U.S. patent application number 11/860856 was filed with the patent office on 2008-03-27 for multi-layered coatings and methods for controlling elution of active agents.
Invention is credited to Ralph A. Chappa.
Application Number | 20080075753 11/860856 |
Document ID | / |
Family ID | 39091795 |
Filed Date | 2008-03-27 |
United States Patent
Application |
20080075753 |
Kind Code |
A1 |
Chappa; Ralph A. |
March 27, 2008 |
MULTI-LAYERED COATINGS AND METHODS FOR CONTROLLING ELUTION OF
ACTIVE AGENTS
Abstract
Embodiments of the invention include multi-layered coatings for
controlling the elution rates of active agents and methods. In an
embodiment, the invention includes a method of applying an elution
control coating to a substrate. The method can include depositing a
coating solution onto the substrate to form a base layer. The
method can also include selecting a desired concentration of the
solvent based on a desired elution rate. The method can further
include removing solvent from the base layer to reach a desired
concentration of the solvent and depositing a layer of parylene on
the base layer. In an embodiment, the invention can include a
medical device including a substrate, a base layer, and a porous
layer. The base layer can include a polymeric matrix and an active
agent dispersed within the polymeric matrix. The porous layer can
include parylene. Other embodiments are also included herein.
Inventors: |
Chappa; Ralph A.; (Prior
Lake, MN) |
Correspondence
Address: |
PAULY, DEVRIES SMITH & DEFFNER, L.L.C.
Plaza VII-Suite 3000, 45 South Seventh Street
MINNEAPOLIS
MN
55402-1630
US
|
Family ID: |
39091795 |
Appl. No.: |
11/860856 |
Filed: |
September 25, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60826823 |
Sep 25, 2006 |
|
|
|
Current U.S.
Class: |
424/426 ;
427/2.1 |
Current CPC
Class: |
A61L 2300/608 20130101;
A61L 27/54 20130101; A61L 31/10 20130101; A61L 27/34 20130101; A61L
27/34 20130101; A61L 31/16 20130101; C08L 65/04 20130101; C08L
65/04 20130101; A61L 31/10 20130101; A61L 2420/08 20130101 |
Class at
Publication: |
424/426 ;
427/2.1 |
International
Class: |
A61F 2/00 20060101
A61F002/00; A61L 27/34 20060101 A61L027/34 |
Claims
1. A method of applying an elution control coating to a substrate
comprising: depositing a coating solution onto the substrate to
form a base layer, the coating solution comprising an active agent,
a polymer, and a solvent; selecting a desired concentration of the
solvent based on a desired elution rate; removing solvent from the
base layer to reach a desired concentration of the solvent; and
depositing a layer of parylene on the base layer.
2. The method of claim 1, wherein depositing a coating solution
onto the substrate to form a base layer comprises spraying a
coating solution onto the substrate.
3. The method of claim 1, the active agent comprising a
macromolecule.
4. The method of claim 1, the active agent selected from the group
consisting of peptides and proteins.
5. The method of claim 1, the active agent selected from the group
consisting of antibodies and antibody derivatives.
6. The method of claim 1, the solvent comprising a non-polar
solvent.
7. The method of claim 1, the solvent comprising a polar
solvent.
8. The method of claim 1, wherein depositing a coating solution
onto a substrate to form a base layer comprises simultaneously
spraying a first coating solution onto the substrate from a first
spray head and spraying a second coating solution onto the
substrate from a second spray head.
9. The method of claim 8, the first coating solution comprising the
active agent and the second coating solution comprising the
polymer.
10. The method of claim 1, the polymer comprising a degradable
polymer and a non-degradable polymer, the first coating solution
comprising the degradable polymer and the active agent and the
second coating solution comprising non-degradable polymer.
11. The method of claim 1, wherein removing solvent from the base
layer comprises inserting the base layer and the substrate into a
vacuum chamber.
12. The method of claim 1, wherein removing solvent from the base
layer comprises inserting the base layer and the substrate into a
vacuum chamber for a period of time greater than about 30
minutes.
13. A method of depositing a multi-layer elution control coating
onto a substrate comprising: depositing a coating solution onto the
substrate to form a base layer, the coating solution comprising an
active agent, a polymer, and a solvent; storing the substrate and
base layer under vacuum for a period of time greater than about 30
minutes to form a degassed base layer; and depositing a layer of
parylene on the degassed base layer.
14. A medical device comprising: a substrate; a base layer disposed
on the substrate, the base layer comprising a polymeric matrix and
an active agent, the active agent dispersed within the polymeric
matrix, the active agent selected from the group consisting of
peptides, proteins, antibodies, and antibody derivatives; and a
porous layer disposed directly on the base layer, the porous layer
comprising parylene.
15. The medical device of claim 14, the base layer comprising a
degradable polymer and a non-degradable polymer, the degradable
polymer and the non-degradable polymer forming an interpenetrating
network, the active agent dispersed within the degradable
polymer.
16. The medical device of claim 14, the polymeric matrix comprising
a hydrophobic polymer.
17. The medical device of claim 14, the polymeric matrix comprising
poly-n-butylmethacrylate and polyethylene-co-vinyl acetate.
18. The medical device of claim 14, the base layer having a
thickness of between about 0.5 microns and about 100 microns.
19. The medical device of claim 14, the top layer comprising
poly(2-chloro-paraxylylene).
20. The medical device of claim 14 configured to elute about 0.1
.mu.g/day to about 3.0 .mu.g/day of the peptide for a period of
time of at least about 30 days.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/826,823, filed Sep. 25, 2006, the content of
which is herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to coatings and methods for
controlling the elution of active agents. More specifically, the
present invention relates to multi-layered coatings and methods for
controlling the elution of active agents.
BACKGROUND OF THE INVENTION
[0003] Active agent elution control coatings are now commonly used
to deliver active agents to tissues of the body. Elution control
coatings can enable the delivery of an active agent over a period
of time in order to optimize therapeutic effect. In addition, when
disposed on a medical device, elution control coatings can enable
site-specific active agent delivery because the medical device can
be positioned as desired within the body of a patient.
[0004] A desirable elution rate for an active agent in one
treatment scenario may be different than a desirable elution rate
for an active agent in another treatment scenario. Therefore, it
can be advantageous to be able to manipulate or change the elution
kinetics of a coating in order to more closely match what is
desirable for a specific treatment scenario.
[0005] Active agents delivered from elution control coatings can
include many different types of compounds including small
hydrophilic molecules, small hydrophobic molecules, macromolecules
such as carbohydrates, peptides, proteins, and the like. Of these
compounds, peptides and proteins can pose a challenge because, in
general, they are susceptible to denaturation. In addition, the
unique properties of peptides and proteins, such as their
relatively large size, can frequently result in them being
delivered either more quickly or more slowly than desired.
[0006] Accordingly, there is a need for coatings that can deliver
active agents at desirable rates and methods of making the same.
There is also a need for coatings that can be used to control the
elution rate of macromolecules such as peptides and proteins.
SUMMARY OF THE INVENTION
[0007] Embodiments of the invention include multi-layered coatings
for controlling the elution rates of active agents and methods of
making the same. In an embodiment, the invention includes a method
of applying an elution control coating to a substrate. The method
can include depositing a coating solution onto the substrate to
form a base layer, the coating solution including an active agent,
a polymer, and a solvent. The method can also include selecting a
desired concentration of the solvent based on a desired elution
rate. The method can further include removing solvent from the base
layer to reach a desired concentration of the solvent and
depositing a layer of parylene on the base layer.
[0008] In an embodiment, the invention can include a method of
depositing a multi-layer elution control coating onto a substrate.
The method can include depositing a coating solution onto the
substrate to form a base layer, the coating solution including an
active agent, a polymer, and a solvent. The method can also include
storing the substrate and base layer under vacuum for a period of
time greater than about 30 minutes to form a degassed base layer
and depositing a layer of parylene on the degassed base layer.
