuses from the first coated
layer, but the second coated layer controls its release from the
surface of the device in a more effective therapeutic profile.
[0118] This arrangement of coated materials has been advantageously
used to control the release of a hydrophilic bioactive agent from
the coating. In one mode of practice, a first coated layer is
prepared that includes a synthetic polymer and a hydrophilic
bioactive agent. For example, the synthetic polymer can be a
non-biodegradable polymer. Exemplary synthetic polymers include
poly(alkyl(meth)acrylates) such as poly(butylmethacrylate);
secondary polymers can be included in the first coated layer. A
hydrophilic bioactive agent is included in the first coated layer.
A second coated layer that includes the hydrophobic polysaccharide
is formed. The second coated layer can be in direct contact with
the first coated layer. Upon implantation, the second coated layer
slows the release of the hydrophilic bioactive agent, which is
otherwise typically released very rapidly.
[0119] 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 an animal, including
but not limited to birds and mammals, including humans.
[0120] 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 an article or
coating that comprises the hydrophobic polysaccharide. 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).
[0121] Articles and coatings 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.
[0122] Antibiotics are art recognized and are substances which
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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] Examples of statins include lovastatin, pravastatin,
simvastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin,
and superstatin.
[0128] 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.
[0129] The bioactive agent can be an immunosuppressive agent, for
example, rapamycin, ABT-578, cyclosporine, everolimus, mycophenolic
acid, sirolimus, tacrolimus, and the like.
[0130] In order to prepare a coating on the surface of a body
member, or an article formed from the hydrophobic polysaccharide, a
composition that includes the hydrophobic polysaccharide can be
prepared. The natural biodegradable polysaccharide is dissolved in
a suitable solvent and the composition is used in a desired
process.
[0131] Examples of solvents that can be used to prepare a
composition 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, and any other optional component present in the
composition.
[0132] In preparing the article, the concentration of the
hydrophobic polysaccharide in a composition can be chosen to
provide an article or coating with desired physical and functional
properties. In some cases a coating composition, such as one for a
spray coating process, can be prepared having the hydrophobic
polysaccharide composition at a concentration in the range of about
5 mg/mL to about 500 mg/mL. 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.
[0133] The hydrophobic polysaccharide can be blended with one or
more other hydrophobic compounds in a composition for preparation
of an article. The other hydrophobic compounds can be hydrophobic
polysaccharides. For example, mixtures of hydrophobic
polysaccharides of different molecular weights can be blended in a
composition and used to prepare an article.
[0134] In some aspects, the composition used to form the coating or
article can include a radiopacifying agent. The presence of a
radiopacifying agent in the formed coating or article can promote
detection of the location of a device following implantation.
[0135] The composition can also include a bioactive agent, such as
one or more of those described herein. The bioactive agent can be
present in the composition at a concentration, which 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 polysaccharide present in the
composition.
[0136] 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 natural biodegradable
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.
[0137] 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).
[0138] 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.
[0139] 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.
[0140] In some cases the coated layer that includes the hydrophobic
polysaccharide 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 polysaccharide.
[0141] 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.
[0142] In other aspects, the hydrophobic polysaccharide is used to
form a medical implant that includes a bioactive agent. The implant
may not have any distinct mechanical properties, such as would be
apparent with an intravascular prosthesis, but rather provides a
mechanism to deliver the bioactive agent to a particular portion of
the body. The implant can have a defined structure and size that is
appropriate for its use at a desired location in the body.
[0143] A medical implant having a defined structure can be formed
by any suitable process, including molding, extruding, shaping,
cutting, casting, and the like. In forming a medical implant, the
concentration of the natural biodegradable polysaccharide may be
higher to provide a more structurally rigid implant.
[0144] In other aspects, the hydrophobic polysaccharide is used to
form a microparticle. The microparticle can also include a
bioactive agent, and it can be used to deliver this bioactive agent
from a coating on a medical article. Generally, microparticles have
a size in the range of 5 nm to 100 .mu.m in diameter, and are
spherical or somewhat spherical in shape. Microparticles that
include a hydrophobic polysaccharide can be prepared by established
techniques, for example, by solvent evaporation (see, for example,
Wichert, B. and Rohdewald, P. (1993) J. Microencapsul. 10:195).
Bioactive agents can also be incorporated into the microparticles
using these techniques and can be formulated to release a desired
amount of the agent over a predetermined period of time. The
bioactive agent can be released from the biodegradable
microparticle upon degradation of the biodegradable microparticle
in vivo.
[0145] Medical articles formed from the hydrophobic polysaccharide,
or that include a biodegradable coating can be treated to sterilize
one or more parts of the article, or the entire medical article.
Sterilization can take place prior to using the medical article
and/or, in some cases, during implantation of the medical
article.
[0146] In some aspects, the invention provides a method for
delivering a bioactive agent from coating or article formed from a
hydrophobic polysaccharide. In performing this method, the article
is placed in a subject. Upon exposure to body fluid the bioactive
agent is released from the coating. The coating can be formulated,
as described herein, to release the bioactive agent over a
prolonged period of time.
