U.S. patent application number 14/259458 was filed with the patent office on 2015-01-29 for pdlla stent coating.
This patent application is currently assigned to Advanced Cardiovascular Systems, Inc.. The applicant listed for this patent is Advanced Cardiovascular Systems, Inc.. Invention is credited to Ni Ding, Wouter E. Roorda.
Application Number | 20150030654 14/259458 |
Document ID | / |
Family ID | 50781196 |
Filed Date | 2015-01-29 |
United States Patent
Application |
20150030654 |
Kind Code |
A1 |
Roorda; Wouter E. ; et
al. |
January 29, 2015 |
PDLLA Stent Coating
Abstract
An amorphous PDLLA stent coating for drug delivery is
disclosed.
Inventors: |
Roorda; Wouter E.; (Palo
Alto, CA) ; Ding; Ni; (San Jose, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Advanced Cardiovascular Systems, Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Advanced Cardiovascular Systems,
Inc.
Santa Clara
CA
|
Family ID: |
50781196 |
Appl. No.: |
14/259458 |
Filed: |
April 23, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11022228 |
Dec 23, 2004 |
8741378 |
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14259458 |
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09894293 |
Jun 27, 2001 |
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11022228 |
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Current U.S.
Class: |
424/423 ;
514/291 |
Current CPC
Class: |
A61L 2420/02 20130101;
A61F 2002/30062 20130101; A61L 31/16 20130101; A61L 2300/216
20130101; A61L 2300/606 20130101; A61K 31/439 20130101; A61F
2002/30064 20130101; A61L 31/08 20130101; A61L 31/10 20130101; A61K
31/436 20130101; A61F 2/82 20130101; A61L 2420/06 20130101; B05D
1/02 20130101 |
Class at
Publication: |
424/423 ;
514/291 |
International
Class: |
A61L 31/16 20060101
A61L031/16; A61K 31/436 20060101 A61K031/436; A61L 31/10 20060101
A61L031/10 |
Claims
1. A stent comprising a coating, the coating consisting of a
poly(D,L-lactic acid) (PDLLA) and a macrocyclic drug, wherein the
PDLLA has a degree of crystallinity of less than 20 percent, the
measurement being by weight of the amount of polymer that is in the
form of crystallites as measured by differential scanning
calorimetry, wherein the coating has a thickness of 0.05 microns to
10 microns, and wherein the stent on which the coating is disposed
is made from a bioabsorbable polymer.
2. The stent of claim 1, wherein the drug is rapamycin.
Description
CROSS-REFERENCE
[0001] This application is a continuation of application Ser. No.
11/022,228, filed on Dec. 23, 2004, which in turn is a
continuation-in-part of application Ser. No. 09/894,293, filed on
Jun. 27, 2001. The entire disclosures of both applications are
incorporated into this document by reference.
BACKGROUND
[0002] Blood vessel occlusions are commonly treated by mechanically
en-hancing blood flow in the affected vessels, such as by employing
a stent. Stents act as scaffoldings, functioning to physically hold
open and, if desired, to expand the wall of the passageway.
Typically stents are capable of being compressed, so that they can
be inserted through small lumens via catheters, and then expanded
to a larger diameter once they are at the desired location.
Examples in the patent literature disclosing stents include U.S.
Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued
to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor.
[0003] FIG. 1 illustrates a conventional stent 10 formed from a
plurality of struts 12. The plurality of struts 12 are radially
expandable and interconnected by connecting elements 14 that are
disposed between adjacent struts 12, leaving lateral openings or
gaps 16 between adjacent struts 12. Struts 12 and connecting
elements 14 define a tubular stent body having an outer,
tissue-contacting surface and an inner surface.
[0004] Stents are used not only for mechanical intervention but
also as vehi-cles for providing biological therapy. Biological
therapy can be achieved by medicating the stents. Medicated stents
provide for the local administration of a therapeutic substance at
the diseased site. Local delivery of a therapeutic substance is a
preferred method of treatment because the substance is concentrated
at a specific site and thus smaller total levels of medication can
be administered in comparison to systemic dos-ages that often
produce adverse or even toxic side effects for the patient.
[0005] One method of medicating a stent involves the use of a
polymeric car-rier coated onto the surface of the stent. A
composition including a solvent, a polymer dissolved in the
solvent, and a therapeutic substance dispersed in the blend is
applied to the stent by immersing the stent in the composition or
by spraying the composition onto the stent. The solvent is allowed
to evaporate, leaving on the stent strut surfaces a coating of the
polymer and the therapeutic substance impregnated in the
polymer.
[0006] A shortcoming of the above-described method of medicating a
stent is the potential for coating defects due to the large amount
of liquid composition applied to the relatively small surface area
of the stent. The liquid composition can flow, wick, and collect as
the amount of composition on the stent increases during the coating
process. As the solvent evaporates, the excess composition hardens,
leaving the excess coating as clumps or pools on the struts or
webbing between the struts.
[0007] Another shortcoming of the above-described method of
medicating a stent is the potential for loss of the therapeutic
substance from the coating or produc-tion of a coating that does
not provide for a suitable residence time of the substance at the
implanted region. Initial portions of a liquid composition
containing a therapeutic substance sprayed onto a stent adhere to
the stent surface. However, as the liquid composition continues to
be applied to the stent, layers of the composition are formed on
top of one another. When exposed to the solvent in the upper
layers, the therapeutic substance in the lower layers can be
re-dissolved into the upper layers of the composition or extracted
out from the coating. Having the therapeutic substance maintained
in merely the upper regions of the coating provides for a short
residence time of the substance at the implanted region, as the
therapeutic substance will be quickly released. Prolonged residence
times in situ may be desirable for a more effective treatment of a
patient.