[0009] In an embodiment, the invention can include a medical device
including a substrate, a base layer, and a porous layer. The base
layer can be disposed on the substrate. The base layer can include
a polymeric matrix and an active agent. The active agent can be
dispersed within the polymeric matrix. The active agent can be
selected from the group consisting of peptides, proteins,
antibodies, and antibody derivatives. The porous layer can be
disposed on the base layer. The porous layer can include
parylene.
[0010] This summary is an overview of some of the teachings of the
present application and is not intended to be an exclusive or
exhaustive treatment of the present subject matter. Further details
are found in the detailed description and appended claims. Other
aspects will be apparent to persons skilled in the art upon reading
and understanding the following detailed description and viewing
the drawings that form a part thereof, each of which is not to be
taken in a limiting sense. The scope of the present invention is
defined by the appended claims and their legal equivalents.
BRIEF DESCRIPTION OF THE FIGURES
[0011] The invention may be more completely understood in
connection with the following drawings, in which:
[0012] FIG. 1 is a cross-sectional view of a multi-layered coating
system in accordance with an embodiment of the invention.
[0013] FIG. 2 is a cross-sectional view of a multi-layered coating
system in accordance with another embodiment of the invention.
[0014] FIG. 3 is a cross-sectional view of a multi-layered coating
system in accordance with another embodiment of the invention.
[0015] FIG. 4 is a perspective view of a stent coated with a
multi-layered coating system in accordance with an embodiment of
the invention.
[0016] FIG. 5 is a perspective view of a coil coated with a
multi-layered coating system in accordance with an embodiment of
the invention.
[0017] FIG. 6 is a graph showing elution of IgG from a medical
device into a test solution over time.
[0018] FIG. 7 is a graph showing elution of IgG from a medical
device into a test solution over time.
[0019] While the invention is susceptible to various modifications
and alternative forms, specifics thereof have been shown by way of
example and drawings, and will be described in detail. It should be
understood, however, that the invention is not limited to the
particular embodiments described. On the contrary, the intention is
to cover modifications, equivalents, and alternatives falling
within the spirit and scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0020] 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.
[0021] 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.
[0022] As described above, a desirable elution rate for an active
agent in one treatment scenario may be different than a desirable
elution rate for an active agent in another treatment scenario.
Therefore, it can be advantageous to be able to manipulate or
change the elution rate of a coating to optimize treatment.
[0023] Elution of some active agents, such as peptides and
proteins, from coatings can pose a particular challenge. The
activity of peptides and proteins is typically dependent on their
three-dimensional structure which can be disrupted by heat,
solvents, changing ionic concentrations, shearing forces, etc.
Therefore, such active agents need to be handled carefully to
preserve their activity. In addition, the size of peptides and
proteins can make it difficult to elute them from a coating at a
desirable rate. Frequently, elution control coatings elute such
active agents either too quickly or too slowly.
[0024] The polymer known as parylene usually forms a continuous
barrier to the passage of molecules. Because of its barrier
properties, parylene has found many industrial uses including as a
protective coating on electronic equipment. However, as shown
herein, a multilayered coating including a top coat of parylene can
be manipulated so that it provides a desirable elution rate of an
active agent such as a peptide or protein. While not intending to
be bound by theory, it is believed that if a parylene layer is
applied while a component, such as a solvent, is out-gassing from
the underlying surface, the resulting parylene layer becomes porous
and can be used to control the elution of active agents such as
peptides and proteins. As shown in example 2 below, the elution
rate of a coating can be manipulated by controlling the amount of a
vaporizable component, such as a solvent, in the coating layer
before a layer of parylene is applied, such as by drying under
vacuum, degassing, or another like technique for removing the
vaporizable component.
[0025] In an embodiment, the invention includes a method of
applying an elution control coating to a substrate including
depositing a coating solution onto the substrate to form a base
layer, the coating solution comprising an active agent, a polymer,
and a solvent; selecting a desired concentration of the solvent
based on a desired elution rate; removing solvent from the base
layer to reach the desired concentration of the solvent; and
depositing a top layer on the base layer, the top layer comprising
parylene.
[0026] Some polymers used to make elution control matrices are
relatively hydrophobic. Hydrophobic polymers can have various
properties that are conducive to creating elution control coatings
with desirable release properties. However, some active agents,
such as peptides and proteins, may elute from a hydrophobic polymer
matrix more quickly than desired for certain applications.
Deposition of a parylene layer over a hydrophobic polymer matrix
can serve to slow down the elution rate of an active agent.
Exemplary hydrophobic polymers are described more fully below.
[0027] In an embodiment, the invention includes a medical device
including a substrate; a base layer disposed on the substrate, the
base layer comprising a hydrophobic polymeric matrix and an active
agent, the active agent dispersed within the hydrophobic polymeric
matrix, the active agent comprising a macromolecule; and a top
layer disposed directly on the base layer, the top layer comprising
parylene and having a thickness of between about 0.01 microns and
about 5 microns.
[0028] Elution control matrices including both degradable and
non-degradable polymers can offer various advantages. By way of
example, combination degradable/non-degradable matrices can have
structural integrity sufficient to prevent portions of the coating
from breaking off or otherwise separating under the conditions of
use. Combination degradable/non-degradable matrices of the
invention can also advantageously preserve activity of an active
agent eluted from the combination degradable/non-degradable matrix.
Deposition of a parylene layer over a combination
degradable/non-degradable matrix can serve to further increase the
structural integrity of the resulting coating. Further, deposition
of a parylene layer over a combination degradable/non-degradable
matrix can provide an additional means of controlling the elution
rate of an active agent eluted from the coating.
[0029] In an embodiment, the invention includes a medical device
including a substrate; a base layer disposed on the substrate, the
base layer comprising a polymeric matrix and an active agent, the
polymer matrix including a degradable polymer and a non-degradable
polymer, the active agent dispersed within the polymeric matrix,
the active agent comprising a macromolecule; and a top layer
disposed on the active agent layer, the top layer comprising
parylene and having a thickness of between about 0.01 microns and
about 5 microns.
[0030] Referring now to FIG. 1, a cross-sectional view of a
multi-layer elution control coating 100 is shown in accordance with
an embodiment of the invention. A base layer 104 is disposed on a
substrate 106. The substrate 106 can include various components as
described more fully below. The base layer 104 may include one or
more degradable polymers, one or more non-degradable polymers, or
combinations of both. In some embodiments, the base layer 104
includes a degradable polymer interspersed with a non-degradable
polymer. In some embodiments the base layer 104 includes a
hydrophobic polymer. One or more base layers can be included. In
some embodiments, multi-layer elution control coatings can include
a first base layer and a second base layer, the second either the
same or different than the first. In some cases, a different
material is disposed between the base layer 104 and the substrate
106. Exemplary degradable and non-degradable polymers are described
in more detail below.
[0031] The base layer 104 can also include one or more active
agents. In some embodiments, an active agent is dispersed within
the base layer 104. As used herein, the term "dispersed" shall
refer to the property of being distributed in a soluble or
insoluble state. As used herein, the term "active agent" means a
compound that has a particular desired activity. For example, an
active agent can be a therapeutic compound that exerts a specific
activity on a subject. Exemplary active agents can include
peptides, proteins, carbohydrates, nucleic acids, lipids,
polysaccharides, synthetic inorganic or organic molecules, or
combinations thereof that cause a desired biological effect when
administered to an animal, including but not limited to birds and
mammals, including humans.
[0032] Active agents used with the invention can specifically
include proteins, protein fragments, peptides, polypeptides, and
the like. Peptides can include any compound containing two or more
amino-acid residues joined by amide bonds formed from the carboxyl
group of one amino acid and the amino group of the next one. By way
of example, peptides can include glycosylated proteins, antibodies
(both monoclonal and polyclonal), antibody derivatives (including
diabodies, f(ab) fragments, humanized antibodies, etc.), cytokines,
growth factors, receptor ligands, enzymes, and the like. In some
embodiments, the active agent is selected from the group consisting
of peptides and proteins. In some embodiments, the active agent is
a macromolecule. Macromolecules can include molecules having a
molecular weight of greater than about 10 kDa. The base layer 104
can be configured to control the rate at which the active agent is
eluted there from.
