U.S. patent application number 11/527826 was filed with the patent office on 2007-02-01 for 40-o-(2-hydroxy)ethyl-rapamycin coated stent.
This patent application is currently assigned to Advanced Cardiovascular Systems, Inc.. Invention is credited to Paul M. Consigny, Dorie M. Happ, Syed F.A. Hossainy, Ty Hu, Jeff Royal, Kurt Scheinpflug, Gordon Stewart, Mark A. Williams.
Application Number | 20070026131 11/527826 |
Document ID | / |
Family ID | 28673588 |
Filed Date | 2007-02-01 |
United States Patent
Application |
20070026131 |
Kind Code |
A1 |
Hossainy; Syed F.A. ; et
al. |
February 1, 2007 |
40-O-(2-hydroxy)ethyl-rapamycin coated stent
Abstract
A method and coating for reducing the release rate of an active
agent from an implantable device, such as a stent, is
disclosed.
Inventors: |
Hossainy; Syed F.A.;
(Fremont, CA) ; Stewart; Gordon; (San Francisco,
CA) ; Williams; Mark A.; (Redwood City, CA) ;
Royal; Jeff; (San Francisco, CA) ; Consigny; Paul
M.; (San Jose, CA) ; Happ; Dorie M.; (San
Jose, CA) ; Scheinpflug; Kurt; (Sunnyvale, CA)
; Hu; Ty; (Mountain View, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA
SUITE 300
SAN FRANCISCO
CA
94111
US
|
Assignee: |
Advanced Cardiovascular Systems,
Inc.
|
Family ID: |
28673588 |
Appl. No.: |
11/527826 |
Filed: |
September 26, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10108004 |
Mar 27, 2002 |
|
|
|
11527826 |
Sep 26, 2006 |
|
|
|
Current U.S.
Class: |
427/2.21 ;
623/1.42 |
Current CPC
Class: |
A61L 27/54 20130101;
A61F 2250/0067 20130101; A61L 2300/606 20130101; A61L 2300/416
20130101; A61F 2/844 20130101; A61L 31/16 20130101; A61L 2300/602
20130101 |
Class at
Publication: |
427/002.21 ;
623/001.42 |
International
Class: |
B05D 5/00 20070101
B05D005/00; A61F 2/82 20070101 A61F002/82 |
Claims
1. A method of preparing a coated stent containing
40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof,
comprising sterilizing the stent while maintaining the peak purity
of the 40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative
thereof, at a level greater than 90%.
2. The method of claim 1, wherein the coating protects the purity
from dropping to a level below 90%.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional application of U.S.
patent Ser. No. 10/108,004, filed on Mar. 27, 2002, the teachings
of which are incorporated herein in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to drug eluting implantable devices,
one example of which is a stent. More particularly, the invention
relates to sustained delivery of 40-O-(2-hydroxy)ethyl-rapamycin
from a stent.
[0004] 2. Description of the Background
[0005] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. A catheter assembly having a
balloon portion is introduced percutaneously into the
cardiovascular system of a patient via the brachial or femoral
artery. The catheter assembly is advanced through the coronary
vasculature until the balloon portion is positioned across the
occlusive lesion. Once in position across the lesion, the balloon
is inflated to a predetermined size to remodel the vessel wall. The
balloon is then deflated to a smaller profile to allow the catheter
to be withdrawn from the patient's vasculature.
[0006] A problem associated with the above procedure includes
formation of intimal flaps or torn arterial linings, which can
collapse and occlude the conduit after the balloon is deflated.
Vasospasms and recoil of the vessel wall also threaten vessel
closure. Moreover, thrombosis and restenosis of the artery may
develop over several months after the procedure, which may
necessitate another angioplasty procedure or a surgical by-pass
operation. To reduce the partial or total occlusion of the artery
by the collapse of arterial lining and to reduce the chance of the
development of thrombosis and restenosis, an expandable,
intraluminal prosthesis, also known as a stent, is implanted in the
lumen to maintain the vascular patency.
[0007] 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. Mechanical
intervention via stents has reduced the rate of restenosis as
compared to balloon angioplasty. Yet, restenosis is still a
significant clinical problem with rates ranging from 20-40%. When
restenosis does occur in the stented segment, its treatment can be
challenging, as clinical options are more limited as compared to
lesions that were treated solely with a balloon.
[0008] Stents are used not only for mechanical intervention but
also as vehicles 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. In order to provide an efficacious concentration
to the treated site, systemic administration of such medication
often produces adverse or even toxic side effects for the patient.
Local delivery is a preferred method of treatment in that smaller
total levels of medication are administered in comparison to
systemic dosages, but are concentrated at a specific site. Local
delivery thus produces fewer side effects and achieves more
favorable results.
[0009] One proposed method of medicating stents involves the use of
a polymeric carrier 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.
[0010] A potential shortcoming of the foregoing method of
medicating stents is that the release rate of the therapeutic
substance may be too high to provide an efficacious treatment. This
shortcoming may be especially pronounced with certain therapeutic
substances. For instance, it has been found that the release rate
of 40-O-(2-hydroxy)ethyl-rapamycin from a standard polymeric
coating is greater than 50% in about 24 hours. Thus, there is a
need for a coating that reduces the release rate of
40-O-(2-hydroxy)ethyl-rapamycin in order to provide a more
efficacious release rate profile. The present invention provides a
coating to meet this need.
SUMMARY
[0011] In accordance with one aspect of the invention, a stent is
disclosed including a radially expandable body and a coating
covering at least a portion of the body, the coating having
40-O-(2-hydroxy)ethyl-rapamycin, or an analog or derivative
thereof, wherein the release rate of the
40-O-(2-hydroxy)ethyl-rapamycin, or the analog or derivative
thereof, in 24 hours after the implantation of the stent is less
than about 50% of the total amount contained in the coating.
[0012] In accordance with a further aspect of the present
invention, a method of inhibiting or eliminating the development of
restenosis following a stent placement procedure is disclosed
including implanting a stent which can elude
40-O-(2-hydroxy)ethyl-rapamycin, or an analog or derivative
thereof, at a release rate of less than 50% of the total amount of
the drug carried by the stent in a 24 hour period following the
implantation procedure.
[0013] In a further aspect, a method of providing drug delivery
capability for a stent is disclosed including coating a stent with
a polymer containing 40-O-(2-hydroxy)ethyl-rapamycin, or analog or
derivative thereof, wherein the coating has an in vivo release rate
of less than 50% of the total amount of the
40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof,
in a 24 hour period.
[0014] In yet another aspect of the present invention, a method of
treating a polymeric coating on a stent to reduce the rate of
release of the drug from the coating is disclosed including
exposing the coating to a temperature of a sufficient degree to
cause modifications in the structure of the polymer which allows
for the reduction of the release rate of the drug through the
polymer.
[0015] Also disclosed, in another aspect, is a method of treating a
coated stent containing a therapeutic substance to reduce the rate
of release of the therapeutic substance from the coating including
subjecting the coating to a stimuli so as to change the property of
at least a region of the coating such that the change of the
property of the region of the coating causes the therapeutic
substance to be released more slowly from the region that has the
changed property.
[0016] In another aspect of the present invention, a method of
preparing a coated stent containing
40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof,
for an implantation procedure is disclosed including sterilizing
the stent while maintaining the peak purity of the
40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof,
at a level greater than 90%.
BRIEF DESCRIPTION OF THE FIGURES
[0017] FIGS. 1A-1C illustrate coatings deposited over an
implantable medical substrate in accordance with various
embodiments of the present invention;
[0018] FIGS. 2-3 are graphs showing the release rate of
40-O-(2-hydroxy)ethyl-rapamycin from stent coatings in accordance
with embodiments of the present invention;
[0019] FIG. 4 is a chromatograph as referred to in Examples 32 and
33; and
[0020] FIG. 5 is a graph showing the release rate of
40-O-(2-hydroxy)ethyl-rapamycin from stent coatings in accordance
with an embodiment of the present invention.
DETAILED DESCRIPTION
Forming an Active Ingredient-Containing Coating
[0021] Herein is disclosed a method of forming a coating for an
implantable device including applying a first composition with
40-O-(2-hydroxy)ethyl-rapamycin, or a functional analog or
structural derivative thereof, to at least a portion of an
implantable device to form a first layer. The release rate of
40-O-(2-hydroxy)ethyl-rapamycin is advantageously controlled by
various methods and coatings as described below. In particular, by
using the methods and coatings of the present invention, the amount
of the 40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative
thereof, is released in less than about 50% in 24 hours.
[0022] 40-O-(2-hydroxy)ethyl-rapamycin is an immunosuppressant
which is under investigation primarily for use with
cyclosporine/steroids to prevent acute rejection episodes in renal
transplant recipients. 40-O-(2-hydroxy)ethyl-rapamycin is also
under investigation for rejection prophylaxis following other types
of transplantation (e.g., lung, liver). The chemical structure for
40-O-(2-hydroxy)ethyl-rapamycin is as follows: ##STR1## Examples of
analogs or derivatives of 40-O-(2-hydroxy)ethyl-rapamycin include
but are not limited to 40-O-(2-hydroxy)propyl-rapamycin and
40-O-(2-hydroxy)ethoxy]ethyl-rapamycin.
[0023] 40-O-(2-hydroxy)ethyl-rapamycin binds to the cytosolic
immunophyllin FKBP12 and inhibits growth factor-driven cell
proliferation, including that of T-cells and vascular smooth muscle
cells. The actions of 40-O-(2-hydroxy)ethyl-rapamycin occur late in
the cell cycle (i.e., late G1 stage) compared to other
immunosuppressive agents such as tacrolimus or cyclosporine which
block transcriptional activation of early T-cell-specific genes.
Since 40-O-(2-hydroxy)ethyl-rapamycin can act as a potent
anti-proliferative agent, it is believed that
40-O-(2-hydroxy)ethyl-rapamycin can be an effective agent to treat
restenosis by being delivered to a local treatment site from a
polymeric coated implantable device such as a stent.