[0008] The present invention addresses such problems by providing
methods of coating implantable devices.
SUMMARY
[0009] A stent is disclosed comprising a coating, the coating
consisting of a poly(D,L-lactic acid) (PDLLA) and a macrocyclic
drug, wherein the PDLLA has a degree of crystallinity of less than
20 percent, the measurement being by weight of the amount of
polymer that is in the form of crystallites as measured by
differential scanning calorimetry, wherein the coating has a
thickness of 0.05 microns to 10 microns, and wherein the stent on
which the coating is disposed is made from a bioabsorbably
polymer.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 illustrates a conventional stent.
DETAILED DESCRIPTION
[0011] This document incorporates by this reference the entire
disclosure of U.S. patent application Ser. No. 09/894,293, which
was filed on Jun. 27, 2001.
[0012] For ease of discussion, the methods detailed herein will be
described with reference to coating a stent. However, the device or
prosthesis coated in accordance with embodiments of the present
invention may be any suitable medical substrate that can be
implanted in a human or veterinary patient. Examples of such
implantable devices include self-expandable stents,
balloon-expandable stents, stent-grafts, grafts (e.g., aortic
grafts), artificial heart valves, cerebrospinal fluid shunts,
pacemaker electrodes, and endocardial leads (e.g., FINELINE and
ENDOTAK, available from Guidant Corporation). The underlying
structure of the device can be of virtually any de-sign. The device
can be made of a metallic material or an alloy such as, but not
limited to, cobalt chromium alloy (ELGILOY), stainless steel
(316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt
chrome alloy L-605, "MP35N," "MP20N," ELASTINITE (Nitinol),
tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,
magnesium, or combinations thereof. "MP35N" and "MP20N" are trade
names for alloys of cobalt, nickel, chromium and molybdenum
available from Standard Press Steel Co., Jenkintown, Pa. "MP35N"
consists of 35% cobalt, 35% nickel, 20% chromium, and 10%
molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20%
chromium, and 10% molybdenum. Devices made from bioabsorbable or
biosta-ble polymers could also be used with the embodiments of the
present invention. In some embodiments, the implantable device is
chosen to specifically exclude any one or any combination of
self-expandable stents, balloon-expandable stents, stent-grafts,
grafts (e.g., aortic grafts), artificial heart valves,
cerebrospinal fluid shunts, pacemaker electrodes, and endocardial
leads (e.g., FINELINE and ENDOTAK, available from Guidant
Corporation). In some embodiments, the implantable device is not a
catheter. In some embodiments in which the implantable device can
be chosen to be a catheter, the implantable device is chosen not to
be a catheter liner.
[0013] The methods of some embodiments of the current invention
comprise adjusting the temperature of an implantable portion of a
medical device to a target temperature, which is always
non-ambient, and then coating the implantable portion of the
medical device with a coating substance. In some embodiments,
adjusting occurs such that the increase or decrease in temperature
only occurs before applying the coating substance begins. In other
embodiments, adjusting occurs such that heating or cooling starts
before and continues during the applying step or the adjusting and
applying steps occur substantially together.
[0014] Different invention embodiments employ different "adjusting"
profiles. For instance, in some profiles, the implantable device is
adjusted to the target temperature before applying a coating
substance and then applying occurs (with or without some amount of
temperature decrease before crimping); alternatively, the
implantable device is adjusted to the target temperature before
applying a coating substance and maintained at or near the target
temperature during applying; alternatively, applying is started,
the implantable medical device is adjusted to the target
temperature, and applying is completed. In some embodiments,
applying begins before the implantable device has reached the
target temperature and continues until or after the target
temperature has been reached.
[0015] For purposes of this disclosure, ambient temperature is the
temperature of the implantable device when it has not been
purposely heated or cooled. In al-ternative embodiments, ambient
temperature is room temperature, 25-30.degree. C., 20-30.degree.
C., 20-25.degree. C., 23-27.degree. C. or 10-30.degree. C.
Similarly, for purposes of this disclosure, a target temperature is
a temperature numerically different from ambient temperature. In
some embodiments, the difference between the target temperature and
ambient is brought about by purposely heating or cooling the
implantable device.
[0016] A target temperature is chosen based on the characteristics
of the components of the coating substance. For instance, if the
solvent of the coating substance is non-volatile or has a low
volatility, the target temperature can be chosen to be above
ambient temperature to improve the evaporation rate. Conversely, if
the coating substance solvent is volatile, the target temperature
can be chosen to be below ambient temperature to lower the
evaporation rate. The identity of the solvent is not the only
characteristic upon which a target temperature can be based. For
instance, if the coating substance comprises a therapeutic
substance, the target temperature can be chosen to minimize thermal
degradation of the therapeutic substance. Alternatively, if a
polymer is used in the coating substance, the target temperature
can be chosen above Tg of the polymer to improve its flow
characteristics during deposition. In other embodiments, if the
solvent of the coating substance has a high boiling point, the
target temperature can be chosen to be above ambient temperature to
improve the evaporation rate. Conversely, if the coating substance
solvent has a low boiling point, the target temperature can be
chosen to be below ambient temperature to lower the evaporation
rate. Similarly, if the solvent is likely to freeze at ambient
temperature during the applying step, the target temperature can be
chosen to maintain it in a molten state to facilitate its removal.