[0033] The base layer 104 can also include one or more solvents.
Solvents can be used to aid in the process of depositing one or
more polymers and one or more active agents in the base layer.
Solvents can include both polar and non-polar solvents. Solvents
can include components that are vaporizable. As used herein, the
term "vaporizable" shall refer to components having the property of
forming a vapor or gas under conditions that can include ambient or
elevated temperatures and atmospheric or vacuum pressures. In some
embodiments, the base layer 104 can include one or more volatile
components. Solvents can include water, alcohols (e.g., methanol,
butanol, propanol, and isopropanol (isopropyl alcohol)), alkanes
(e.g., halogenated or unhalogenated alkanes such as chloroform,
hexane, and cyclohexane), amides (e.g., dimethylformamide), ethers
(e.g., THF and dioxolane), ketones (e.g., methylethylketone),
aromatic compounds (e.g., toluene and xylene), nitriles (e.g.,
acetonitrile) and esters (e.g., ethyl acetate). In some
embodiments, one or more polymers of the base layer 104 are soluble
in the solvent. In some embodiments, one or more active agents of
the base layer 104 are soluble in the solvent. The solvent can be
non-polymeric.
[0034] The base layer 104 can be deposited onto the substrate 106
using any of a variety of coating techniques including dip-coating,
spray-coating (including both gas-atomization and ultrasonic
atomization), fogging, brush coating, press coating, blade coating,
and the like. The base layer 104 may be applied as a coating
solution and may be applied under conditions where atmospheric
characteristics such as relative humidity, temperature, gaseous
composition, and the like are controlled. In some embodiments, the
coating solution is applied using a spray technique. Exemplary
spray coating equipment that can be used to apply components of the
invention can be found in U.S. Pat. No. 6,562,136; U.S. Pat. No.
7,077,910; U.S. Pub. App. No. US 2004/0062875; U.S. Pub. App. No.
2005/0158449; U.S. Pub. App. No. 2006/0088653; U.S. Pub. App. No.
2005/0196424; and U.S. Pub. App. No. 2007/0128343, the contents of
which are all hereby incorporated by reference.
[0035] The thickness of the base layer 104 can depend on many
factors including, for example, the specific polymers used in the
matrix, the desired loading of active agent within the base layer
104, the type of medical device being coated, etc. In some
embodiments, the base layer 104 is from about 0.5 microns to about
500 microns thick.
[0036] A top layer 102 is disposed on the base layer 104. In some
embodiments, the top layer 102 is disposed directly upon the base
layer 104. In other embodiments, a different material or layer is
disposed between the top layer 102 and the base layer 104. The top
layer 102 can comprise parylene. The term "parylene" as used herein
shall refer to a polymer belonging to the group of polymers based
on p-xylylene (substituted or unsubstituted). Parylenes have the
repeating structure
-(p-CH.sub.2--C.sub.6H.sub.4--CH.sub.2).sub.n--. Common parylene
polymers include poly(2-chloro-paraxylylene) ("parylene C"),
poly(paraxylylene) ("parylene N"), and
poly(2,5-dichloro-paraxylylene) ("parylene D"). In a particular
embodiment, the top layer 102 includes poly(2-chloro-paraxylylene)
("parylene C"). The top layer 102 can also include mono-, di-,
tri-, and tetra-halo substituted polyparaxylylenes. In an
embodiment, the top layer 102 includes mono-, di-, tri-, or
tetra-chloro substituted polyparaxylylene. In an embodiment, the
top layer 102 includes mono-, di-, tri-, or tetra-fluoro
substituted polyparaxylylene. Other parylene derivatives can used
including poly(dimethoxy-p-xylylene), poly(sulfo-p-xylylene),
poly(iodo-p-xylylene), poly(trifluoro-p-xylylene),
poly(difluoro-p-xylylene), and poly(fluoro-p-xylylene).
[0037] Deposition of the top layer 102 can be performed using
various techniques. In an embodiment, the top layer 102 can be
deposited using a vacuum vapor deposition system. In some vacuum
vapor deposition systems a polymer charge is vaporized in a
vaporization chamber and then passes through a cracking chamber
where parylene dimer vapor is cracked into activated monomer vapor.
Vaporized activated monomer is then usually deposited onto a
substrate in a deposition chamber. An exemplary vacuum deposition
system is the PDS-2010 LABCOTER.RTM. available from Specialty
Coating Systems (Indianapolis, Ind.).
[0038] As shown in the examples below, the condition of the base
layer 104 while the top layer 102 is being deposited can affect the
resulting elution rate of the multi-layer elution control coating.
While not intending to be bound by theory, if the top layer 102 is
applied while a component, such as a solvent, is out-gassing or
evaporating from the base layer 104, the parylene layer can be made
porous. As such, the elution rate of an active agent from the
multi-layer elution control coating 100 can be decreased by
decreasing the amount of vaporizable components therein prior to
depositing the top layer 102 onto the base layer 104. Conversely,
the elution rate of an active agent from the multi-layer elution
control coating 100 can be increased by increasing the amount of
vaporizable components therein prior to depositing the top layer
102 onto the base layer 104.
[0039] The concentration of vaporizable components in the base
layer 104 can be increased or decreased in various ways. In some
embodiments, a smaller amount of vaporizable components are added
to a coating solution that is used to form the base layer 104. In
other embodiments, vaporizable components are removed from the base
layer 104 after it is first applied to a substrate. It will be
appreciated that vaporizable components can be removed from the
base layer 104 in various ways. For example, the base layer 104, as
deposited onto a substrate, can simply be stored at ambient
temperature for a period of time. Alternatively, the base layer 104
can be held at an elevated temperature for a period of time.
However, elevated temperatures can contribute to degradation or
denaturation of peptides and proteins. Another method of removing
vaporizable components from the base layer 104 can include storing
it under vacuum conditions for a period of time. In some
embodiments, a base layer 104 disposed on a substrate is stored
under vacuum for a period of time greater than about 30 minutes. In
some embodiments, a base layer 104 disposed on a substrate is
stored under vacuum for a period of time greater than about one
hour. In some embodiments, a base layer 104 disposed on a substrate
is stored under vacuum for a period of time greater than about
twelve hours. In some embodiments, a base layer 104 disposed on a
substrate is stored under vacuum for a period of time greater than
about one day. In some embodiments, a base layer 104 disposed on a
substrate is stored under vacuum for a period of time greater than
about one week.
[0040] In addition to other aspects, the thickness of the top layer
102 can impact the elution rate of an active agent passing the top
layer 102. In general, the thicker the top layer 102 is, the slower
the resulting elution rate will be. In some embodiments, the top
layer 102 is from about 0.01 microns to about 5.0 microns
thick.
[0041] In some embodiments, the base layer 104 is not disposed on a
substrate. By way of example, the base layer 104 can form a bead or
a film and the top layer 102 can be disposed over the base layer
104.
[0042] FIG. 2 shows a cross-sectional view of a multi-layer elution
control coating disposed on a substrate in accordance with another
embodiment of the invention. A base layer 204 is disposed on a
substrate 206. The base layer 204 can include one or more polymers
and/or one or more active agents. The base layer 204 can surround
the substrate 206. A top layer 202 is disposed on the base layer
204. The top layer 202 can include parylene. The top layer 202 can
completely cover the base layer 204.
[0043] FIG. 3 shows a cross-sectional view of a multi-layer elution
control coating disposed on a substrate in accordance with another
embodiment of the invention. An underlying layer 305 is disposed on
a substrate 306. The underlying layer 305 can include one or more
polymers. The underlying layer 305 can also include one or more
active agents. In some embodiments, the underlying layer 305 can be
configured to elute an active agent. In some embodiments, the
underlying layer 305 includes parylene. In some embodiments, the
underlying layer 305 can improve adhesion of the other layers to
the substrate 306. A base layer 304 is disposed on the underlying
layer 305. The base layer 304 can include one or more polymers
and/or one or more active agents. A top layer 302 is disposed on
the base layer 304. The top layer 302 can include parylene.