[0024] The composition including 40-O-(2-hydroxy)ethyl-rapamycin
can be applied to the implantable device in various ways. In one
embodiment, a first layer can be formed on the implantable device
by (1) immersing the implantable device into a solution containing
40-O-(2-hydroxy)ethyl-rapamycin dissolved in a suitable solvent, or
(2) spray coating the implantable device with the same solution
containing 40-O-(2-hydroxy)ethyl-rapamycin to form a reservoir
layer. In this embodiment, the implantable device can include
cavities or micro-pores for containing the
40-O-(2-hydroxy)ethyl-rapamycin.
[0025] The 40-O-(2-hydroxy)ethyl-rapamycin can also be blended with
a polymer and applied to the implantable device to form the
reservoir layer. "Polymer," "poly," and "polymeric" are defined as
compounds that are the product of a polymerization reaction and are
inclusive of homopolymers, copolymers, terpolymers etc., including
random, alternating, block, and graft variations thereof. The
polymers should have a high capacity of adherence to the surface of
an implantable device, such as a metallic surface of a stent, and a
high capacity of adherence to polymeric surfaces.
[0026] In accordance with one embodiment, when the
40-O-(2-hydroxy)ethyl-rapamycin is blended with a polymer for the
reservoir layer, the ratio of 40-O-(2-hydroxy)ethyl-rapamycin, or
analog or derivative thereof, to polymer by weight in the reservoir
layer is about 1:2.8 to about 1:1. It has been found that this
particular range of 40-O-(2-hydroxy)ethyl-rapamycin:polymer ratio
provides a beneficial release rate of the
40-O-(2-hydroxy)ethyl-rapamycin from the polymer matrix.
[0027] In accordance with another embodiment, when the
40-O-(2-hydroxy)ethyl-rapamycin is blended with a polymer for the
reservoir layer, the 40-O-(2-hydroxy)ethyl-rapamycin, or analog or
derivative thereof, is in the amount of about 50 .mu.g to about 500
.mu.g, more narrowly about 90 .mu.g to about 350 .mu.g, and the
polymer is in the amount of about 50 .mu.g to about 1000 .mu.g,
more narrowly about 90 .mu.g to about 500 .mu.g. These particular
ranges of amounts for 40-O-(2-hydroxy)ethyl-rapamycin and a polymer
can provide a beneficial release rate of the
40-O-(2-hydroxy)ethyl-rapamycin from the polymer matrix.
[0028] When the polymer solution is being prepared, a predetermined
amount of a polymer can be added to a predetermined amount of a
compatible solvent. "Solvent" is defined as a liquid substance or
composition that is compatible with the components of the
composition and is capable of dissolving the component(s) at the
concentration desired in the composition. Representative examples
of solvents include chloroform, acetone, water (buffered saline),
dimethylsulfoxide (DMSO), propylene glycol methyl ether (PM,)
iso-propylalcohol (IPA), n-propylalcohol, methanol, ethanol,
tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide
(DMAC), benzene, toluene, xylene, hexane, cyclohexane, pentane,
heptane, octane, nonane, decane, decalin, ethyl acetate, butyl
acetate, isobutyl acetate, isopropyl acetate, butanol, diacetone
alcohol, benzyl alcohol, 2-butanone, cyclohexanone, dioxane,
methylene chloride, carbon tetrachloride, tetrachloroethylene,
tetrachloro ethane, chlorobenzene, 1,1,1-trichloroethane,
formamide, hexafluoroisopropanol, 1,1,1-trifluoroethanol, and
hexamethyl phosphoramide and a combination thereof.
[0029] The polymer can be added to the solvent at ambient pressure
and under anhydrous atmosphere. If necessary, gentle heating and
stirring and/or mixing can be employed to effect dissolution of the
polymer into the solvent, for example 12 hours in a water bath at
about 60.degree. C.
[0030] Sufficient amounts of 40-O-(2-hydroxy)ethyl-rapamycin can
then be dispersed in the blended composition of the polymer and the
solvent. The polymer can comprise from about 0.1% to about 35%,
more narrowly from about 0.5% to about 20% by weight of the total
weight of the composition, the solvent can comprise from about
59.9% to about 99.8%, more narrowly from about 79% to about 99% by
weight of the total weight of the composition, and the
40-O-(2-hydroxy)ethyl-rapamycin can comprise from about 0.1% to
about 40%, more narrowly from about 1% to about 9% by weight of the
total weight of the composition. More than 9% by weight of the
40-O-(2-hydroxy)ethyl-rapamycin could adversely affect
characteristics that are desirable in the polymeric coating, such
as adhesion of the coating to the device. With the use of the
optional primer layer, weight ratios of more than 9% for the active
ingredient are achievable without compromising the effectiveness of
the adhesion. Selection of a specific weight ratio of the polymer
and solvent is dependent on factors such as, but not limited to,
the material from which the device is made, the geometrical
structure of the device, and the type and amount of the active
ingredient employed.
[0031] Optionally, a second solvent, such as tetrahydrofuran (THF)
or dimethylformamide (DMF), can be used to improve the solubility
of the 40-O-(2-hydroxy)ethyl-rapamycin in the composition. The
second solvent can be added to the composition or the
40-O-(2-hydroxy)ethyl-rapamycin can be added to the second solvent
prior to mixture with the blend.
[0032] The 40-O-(2-hydroxy)ethyl-rapamycin should be in true
solution or saturated in the blended composition. If the
40-O-(2-hydroxy)ethyl-rapamycin is not completely soluble in the
composition, operations including mixing, stirring, and/or
agitation can be employed to effect homogeneity of the residues.
The 40-O-(2-hydroxy)ethyl-rapamycin can also be first added to the
second solvent prior to admixing with the composition. The
40-O-(2-hydroxy)ethyl-rapamycin may be added so that the dispersion
is in fine particles.
[0033] Representative examples of polymers that can be combined
with 40-O-(2-hydroxy)ethyl-rapamycin for the reservoir layer
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 polyvinyl 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 monomers 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;
rayon-triacetate; cellulose acetate; cellulose butyrate; cellulose
acetate butyrate; cellophane; cellulose nitrate; cellulose
propionate; cellulose ethers; and carboxymethyl cellulose.
[0034] Ethylene vinyl alcohol is functionally a very suitable
choice of polymer. Ethylene vinyl alcohol copolymer refers to
copolymers comprising residues of both ethylene and vinyl alcohol
monomers. One of ordinary skill in the art understands that
ethylene vinyl alcohol copolymer may also be a terpolymer so as to
include small amounts of additional monomers, for example less than
about five (5) mole percentage of styrenes, propylene, or other
suitable monomers. Ethylene vinyl alcohol copolymers are available
commercially from companies such as Aldrich Chemical Company,
Milwaukee, Wis., or EVAL Company of America, Lisle, Ill., or can be
prepared by conventional polymerization procedures that are well
known to one of ordinary skill in the art.
[0035] The copolymer of EVAL allows for good control capabilities
of the release rate of the 40-O-(2-hydroxy)ethyl-rapamycin. As a
general rule, an increase in the amount of the ethylene comonomer
content decreases the rate that the 40-O-(2-hydroxy)ethyl-rapamycin
is released from the copolymer matrix. The release rate of the
40-O-(2-hydroxy)ethyl-rapamycin typically decreases as the
hydrophilicity of the copolymer decreases. An increase in the
amount of the ethylene comonomer content increases the overall
hydrophobicity of the copolymer, especially as the content of vinyl
alcohol is concomitantly reduced. It is also thought that the
release rate and the cumulative amount of the active ingredient
that is released is directly proportional to the total initial
content of the ingredient in the copolymer matrix. Accordingly, a
wide spectrum of release rates can be achieved by modifying the
ethylene comonomer content and the initial amount of the
40-O-(2-hydroxy)ethyl-rapamycin.
[0036] Besides 40-O-(2-hydroxy)ethyl-rapamycin, another active
agent can also be added to the first composition. The additional
active agent may be any substance capable of exerting a therapeutic
or prophylactic effect in the practice of the present invention.
Examples of such active agents include antiproliferative,
antineoplastic, antiinflammatory, antiplatelet, anticoagulant,
antifibrin, antithrombin, antimitotic, antibiotic, and antioxidant
substances as well as combinations thereof. A suitable example of
an antiproliferative substance is actinomycin D, or derivatives and
analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul
Avenue, Milwaukee, Wis. 53233; or COSMEGEN available from Merck).
Synonyms of actinomycin D include dactinomycin, actinomycin IV,
actinomycin I.sub.1, actinomycin X.sub.1, and actinomycin C.sub.1.
Examples of suitable antineoplastics include paclitaxel and
docetaxel. Examples of suitable antiplatelets, anticoagulants,
antifibrins, and antithrombins include aspirin, sodium heparin, low
molecular weight heparin, hirudin, argatroban, forskolin,
vapiprost, prostacyclin and 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), and 7E-3B.RTM. (an antiplatelet drug from Centocor).
Examples of suitable antimitotic agents include methotrexate,
azathioprine, vincristine, vinblastine, fluorouracil, adriamycin,
and mutamycin. Examples of suitable cytostatic or antiproliferative
agents include angiopeptin (a somatostatin analog from Ibsen),
angiotensin converting enzyme inhibitors such as CAPTOPRIL
(available from Squibb), CILAZAPRIL (available from
Hoffman-LaRoche), or LISINOPRIL (available from Merck & Co.,
Whitehouse Station, N.J.); calcium channel blockers (such as
Nifedipine), colchicine, fibroblast growth factor (FGF)
antagonists, histamine antagonist, LOVASTATIN (an inhibitor of
HMG-CoA reductase, a cholesterol lowering drug from Merck &
Co.), monoclonal antibodies (such as PDGF receptors),
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitor (available form Glazo), Seramin (a PDGF antagonist),
serotonin blockers, thioprotease inhibitors, triazolopyrimidine (a
PDGF antagonist), and nitric oxide. Other therapeutic substances or
agents that may be appropriate include alpha-interferon;
genetically engineered epithelial cells; dexamethasone; rapamycin;
estradiol; clobetasol propionate; cisplatin; insulin sensitizers;
receptor tyrosine kinase inhibitors; and carboplatin. Exposure of
the composition to the active ingredient should not adversely alter
the active ingredient's composition or characteristic. Accordingly,
the particular active ingredient is selected for compatibility with
the blended composition.