Those of ordinary skill in the art will be able to identify other
characteristics of components of the coating substance that can be
improved by applying the substances to an implantable device that
is at a non-ambient target temperature.
[0017] In some embodiments, the target temperature is chosen to be
above ambient temperature if the solvent is non-volatile or has low
volatility. In some embodiments, non-volatile and having low
volatility take their standard meanings as rec-ognized by those of
ordinary skill in the art. In these or other embodiments,
non-volatile and having low volatility means that the solvent has a
volatility such that it does not substantially evaporate in a
scientifically or commercially reasonable time as that time would
be understood by one of ordinary skill in the art.
[0018] In some embodiments, non-volatile or having a low volatility
means that when a solution composed of at least the solvent is
applied to an implantable device the solvent does not substantially
evaporate within 30 sec, 60 sec, 2 min, 5 min, 10 min, 15 min, 30
min, or 60 min at ambient temperature and pressure. In some
embodiments, the target temperature is chosen to be below ambient
temperature if the solvent is volatile. In some embodiments,
volatile takes its standard meanings as rec-ognized by those of
ordinary skill in the art. In these or other embodiments, volatile
means the solvent substantially evaporates fast enough to
compromise the coating in a scientifically or commercially
unreasonable manner as that would be understood by one of ordinary
skill in the art. In some embodiments, volatile means that when a
solution composed of at least the solvent is applied to an
implantable device the solvent substantially evaporates within
<30 sec, <20 sec, <15 sec, <10 sec, <8 sec, <5
sec, <4 sec, <3 sec, <2 sec, or <1 sec at ambient
temperature and pressure. In some embodiments, the target
temperature is chosen to be below the decomposition region for a
therapeutic substance.
[0019] In some embodiments that use coating substances to form
primer layers, the target temperature can be chosen higher than
ambient. In some embodiments that use coating substances to form
topcoat layers, the target temperature can be chosen close to
ambient or lower than ambient temperature.
[0020] In some embodiments, adjusting the temperature of the
implantable device comprises adjusting the temperature to a target
temperature and then letting the temperature fluctuate
thereafter.
[0021] In some embodiments, adjusting the temperature of the
implantable medical device to a target temperature means adjusting
the temperature to within .+-.1.degree. C., .+-.2.degree. C.,
.+-.3.degree. C., .+-.4.degree. C., .+-.5.degree. C., .+-.6.degree.
C., .+-.7.degree. C., .+-.8.degree. C., .+-.9.degree. C.,
.+-.10.degree. C., .+-.12.degree. C., .+-.15.degree. C., or
.+-.20.degree. C. of the target temperature before, during, or
after the applying step begins.
[0022] "Adjusting" the temperature of the medical device comprises
placing the object that is to have its temperature adjusted into
thermal contact with a heat source. For purposes of this
disclosure, thermal contact with a heat source means heat source
arrangement vis-a-vis the object so that energy would flow or be
carried from the heat source to the object. Thermal contact is a
generic term at least encompassing an arrangement of the object
such that radiation, conduction, or convection from the heat source
would transfer energy. In some embodiments, thermal contact is
defined to exclude any of radiation, conduction, convection, or any
combination of these. Furthermore no invention embodiments use a
convection oven or an ultrasound energy source.
[0023] In some embodiments, "maintained near the target
temperature" means that the temperature of the implantable device,
when it contacts the coating substance, is the same as the target
temperature or within .+-.1.degree. C., .+-.2.degree. C.,
.+-.3.degree. C., .+-.4.degree. C., .+-.5.degree. C., .+-.6.degree.
C., .+-.7.degree. C., .+-.8.degree. C., .+-.9.degree. C.,
.+-.10.degree. C., .+-.12.degree. C., .+-.15.degree. C., or
.+-.20.degree. C. of the target temperature.
[0024] In some embodiments, "maintained at the target temperature
during the applying step" means keeping the temperature of the
implantable device the same as the target temperature or within
.+-.1.degree. C., .+-.2.degree. C., .+-.3.degree. C., .+-.4.degree.
C., .+-.5.degree. C., .+-.6.degree. C., .+-.7.degree. C.,
.+-.8.degree. C., .+-.9.degree. C., .+-.10.degree. C.,
.+-.12.degree. C., .+-.15.degree. C., or .+-.20.degree. C. of the
target temperature.
[0025] The applying step forms a coating on an implantable medical
device such as a stent; it is accomplished in some embodiments by
spraying a composition onto the stent. A spray apparatus, such as
EFD 780S spray device with VALVEMATE 7040 control system
(manufactured by EFD Inc., East Providence, R.I.), can be used to
apply the composition to the stent. EFD 780S spray device is an
air-assisted external mixing atomizer. The composition is atomized
into small droplets by air and uniformly applied to the stent
surfaces. The atomization pressure can be maintained at a range of
about 5 psi to about 20 psi. The droplet size depends on factors
such as vis-cosity of the solution, surface tension of the solvent,
and atomization pressure. Other types of spray applicators,
including air-assisted internal mixing atomizers and ultrasonic
applicators, can also be used for the application of the
composition.