Substrates
[0044] It will be appreciated that embodiments of the invention can
be used in conjunction with various types of substrates. Exemplary
substrates can include metals, polymers, ceramics, and natural
materials. Metals can include, but are not limited to, cobalt,
chromium, nickel, titanium, tantalum, iridium, tungsten and alloys
such as stainless steel, nitinol or cobalt chromium. Suitable
metals can also include the noble metals such as gold, silver,
copper, platinum, and alloys including the same.
[0045] Substrate polymers include those formed of synthetic
polymers, including oligomers, homopolymers, and copolymers
resulting from either addition or condensation polymerizations.
Examples include, but 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, styrene, vinyl
chloride, vinyl acetate, vinyl pyrrolidone, and vinylidene
difluoride, condensation polymers including, but are not limited
to, polyamides such as polycaprolactam, polylauryl lactam,
polyhexamethylene adipamide, and polyhexamethylene dodecanediamide,
and also polyurethanes, polycarbonates, polysulfones, poly(ethylene
terephthalate), polytetrafluoroethylene, polyethylene,
polypropylene, polylactic acid, polyglycolic acid, polysiloxanes
(silicones), cellulose, and polyetheretherketone.
[0046] Embodiments of the invention can also include the use of
ceramics as a substrate. Ceramics include, but are not limited to,
silicon nitride, silicon carbide, zirconia, and alumina, as well as
glass, silica, and sapphire.
[0047] Certain natural materials can also be used in some
embodiments including human tissue, when used as a component of a
device, such as bone, cartilage, skin and enamel; and other organic
materials such as wood, cellulose, compressed carbon, rubber, silk,
wool, and cotton. Substrates can also include carbon fiber.
Substrates can also include resins, polysaccharides, silicon, or
silica-based materials, glass, films, gels, and membranes.
Medical Devices
[0048] It will be appreciated that embodiments of the invention can
be used in conjunction with, and can include, many different types
of medical devices. For example, in FIG. 4 a perspective view of a
stent 400 is shown in accordance with an embodiment of the
invention. The stent 400 is fabricated with a mesh-type
construction and includes a plurality of wires or struts 402 that
can be made of various materials including metals and polymers. A
multi-layer elution control coating including a base layer and a
top layer can be deposited on the wires or struts 402. In FIG. 5, a
perspective view of a coil 500 is shown in accordance with an
embodiment of the invention. The coil 500 includes a curved wire
502 that can be made of various materials including metals and
polymers. A multi-layer elution control coating including a base
layer and a top layer can be deposited on the coil 500.
Specifically, a multi-layer elution control coating can be
deposited on the curved wire 502.
[0049] Embodiments of the invention can include and can be used
with both implantable devices and non-implantable medical devices.
Embodiments of the invention can include and can be used with
implantable, or transitorily implantable, devices including, but
not limited to, vascular devices such as grafts (e.g., abdominal
aortic aneurysm grafts, etc.), stents (e.g., self-expanding stents
typically made from nitinol, balloon-expanded stents typically
prepared from stainless steel, degradable coronary stents, etc.),
catheters (including arterial, intravenous, blood pressure, stent
graft, etc.), valves (e.g., polymeric or carbon mechanical valves,
tissue valves, valve designs including percutaneous, sewing cuff,
and the like), embolic protection filters (including distal
protection devices), vena cava filters, aneurysm exclusion devices,
artificial hearts, cardiac jackets, and heart assist devices
(including left ventricle assist devices), implantable
defibrillators, electro-stimulation devices and leads (including
pacemakers, lead adapters and lead connectors), implanted medical
device power supplies (e.g., batteries, etc.), peripheral
cardiovascular devices, atrial septal defect closures, left atrial
appendage filters, valve annuloplasty devices (e.g., annuloplasty
rings), mitral valve repair devices, vascular intervention devices,
ventricular assist pumps, and vascular access devices (including
parenteral feeding catheters, vascular access ports, central venous
access catheters); surgical devices such as sutures of all types,
staples, anastomosis devices (including anastomotic closures),
suture anchors, hemostatic barriers, screws, plates, clips,
vascular implants, tissue scaffolds, cerebro-spinal fluid shunts,
shunts for hydrocephalus, drainage tubes, catheters including
thoracic cavity suction drainage catheters, abscess drainage
catheters, biliary drainage products, and implantable pumps;
orthopedic devices such as joint implants, acetabular cups,
patellar buttons, bone repair/augmentation devices, spinal devices
(e.g., vertebral disks and the like), bone pins, cartilage repair
devices, and artificial tendons; dental devices such as dental
implants and dental fracture repair devices; drug delivery devices
such as drug delivery pumps, implanted drug infusion tubes, drug
infusion catheters, and intravitreal drug delivery devices;
ophthalmic devices including orbital implants, glaucoma drain
shunts and intraocular lenses; urological devices such as penile
devices (e.g., impotence implants), sphincter, urethral, prostate,
and bladder devices (e.g., incontinence devices, benign prostate
hyperplasia management devices, prostate cancer implants, etc.),
urinary catheters including indwelling ("Foley") and non-indwelling
urinary catheters, and renal devices; synthetic prostheses such as
breast prostheses and artificial organs (e.g., pancreas, liver,
lungs, heart, etc.); respiratory devices including lung catheters;
neurological devices such as neurostimulators, neurological
catheters, neurovascular balloon catheters, neuro-aneurysm
treatment coils, and neuropatches; ear nose and throat devices such
as nasal buttons, nasal and airway splints, nasal tampons, ear
wicks, ear drainage tubes, tympanostomy vent tubes, otological
strips, laryngectomy tubes, esophageal tubes, esophageal stents,
laryngeal stents, salivary bypass tubes, and tracheostomy tubes;
biosensor devices including glucose sensors, cardiac sensors,
intra-arterial blood gas sensors; oncological implants; and pain
management implants.
[0050] Classes of non-implantable devices can include dialysis
devices and associated tubing, catheters, membranes, and grafts;
autotransfusion devices; vascular and surgical devices including
atherectomy catheters, angiographic catheters, intraaortic balloon
pumps, intracardiac suction devices, blood pumps, blood oxygenator
devices (including tubing and membranes), blood filters, blood
temperature monitors, hemoperfusion units, plasmapheresis units,
transition sheaths, dialators, intrauterine pressure devices, clot
extraction catheters, percutaneous transluminal angioplasty
catheters, electrophysiology catheters, breathing circuit
connectors, stylets (vascular and non-vascular), coronary guide
wires, peripheral guide wires; dialators (e.g., urinary, etc.);
surgical instruments (e.g. scalpels and the like); endoscopic
devices (such as endoscopic surgical tissue extractors, esophageal
stethoscopes); and general medical and medically related devices
including blood storage bags, umbilical tape, membranes, gloves,
surgical drapes, wound dressings, wound management devices,
needles, percutaneous closure devices, transducer protectors,
pessary, uterine bleeding patches, PAP brushes, clamps (including
bulldog clamps), cannulae, cell culture devices, materials for in
vitro diagnostics, chromatographic support materials, infection
control devices, colostomy bag attachment devices, birth control
devices; disposable temperature probes; and pledgets.
[0051] In some aspects, embodiments of the invention can include
and be utilized in conjunction with ophthalmic devices. Suitable
ophthalmic devices in accordance with these aspects can provide
bioactive agent to any desired area of the eye. In some aspects,
the devices can be utilized to deliver 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.
[0052] In some aspects, embodiments of the invention can be
utilized in conjunction with ophthalmic devices configured for
placement at an external or internal site of the eye. Suitable
external devices 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.