[0037] The dosage or concentration of
40-O-(2-hydroxy)ethyl-rapamycin or other active agent required to
produce a therapeutic effect should be less than the level at which
the 40-O-(2-hydroxy)ethyl-rapamycin or other active agent produces
unwanted toxic effects and greater than the level at which
non-therapeutic results are obtained. The dosage or concentration
of 40-O-(2-hydroxy)ethyl-rapamycin or other active agent required
to inhibit the desired cellular activity of the vascular region,
for example, can depend upon factors such as the particular
circumstances of the patient; the nature of the trauma; the nature
of the therapy desired; the time over which the ingredient
administered resides at the vascular site; and if other bioactive
substances are employed, the nature and type of the substance or
combination of substances. Therapeutically effective dosages can be
determined empirically, for example by infusing vessels from
suitable animal model systems and using immunohistochemical,
fluorescent or electron microscopy methods to detect the agent and
its effects, or by conducting suitable in vitro studies. Standard
pharmacological test procedures to determine dosages are understood
by one of ordinary skill in the art.
Forming a Barrier Layer to Reduce the Rate of Release
[0038] In some coatings, the release rate of the
40-O-(2-hydroxy)ethyl-rapamycin may be too high to be clinically
useful. For example, in Example 22 below, the percentage of
40-O-(2-hydroxy)ethyl-rapamycin released from a stent coating
without a barrier layer in 24 hours was determined to be 58.55 as
measured in a porcine serum release rate procedure. The release
rate from the coating of Example 22 may be too high for a treatment
using 40-O-(2-hydroxy)ethyl-rapamycin as the active agent. The
barrier layer of the present invention can reduce the rate of
release or delay the time at which the
40-O-(2-hydroxy)ethyl-rapamycin is released from the reservoir
layer.
[0039] In accordance with one embodiment, the barrier layer can be
applied on a selected region of the reservoir layer to form a rate
reducing member. The composition for the barrier layer can be
substantially free of active agents. Alternatively, for maximum
blood compatibility, compounds such as polyethylene glycol,
heparin, heparin derivatives having hydrophobic counterions, or
polyethylene oxide can be added to the barrier layer.
[0040] The choice of polymer for the barrier layer can be the same
as the selected polymer for the reservoir. The use of the same
polymer, as described for some of the embodiments, significantly
reduces or eliminates any interfacial incompatibilities, such as
lack of adhesion, which may exist in the employment of two
different polymeric layers.
[0041] Representative examples of polymers that can be used for a
barrier layer can include polytetrafluoroethylene, perfluoro
elastomers, ethylene-tetrafluoroethylene copolymer,
fluoroethylene-alkyl vinyl ether copolymer,
polyhexafluoropropylene, low density linear polyethylenes having
high molecular weights, ethylene-olefin copolymers, atactic
polypropylene, polyisobutene, polybutylenes, polybutenes,
styrene-ethylene-styrene block copolymers, styrene-butylene-styrene
block copolymers, styrene-butadiene-styrene block copolymers, and
ethylene methacrylic acid copolymers of low methacrylic acid
content.
[0042] Ethylene vinyl alcohol is functionally a very suitable
choice of polymer. The copolymer allows for good control
capabilities over the release rate of the
40-O-(2-hydroxy)ethyl-rapamycin. As a general rule, an increase in
the amount of the ethylene comonomer content decreases the rate
that the 40-O-(2-hydroxy)ethyl-rapamycin is released from the
copolymer matrix. The release rate of the
40-O-(2-hydroxy)ethyl-rapamycin decreases as the hydrophilicity of
the polymer decreases. An increase in the amount of the ethylene
comonomer content increases the overall hydrophobicity of the
copolymer, especially as the content of vinyl alcohol is
concomitantly reduced.
[0043] Fluoropolymers are also a suitable choice for the barrier
layer composition. For example, polyvinylidene fluoride (otherwise
known as KYNAR, available from ATOFINA Chemicals, Philadelphia,
Pa.) can be dissolved in HFE FLUX REMOVER (Techspray, Amarillo,
Tex.) and can optionally be combined with EVAL to form the barrier
layer composition. Also, solution processing of fluoropolymers is
possible, particularly the low crystallinity varieties such as
CYTOP available from Asahi Glass and TEFLON AF available from
DuPont. Solutions of up to about 15% (wt/wt) are possible in
perfluoro solvents, such as FC-75 (available from 3M under the
brand name FLUORINERT), which are non-polar, low boiling solvents.
Such volatility allows the solvent to be easily and quickly
evaporated following the application of the polymer-solvent
solution to the implantable device.
[0044] In one embodiment, polybutylmethacrylate can be used for the
barrier layer. Polybutylmethacrylate, for example, can be dissolved
in a solution of xylene, acetone and HFE FLUX REMOVER.
[0045] The barrier layer can also be
styrene-ethylene/butylene-styrene block copolymer.
Styrene-ethylene/butylene-styrene block copolymer, e.g., Kraton
G-series, can be dissolved in non-polar solvents such as, but not
limited to, toluene, xylene, and decalin.
[0046] Other choices of polymers for the rate-limiting membrane
include, but are not limited to, ethylene-anhydride copolymers;
ethylene vinyl acetate copolymers having, for example, a mol % of
vinyl acetate of from about 9% to about 25%; and ethylene-acrylic
acid copolymers having, for example, a mol % of acrylic acid of
from about 2% to about 25%. The ethylene-anhydride copolymer
available from Bynel adheres well to EVAL and thus would function
well as a barrier layer over a reservoir layer made from EVAL. The
copolymer can be dissolved in organic solvents, such as
dimethylsulfoxide and dimethylacetamide. Ethylene vinyl acetate
polymers can be dissolved in organic solvents, such as toluene and
n-butyl acetate. Ethylene-acrylic acid copolymers can be dissolved
in organic solvents, such as methanol, isopropyl alcohol, and
dimethylsulfoxide.
[0047] Yet another choice of polymer for the rate-limiting membrane
is a cross-linked silicone elastomer. Loose silicone and silicone
with very low cross-linking are thought to cause an inflammatory
biological response. However, it is believed that a thoroughly
cross-linked silicone elastomer, having low levels of leachable
silicone polymer and oligomer, is an essentially non-inflammatory
substance. Silicone elastomers, such as Nusil MED-4750, MED-4755,
or MED2-6640, having high tensile strengths, for example between
1200 psi and 1500 psi, will likely have the best durability during
crimping, delivery, and expansion of a stent as well as good
adhesion to a reservoir layer, e.g., EVAL or the surface of an
implantable device.
[0048] The embodiments of the composition for a rate-reducing
membrane or diffusion barrier layer are prepared by methods wherein
all components are combined, then blended. More particularly, a
predetermined amount of a polymer can be added to a predetermined
amount of a compatible solvent. The selected solvent should be
capable of placing the polymer into solution at the concentration
desired.
[0049] The polymer can be added to the solvent at ambient pressure
and under anhydrous atmosphere. If necessary, gentle heating and
stirring and/or mixing can be employed to effect dissolution of the
polymer into the solvent, for example 12 hours in a water bath at
about 60.degree. C. The polymer can comprise from about 0.1% to
about 35%, more narrowly from about 1% to about 20% by weight of
the total weight of the composition, and the solvent can comprise
from about 65% to about 99.9%, more narrowly from about 80% to
about 98% by weight of the total weight of the composition.
Selection of a specific weight ratio of the polymer and solvent is
dependent on factors such as, but not limited to, the type of
polymer and solvent employed, the type of underlying reservoir
layer, and the method of application.
[0050] In an embodiment, the barrier layer contains a polymer in
the amount of about 25 .mu.g to about 500 .mu.g, more narrowly
about 65 .mu.g to about 350 .mu.g. This particular range for the
amount of barrier polymer can provide a beneficial release rate of
the 40-O-(2-hydroxy)ethyl-rapamycin from the polymer matrix.
Forming a Primer Layer
[0051] The presence of an active ingredient in a polymeric matrix
can interfere with the ability of the matrix to adhere effectively
to the surface of the device. Increasing the quantity of the active
ingredient reduces the effectiveness of the adhesion. High drug
loadings in the coating can hinder the retention of the coating on
the surface of the device. A primer layer can serve as a
functionally useful intermediary layer between the surface of the
device and an active ingredient-containing or reservoir coating.
The primer layer provides an adhesive tie between the reservoir
coating and the device--which, in effect, would also allow for the
quantity of the active ingredient in the reservoir coating to be
increased without compromising the ability of the reservoir coating
to be effectively contained on the device during delivery and, if
applicable, expansion of the device.
[0052] The composition for a primer layer is prepared by
conventional methods wherein all components are combined, then
blended. More particularly, a predetermined amount of a polymer or
a prepolymer can be added to a predetermined amount of a solvent or
a combination of solvents. The mixture can be prepared at ambient
pressure and under anhydrous atmosphere. Heating and stirring
and/or mixing can be employed to effect dissolution of the polymer
into the solvent.
[0053] Representative examples of suitable polymers for the primer
layer include, but are not limited to, polyisocyanates, such as
triisocyanurate and polyurethanes with polyisocyanate and/or
polyisocyanate moieties based on diphenylmethane diisocyanate;
acrylates, such as copolymers of ethyl acrylate and methacrylic
acid; titanates, such as tetra-iso-propyl titanate and
tetra-n-butyl titanate; zirconates, such as n-propyl zirconate and
n-butyl zirconate; silane coupling agents, such as
3-aminopropyltriethoxysilane and (3-glydidoxypropyl)
methyldiethoxysilane; high amine content polymers, such as
polyethyleneamine, polyallylamine, and polylysine; polymers with a
high content of hydrogen bonding groups, such as
polyethylene-co-polyvinyl alcohol, ethylene vinyl acetate, and
melamine formaldehydes; and unsaturated polymers and prepolymers,
such as polycaprolactone diacrylates, polyacrylates with at least
two acrylate groups, and polyacrylated polyurethanes. With the use
of unsaturated prepolymers, a free radical or UV initiator can be
added to the composition for the thermal or UV curing or
cross-linking process, as is understood by one of ordinary skill in
the art.