[0026] During the application of the composition, the stent can be
rotated about the stent's central longitudinal axis. Rotation of
the stent can be from about 0.1 rpm to about 300 rpm, more narrowly
from about 1 rpm to about 10 rpm. By way of example, the stent can
rotate at about 3 rpm. The stent can also be moved in a linear
direction along the same axis. The stent can be moved at about 1
mm/second to about 12 mm/second, for example about 6 mm/second, or
for a minimum of at least two passes (i.e., back and forth past the
spray nozzle).
[0027] The flow rate of the composition from the spray nozzle can
be from about 0.01 mg/second to about 1.0 mg/second, more narrowly
about 0.1 mg/second. Only a small percentage of the composition
that is delivered from the spray nozzle is ultimately deposited on
the stent. By way of example, when a composition is sprayed to
deliver about 1 mg of solids, only about 100 micrograms or about
10% of the solids sprayed will likely be deposited on the stent.
Multiple repetitions for applying the composition can be performed,
wherein each repetition can be, for example, about 0.5 second to
about 5 seconds in duration. In these or other embodiments, the
steps can be repeated 2-100, 2-50, 30-100, 20-50, 50-100, or
greater than 100 times. The amount of coating applied by each
repetition can be about 1 microgram/cm.sup.2 (of stent surface) to
about 50 micrograms/cm.sup.2, for example less than about 20
micrograms/cm.sup.2 per 1-second spray.
[0028] Each repetition can be followed by removal of a significant
amount of the solvent(s). The removal of the solvent(s) can be
performed following a waiting period of about 0.1 second to about 5
seconds after the application of the coating composition so as to
allow the liquid sufficient time to flow and spread over the stent
surface before the solvent(s) is removed to form a coating. The
waiting period is particularly suitable if the coating composition
contains a volatile solvent, such as solvents having boiling points
>130.degree. C. at ambient pressure, since such solvents are
typically removed quickly.
[0029] The applying step excludes immersing the
temperature-adjusted implantable device into the coating
substance.
[0030] Removal of the solvent(s) can be induced by the application
of a warm gas. The application of a warm gas between each
repetition prevents coating defects and minimizes interaction
between the active agent and the solvent. Any suitable gas can be
employed, examples of which include air or nitrogen. The
temperature of the warm gas can be from about 25.degree. C. to
about 200.degree. C., more narrowly from about 40.degree. C. to
about 90.degree. C. The flow speed of the gas can be from about 0.5
feet.sup.3/second (0.01 meters.sup.3/second) to about 50
feet.sup.3/second (1.42 meters.sup.3/second), more narrowly about
2.5 feet.sup.3/second (0.07 meters.sup.3/second) to about 15
feet.sup.3/second (0.43 meters.sup.3/second). The gas can be
applied for about 1 second to about 100 seconds, more narrowly for
about 2 seconds to about 20 seconds. By way of example, warm gas
applications can be performed at a temperature of about 60.degree.
C., at a flow speed of about 10 feet.sup.3/second, and for about 10
seconds.
[0031] In one embodiment, the stent can be warmed to a temperature
of from about 35.degree. C. to about 80.degree. C. prior to the
application of the coating composition so as to facilitate faster
removal of the solvent(s). The particular temperature selected
depends, at least in part, on the particular active agent employed
in the coating composition. By way of example, pre-heating of the
stent prior to applying a composition containing actinomycin D
should be performed at a temperature not greater than about
55.degree. C. Pre-heating is particularly suitable for embodiments
in which the solvent(s) employed in the coating composition has a
high boiling point, i.e., volatile solvents having boiling points
of, for example, >130.degree. C. at ambient pressure (e.g.,
dimethylsulfoxide (DMSO), dimethylformamide (DMF), and
dimethylacetamide (DMAC)).
[0032] Any suitable number of repetitions of applying the
composition followed by removing the solvent(s) can be performed to
form a coating of a desired thickness or weight. Excessive
application of the polymer can, however, cause coating defects. In
embodiments in which the coating composition contains a volatile
solvent, a waiting period of from about 0.1 second to about 20
seconds can be employed between solvent removal of one repetition
and composition application of the subsequent repetition so as to
ensure that the wetting rate of the coating composition is slower
than the evaporation rate of the solvent within the composition,
thereby pro-moting coating uniformity.
[0033] Operations such as wiping, centrifugation, or other web
clearing acts can also be performed to achieve a more uniform
coating. Briefly, wiping refers to the physical removal of excess
coating from the surface of the stent; and centrifugation refers to
rapid rotation of the stent about an axis of rotation. The excess
coating can also be vacuumed off of the surface of the stent.
[0034] In accordance with one embodiment, the stent can be at least
partially pre-expanded prior to the application of the composition.
For example, the stent can be radially expanded about 20% to about
60%, more narrowly about 27% to about 55%--the measurement being
taken from the stent's inner diameter at an expanded position as
compared to the inner diameter at the unexpanded position. The
expansion of the stent, for increasing the interspace between the
stent struts during the application of the composition, can further
prevent "cob web" formation between the stent struts.
[0035] A final heat treatment can be conducted to remove
essentially all of the solvent(s) from the composition on the
stent. The heat treatment can be conducted at about 30.degree. C.
to about 200.degree. C. for about 15 minutes to about 16 hours,
more narrowly at about 50.degree. C. to about 100.degree. C. for
about 1 hour to about 4 hours. By way of example, the heat
treatment can be conducted at about 75.degree. C. for 1 hour. The
temperature of ex-posure should not adversely affect the
characteristics of the active agent or of the coating. The heating
can be conducted in an anhydrous atmosphere and at ambient
pressure. The heating can, alternatively, be conducted under a
vacuum condition. It is understood that essentially all of the
solvent(s) will be removed from the composition but traces or
residues can remain blended in the coating.