[0053] Devices configured for placement at an internal site of the
eye can reside within any desired area of the eye. In some aspects,
the ophthalmic devices 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. Nos. 6,719,750 B2 ("Devices for Intraocular Drug Delivery,"
Varner et al.) and 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
2003/0014036 A1 ("Reservoir Device for Intraocular Drug Delivery,"
Varner et al.); and U.S. application Ser. Nos. 11/204,195 (filed
Aug. 15, 2005, Anderson et al.), 11/204,271 (filed Aug. 15, 2005,
Anderson et al.), 11/203,981 (filed Aug. 15, 2005, Anderson et
al.), 11/203,879 (filed Aug. 15, 2005, Anderson et al.), 11/203,931
(filed Aug. 15, 2005, Anderson et al.); and related
applications.
[0054] In some aspects, the ophthalmic devices can be configured
for placement 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.
[0055] Suitable ophthalmic devices can 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.
Hydrophobic Polymers
[0056] In an embodiment, the base layer can include a hydrophobic
polymer. One method of defining the hydrophobicity of a polymer is
by the solubility parameter (or Hildebrand parameter) of the
polymer. The solubility parameter describes the attractive strength
between molecules of the material. The solubility parameter is
represented by Equation 1:
.delta.=(.DELTA.E.sup.v/V).sup.1/2 (Equation 1)
[0057] where
[0058] .delta.=solubility parameter ((cal/cm.sup.3).sup.1/2)
[0059] .delta.E.sup.v=energy of vaporization (cal)
[0060] V=molar volume (cm.sup.3)
[0061] Solubility parameters cannot be calculated for polymers from
heat of vaporization data because of their nonvolatility.
Accordingly, solubility parameters must be calculated indirectly.
One method involves identifying solvents in which a polymer
dissolves without a change in heat or volume and then defining the
solubility parameter of the polymer to be the same as the
solubility parameters of the identified solvents. A more complete
discussion of solubility parameters and methods of calculating the
same can be found in Brandup et al., Polymer Handbook, 4th Ed.,
John Wiley & Sons, N.Y. (1999) beginning at VII p. 675.
[0062] As a general rule, the value of the solubility parameter
.delta. is inversely proportional to the degree of hydrophobicity
of a polymer. Thus, polymers that are very hydrophobic may have a
low solubility parameter value. This general proposition is
particularly applicable for polymers having a glass transition
temperature below physiological temperature. In an embodiment,
hydrophobic polymers used with the invention have a solubility
parameter less than about 11.0 (cal/cm.sup.3).sup.1/2. In an
embodiment, hydrophobic polymers used with the invention have a
solubility parameter of less than about 10.0
(cal/cm.sup.3).sup.1/2.
Degradable Polymers
[0063] In an embodiment, the base layer can include one or more
degradable polymers. The term "degradable" as used herein with
reference to polymers, shall refer to those natural or synthetic
polymers that break down under physiological conditions into
constituent components over a period of time. By way of example,
many degradable polymers include hydrolytically unstable linkages
in the polymeric backbone. The cleavage of these unstable linkages
leads to degradation of the polymer. The terms "erodible",
"bioerodible", "biodegradable" and "non-durable" shall be used
herein interchangeably with the term "degradable". Degradable
polymers can include both natural or synthetic polymers. Examples
of degradable polymers can include those with hydrolytically
unstable linkages in the polymeric backbone. Degradable polymers of
the invention can include both those with bulk erosion
characteristics and those with surface erosion characteristics.
[0064] Synthetic degradable polymers can include: degradable
polyesters (such as poly(glycolic acid), poly(lactic acid),
poly(lactic-co-glycolic acid), poly(dioxanone), polylactones (e.g.,
poly(caprolactone)), poly(3-hydroxybutyrate),
poly(3-hydroxyvalerate), poly(valerolactone), poly(tartronic acid),
poly(B-malonic acid), poly(propylene fumarate)); degradable
polyesteramides; degradable polyanhydrides (such as poly(sebacic
acid), poly(1,6-bis(carboxyphenoxy)hexane,
poly(1,3-bis(carboxyphenoxy)propane); degradable polycarbonates
(such as tyrosine-based polycarbonates); degradable
polyiminocarbonates; degradable polyarylates (such as
tyrosine-based polyarylates); degradable polyorthoesters;
degradable polyurethanes; degradable polyphosphazenes; and
degradable polyhydroxyalkanoates; and copolymers thereof.
[0065] Natural or naturally-based degradable polymers can include
polysaccharides and modified polysaccharides such as starch,
cellulose, chitin, chitosan, and copolymers thereof.
[0066] Specific examples of degradable polymers include poly(ether
ester) multiblock copolymers based on poly(ethylene glycol) (PEG)
and poly(butylene terephthalate) that can be described by the
following general structure:
[--(OCH.sub.2CH.sub.2).sub.n--O--C(O)--C.sub.6H.sub.4--C(O)--]x[--O--(CH-
.sub.2).sub.4--O--C(O)--C.sub.6H.sub.4--C(O)--]y,
where --C.sub.6H.sub.4-- designates the divalent aromatic ring
residue from each esterified molecule of terephthalic acid, n
represents the number of ethylene oxide units in each hydrophilic
PEG block, x represents the number of hydrophilic blocks in the
copolymer, and y represents the number of hydrophobic blocks in the
copolymer. n can be selected such that the molecular weight of the
PEG block is between about 300 and about 4000. X and y can be
selected so that the multiblock copolymer contains from about 55%
up to about 80% PEG by weight. The block copolymer can be
engineered to provide a wide array of physical characteristics
(e.g., hydrophilicity, adherence, strength, malleability,
degradability, durability, flexibility) and active agent release
characteristics (e.g., through controlled polymer degradation and
swelling) by varying the values of n, x and y in the copolymer
structure.
[0067] Degradable polyesteramides can include those formed from the
monomers OH-x-OH, z, and COOH-y-COOH, wherein x is alkyl, y is
alkyl, and z is leucine or phenylalanine.
[0068] Degradable polymeric materials can also be selected from:
(a) non-peptide polyamino polymers; (b) polyiminocarbonates; (c)
amino acid-derived polycarbonates and polyarylates; and (d)
poly(alkylene oxide) polymers.
[0069] In an embodiment, the degradable polymeric material is
composed of a non-peptide polyamino acid polymer. Exemplary
non-peptide polyamino acid polymers are described, for example, in
U.S. Pat. No. 4,638,045 ("Non-Peptide Polyamino Acid Bioerodible
Polymers," Jan. 20, 1987). Generally speaking, these polymeric
materials are derived from monomers, including two or three amino
acid units having one of the following two structures illustrated
below:
##STR00001##
[0070] wherein the monomer units are joined via hydrolytically
labile bonds at not less than one of the side groups R.sub.1,
R.sub.2, and R.sub.3, and where R.sub.1, R.sub.2, R.sub.3 are the
side chains of naturally occurring amino acids; Z is any desirable
amine protecting group or hydrogen; and Y is any desirable carboxyl
protecting group or hydroxyl. Each monomer unit comprises naturally
occurring amino acids that are then polymerized as monomer units
via linkages other than by the amide or "peptide" bond. The monomer
units can be composed of two or three amino acids united through a
peptide bond and thus comprise dipeptides or tripeptides.
Regardless of the precise composition of the monomer unit, all are
polymerized by hydrolytically labile bonds via their respective
side chains rather than via the amino and carboxyl groups forming
the amide bond typical of polypeptide chains. Such polymer
compositions are nontoxic, are degradable, and can provide
zero-order release kinetics for the delivery of active agents in a
variety of therapeutic applications. According to these aspects,
the amino acids are selected from naturally occurring L-alpha amino
acids, including alanine, valine, leucine, isoleucine, proline,
serine, threonine, aspartic acid, glutamic acid, asparagine,
glutamine, lysine, hydroxylysine, arginine, hydroxyproline,
methionine, cysteine, cystine, phenylalanine, tyrosine, tryptophan,
histidine, citrulline, ornithine, lanthionine, hypoglycin A,
.beta.-alanine, .gamma.-amino butyric acid, .alpha. aminoadipic
acid, canavanine, venkolic acid, thiolhistidine, ergothionine,
dihydroxyphenylalanine, and other amino acids well recognized and
characterized in protein chemistry.