[0054] Representative examples of polymers that can be used for the
primer material also include those polymers that can be used for
the reservoir layer as described above. The use of the same polymer
significantly reduces or eliminates any interfacial
incompatibilities, such as lack of an adhesive tie or bond, which
may exist with the employment of two different polymeric
layers.
[0055] Ethylene vinyl alcohol is a very suitable choice of polymer
for the primer layer. The copolymer possesses good adhesive
qualities to the surface of a stent, particularly stainless steel
surfaces, and has illustrated the ability to expand with a stent
without any significant detachment of the copolymer from the
surface of the stent. The copolymer can comprise a mole percent of
ethylene of from about 27% to about 48%.
[0056] By way of example, and not limitation, the polymer can
comprise from about 0.1% to about 35%, more narrowly from about 1%
to about 20% by weight of the total weight of the composition, and
the solvent can comprise from about 65% to about 99.9%, more
narrowly from about 80% to about 98% by weight of the total weight
of the primer composition. A specific weight ratio is dependent on
factors such as the material from which the implantable device is
made, the geometrical structure of the device, the choice of
polymer-solvent combination, and the method of application.
[0057] In accordance with another embodiment, a fluid can be added
to the composition to enhance the wetting of the primer composition
for a more uniform coating application. To enhance the wetting of
the composition, a suitable fluid typically has a high capillary
permeation. Capillary permeation or wetting is the movement of a
fluid on a solid substrate driven by interfacial energetics.
Capillary permeation is quantitated by a contact angle, defined as
an angle at the tangent of a droplet in a fluid phase that has
taken an equilibrium shape on a solid surface. A low contact angle
indicates a higher wetting liquid. A suitably high capillary
permeation corresponds to a contact angle less than about
90.degree.. The wetting fluid, typically, should have a viscosity
not greater than about 50 centipoise, narrowly about 0.3 to about 5
centipoise, more narrowly about 0.4 to about 2.5 centipoise. The
wetting fluid, accordingly, when added to the composition, reduces
the viscosity of composition.
[0058] The wetting fluid should be compatible with the polymer and
the solvent and should not precipitate the polymer. The wetting
fluid can also act as the solvent. Useful examples of the wetting
fluid include, but are not limited to, tetrahydrofuran (THF),
dimethylformamide (DMF), 1-butanol, n-butyl acetate, dimethyl
acetamide (DMAC), and mixtures and combinations thereof.
Forming a Finishing Layer
[0059] Depending on the polymer used for the reservoir or barrier
layers, it may be advantageous to form a finishing layer that is
especially biocompatible on the surface of the coating that is
exposed to the biological lumen when inserted into a patient.
Representative examples of suitable biocompatible polymers or
biocompatible agents for the finishing layer include, but are not
limited to ethylene vinyl alcohol copolymer, polyethylene oxide,
polyethylene glycol, hyaluronic acid, polyvinyl pyrrolidone,
heparin, heparin derivatives such as those having hydrophobic
counterions, and phosphylcholine.
Methods For Applying the Compositions to the Device
[0060] Application of the composition can be by any conventional
method, such as by spraying the composition onto the prosthesis or
by immersing the prosthesis in the composition. Operations such as
wiping, centrifugation, blowing, or other web-clearing acts can
also be performed to achieve a more uniform coating. Briefly,
wiping refers to physical removal of excess coating from the
surface of the stent; centrifugation refers to rapid rotation of
the stent about an axis of rotation; and blowing refers to
application of air at a selected pressure to the deposited coating.
Any excess coating can also be vacuumed off the surface of the
device. The addition of a wetting fluid leads to a consistent
application of the composition which also causes the coating to be
uniformly deposited on the surface of the prosthesis.
[0061] With the use of the thermoplastic polymers for the primer,
such as ethylene vinyl alcohol copolymer, polycaprolactone,
poly(lactide-co-glycolide), poly(hydroxybutyrate), etc., the
deposited primer composition should be exposed to a heat treatment
at a temperature in a 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. Unexpected 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 a stent. The device should be exposed to
the heat treatment for any suitable duration of time that would
allow for the formation of the primer coating on the surface of the
device as well as for the evaporation of the solvent or combination
of solvent and wetting fluid. It is understood that essentially all
of the solvent and the wetting fluid will be removed from the
composition, but traces or residues may remain blended with the
polymer.
[0062] Table 1 lists the T.sub.g and T.sub.m for some of the
polymers used in the embodiments of the present invention. T.sub.g
and T.sub.m of polymers are attainable by one of ordinary skill in
the art. The cited exemplary temperature and time for exposure are
provided by way of illustration and are not meant to be limiting.
TABLE-US-00001 TABLE 1 Exemplary Exemplary Duration of T.sub.g
T.sub.m Temperature Time For Polymer (.degree. C.) (.degree. C.)
(.degree. C.) Heating EVAL 55 165 140 4 hours polycaprolactone -60
60 50 2 hours ethylene vinyl 36 63 45 2 hours acetate (e.g., 33%
vinyl acetate content) Polyvinyl alcohol 75-85* 200-220* 165 2
hours *Exact temperature depends on the degree of hydrolysis which
is also known as the amount of residual acetate.
[0063] With the use of one of the aforementioned thermoset primer
polymers, the use of initiators may be required. By way of example,
epoxy systems consisting of diglycidyl ether of bisphenol A resins
can be cured with amine curatives, thermoset polyurethane
prepolymers can cured with polyols, polyamines, or water
(moisture), and acrylated urethane can be cured with UV light. If
baked, the temperature can be above the T.sub.g of the selected
polymer.
[0064] With the use of the inorganic primer polymers, such as
silanes, titanates, and zirconates, the solvent is allowed to
evaporate.
[0065] The composition containing the active ingredient can be
applied to a designated region of the primer coating or the surface
of the device. The solvent(s) or the combination of solvent(s) and
the wetting fluid is removed from the composition by allowing the
solvent(s) or combination of the solvent(s) and the wetting fluid
to evaporate. The evaporation can be induced by heating the device
at a predetermined temperature for a predetermined period of time.
For example, the device can be heated at a temperature of about
60.degree. C. for about 12 hours to about 24 hours. The heating can
be conducted in an anhydrous atmosphere and at ambient pressure and
should not exceed the temperature which would adversely affect the
active ingredient. The heating can also be conducted under a vacuum
condition. It is understood that essentially all of the solvent and
the wetting fluid will be removed from the composition, but traces
or residues may remain blended with the polymer.
[0066] The diffusion barrier layer can be formed on a designated
region of the active ingredient-containing coating subsequent to
the evaporation of the solvent(s) or solvent(s)/wetting fluid and
the drying of the polymer for the active ingredient-containing
coating. Alternatively, in embodiments in which a polymeric
reservoir coating is not employed, the rate-reducing membrane may
be formed directly over active-ingredient containing cavities
within the surface of the prosthesis. The diffusion barrier layer
can be applied by spraying the composition onto the device or
immersing the device in the composition, then drying the polymer.
The above-described processes can be similarly repeated for the
formation of the diffusion barrier layer.
Thermal Treatment of the Coating
[0067] After the coating has been formed on the implantable device,
depending on the polymers used in the coating, the
40-O-(2-hydroxy)ethyl-rapamycin can diffuse from the polymer matrix
at a rate that could be too high for certain clinical conditions.
Accordingly, the coating can be exposed to a temperature that is
effective to decrease the diffusion rate of the
40-O-(2-hydroxy)ethyl-rapamycin from the polymer matrix. In
particular, the coating can be exposed to a sufficient temperature
effective to decrease the release rate of the
40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof,
by about 50% as compared to a control group, as demonstrated in
Example 17 below.
[0068] Typically, the temperature will be between the glass
transition temperature (T.sub.g) and the melting temperature
(T.sub.m) of the polymer. For example, the temperature can be the
annealing temperature of the polymer (about equal to
T.sub.g+T.sub.m/2). The thermal treatment can be conducted in an
anhydrous atmosphere and at ambient pressure. The treatment can
also be conducted under a vacuum condition.
[0069] The exposure temperature should not adversely affect the
characteristics of the 40-O-(2-hydroxy)ethyl-rapamycin or other
active agents present in the coating. In order to prevent possible
degradation of the active agents or the polymers in the coating,
additives can be mixed with the polymer before or during the
coating process to shift the thermal profile of the polymer (i.e.,
decrease the T.sub.g and T.sub.m of the polymer). For example, a
plasticizer, which is usually a low molecular weight nonvolatile
molecule, can be dissolved with the polymer before the application
process. The plasticizer can be an active agent. A representative
example of an additive is dioctyl phthalate.
[0070] In one embodiment, one of the polymers in the coating
exposed to the temperature is a semi-crystalline (e.g., polyvinyl
chloride and EVAL) polymer. Without being bound by any particular
theory, it is believed that the diffusion rate of the active agent
from the polymer is decreased because the thermal radiation
increases the percent crystallinity of the polymer. Others types of
energy, such as RF energy, can also be used to increase the percent
crystallinity. "Percent crystallinity" refers to the percentage of
the polymer material that is in a crystalline form. Those of
ordinary skill in the art understand that there are several methods
for determining the percent crystallinity in polymers. These
methods are, for example, described in L. H. Sperline, Introduction
to Physical Polymer Science (3rd ed. 2001). The first involves the
determination of the heat of fusion of the whole sample by
calorimetric methods. The heat of fusion per mole of crystalline
material can be estimated independently by melting point depression
experiments.
[0071] A second method involves the determination of the density of
the crystalline portion via X-ray analysis of the crystal
structure, and determining the theoretical density of a 100%
crystalline material. The density of the amorphous material can be
determined from an extrapolation of the density from the melt to
the temperature of interest. Then the percent crystallinity is
given by: % .times. Crystallinity = .rho. expt .times. .times. 1 -
.rho. amorph .rho. 100 .times. % .times. cryst - .rho. amorph 100
##EQU1## where .rho..sub.exptl represents the experimental density,
and .rho..sub.amorph and .rho..sub.100% cryst are the densities of
the amorphous and crystalline portions, respectively.