[0036] By way of example, and not limitation, the coating, referred
to herein as the primary or reservoir coating, can have a thickness
of about 0.05 microns to about 10 microns. The particular thickness
of the coating is based on the type of procedure for which the
stent is employed and the amount, if any, of active agent that is
desired to be delivered. Applying a plurality of reservoir coating
layers, containing the same or different active agents, onto the
stent can further increase the amount of the active ingredient to
be carried by the stent, without causing coating defects.
[0037] In accordance with one embodiment, the coating substance can
include a solvent and a polymer dissolved in the solvent. The
coating substance can also include active agents, radiopaque
elements, or radioactive isotopes. Representative examples of
polymers that can be used to coat a stent include ethylene vinyl
alcohol copolymer (commonly known by the generic name EVOH or by
the trade name EVAL), poly(hydroxyvalerate); poly(L-lactic acid);
polycaprolactone; poly(lactide-co-glycolide);
poly(hydroxybutyrate); poly(hydroxybutyrate-co-valerate);
polydioxanone; polyorthoester; polyanhydride; poly(glycolic acid);
poly(D,L-lactic acid); poly(glycolic acid-co-trimethylene
carbonate); polyphosphoester; polyphosphoester urethane; poly(amino
acids); cyanoacrylates; poly(trimethylene carbonate);
poly(iminocarbonate); copoly(ether-esters) (e.g. PEO/PLA);
polyalkylene oxalates; polyphosphazenes; biomolecules, such as
fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic
acid; polyurethanes; silicones; polyesters; polyolefins;
polyisobutylene and ethylene-alphaolefin copolymers; acrylic
polymers and copolymers; vinyl halide polymers and copolymers, such
as polyvinyl chloride; polyvinyl ethers, such as poly-vinyl methyl
ether; polyvinylidene halides, such as polyvinylidene fluoride and
polyvinylidene chloride; polyacrylonitrile; polyvinyl ketones;
polyvinyl aromatics, such as polystyrene; polyvinyl esters, such as
polyvinyl acetate; copolymers of vinyl mono-mers with each other
and olefins, such as ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl
acetate copolymers; polyamides, such as Nylon 66 and
polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes;
polyimides; polyethers; epoxy resins; polyurethanes; rayon;
ray-on-triacetate; cellulose; cellulose acetate; cellulose
butyrate; cellulose acetate butyrate; cellophane; cellulose
nitrate; cellulose propionate; cellulose ethers; and carboxymethyl
cellulose.
[0038] In some embodiments, the polymer or the processing
conditions of the method are selected such that the polymer is
non-crystalline. A crystalline polymer is one in which upon
analysis a detectable pattern may be observed when using
conventional x-ray scattering techniques. Such conventional
techniques are disclosed, for example, in "The Structure of
Crystalline Polymers", Tadokoro, H. (Wiley Inter-science, 1979).
The degree of crystallinity of a polymer is the measurement by
weight of the amount of polymer that is in the form of
crystallites, as measured by differential scanning calorimetry. For
purposes of this disclosure, a polymer that is non-crystalline has
a degree of crystallinity of less than about 20 percent.
[0039] "Solvent" is defined as a liquid substance or composition
that is compatible with the polymer and is capable of dissolving
the polymer at the concentration desired in the composition.
Examples of solvents include, but are not limited to,
dimethylsulfoxide (DMSO), chloroform, acetone, water (buffered
saline), xylene, methanol, ethanol, 1-propanol, tetrahydrofuran,
1-butanone, dimethylformamide, dimethylacetamide, cyclohexanone,
ethyl acetate, methylethylketone, propylene glycol monomethylether,
isopropanol, isopropanol admixed with water,
N-methylpyrroli-dinone, toluene, and combinations thereof.
[0040] The therapeutic agent can inhibit vascular, smooth muscle
cell activi-ty. More specifically, the therapeutic agent can aim at
inhibiting abnormal or inappro-priate migration or proliferation of
smooth muscle cells to prevent, inhibit, reduce, or treat
restenosis. The therapeutic agent can also include any substance
capable of ex-erting a therapeutic or prophylactic effect in the
practice of the present invention. Useful therapeutic agents can
include therapeutic agents selected form antibiotics;
anticoagulants; antifibrins; antiinflammatories; antimitotics;
antineoplastics; antioxi-dants; antiplatelets; antiproliferatives;
antithrombins; and their combinations. Other useful therapeutic
agents include actinomycin D or derivatives and analogs thereof
(manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue,
Milwaukee, Wis. 53233; or COSMEGEN available from Merck);
dactinomycin; actinomycin IV; actinomycin I.sub.1; actinomycin
X.sub.1; actinomycin C.sub.1; paclitaxel; docetaxel; aspirin;
sodium heparin; low molecular weight heparin; hirudin; argatroban;
forskolin; vapiprost; prostacyclin; prostacyclin analogs; dextran;
D-phe-pro-arg-chloromethylketone (synthetic antithrombin);
dipyridamole; glycoprotein IIb/IIIa platelet membrane receptor
antagonist; recombinant hirudin; thrombin inhibitor (available from
Biogen); 7E-3B.RTM. (an antiplatelet drug from Centocor);
methotrexate; azathioprine; vincristine; vinblastine; fluorouracil;
adriamycin; mutamycin; angiopeptin (a somatostatin analog from
Ibsen); angiotensin converting enzyme inhibitors; CAPTOPRIL
(available from Squibb); CI-LAZAPRIL (available from
Hoffman-LaRoche); LISINOPRIL (available from Merck & Co.,
Whitehouse Station, N.J.); calcium channel blockers; Nifedipine;
colchicinefib-roblast growth factor (FGF) antagonists; histamine
antagonist; LOVASTATIN (an inhibitor of HMG-CoA reductase, a
cholesterol lowering drug from Merck & Co.); mon-oclonal
antibodies (such as PDGF receptors); nitroprusside;
phosphodiesterase inhibitors; prostaglandin inhibitor (available
from Glazo); Seramin (a PDGF antagonist); serotonin blockers;
thioprotease inhibitors; triazolopyrimidine (a PDGF antagonist);
nitric oxide; alpha-interferon; genetically engineered epithelial
cells; dexamethasone; estradiol; clobetasol propionate; cisplatin;
insulin sensitizers; receptor tyrosine kinase inhibitors;
carboplatin; Rapamycin; 40-O-(2-hydroxy)ethyl-rapamycin, or a
functional analog or structural derivative thereof;
40-O-(3-hydroxy)propyl-rapamycin;
40-O-2-(2-hydroxy)ethoxyethyl-rapamycin and their combinations.