[0071] Degradable polymers of the invention can also include
polymerized polysaccharides such as those described in U.S. Publ.
Pat. Application No. 2005/0255142, entitled "COATINGS FOR MEDICAL
ARTICLES INCLUDING NATURAL BIODEGRADABLE POLYSACCHARIDES", U.S.
Publ. Pat. Application No. 2007/0065481, entitled "COATINGS
INCLUDING NATURAL BIODEGRADABLE POLYSACCHARIDES AND USES THEREOF",
and in U.S. Application No. 60/782,957, entitled "HYDROPHOBIC
DERIVATIVES OF NATURAL BIODEGRADABLE POLYSACCHARIDES", all of which
are herein incorporated by reference.
[0072] Degradable polymers of the invention can also include
dextran based polymers such as those described in U.S. Pat. No.
6,303,148, entitled "PROCESS FOR THE PREPARATION OF A CONTROLLED
RELEASE SYSTEM". Exemplary dextran based degradable polymers
including those available commercially under the trade name
OCTODEX.
[0073] Degradable polymers of the invention can further include
collagen/hyaluronic acid polymers.
[0074] Degradable polymers of the invention can include multi-block
copolymers, comprising at least two hydrolysable segments derived
from pre-polymers A and B, which segments are linked by a
multi-functional chain-extender and are chosen from the
pre-polymers A and B, and triblock copolymers ABA and BAB, wherein
the multi-block copolymer is amorphous and has one or more glass
transition temperatures (Tg) of at most 37.degree. C. (Tg) at
physiological (body) conditions. The pre-polymers A and B can be a
hydrolysable polyester, polyetherester, polycarbonate,
polyestercarbonate, polyanhydride or copolymers thereof, derived
from cyclic monomers such as lactide (L,D or L/D), glycolide,
.epsilon.-caprolactone, .delta.-valerolactone, trimethylene
carbonate, tetramethylene carbonate, 1,5-dioxepane-2-one,
1,4-dioxane-2-one (para-dioxanone) or cyclic anhydrides
(oxepane-2,7-dione). The composition of the pre-polymers can be
chosen in such a way that the maximum glass transition temperature
of the resulting copolymer is below 37.degree. C. at body
conditions. To fulfill the requirement of a Tg below 37.degree. C.,
some of the above-mentioned monomers or combinations of monomers
can be more preferred than others. This may by itself lower the Tg,
or the pre-polymer is initiated with a polyethylene glycol with
sufficient molecular weight to lower the glass transition
temperature of the copolymer. The degradable multi-block copolymers
can include hydrolysable sequences being amorphous and the segments
can be linked by a multifunctional chain-extender, the segments
having different physical and degradation characteristics. For
example, a multi-block co-polyester consisting of a
glycolide-.epsilon.-caprolactone segment and a lactide-glycolide
segment can be composed of two different polyester pre-polymers. By
controlling the segment monomer composition, segment ratio and
length, a variety of polymers with properties that can easily be
tuned can be obtained.
Non-Degradable Polymers
[0075] Embodiments of the invention can include one or more
non-degradable (durable) polymers in the base layer. In an
embodiment, the non-degradable polymer includes a plurality of
polymers, including a first polymer and a second polymer. When the
coating solution contains only one polymer, it can be either a
first or second polymer as described herein. As used herein, term
"(meth)acrylate" when used in describing polymers shall mean the
form including the methyl group (methacrylate) or the form without
the methyl group (acrylate).
[0076] First polymers of the invention can include a polymer
selected from the group consisting of poly(alkyl(meth)acrylates)
and poly(aromatic(meth)acrylates), where "(meth)" will be
understood by those skilled in the art to include such molecules in
either the acrylic and/or methacrylic form (corresponding to the
acrylates and/or methacrylates, respectively). An exemplary first
polymer is poly(n-butyl methacrylate) (pBMA). Such polymers are
available commercially, e.g., from Aldrich, with molecular weights
ranging from about 200,000 Daltons to about 320,000 Daltons, and
with varying inherent viscosity, solubility, and form (e.g., as
crystals or powder). In some embodiments, poly(n-butyl
methacrylate) (pBMA) is used with a molecular weight of about
200,000 Daltons to about 300,000 Daltons.
[0077] Examples of suitable first polymers also include polymers
selected from the group consisting of poly(aryl(meth)acrylates),
poly(aralkyl(meth)acrylates), and
poly(aryloxyalkyl(meth)acrylates). Such terms are used to describe
polymeric structures wherein at least one carbon chain and at least
one aromatic ring are combined with acrylic groups, typically
esters, to provide a composition. In particular, exemplary
polymeric structures include those with aryl groups having from 6
to 16 carbon atoms and with weight average molecular weights from
about 50 to about 900 kilodaltons. Suitable
poly(aralkyl(meth)acrylates), poly(arylalky(meth)acrylates) or
poly(aryloxyalkyl(meth)acrylates) can be made from aromatic esters
derived from alcohols also containing aromatic moieties. Examples
of poly(aryl(meth)acrylates) include poly(9-anthracenyl
methacrylate), poly(chlorophenylacrylate),
poly(methacryloxy-2-hydroxybenzophenone),
poly(methacryloxybenzotriazole), poly(naphthylacrylate) and
-methacrylate), poly(4-nitrophenyl acrylate),
poly(pentachloro(bromo, fluoro)acrylate) and -methacrylate), and
poly(phenyl acrylate) and -methacrylate). Examples of
poly(aralkyl(meth)acrylates) include poly(benzyl acrylate) and
-methacrylate), poly(2-phenethyl acrylate) and -methacrylate, and
poly(1-pyrenylmethyl methacrylate). Examples of
poly(aryloxyalkyl(meth)acrylates) include poly(phenoxyethyl
acrylate) and -methacrylate), and poly(polyethylene glycol phenyl
ether acrylates) and -methacrylates with varying polyethylene
glycol molecular weights.
[0078] Examples of suitable second polymers are available
commercially and include poly(ethylene-co-vinyl acetate) (pEVA)
having vinyl acetate concentrations of between about 10% and about
50% (12%, 14%, 18%, 25%, 33% versions are commercially available),
in the form of beads, pellets, granules, etc. pEVA co-polymers with
lower percent vinyl acetate become increasingly insoluble in
typical solvents, whereas those with higher percent vinyl acetate
become decreasingly durable.
[0079] An exemplary polymer mixture includes mixtures of pBMA and
pEVA. This mixture of polymers can be used with absolute polymer
concentrations (i.e., the total combined concentrations of both
polymers in the coating material), of between about 0.25 wt. % and
about 99 wt. %. This mixture can also be used with individual
polymer concentrations in the coating solution of between about
0.05 wt. % and about 99 wt. %. In one embodiment the polymer
mixture includes pBMA with a molecular weight of from 100
kilodaltons to 900 kilodaltons and a pEVA copolymer with a vinyl
acetate content of from 24 to 36 weight percent. In an embodiment
the polymer mixture includes pBMA with a molecular weight of from
200 kilodaltons to 300 kilodaltons and a pEVA copolymer with a
vinyl acetate content of from 24 to 36 weight percent. The
concentration of the active agent or agents dissolved or suspended
in the coating mixture can range from 0.01 to 99 percent, by
weight, based on the weight of the final coating material.
[0080] Second polymers can also comprise one or more polymers
selected from the group consisting of (i)
poly(alkylene-co-alkyl(meth)acrylates, (ii) ethylene copolymers
with other alkylenes, (iii) polybutenes, (iv) diolefin derived
non-aromatic polymers and copolymers, (v) aromatic group-containing
copolymers, and (vi) epichlorohydrin-containing polymers.