[0072] A third method stems from the fact that X-ray diffraction
depends on the number of electrons involved and is thus
proportional to the density. Besides Bragg diffraction lines for
the crystalline portion, there is an amorphous halo caused by the
amorphous portion of the polymer. The amorphous halo occurs at a
slightly smaller angle than the corresponding crystalline peak,
because the atomic spacings are larger. The amorphous halo is
broader than the corresponding crystalline peak, because of the
molecular disorder. This third method can be quantified by the
crystallinity index, CI, where CI = A c A a + A c . ##EQU2## and
where A.sub.c and A.sub.a represent the area under the Bragg
diffraction line and corresponding amorphous halo,
respectively.
[0073] The heat emitter used to thermal treat the coating can be
any apparatus that emits thermal radiation. For example, the heat
emitter can be a cauterizer tip. The heat emitter can also be a
blower that includes a heating device so that the blower can direct
a warm gas (e.g., air, argon or nitrogen) onto the implantable
device. The heating device can be any heating device as known by
those of ordinary skill in the art. For example, the heating device
can be an electric heater incorporating heating coils.
[0074] In one embodiment of the present invention, the thermal
radiation from the heat emitter can be directed to only certain
portions of the implantable device or only for certain durations so
that the diffusion rates of the 40-O-(2-hydroxy)ethyl-rapamycin
from the polymer differs in various portions of the coating. In one
example, the implantable device can have two or more segments along
the longitudinal axis of the implantable device, such as a first
segment, a second segment and a third segment. The thermal
radiation could be directed substantially only at the first segment
and the third segment, for instance, by using a cauterizer tip.
Alternatively, the thermal radiation could be set higher for the
first and third segments, or the thermal radiation could be
directed at the first and third segments for a longer duration than
the second segment. As a result, the polymer along the first
segment and the third segment would have a greater percent
crystallinity than the polymer along the second segment. Therefore,
the diffusion rates of the active agent from the polymer matrix
along the first segment and the third segment would be less than
the diffusion rate along the second segment.
[0075] In another embodiment, by limiting the time that the coating
is exposed to thermal radiation so that the percent crystallinity
is not maximized throughout the entire thickness of the coating,
the shallower regions of the coating will have a higher percent
crystallinity than the deeper regions. In a particular example, if
the coating has four regions with the fourth region as the deepest,
by limiting the thermal treatment, the first or shallowest region
would have a higher percent crystallinity than the fourth or
deepest region. One of ordinary skill in the art will understand
that the duration and temperature of the exposure will depend on
the desired diffusion rate of the polymer, and the inherent
characteristics of the polymers used in the coating.
Sterilization of the Implantable Device
[0076] After the implantable device has been coated according to
the various embodiments of the present invention, the implantable
device can be sterilized by various methods. According to
conventional thought, a coating containing
40-O-(2-hydroxy)ethyl-rapamycin cannot be sterilized with many
techniques because the 40-O-(2-hydroxy)ethyl-rapamycin is degraded
by the processes. For example, it was thought that a polymer
coating containing 40-O-(2-hydroxy)ethyl-rapamycin could not be
sterilized with an e-beam procedure because the free radicals
produced during the process would degrade the
40-O-(2-hydroxy)ethyl-rapamycin. Similarly, it has been thought
that exposing a coating with 40-O-(2-hydroxy)ethyl-rapamycin to
ethylene oxide or peroxide gas would also degrade the
40-O-(2-hydroxy)ethyl-rapamycin. However, it has unexpectedly been
found that the coatings of the present invention protect the
40-O-(2-hydroxy)ethyl-rapamycin during sterilization procedures
(e.g., using an e-beam or ethylene oxide process). In fact,
subsequent to sterilization, the peak purity of the
40-O-(2-hydroxy)ethyl-rapamycin has been greater than 90% when
included in the coatings of the present invention.
[0077] In an embodiment of the present invention, the particular
procedure used to sterilize the coating can also be used to expose
the coating to a temperature that is effective to decrease the
diffusion rate of the 40-O-(2-hydroxy)ethyl-rapamycin from the
polymer matrix. In particular, during the sterilization procedure
(e.g., the ethylene oxide procedure) the coating can be exposed to
a sufficient temperature effective to decrease the release rate of
the 40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative
thereof, by about 50% as compared to a control group.
Examples of the Device
[0078] 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, Santa Clara,
Calif.). The underlying structure of the device can be of virtually
any design. The device can be made of a metallic material or an
alloy such as, but not limited to, cobalt chromium 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
biostable polymers could also be used with the embodiments of the
present invention.
[0079] The embodiments of the present invention may be particularly
useful for the coatings of small vessel stents. Small vessels
stents can be generally categorized as having inner diameters of
less than 2.5 mm in an expanded state. Because of their small size,
small vessel stents offer unique challenges for drug delivery. In
particular, as compared to conventionally sized stents, small
vessel stents have a greater surface:volume ratio. Therefore, when
a small vessel stent is inserted into a biological lumen, the
vessel tissue surrounding a small vessel stent is exposed to a
greater concentration of polymer and active agent.
[0080] The various embodiments of the present invention can be used
to address some of the challenges offered by the use of small
vessel stents. For example, it is thought that it is especially
important that small vessel stents have lower amounts of polymer in
their coatings, as compared to larger sized stents, in order to
reduce the risk of an inflammatory response by the vessel tissue.
However, it may also be important to have a barrier layer on the
stent coating in order to have a low release rate of the active
agents, such as 40-O-(2-hydroxy)ethyl-rapamycin. With the inclusion
of the barrier layer, the amount of polymer on the coating may be
sufficient to cause an unwanted inflammatory response. In order to
address these countervailing concerns, one approach would be to
provide a thinner barrier layer on the polymer matrix as compared
to larger sized stents, and then heat treat the barrier layer to
increase the crystallinity of the barrier layer polymer, thereby
decreasing the release rate of the active agent from the reservoir
region. In an alternative embodiment, the polymer used for the
barrier layer can initially have a very high percent crystallinity.
In yet another embodiment, the reservoir layer can be heat treated
to reduce the release rate of active agent from the reservoir
region without the use of a barrier layer.
[0081] In another particular example, it is thought that it is
especially important for small vessel stents to have a
biocompatible coating. One approach to address this need is to
provide a finishing layer on the stent that contains a highly
biocompatible polymer such as polyethylene glycol, or biocompatible
agents such as heparin. For example, a finishing layer can be
applied over a barrier layer so that the coating offers a usefully
low release rate of an active agent and also provides a highly
biocompatible coating.
Coating
[0082] Some of the various embodiments of the present invention are
illustrated by FIGS. 1A, 1B, and 1C. The Figures have not been
drawn to scale, and the thickness of the various layers have been
over or under emphasized for illustrative purposes.
[0083] Referring to FIG. 1A, a body of a medical substrate 20, such
as a stent, is illustrated having a surface 22. Medical substrate
20 includes cavities or micro-pores 24 formed in the body for
releasably containing an active ingredient, as illustrated by
dotted region 26. A barrier layer or rate-reducing membrane 28 is
disposed on surface 22 of medical substrate 20, covering cavities
24. Barrier layer 28 functions to reduce the rate of release of an
active agent (e.g., 40-O-(2-hydroxy)ethyl-rapamycin) from medical
substrate 20.
[0084] Referring to FIG. 1B, medical substrate 20 is illustrated
having a primer layer 30 formed on surface 22. An active
agent-containing or reservoir coating 32 is deposited on primer
layer 30. Primer layer 30 serves as an intermediary layer for
increasing the adhesion between reservoir coating 32 and surface
22. Increasing the amount of active ingredient admixed within the
polymer diminishes the adhesiveness of reservoir layer 32 to
surface 22. Accordingly, using an active agent-free polymer as an
intermediary primer layer 30 allows for a higher active ingredient
content for reservoir layer 32. Barrier layer 28 is formed over at
least a selected portion of reservoir layer 32. One of ordinary
skill in the art can appreciate that barrier layer 28 can be
deposited only on selected areas of reservoir layer 32 so as to
provide a variety of selected release parameters. Such selected
patterns may become particularly useful if a combination of active
agents are used, each of which requires a different release
parameter.
[0085] FIG. 1C illustrates medical substrate 20 having a first
reservoir layer 32A disposed on a selected portion of surface 22 of
medical substrate 20. First reservoir layer 32A contains a first
active agent, e.g., 40-O-(2-hydroxy)ethyl-rapamycin. A second
reservoir layer 32B can also be disposed on surface 22. Second
reservoir layer 32B contains a second active ingredient, e.g.,
taxol. First and second reservoir layers 32A and 32B are covered by
first and second barrier layers 28A and 28B, respectively. In
accordance with one embodiment, the polymeric material in barrier
layer 28B has been exposed to thermal treatment, whereas the
polymeric material in barrier layer 28A has not. As a result, the
polymeric material in barrier 28B has a higher percent
crystallinity than the polymeric material in barrier layer 28A.
Accordingly, by producing a coating such as the one shown in FIG.
1C, a wide array of release parameters can be obtained for any
selected combination of active agents.
[0086] Barrier layer 28 can have any suitable thickness, as the
thickness of barrier layer 28 is dependent on parameters such as,
but not limited to, the desired rate of release and the procedure
for which the stent will be used. For example, barrier layer 28 can
have a thickness of about 0.1 to about 10 microns, more narrowly
from about 0.25 to about 5 microns.
[0087] By way of example, and not limitation, the impregnated
reservoir layer 32 can have a thickness of about 0.5 microns to
about 1.5 microns. The particular thickness of reservoir layer 32
is based on the type of procedure for which medical substrate 20 is
employed and the amount of the active agent to be delivered. The
amount of the active agent to be included on the prosthesis can be
further increased by applying a plurality of reservoir layers 32 on
top of one another. The optional primer layer 30 can have any
suitable thickness, examples of which can be in the range of about
0.1 to about 10 microns, more narrowly about 0.1 to about 2
microns.
Method of Use
[0088] In accordance with the above-described method, the active
agent can be applied to a device, e.g., a stent, retained on the
device during delivery and released at a desired control rate and
for a predetermined duration of time at the site of implantation. A
stent having the above-described coating layers is useful for a
variety of medical procedures, including, by way of example,
treatment of obstructions caused by tumors in bile ducts,
esophagus, trachea/bronchi and other biological passageways. A
stent having the above-described coating layers is particularly
useful for treating occluded regions of blood vessels caused by
abnormal or inappropriate migration and proliferation of smooth
muscle cells, thrombosis, and restenosis. Stents may be placed in a
wide array of blood vessels, both arteries and veins.