[0041] Individual embodiments exist in which the therapeutic agent
is selected to specifically exclude any one of or any combination
of the therapeutic agents or therapeutic agent families described
above.
[0042] Some invention embodiments comprise a therapeutic agent or
therapeutic agent combination, and some require a therapeutic agent
or combination of therapeutic agents. Of the therapeutic agents
specifically listed above, some invention embodiments exclude a
single or any combination of these therapeutic agents.
[0043] Examples of radiopaque elements include, but are not limited
to, gold, tantalum, and platinum. An example of a radioactive
isotope is P.sup.32. Sufficient amounts of such substances may be
dispersed in the composition such that the substances are not
present in the composition as agglomerates or flocs.
[0044] The methods for coating an implantable device, such as a
stent, according to embodiments of the present invention, can be
used to create a multi-layer structure that can include any one or
any combination of the following four layers:
[0045] (a) a primer layer;
[0046] (b) a drug-polymer layer (also referred to as "reservoir" or
"reservoir layer") or a polymer-free drug layer; and
[0047] (c) a topcoat layer, which is likewise drug containing or
drug free.
[0048] (d) a finishing layer, for biocompatibility possessing
biobeneficial properties.
[0049] In some embodiment, an optional primer layer can be formed
prior to the primary or reservoir coating to increase the retention
of the primary or reservoir coating on the surface of the stent,
particularly metallic surfaces such as stainless steel. The primer
layer can act as an intermediary adhesive tie layer between the
surface of the device and a reservoir coating carrying an active
agent, allowing for the quantity of the active agent to be
increased in the reservoir coating.
[0050] To form an optional primer layer on the surface of the
stent, an embodiment of the above-described composition that is
free from active agents is applied to the surface of the stent.
Ethylene vinyl alcohol copolymer, for example, adheres very well to
metallic surfaces, particularly stainless steel. Accordingly, the
copolymer provides for a strong adhesive tie between the reservoir
coating and the surface of the stent. With the use of thermoplastic
polymers such as, but not limited to, ethylene vinyl alcohol
copolymer, polycaprolactone, poly(lactide-co-glycolide), and
poly(hydroxybutyrate), the deposited primer composition should be
exposed to a heat treatment at a temperature range greater than
about the glass transition temperature (T.sub.g) and less than
about the melting temperature (T.sub.m) of the selected polymer.
Unex-pected results have been discovered with treatment of the
composition under this temperature range, specifically strong
adhesion or bonding of the coating to the metallic surface of the
stent. The prosthesis should be exposed to the heat treatment for
any suitable duration of time that will allow for the formation of
the primer layer on the surface of the stent and for the
evaporation of the solvent employed. By way of example and not
limitation, the optional primer layer can have a thickness of about
0.01 microns to about 2 microns. The application of the primary or
reservoir coating should be performed subsequent to the drying of
the optional primer layer.
[0051] In another embodiment, an optional diffusion barrier can be
formed over a reservoir coating containing an active agent to help
control the rate at which the active agent is released from the
coated stent. An embodiment of the composition, free from any
active agents, can be applied to a selected portion of the primary
or reservoir coating subsequent to the drying of the reservoir
coating. Application of the composition and evaporation of the
solvent to form the diffusion barrier can be accomplished via
embodiments of the above-described method of the present invention.
The diffusion barrier can have a thickness of about 0.2 microns to
about 10 microns. It is understood by one of ordinary skill in the
art that the thickness of the diffusion barrier is based on factors
such as the type of stent, the type of procedure for which the
stent is employed, and the rate of release that is desired. As
described above with reference to the primary or reservoir coating,
a final heat treatment can be conducted to remove essentially all
of the solvent(s) from the optional diffusion barrier.
[0052] Either of the four layers or any combination of them can be
formed using invention methods.
EXAMPLES
[0053] The embodiments of the present invention will be illustrated
by the following set forth examples, which are being given by way
of illustration only and not by way of limitation. All parameters
and data are not to be construed to unduly limit the scope of the
embodiments of the invention.