[0081] Poly(alkylene-co-alkyl(meth)acrylates) include those
copolymers in which the alkyl groups are either linear or branched,
and substituted or unsubstituted with non-interfering groups or
atoms. Such alkyl groups can comprise from 1 to 8 carbon atoms,
inclusive. Such alkyl groups can comprise from 1 to 4 carbon atoms,
inclusive. In an embodiment, the alkyl group is methyl. In some
embodiments, copolymers that include such alkyl groups can comprise
from about 15% to about 80% (wt) of alkyl acrylate. When the alkyl
group is methyl, the polymer contains from about 20% to about 40%
methyl acrylate in some embodiments, and from about 25% to about
30% methyl acrylate in a particular embodiment. When the alkyl
group is ethyl, the polymer contains from about 15% to about 40%
ethyl acrylate in an embodiment, and when the alkyl group is butyl,
the polymer contains from about 20% to about 40% butyl acrylate in
an embodiment.
[0082] Alternatively, second polymers can comprise ethylene
copolymers with other alkylenes, which in turn, can include
straight and branched alkylenes, as well as substituted or
unsubstituted alkylenes. Examples include copolymers prepared from
alkylenes that comprise from 3 to 8 branched or linear carbon
atoms, inclusive. In an embodiment, copolymers prepared from
alkylene groups that comprise from 3 to 4 branched or linear carbon
atoms, inclusive. In a particular embodiment, copolymers prepared
from alkylene groups containing 3 carbon atoms (e.g., propene). By
way of example, the other alkylene is a straight chain alkylene
(e.g., 1-alkylene). Exemplary copolymers of this type can comprise
from about 20% to about 90% (based on moles) of ethylene. In an
embodiment, copolymers of this type comprise from about 35% to
about 80% (mole) of ethylene. Such copolymers will have a molecular
weight of between about 30 kilodaltons to about 500 kilodaltons.
Exemplary copolymers are selected from the group consisting of
poly(ethylene-co-propylene), poly(ethylene-co-1-butene),
polyethylene-co-1-butene-co-1-hexene) and/or
poly(ethylene-co-1-octene).
[0083] "Polybutenes" include polymers derived by homopolymerizing
or randomly interpolymerizing isobutylene, 1-butene and/or
2-butene. The polybutene can be a homopolymer of any of the isomers
or it can be a copolymer or a terpolymer of any of the monomers in
any ratio. In an embodiment, the polybutene contains at least about
90% (wt) of isobutylene or 1-butene. In a particular embodiment,
the polybutene contains at least about 90% (wt) of isobutylene. The
polybutene may contain non-interfering amounts of other ingredients
or additives, for instance it can contain up to 1000 ppm of an
antioxidant (e.g., 2,6-di-tert-butyl-methylphenol). By way of
example, the polybutene can have a molecular weight between about
150 kilodaltons and about 1,000 kilodaltons. In an embodiment, the
polybutene can have between about 200 kilodaltons and about 600
kilodaltons. In a particular embodiment, the polybutene can have
between about 350 kilodaltons and about 500 kilodaltons.
Polybutenes having a molecular weight greater than about 600
kilodaltons, including greater than 1,000 kilodaltons are available
but are expected to be more difficult to work with.
[0084] Additional alternative second polymers include
diolefin-derived, non-aromatic polymers and copolymers, including
those in which the diolefin monomer used to prepare the polymer or
copolymer is selected from butadiene
(CH.sub.2.dbd.CH--CH.dbd.CH.sub.2) and/or isoprene
(CH.sub.2.dbd.CH--C(CH.sub.3).dbd.CH.sub.2). In an embodiment, the
polymer is a homopolymer derived from diolefin monomers or is a
copolymer of diolefin monomer with non-aromatic mono-olefin
monomer, and optionally, the homopolymer or copolymer can be
partially hydrogenated. Such polymers can be selected from the
group consisting of polybutadienes prepared by the polymerization
of cis-, trans- and/or 1,2-monomer units, or from a mixture of all
three monomers, and polyisoprenes prepared by the polymerization of
cis-1,4- and/or trans-1,4-monomer units. Alternatively, the polymer
is a copolymer, including graft copolymers, and random copolymers
based on a non-aromatic mono-olefin monomer such as acrylonitrile,
and an alkyl(meth)acrylate and/or isobutylene. In an embodiment,
when the mono-olefin monomer is acrylonitrile, the interpolymerized
acrylonitrile is present at up to about 50% by weight; and when the
mono-olefin monomer is isobutylene, the diolefin is isoprene (e.g.,
to form what is commercially known as a "butyl rubber"). Exemplary
polymers and copolymers have a molecular weight between about 150
kilodaltons and about 1,000 kilodaltons. In an embodiment, polymers
and copolymers have a molecular weight between about 200
kilodaltons and about 600 kilodaltons.
[0085] Additional alternative second polymers include aromatic
group-containing copolymers, including random copolymers, block
copolymers and graft copolymers. In an embodiment, the aromatic
group is incorporated into the copolymer via the polymerization of
styrene. In a particular embodiment, the random copolymer is a
copolymer derived from copolymerization of styrene monomer and one
or more monomers selected from butadiene, isoprene, acrylonitrile,
a C.sub.1-C.sub.4 alkyl(meth)acrylate (e.g., methyl methacrylate)
and/or butene. Useful block copolymers include copolymer containing
(a) blocks of polystyrene, (b) blocks of an polyolefin selected
from polybutadiene, polyisoprene and/or polybutene (e.g.,
isobutylene), and (c) optionally a third monomer (e.g., ethylene)
copolymerized in the polyolefin block. The aromatic
group-containing copolymers contain about 10% to about 50% (wt.) of
polymerized aromatic monomer and the molecular weight of the
copolymer is from about 300 kilodaltons to about 500 kilodaltons.
In an embodiment, the molecular weight of the copolymer is from
about 100 kilodaltons to about 300 kilodaltons.
[0086] Additional alternative second polymers include
epichlorohydrin homopolymers and poly(epichlorohydrin-co-alkylene
oxide) copolymers. In an embodiment, in the case of the copolymer,
the copolymerized alkylene oxide is ethylene oxide. By way of
example, epichlorohydrin content of the epichlorohydrin-containing
polymer is from about 30% to 100% (wt). In an embodiment,
epichlorohydrin content is from about 50% to 100% (wt). In an
embodiment, the epichlorohydrin-containing polymers have a
molecular weight from about 100 kilodaltons to about 300
kilodaltons.
[0087] Non-degradable polymers can also include those described in
U.S. Pat. App. No. 2007/0026037, entitled "DEVICES, ARTICLES,
COATINGS, AND METHODS FOR CONTROLLED ACTIVE AGENT RELEASE OR
HEMOCOMPATIBILITY", the contents of which is herein incorporated by
reference. As a specific example, non-degradable polymers can
include random copolymers of butyl
methacrylate-co-acrylamido-methyl-propane sulfonate (BMA-AMPS). In
some embodiments, the random copolymer can include AMPS in an
amount equal to about 0.5 mol. % to about 40 mol.
[0088] The present invention may be better understood with
reference to the following examples. These examples are intended to
be representative of specific embodiments of the invention, and are
not intended as limiting the scope of the invention.
EXAMPLES
Example 1
Parylene Coat Over Non-Degradable Hydrophobic Matrix
[0089] Poly-n-butylmethacrylate (PBMA) and polyethylene-co-vinyl
acetate (PEVA) were combined in a solvent of chloroform to form a
non-degradable polymer solution having 10 mg/ml PBMA and 10 mg/ml
PEVA (total solids concentration of 20 mg/ml).
[0090] IgG rabbit anti-goat antibodies were obtained from
Sigma-Aldrich, St. Louis, Mo. The IgG rabbit anti-goat antibodies
were combined with non-specific IgG rabbit antibodies at a ration
of 10:1 non-specific to specific in PBS (phosphate buffered saline)
to form an IgG solution.