Representative examples of sites include the iliac, renal, and
coronary arteries.
[0089] Briefly, an angiogram is first performed to determine the
appropriate positioning for stent therapy. Angiography is typically
accomplished by injecting a radiopaque contrasting agent through a
catheter inserted into an artery or vein as an x-ray is taken. A
guidewire is then advanced through the lesion or proposed site of
treatment. Over the guidewire is passed a delivery catheter, which
allows a stent in its collapsed configuration to be inserted into
the passageway. The delivery catheter is inserted either
percutaneously, or by surgery, into the femoral artery, brachial
artery, femoral vein, or brachial vein, and advanced into the
appropriate blood vessel by steering the catheter through the
vascular system under fluoroscopic guidance. A stent having the
above-described coating layers may then be expanded at the desired
area of treatment. A post insertion angiogram may also be utilized
to confirm appropriate positioning.
EXAMPLES
[0090] The embodiments of the present invention will be illustrated
by the following set forth examples.
Example 1
[0091] 35 13 mm PENTA stents (available from Guidant Corporation)
were coated by spraying a 2% (w/w) solution of
poly(ethylene-co-vinyl alcohol) (44 mole % ethylene) ("EVAL") in
98% (w/w) dimethylacetamide. The solvent was removed by baking at
140.degree. C. for 2 hours. A solution of 1.9% (w/w) EVAL and 0.7%
(w/w) 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 68.2% (w/w)
dimethylacetamide and 29.2% (w/w) ethanol was spray coated onto the
stents to a thickness with a target of 175 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin on each stent. The stents were then
baked at 50.degree. C. for 2 hours. A barrier layer was formed by
spraying the stents with a 4% (w/w) solution of EVAL in a mixture
of 76% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2
hour bake at 50.degree. C. was performed to remove the solvent.
[0092] A select number of stents were analyzed to compare the
target coating formulation with the final coating formulation. The
results are as follows: For the primer layer, there was a target
dry weight of 40 .mu.g of polymer, and a measured average dry
weight of 43.+-.3 .mu.g of polymer. For the reservoir layer, the
target drug:polymer ratio was 1:2.857, the target dry weight for
the entire reservoir coating was 675 .mu.g and the average actual
dry weight was 683.+-.19 .mu.g. Also for the reservoir layer, the
average total drug content of the stent coatings was determined by
the process described in Example 2. The average drug content was
133 .mu.g or 152 .mu.g/cm.sup.2. For the barrier layer, the target
dry weight of polymer was 300 .mu.g and the measured average dry
weight was 320.+-.13 .mu.g.
Example 2
[0093] A drug-coated stent was placed in a volumetric flask. An
appropriate amount of the extraction solvent acetonitrile with
0.02% BHT as protectant was added (e.g., in a 10 ml volumetric
flask, with about 9 ml solvent added). The flask was sonicated for
a sufficient time to extract all of the drug from the reservoir
region. Then, the solution in the flask was filled to mark with the
solvent solution. The drug solution was the analyzed by HPLC. The
HPLC system consisted of a Waters 2690 system with an analytical
pump, a column compartment (set at 40.degree. C.), an auto-sampler,
and a 996 PDA detector. The column was an YMC Pro C18 (150
mm.times.4.6 I.D., 3 .mu.m particle size), maintained at a
temperature of 40.degree. C. The mobile phase consisted of 75%
acetonitrile and 25% 20 mMolar ammonium acetate. The flow rate was
set on 1 ml/min. The HPLC release rate results were quantified by
comparing the results with a reference standard. The total drug
content of the stent was then calculated.
Example 3
[0094] 34 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of 1.9%
(w/w) EVAL and 1.1% (w/w) 40-O-(2-hydroxy)ethyl-rapamycin in a
mixture of 67.9% (w/w) dimethylacetamide and 29.1% (w/w) ethanol
was spray coated onto the stents to a thickness with a target of
275 .mu.g of 40-O-(2-hydroxy)ethyl-rapamycin on each stent. The
stents were then baked at 50.degree. C. for 2 hours. A barrier
layer was formed by spraying the stents with a 4% (w/w) solution of
EVAL in a mixture of 76% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0095] A select number of stents were analyzed to compare the
target coating formulation with the final coating formulation. The
results are as follows: For the primer layer, there was a target
dry weight of 40 .mu.g of polymer, and a measured average dry
weight of 43.+-.3 .mu.g of polymer. For the reservoir layer, the
target drug:polymer ratio was 1:1.75, the target dry weight for the
entire reservoir coating was 757 .mu.g and the average actual dry
weight was 752.+-.23 .mu.g. Also for the reservoir layer, the
average total drug content of the stent coatings was determined by
the process described in Example 2. The average drug content was
205 .mu.g or 235 .mu.g/cm.sup.2. For the barrier layer, the target
dry weight of polymer was 200 .mu.g and the measured average dry
weight was 186.+-.13 .mu.g.
Example 4
[0096] 24 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of 1.9%
(w/w) EVAL and 1.2% (w/w) 40-O-(2-hydroxy)ethyl-rapamycin in a
mixture of 67.8% (w/w) dimethylacetamide and 29.1% (w/w) ethanol
was spray coated onto the stents to a thickness with a target of
325 .mu.g of 40-O-(2-hydroxy)ethyl-rapamycin on each stent. The
stents were then baked at 50.degree. C. for 2 hours. A barrier
layer was formed by spraying the stents with a 4% (w/w) solution of
EVAL in a mixture of 76% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0097] A select number of stents were analyzed to compare the
target coating formulation with the final coating formulation. The
results are as follows: For the primer layer, there was a target
dry weight of 40 .mu.g of polymer, and a measured average dry
weight of 41.+-.2 .mu.g of polymer. For the reservoir layer, the
target drug:polymer ratio was 1:1.6, the target dry weight for the
entire reservoir coating was 845 .mu.g and the average actual dry
weight was 861.+-.16 .mu.g. Also for the reservoir layer, the
average total drug content of the stent coatings was determined by
the process described in Example 2. The average drug content was
282 .mu.g or 323 .mu.g/cm.sup.2. For the barrier layer, the target
dry weight of polymer was 125 .mu.g and the measured average dry
weight was 131.+-.9 .mu.g.
Example 5
[0098] This Example 5 is referred to as the "Release Rate Profile
Procedure." A drug-coated stent was placed on a stent holder of a
Vankel Bio-Dis release rate tester (Vankel, Inc., Cary, N.C.). The
stent was dipped into an artificial medium which stabilizes the
40-O-(2-hydroxy)ethyl-rapamycin in the testing solution, including
a phosphate buffer saline solution (10 mM, pH 7.4) with 1% TRITON
X-100 (Sigma Corporation), for a designated amount of time (e.g., 3
hours). Then the solution was analyzed for the amount of drug
released from the stent coating using an HPLC process. The HPLC
system consisted of a Waters 2690 system with an analytical pump, a
column compartment (set at 40.degree. C.), an auto-sampler, and a
996 PDA detector. The column was an YMC Pro C18 (150 mm.times.4.6
I.D., 3 .mu.m particle size), maintained at a temperature of
40.degree. C. The mobile phase consisted of 75% acetonitrile and
25% 20 mMolar ammonium acetate. The flow rate was set on 1 ml/min.
After the drug solution was analyzed by HPLC the results were
quantified by comparing the release rate results with a reference
standard.
[0099] If the experimental protocol required that the stent coating
be subjected to experimental conditions for an additional time, the
stent was then dipped in a fresh medium solution for the necessary
amount of time (e.g., another 3 hours) and the drug released in the
solution was analyzed again according to the HPLC procedure
described above. The procedure was repeated according to the number
of data points required. The release rate profile could then be
generated by plotting cumulative drug released in the medium vs.
time.
Example 6
[0100] The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the
stents with coatings produced by the processes under Examples 1, 3
and 4 were tested using the in vitro HPLC process as described in
Example 5. The solution for each stent underwent two HPLC runs, and
the results were averaged.
[0101] The following Table 2 summarizes the results of the release
rate procedure for two stents from Example 1: TABLE-US-00002 TABLE
2 Time (hrs) 3 6 9 12 23 32 48 Cumulative 3.72 5.62 7.12 8.43 12.28
15.31 20.28 Release from Stent 1 (.mu.g) Cumulative 4.18 6.53 8.54
10.29 15.64 19.66 26.3 Release from Stent 2 (.mu.g)
[0102] The following Table 3 summarizes the results of the release
rate procedure for two stents from Example 3: TABLE-US-00003 TABLE
3 Time (hrs) 3 6 9 12 23 32 48 Cumulative 29.73 45.35 57.79 68.19
95.2 110.85 130.75 Release from Stent 1 (.mu.g) Cumulative 26.36
41.2 53.5 63.99 93.93 112.31 135.7 Release from Stent 2 (.mu.g)
[0103] The following Table 4 summarizes the results of the release
rate procedure for two stents from Example 4: TABLE-US-00004 TABLE
4 Time (hrs) 3 6 9 12 23 32 48 Cumulative 46.24 67.4 82.79 94.92
124.72 141.96 165.12 Release from Stent 1 (.mu.g) Cumulative 44.66
66.74 82.26 94.49 123.92 140.07 159.65 Release from Stent 2
(.mu.g)
[0104] A comparison of the release rates for the stents from
Examples 1, 3 and 4 is graphically shown in FIG. 2.