Example 1
[0054] Four 8 mm Multi-Link TETRA stents (available from Guidant
Corporation) were coated using embodiments of the method of the
present invention. The stents were cleaned by sonication in water,
followed by sonication in isopropanol. The stents were dried at
70.degree. C. and plasma cleaned in an argon plasma chamber.
[0055] Each unexpanded stent was positioned on a mandrel such that
the mandrel contacted the stent at its opposing ends. An EFD 780S
spray device with VALVEMATE 7040 control system (manufactured by
EFD Inc., East Providence, R.I.) was used to apply the coating
compositions to the stents. The spray nozzle was adjusted to
provide a distance from the nozzle tip to the outer surface of the
stent of approximately 4.5 cm and a spray angle of approximately
90.degree. relative to the horizontal stents. The atomization
pressure was set to be maintained throughout the coating process at
20 psi.
[0056] Each stent was passed under the spray nozzle for about 2
seconds. A composition containing 2% (w/w) poly-n-butyl
methacrylate (PBMA) 337K in cyclo-hexanone:ethyl acetate (1:1) was
sprayed onto one stent. A composition containing 2% (w/w) PBMA 649K
in cyclohexanone:ethyl acetate (1:1) was sprayed onto two stents. A
composition containing 2% (w/w) PBMA 857K in cyclohexanone:ethyl
acetate (1:1) was sprayed onto one stent. Each stent was rotated
about the stent's central longitudinal axis at a speed of 3 rpm
during coating. After a waiting period of 1 second following the
application of the respective compositions, warm air of
approximately 80.degree. C. was directed from an air gun onto each
stent for 15 seconds to remove most of the solvents. The
spraying-blowing cycle was repeated to deposit thirty-four layers
on each stent, with a wait time of 5 seconds between each cycle.
The coated stent was allowed to dry for about 60 minutes under
vacuum conditions in an oven at a temperature of about 70.degree.
C. Each of the four coated stents had a uniform, smooth coating. In
addition, the stent sprayed with 2% (w/w) PBMA 857K in
cyclohexa-none:ethyl acetate (1:1) was submitted for a simulated
use test and was found to have good mechanical properties, no
cracking, and good coating adhesion.
Example 2
[0057] An 8 mm Multi-Link TETRA stent was coated using embodiments
of the method of the present invention. The stent was cleaned by
placement in an ultrasonic bath of isopropyl alcohol solution for
15 minutes. The stent was dried and plasma cleaned in a plasma
chamber.
[0058] A composition containing 2% (w/w) poly-n-butyl methacrylate
(PBMA) and 2% (w/w) quinoline yellow dye in
chloroform:cyclohexanone (9:1) was prepared.
[0059] The unexpanded stent was positioned on a mandrel such that
the mandrel contacted the stent at its opposing ends. An EFD 780S
spray device with VALVEMATE 7040 control system was used to apply
the coating composition to the stent. The spray nozzle was adjusted
to provide a distance from the nozzle tip to the outer surface of
the stent of 1.25 inches (3.18 cm) and a spray angle of
approximately 90.degree. relative to the horizontal stent. The
atomization pressure was set to be maintained throughout the
coating process at 15 psi.
[0060] The stent was passed under the spray nozzle for about 1
second. The stent was rotated about the stent's central
longitudinal axis at a speed of 3 rpm during coating. Warm air of
approximately 100.degree. C. was directed from an air gun onto the
stent for 4 seconds to remove most of the solvents. The
spraying-heating cycle was repeated to deposit forty layers on the
stent, depositing about 300 micrograms of coating. The coated stent
was allowed to dry for about 3 hours under vacuum conditions at a
temperature of about 75.degree. C. The coated stent had a uniform,
smooth coating with an estimated dye content of about 130
micrograms or 43% of the total amount of coating deposited.
Example 3
[0061] An 8 mm Multi-Link TETRA stent was coated using embodiments
of the method of the present invention. The stent was cleaned by
placement in an ultrasonic bath of isopropyl alcohol solution for
15 minutes. The stent was dried and plasma cleaned in a plasma
chamber.
[0062] A primer composition containing 2% (w/w) poly-n-butyl
methacrylate (PBMA) was prepared. A reservoir composition
containing 2% (w/w) PBMA and 2.7% (w/w) ethyl eosin dye in
methanol:cyclohexanone (1:1) was also prepared. In addition, a
diffusion barrier composition containing 2% (w/w) PBMA was
prepared.
[0063] The unexpanded stent was positioned on a mandrel such that
the mandrel contacted the stent at its opposing ends. An EFD 780S
spray device with VALVEMATE 7040 control system was used to apply
the various compositions to the stent. The spray nozzle was
adjusted to provide a distance from the nozzle tip to the outer
surface of the stent of 1.25 inches (3.18 cm) and a spray angle of
approximately 90.degree. relative to the horizontal stent. The
atomization pressure was set to be maintained throughout the
coating process at 15 psi. The stent was rotated about the stent's
central longitudinal axis at a speed of 3 rpm during coating.
[0064] The primer composition was applied to the stent by passing
the stent under the spray nozzle for about 0.75 second. Warm air of
approximately 100.degree. C. was directed from an air gun onto the
stent for 8 seconds to remove most of the solvents and form a
primer layer on the stent. The reservoir composition was then
applied to the primered stent by passing the stent under the spray
nozzle for about 0.75 second. Warm air of approximately 100.degree.