[0147] In some cases, depending on the properties of the article or
coating formed from the hydrophobic polysaccharide, a carbohydrase
can promote the degradation of the biodegradable coating. The
carbohydrase that contacts the coating or article can specifically
degrade the natural biodegradable polysaccharide. This may occur
before, during, or 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).
[0148] 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).
[0149] In some aspects, the carbohydrase can be administered to a
subject to increase the local concentration, for example in the
serum or the tissue surrounding the implanted device, so that the
carbohydrase may promote the degradation of the coating. 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.
[0150] In other cases, the carbohydrase can be provided on a
portion of the article. For example the carbohydrase may be eluted
from a portion of the article that does not include hydrophobic
polysaccharide. In this aspect, as the carbohydrase is released it
locally acts upon the coating to cause its degradation and promote
the release of the bioactive agent.
[0151] The invention will be further described with reference to
the following non-limiting Examples.
EXAMPLE 1
[0152] 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
[0153] 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
[0154] 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
[0155] 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
[0156] 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
[0157] 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
[0158] 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 mls) 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
[0159] 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
[0160] 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
[0161] 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
[0162] 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
[0163] 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
[0164] 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
[0165] 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
[0166] 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
[0167] 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
[0168] 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).
EXAMPLE 18
Release of Lidocaine from Stainless Steel Stents
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] 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
[0175] 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 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
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
Preparation of Hydrophobic MD-Triamcinolone Implants
[0176] Triamcinolone acetonide-releasing medical implants were
prepared by combining various hydrophobic maltodextrin (MD)
polymers with triamcinolone acetonide (TA) in various ratios. In
some cases a hydrophilic polymer was added to the hydrophobic MD
and TA. Implants were prepared using hydrophobic MDs, TA, and
hydrophilic polymers in the amounts as shown in Table 2.
[0177] The ingredients were heated and mixed in an extruder
(DACA.TM. Microcompounder; DACA Instruments, Santa Barbara Calif.).
Total batch size for an individual preparation was 4 grams. For
example 2 g of MD-Hex (DS 2.5).about.3 kDa was mixed with 2 g of
triamcinolone acetonide (Pharmacia & Upjohn Company) the
preparation of implant sample A. Ingredients were fed in dry
(powder of pellet) form to the feed section of the heated extruder.
For preparations containing MD-But 2.0 the extruder was heated to a
temperature of approximately 150.degree. C. For preparations
containing MD-But 2.0 the extruder was heated to a temperature of
approximately 150.degree. C. For preparations containing MD-Hex
2.5, MD-Hep 2.5, or if the preparation included a hydrophilic
polymer, the extruder was heated to a temperature of approximately
110.degree. C. The extruder heated, mixed, and recirculated the
ingredients to create a uniform mixture. The polymeric ingredients
melted and blended together, and the TA is uniformly blended into
the polymer melt. Processing temperatures did not melt PVP in the
PVP-containing mixtures. The ingredients were mixed for an average
of about 6 minutes before being extruded. Solvent was not added, so
the original polymorphic form of the TA during the extrusion
process was maintained. After melting and mixing, the mixture was
extruded out of a die and elongated into a cylindrical shape with
diameter in the range of about 250 .mu.m to about 650 .mu.m. Other
diameters, such in the range of about 100 .mu.m to 1000 .mu.m, can
be prepared. Upon cooling and solidification, the resulting
cylinders were cut to the desired length, typically 3-6 mm, to
create the implant.
TABLE-US-00002 TABLE 2 Hydrophobic Polymeric Polysaccharide TA
Additive Sample Type amount amount type Amount A MD-Hex 50% wt/wt
50% wt/wt (--) (DS 2.5) DE5 B MD-Hep 50% wt/wt 50% wt/wt (--) (DS
2.5) DE5 C MD-Hex 50% wt/wt 50% wt/wt (--) (DS 2.5) DE10 traD
MD-Hex 50% wt/wt 40% wt/wt PVP 10% wt/wt (DS 2.5) DE5 30 kDa E
MD-Hep 50% wt/wt 40% wt/wt PVP 10% wt/wt (DS 2.5) DE5 30 kDa F
MD-Hex 50% wt/wt 40% wt/wt PEG 10% wt/wt (DS 2.5) DE5 20 kDa G
MD-Hep 50% wt/wt 40% wt/wt PEG 10% wt/wt (DS 2.5) DE5 20 kDa H
MD-Hex 50% wt/wt 40% wt/wt PEG 10% wt/wt (DS 2.5) DE10 20 kDa I
MD-Pro 70% wt/wt 30% wt/wt (--) (DS 2.5) DE5 J MD-But 50% wt/wt 50%
wt/wt (--) (DS 2.0) DE5 K MD-But 70% wt/wt 30% wt/wt (--) (DS 2.0)
DE5 L MD-Hex 70% wt/wt 30% wt/wt (--) (DS 2.5) DE5
* * * * *