Example 7
[0105] The following Example 7 is referred to as the "3 day In Vivo
Release Rate Procedure" or the "9 day In Vivo Release Rate
Procedure," depending on the number of days the stents are inserted
into the experimental animal. The following are the materials used
for this Example:
[0106] 1. Experimental animal: One 30-45 kg Yorkshire cross
pig;
[0107] 2. BMW.TM. wires 0.014'', 190 cm;
[0108] 3. Guide wire 0.035'', 190 cm;
[0109] 4. Viking guide catheters, 7F;
[0110] 5. Introducer sheaths (8-10F);
[0111] 6. ACS 20/20 Indeflator.TM. Inflation Device;
[0112] 7. Saline; solution with heparin;
[0113] 8. Nitroglycerin, Lidocaine, other inotropic/chronotropic
drugs;
[0114] 9. Standard surgical equipment, anesthetic, and medications
as necessary;
[0115] 10. Respiratory and hemodynamic monitoring systems;
[0116] 11. Positive pressure ventilator and associated breathing
circuits;
[0117] 12. ACT machine and accessories;
[0118] 13. PTCA accessories;
[0119] 14. Ambulatory defibrillator;
[0120] 1. Fluoroscopy equipment; and
[0121] 15. Non-ionic contrast agent;
[0122] The following was the procedure used for this Example:
A. Animal Preparation.
[0123] 2. Administer Aspirin (325 mg PO) once daily starting one
day prior to stent implantation. [0124] 3. Sedate the pig. [0125]
4. Intubate the trachea via an oral approach. [0126] 5. Deliver
isoflurane (up to about 5%) to achieve and maintain an adequate
plane of anesthesia. [0127] 6. Shave the sheath introduction area
free of hair and scrub the surgical site with surgical soap and/or
antiseptic solution. [0128] 7. Place a 7F introducer sheath into
the right or left femoral artery. [0129] 8. Obtain an arterial
blood sample for a baseline ACT. [0130] 9. Administer heparin 200
units/kg IV (not to exceed 100,000 units) and obtain a blood sample
for measurement of ACT 5-10 minutes later. [0131] 10. Repeat
heparin as needed to maintain ACT .gtoreq.300 seconds. [0132] 11.
Measure and record arterial blood pressure, heart rate and
electrocardiogram (ECG). B. Angiography for Vessel Selection.
[0133] 1. Advance the guiding catheter over the guidewire into the
aortic arch and cannulate the desired vessel. [0134] 2. Administer
nitroglycerin (200 .mu.g) intra-luminally prior to baseline
angiography. [0135] 3. Perform baseline angiogram and record images
on cine. [0136] 4. With the diameter of the guiding catheter as a
reference, select vasculature that will allow a target stent to
artery ratio of about 1.1:1.0. C. Stent Preparation and Deployment.
[0137] 1. Perform online QCA and measure baseline proximal, target,
and distal reference sites. [0138] 2. Administer nitroglycerin (200
.mu.g) intra-luminally prior to stent deployment, then as needed to
control coronary artery vasospasm. [0139] 3. Inspect the stent
delivery system. Ensure that the stent is correctly positioned on
the balloon. Inspect the stent for any abnormalities. [0140] 4.
Flush guidewire lumen with heparinized saline until fluid exits the
guidewire notch. [0141] 5. Prepare Indeflator/syringe with diluted
(approximately 50:50) contrast medium. [0142] 6. Attach syringe to
test catheter inflation port; use standard techniques to fill the
inflation lumen with diluted contrast. [0143] 7. Purge syringe and
test catheter inflation lumen of all air. [0144] 8. Purge
Indeflator of all air and attach to test catheter inflation port.
[0145] 9. Position an appropriate guidewire in the distal bed of
the target artery. [0146] 10. Insert the stent delivery system
through the guiding catheter over the guidewire. [0147] 11. Advance
the stent delivery system to the pre-selected arterial deployment
site. [0148] 12. Position balloon for inflation. [0149] 13. Refer
to IFU for inflation strategy. If no IFU available, inflate the
balloon at a slow steady rate to a pressure that expands the stent
to the desired diameter. Hold at this pressure for 30 seconds.
[0150] 14. Record inflated balloon by pulling image on cine.
Perform on-line QCA and measure the inflated balloon diameter.
[0151] 15. Deflate balloon by pulling negative pressure. While
withdrawing the system, observe tactually and fluoroscopically.
Record any resistance. [0152] 16. Administer nitroglycerin (200
.mu.g) intra-luminally. [0153] 17. Assess patency, deployment, and
placement of stent via coronary angiography. [0154] 18. Assess TIMI
angiographic low grade. [0155] 19. Record on cine and video. [0156]
20. Measure post-proximal, target, and distal MLD with QCA. [0157]
21. Repeat Section C with remaining stent delivery system. [0158]
22. Measure and record heart rate, arterial blood pressure and
electrocardiogram (ECG). D. Stent Procedure End. [0159] 1. Remove
the guidewire, guiding catheter and introducer sheath. [0160] 2.
Remove introducer sheath from the femoral artery. [0161] 3. Apply
pressure to the femoral artery at the side of sheath entry. [0162]
4. Allow the animal to recover from anesthesia in an individual
cage. [0163] 5. Give Buprenorphine (0.05 mg/kg) PRN as needed for
pain. [0164] 6. Administer Ticlopidine (250 mg PO) and aspirin (325
mg PO) once daily until date of follow-up angiography. E. Study
End. [0165] 1. Euthanize the pig with an overdose of barbiturates
and/or potassium chloride. [0166] 2. Excise the heart without
flushing the vessels. [0167] 3. Harvest all stented arteries.
[0168] 4. Remove the stent from all treated arteries and place them
in dark colored amber vials for subsequent drug concentration
analysis. [0169] 5. Snap freeze the arterial tissue in liquid
nitrogen and store at -70.degree. C. until subsequent analysis of
tissue for drug concentrations as determined by HPLC.
[0170] The stents harvested from the experimental animals were
tested using an HPLC procedure to determine how much drug remained
on the stents. A drug-coated stent removed from the experimental
animal was placed in a volumetric flask. An appropriate amount of
the extraction solvent acetonitrile with 0.02% BHT as protectant
was added (e.g., in a 10 ml volumetric flask, with about 9 ml
solvent added). The flask was sonicated for a sufficient time to
extract all of the drug from the reservoir region. Then, the
solution in the flask was filled to mark with the solvent solution.
The HPLC system consisted of a Waters 2690 system with an
analytical pump, a column compartment (set at 40.degree. C.), an
auto-sampler, and a 996 PDA detector. The column was an YMC Pro C18
(150 mm.times.4.6 I.D., 3 .mu.m particle size), maintained at a
temperature of 40.degree. C. The mobile phase consisted of 75%
acetonitrile and 25% 20 mMolar ammonium acetate. The flow rate was
set on 1 ml/min. The HPLC release rate results were quantified by
comparing the results with a reference standard. The total drug
released in vivo was the difference between the average drug loaded
on the stents and the amount of drug remaining on the stents after
the stent implantation into the experimental animal.
Example 8
[0171] The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the
stents with coatings produced by the process under Example 1 were
tested using a 3 day in vivo process as described in Example 7. In
particular, stents from Example 1 were implanted into experimental
animals and then the stents were tested by HPLC to determine how
much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent
coating into the blood vessel. According to the HPLC analysis, 21.8
.mu.g of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the
coating in 3 days, or 16.4% of the total drug content of the
coating.
Example 9
[0172] The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the
stents with coatings produced by the process under Example 3 were
tested using a 3 day in vivo process as described in Example 7. In
particular, stents from Example 3 were implanted into experimental
animals and then the stents were tested by HPLC to determine how
much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent
coating into the blood vessel. According to the HPLC analysis, 7.8
.mu.g of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the
coating in 3 days, or 3.8% of the total drug content of the
coating.
Example 10
[0173] The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the
stents with coatings produced by the process under Example 4 were
tested using a 3 day in vivo process as described in Example 7. In
particular, stents from Example 4 were implanted into experimental
animals and then the stents were tested by HPLC to determine how
much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent
coating into the blood vessel. According to the HPLC analysis, 50.8
.mu.g of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the
coating in 3 days, or 18% of the total drug content of the
coating.
Example 11
[0174] The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the
stents with coatings produced by the process under Example 3 were
tested using a 9 day in vivo process as described in Example 7. In
particular, stents from Example 3 were implanted into experimental
animals and then the stents were tested by HPLC to determine how
much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent
coating into the blood vessel. According to the HPLC analysis,
29.7% of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the
coating in 9 days.
Example 12
[0175] The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the
stents with coatings produced by the process under Example 4 were
tested using a 9 day in vivo process as described in Example 7. In
particular, stents from Example 4 were implanted into experimental
animals and then the stents were tested by HPLC to determine how
much 40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent
coating into the blood vessel. According to the HPLC analysis,
39.4% of the 40-O-(2-hydroxy)ethyl-rapamycin was released from the
coating in 9 days.
Example 13
[0176] A 13 mm PIXEL stent (available from Guidant Corporation) was
coated. The stent had a yellowish-gold coating that included
ethylene vinyl alcohol copolymer and actinomycin D. The ends of the
stent were heated with a cauterizer tip for fifteen (15) seconds at
a current setting of 2.2 Amps, which corresponded to a temperature
of about 106.degree. C. at a distance of about 0.006 inches from
the stent.
[0177] After the stent was exposed to heat from the cauterizer tip,
the stent was submerged in a 50% (w/w) methanol:water bath. After
twenty-four (24) hours, the stent was observed to have drug present
at the stent end rings as indicated by a yellowish hue. The middle
section of the stent, however, was clear, indicating that the drug
had been released through the polymer. This process was repeated on
40 stents yielding similar results for all the stents.
Example 14
[0178] 13 mm PIXEL stents were coated. The stents had
yellowish-gold coatings that included ethylene vinyl alcohol
copolymer and actinomycin D. The stents were separated into three
experimental groups, and the ends of the stents were heated with a
cauterizer tip according to the parameters shown in Table 5 for
each group. After the stents were exposed to heat from the
cauterizer tip, the stent was submerged in a 50% (w/w)
methanol:water bath. After twenty-four (24) hours, the stents were
observed as summarized in Table 5. TABLE-US-00005 TABLE 5 Exposure
Experimental Current Time Group (Amps) (Seconds) Observation 1 2.0
10 Least gold coloration in the end sections compared to the stents
from Experimental Groups 2 and 3, indicating the least amount of
drug remaining in the stent coating. 2 2.2 8 Moderate gold
coloration in the end sections. 3 2.4 5 Most gold coloration in the
end sections compared to the stents from Experimental Groups 1 and
2 indicating the most amount of drug remaining in the stent
coating.