C. was directed from an air gun onto the stent for 4 seconds to
remove most of the solvents. The spraying-heating cycle was
repeated to deposit forty layers on the stent, depositing about 419
micrograms of the reservoir coating. The coated stent was allowed
to dry for about 3 hours under vacuum conditions at a temperature
of about 75.degree. C. The barrier layer composition was then
applied to the reservoir-coated stent by passing the stent under
the spray nozzle for about 0.75 second. Warm air of approximately
100.degree. C. was directed from an air gun onto the stent for 4
seconds to remove most of the solvents. The spraying-heating cycle
was repeated to deposit about 70 micrograms of the diffusion
barrier. The coated stent was allowed to dry overnight under vacuum
conditions at a temperature of about 75.degree. C. The coated stent
had a uniform, smooth coating with an estimated dye content of
about 224 micrograms or 53% of the total amount of coating
deposited.
Example 4
[0065] An 8 mm Multi-Link TETRA stent was coated using embodiments
of the method of the present invention. The stent was cleaned by
placement in an ultrasonic bath of isopropyl alcohol solution for
15 minutes. The stent was dried and plasma cleaned in a plasma
chamber.
[0066] A composition containing 2% (w/w) poly-n-butyl methacrylate
(PBMA) and 2% (w/w) quinoline yellow dye in
chloroform:cyclohexanone (9:1) was prepared.
[0067] The unexpanded stent was positioned on a mandrel such that
the mandrel contacted the stent at its opposing ends. An EFD 780S
spray device with VALVEMATE 7040 control system was used to apply
the composition to the stent. The spray nozzle was adjusted to
provide a distance from the nozzle tip to the outer surface of the
stent of 1.25 inches (3.18 cm) and a spray angle of approximately
90.degree. relative to the horizontal stent. The atomization
pressure was set to be maintained throughout the coating process at
15 psi.
[0068] The stent was passed under the spray nozzle for about 1.5
second. The stent was rotated about the stent's central
longitudinal axis at a speed of 3 rpm during coating. Warm air of
approximately 100.degree. C. was directed from an air gun onto the
stent for 4 seconds to remove most of the solvents. The
spraying-heating cycle was repeated to deposit 3 layers on the
stent, depositing about 115 micrograms of coating. The coated stent
was allowed to dry for about 3 hours under vacuum conditions at a
temperature of about 75.degree. C. The coated stent had a uniform,
smooth coating with an estimated dye content of about 38 micrograms
or 33% of the total amount of coating deposited.
Example 5
[0069] To determine the maximum amount of coating that could be
deposited on an 8 mm stent without visible webbing, a Multi-Link
TETRA stent was coated using the same coating composition and
parameters as described in Example 4. The spraying-heating cycle
was repeated until 790 micrograms of coating had been deposited on
the stent, at which time no webbing was observed.
Example 6
[0070] An 8 mm Multi-Link TETRA stent was coated using embodiments
of the method of the present invention. The stent was cleaned by
placement in an ultrasonic bath of isopropyl alcohol solution for
15 minutes. The stent was dried and plasma cleaned in a plasma
chamber.
[0071] A composition containing 2% (w/w) poly-n-butyl methacrylate
(PBMA) and 2% (w/w) solvent blue dye in chloroform:cyclohexanone
(9:1) was prepared.
[0072] The unexpanded stent was positioned on a mandrel such that
the mandrel contacted the stent at its opposing ends. An EFD 780S
spray device with VALVEMATE 7040 control system was used to apply
the composition to the stent. The spray nozzle was adjusted to
provide a distance from the nozzle tip to the outer surface of the
stent of 1.25 inches (3.18 cm) and a spray angle of approximately
90.degree. relative to the horizontal stent. The atomization
pressure was set to be maintained throughout the coating process at
15 psi.
[0073] The stent was passed under the spray nozzle for about 1.5
seconds. The stent was rotated about the stent's central
longitudinal axis at a speed of 3 rpm during coating. Warm air of
approximately 100.degree. C. was directed from an air gun onto the
stent for 4 seconds to remove most of the solvents. The
spraying-heating cycle was repeated to deposit about 130 micrograms
of coating. The coated stent was allowed to dry for about 3 hours
under vacuum conditions at a temperature of about 75.degree. C. The
coated stent had a uniform, smooth coating with a estimated dye
content of about 85 micrograms or 66% of the total amount of
coating deposited.
[0074] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from the embodiments of this invention in its broader
aspects and, therefore, the appended claims are to encompass within
their scope all such changes and modifications as fall within the
true spirit and scope of the embodiments of this invention.
Additionally, various embodiments have been described above. For
convenience's sake, combinations of aspects (such as monomer type
or gas flow rate) composing invention embodiments have been listed
in such a way that one of ordinary skill in the art may read them
exclusive of each other when they are not necessarily intended to
be exclusive. But a recitation of an aspect for one embodiment is
meant to disclose its use in all embodiments in which that aspect
can be incorporated without undue experimentation. In like manner,
a recitation of an aspect as composing part of an embodiment is a
tacit recognition that a supplementary embodiment exists that
specifically excludes that aspect.
[0075] Moreover, some embodiments recite ranges. When this is done,
it is meant to disclose the ranges as a range, and to disclose each
and every point within the range, including end points. For those
embodiments that disclose a specific value or condition for an
aspect, supplementary embodiments exist that are otherwise
identical, but that specifically exclude the value or the
conditions for the aspect.
* * * * *