[0091] MP-35N alloy coils (N=7) were simultaneously coated with
both the non-degradable polymer solution and the IgG solution. The
non-degradable polymer solution was applied onto the exterior
surface of a first ultrasonic nozzle (60 KHz ultrasonic nozzle from
Sono-Tek, Milton, N.Y., operating at about 0.5 to 1.5 watts) at a
rate of 0.025 mL/minute. Simultaneously, the IgG solution was
applied onto the exterior surface of a second ultrasonic nozzle (60
KHz ultrasonic nozzle from Sono-Tek, Milton, N.Y., operating at
about 0.5 to 1.5 watts) at a rate of 0.025 mL/minute. Both
ultrasonic spray nozzles were directed at the coils. Coils were
then passed back and forth under the spray nozzles and rotated a
plurality of times. This treatment resulted in a coating having
approximately 50 wt. % IgG, 25 wt. % PBMA, and 25 wt. % PEVA. The
total protein loading (specific and non-specific IgG) was
calculated to be about 656 .mu.g on average. The total active
protein loading was calculated to be about 66 .mu.g on average.
After coating, the coils were dried in a vacuum chamber at ambient
temperature for 24 hours.
[0092] Next, a layer of parylene C was vapor deposited onto two
sets of coils. Specifically, for a first set (N=2) 0.5 grams of
parylene C dimer (Specialty Coating Systems, Indianapolis, Ind.)
was loaded into a vapor deposition system PDS-2010 LABCOTER.RTM.
(Specialty Coating Systems, Indianapolis, Ind.). A coating cycle
was then initiated and a layer of parylene approximately 0.1 to 0.3
microns thick was deposited onto the first set of coils under
vacuum. For a second set (N=2), 1.0 gram of parylene C dimer was
loaded into the vapor deposition system. A coating cycle was then
initiated and a layer of parylene approximately 0.4 to 0.6 microns
thick was deposited onto the second set of coils under vacuum. For
a control set (N=3), no parylene was deposited.
[0093] The elution rate of the IgG antibodies from the three sets
of coils was then evaluated. Coils were placed in microcentrifuge
tubes in 500 .mu.L of a solution of 1.times.PBS. At predetermined
intervals for 63 days, 200 .mu.L of the eluent solution was
removed, divided into two 100 .mu.L aliquots, and placed into two
96 well plates. The remaining 300 .mu.L was removed from the
microcentrifuge tube, and 0.5 mL of fresh eluent solution
(1.times.PBS) was added to the microcentrifuge tube having the
coil. The eluent samples were also analyzed for total IgG release
(specific and non-specific) using the Bradford method assay (dye
obtained from Sigma Chemical Co., St. Louis, Mo.). The results are
shown in Table 1 below and in FIG. 6.
TABLE-US-00001 TABLE 1 Cumulative IgG Release (% of Total IgG) Days
Control 0.5 g parylene 1.0 g parylene 0 0.00% 0.00% 0.00% 0.29
16.95% 2.81% 0.63% 3.7 25.44% 18.54% 11.63% 4.78 26.92% 21.38%
14.59% 5.78 27.90% 23.11% 16.54%
[0094] This example shows that parylene can be used as a top layer
and can be made porous enough to allow for the elution of a
macromolecule such as a peptide or a protein. This example further
shows that the amount of parylene deposited can affect the elution
rate of the resulting coating.
Example 2
Effects of Vacuum Drying on Elution Rate
[0095] Poly-n-butylmethacrylate (PBMA) and polyethylene-co-vinyl
acetate (PEVA) were combined in a solvent of chloroform to form a
non-degradable polymer solution having 12.5 mg/ml PBMA and 12.5
mg/ml PEVA (total solids concentration of 25 mg/ml).
[0096] IgG rabbit anti-goat antibodies were obtained from
Sigma-Aldrich, St. Louis, Mo. The IgG rabbit anti-goat antibodies
were combined with non-specific IgG rabbit antibodies at a ration
of 10:1 non-specific to specific in PBS (phosphate buffered saline)
to form an IgG solution with a concentration of 20 mg/ml of
IgG.
[0097] MP-35N alloy coils (N=4) were segregated into two
experimental groups (Group 1 (N=2) and Group 2 (N=4)). The
non-degradable polymer solution and the IgG solution were
simultaneously deposited onto the coils. Specifically, the
non-degradable polymer solution was applied onto the exterior
surface of a first ultrasonic nozzle (60 KHz ultrasonic nozzle from
Sono-Tek, Milton, N.Y., operating at about 0.5 to 1.5 watts) at a
rate of 0.04 mL/minute. Simultaneously, the IgG solution was
applied onto the exterior surface of a second ultrasonic nozzle (60
KHz ultrasonic nozzle from Sono-Tek, Milton, N.Y., operating at
about 0.5 to 1.5 watts) at a rate of 0.02 mL/minute. Both
ultrasonic spray nozzles were directed at the coils. The coils were
passed back and forth under the spray nozzles and rotated a
plurality of times. This treatment resulted in a coating having
approximately 40 wt. % IgG, 30 wt. % PBMA, and 30 wt. % PEVA. The
total protein loading (specific and non-specific IgG) was
calculated to be about 710 .mu.g on average for the coils of Group
1 and about 685 .mu.g on average for the coils of Group 2.
[0098] After coating with the non-degradable polymer solution and
the IgG solution, the coils of Group 1 were dried in a vacuum
chamber at ambient temperature for about 12-16 hours. However, the
coils of Group 2 were not dried in a vacuum chamber. Rather, the
coils of Group 2 were dried for the same length of time under
ambient temperature and pressure conditions.
[0099] Next, a layer of parylene C was vapor deposited onto the
coils of Group 1 and Group 2. Specifically, 2.0 grams of parylene C
dimer (Specialty Coating Systems, Indianapolis, Ind.) was loaded
into a vapor deposition system PDS-2010 LABCOTER.RTM. (Specialty
Coating Systems, Indianapolis, Ind.). A coating cycle was then
initiated and a layer of parylene approximately 0.8 to 1.2 microns
thick was deposited onto the coils of both experimental groups.
Specifically, about 59.5 .mu.g of parylene was deposited onto the
coils of Group 1 and about 57 .mu.g of parylene was deposited onto
the coils of Group 2.
[0100] The elution rate of the IgG antibodies from the coils of
Group 1 and Group 2 was then evaluated as described above in
Example 1. The results are shown below in Table 2 and in FIG.
7.
TABLE-US-00002 TABLE 2 Cumulative IgG Release (% of Total IgG) Days
Vacuum Dried Not-Vacuum Dried 0 0.00% 0.00% 1 0.76% 0.79% 4 2.37%
3.00% 7 5.09% 6.27% 22 11.78% 13.77% 28 12.72% 16.14%
[0101] This example shows that treatment of a material before a
parylene layer is applied can affect the resulting elution rate of
an active agent. Specifically, this example shows that exposing an
underlying material to conditions, such as vacuum conditions, that
promote vaporization of certain components before a parylene layer
is applied can slow down the elution rate of an active agent from
the resulting coating.
[0102] It should be noted that, as used in this specification and
the appended claims, the singular forms "a," "an," and "the"
include plural referents unless the content clearly dictates
otherwise. Thus, for example, reference to a composition containing
"a compound" includes a mixture of two or more compounds. It should
also be noted that the term "or" is generally employed in its sense
including "and/or" unless the content clearly dictates
otherwise.
[0103] It should also be noted that, as used in this specification
and the appended claims, the phrase "configured" describes a
system, apparatus, or other structure that is constructed or
configured to perform a particular task or adopt a particular
configuration to. The phrase "configured" can be used
interchangeably with other similar phrases such as arranged and
configured, constructed and arranged, constructed, manufactured and
arranged, and the like.
[0104] All publications and patent applications in this
specification are indicative of the level of ordinary skill in the
art to which this invention pertains. All publications and patent
applications are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated by reference.
[0105] The invention has been described with reference to various
specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be
made while remaining within the spirit and scope of the
invention.
* * * * *