[0179] It was observed that the coating in the middle section of
the stents, which did not have significant exposure to heat from
the cauterizer tip, was clear. This indicates that the drug had
been eluted from the stents. On the other hand, the end rings of
the stents which had been exposed to heat from the cauterizer tip
still appeared gold in color, indicating the presence of drug in
the stent coating. The results above indicate that varying the
amount of time and heat exposure can modify the elution rate of
drug from the stent.
Example 15
[0180] 8 mm PIXEL stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0181] A select number of stents were analyzed to compare the
target coating formulation with the final coating formulation. The
results are as follows: For the primer layer, there was a target
dry weight of 26 .mu.g of polymer, and a measured average dry
weight of 28.+-.3 .mu.g of polymer. For the reservoir layer, the
target drug:polymer ratio was 1:1.25, and the measured average drug
content was 128 .mu.g. For the barrier layer, the measured average
dry weight was 84 .mu.g.
Example 16
[0182] 8 mm PIXEL stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0183] A select number of stents were analyzed to compare the
target coating formulation with the final coating formulation. The
results are as follows: For the primer layer, there was a target
dry weight of 26 .mu.g of polymer, and a measured average dry
weight of 28.+-.2 .mu.g of polymer. For the reservoir layer, the
target drug:polymer ratio was 1:1.5, and the measured average drug
content was 130 .mu.g. For the barrier layer, the measured average
dry weight was 81 .mu.g.
[0184] After the solvent had been substantially removed and the
coatings had been formed, a select number of stents were then heat
treated by exposing the stents to a heat of 80.degree. C. for 2
hours.
Example 17
[0185] The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the
stents with coatings produced by the processes under Examples 15
and 16 were tested using the process described in Example 5. The
following Table 6 summarizes the results of the release rate
procedure for three stents from Example 15: TABLE-US-00006 TABLE 6
Time (hrs) 3 6 9 12 24 32 48 Cumulative 15.44 24.63 32.20 38.43
56.04 64.81 77.36 Release from Stent 1 (.mu.g) Cumulative 12.70
21.29 28.57 34.55 51.19 59.27 71.15 Release from Stent 2 (.mu.g)
Cumulative 13.00 21.92 29.31 35.40 52.55 60.48 72.05 Release from
Stent 3 (.mu.g)
[0186] The following Table 7 summarizes the results of the release
rate procedure for three stents from Example 16: TABLE-US-00007
TABLE 7 Time (hrs) 3 6 9 12 24 32 48 Cumulative 5.52 9.37 12.73
15.71 24.33 29.20 38.02 Release from Stent 1 (.mu.g) Cumulative
6.73 10.86 14.39 17.41 25.99 30.29 38.00 Release from Stent 2
(.mu.g) Cumulative 5.76 9.14 12.02 14.50 21.21 24.61 31.23 Release
from Stent 3 (.mu.g)
[0187] A comparison of the release rates for the stents from
Examples 15-16 is graphically shown in FIG. 3. The results
unexpectedly show that the stent coatings that were exposed to
thermal treatment in Example 16 have a significantly lower release
rate than the stent coatings of Example 15.
Example 18
[0188] This Example 18 is referred to as the "Porcine Serum Release
Rate Procedure." A drug-coated stent was placed on a stent holder
of a Vankel Bio-Dis release rate tester. The stent was dipped into
porcine serum, with 0.1% sodium azide added, for 24 hrs. The stent
was removed from the porcine serum and the drug solution analyzed
by an HPLC procedure to determine how much drug was released into
the porcine serum. The HPLC system consisted of a Waters 2690
system with an analytical pump, a column compartment (set at
40.degree. C.), an auto-sampler, and a 996 PDA detector. The column
was an YMC Pro C18 (150 mm.times.4.6 I.D., 3 .mu.m particle size),
maintained at a temperature of 40.degree. C. The mobile phase
consisted of 75% acetonitrile and 25% 20 mMolar ammonium acetate.
The flow rate was set on 1 ml/min. The HPLC release rate results
were quantified by comparing the results with a reference
standard.
Example 19
[0189] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0190] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
45.+-.1 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1, and the measured average drug content was 151 .mu.g
as determined by Example 2. For the barrier layer, the measured
average dry weight was 234 .mu.g.
[0191] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 32.6
.mu.g, or 21.6% of the total.
Example 20
[0192] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0193] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
44.+-.3 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.8, and the measured average drug content was 97 .mu.g
as determined by Example 2. For the barrier layer, the measured
average dry weight was 184 .mu.g.
[0194] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 24.1
.mu.g, or 24.8% of the total.
Example 21
[0195] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0196] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
41.+-.1 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.8, and the measured average drug content was 227
.mu.g as determined by Example 2. For the barrier layer, the
measured average dry weight was 181 .mu.g.
[0197] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 27.5
.mu.g, or 12.1% of the total.
Example 22
[0198] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. No
barrier layer was applied for this Example.
[0199] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
44.+-.2 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.8, and the measured average drug content was 221
.mu.g as determined by Example 2.
[0200] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 129.4
.mu.g, or 58.55% of the total.
Example 23
[0201] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0202] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
42 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.5, and the measured average drug content was 184
.mu.g as determined by Example 2. For the barrier layer, the
measured average dry weight was 81 .mu.g.
[0203] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 70.1
.mu.g, or 38.1% of the total.
Example 24
[0204] 8 mm PIXEL stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0205] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
45.+-.1 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.75, and the measured average drug content was 200
.mu.g as determined by Example 2. For the barrier layer, the
measured average dry weight was 180 .mu.g.
[0206] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 39.0
.mu.g, or 19.5% of the total.
Example 25
[0207] 8 mm PIXEL stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0208] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
41.+-.4 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1, and the measured average drug content was 167 .mu.g
as determined by Example 2. For the barrier layer, the measured
average dry weight was 184 .mu.g.
[0209] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 6.0
.mu.g, or 3.6% of the total.
Example 26
[0210] 8 mm PIXEL stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0211] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 26 .mu.g of polymer, and a measured average dry weight of
24.+-.2 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.25, and the measured average drug content was 120
.mu.g as determined by Example 2. For the barrier layer, the
measured average dry weight was 138 .mu.g.
[0212] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 11.0
.mu.g, or 9.2% of the total.
Example 27
[0213] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
1% (w/w) polybutylmethacrylate, 5.7% (w/w) acetone, 50% (w/w)
xylene and 43.3% (w/w) HFE FLUX REMOVER (Techspray, Amarillo,
Tex.). Another 2 hour bake at 50.degree. C. was performed to remove
the solvent.
[0214] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
44.+-.4 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1, and the measured average drug content was 183 .mu.g
as determined by Example 2. For the barrier layer, the measured
average dry weight was 168 .mu.g.
[0215] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 21.6
.mu.g, or 11.8% of the total.
Example 28
[0216] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
1% (w/w) polybutylmethacrylate, 5.7% (w/w) acetone, 50% (w/w)
xylene and 43.3% (w/w) HFE FLUX REMOVER. Another 2 hour bake at
50.degree. C. was performed to remove the solvent.
[0217] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
41.+-.2 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.8, and the measured average drug content was 102
.mu.g as determined by Example 2. For the barrier layer, the
measured average dry weight was 97 .mu.g.
[0218] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 9.1
.mu.g, or 8.9% of the total.
Example 29
[0219] 8 mm PIXEL stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
1% (w/w) polybutylmethacrylate, 5.7% (w/w) acetone, 50% (w/w)
xylene and 43.3% (w/w) HFE FLUX REMOVER (Techspray, Amarillo,
Tex.). Another 2 hour bake at 50.degree. C. was performed to remove
the solvent.
[0220] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 26 .mu.g of polymer, and a measured average dry weight of
27.+-.2 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.25, and the measured average drug content was 120
.mu.g as determined by Example 2. For the barrier layer, the
measured average dry weight was 68 .mu.g.
[0221] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 22.0
.mu.g, or 18.3% of the total.
Example 30
[0222] A select number of stents from Example 3 were tested for the
drug release rate from the coatings according to the procedure
described in Example 18. It was determined that the average drug
released in 24 hours was 22.8 .mu.g, or 11.1% of the total.
Example 31
[0223] A select number of stents from Example 4 were tested for the
drug release rate from the coatings according to the procedure
described in Example 18. It was determined that the average drug
released in 24 hours was 57.0 .mu.g, or 20.2% of the total.
Example 32
[0224] Two stents were coated by spraying a 2% (w/w) solution of
EVAL and 98% (w/w) dimethylacetamide to'form a primer layer. For
the primer layer, there was a target dry weight of 100 .mu.g of
polymer, and the measured dry weights were 93 .mu.g and 119 .mu.g,
respectively. The two stents were then coated with an
EVAL-40-O-(2-hydroxy)ethyl-rapamycin blend at a drug:polymer ratio
of 2:1 to produce a reservoir layer. After application, it was
determined that the reservoir layers had weights of 610 .mu.g and
590 .mu.g, respectively. From the total weight of the reservoir
layers and the drug:polymer ratio, it was estimated that the
coatings contained about 407 .mu.g and 393 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin, respectively. Polymeric barrier
layers were also applied to the stents and it was determined that
the weights of the barrier layers were 279 .mu.g and 377 .mu.g,
respectfully.
[0225] The stents from this Example were then sterilized using an
ethylene oxide sterilization process. In particular, the stents
were placed in a chamber and exposed to ethylene oxide gas for 6
hours at 130-140.degree. F., with a relative humity of 45-80%. The
stents were then aerated for about 72 hours at 110-130.degree.
F.
[0226] After sterilization, the coatings were then analyzed using
an HPLC to determine the peak purity of the drug in the stent
coatings. It was determined that the
40-O-(2-hydroxy)ethyl-rapamycin in the coatings had peak purities
of about greater than 95%. FIG. 4 is a chromatograph showing the
peak purity the 40-O-(2-hydroxy)ethyl-rapamycin in one of the
coatings, labeled "ETO," as compared to a reference standard for
40-O-(2-hydroxy)ethyl-rapamycin, labeled "Ref. Std."
Example 33
[0227] Two stents were coated by spraying a 2% (w/w) solution of
EVAL and 98% (w/w) dimethylacetamide to form a primer layer. For
the primer layer, there was a target dry weight of 100 .mu.g of
polymer, and the measured dry weights were 99 .mu.g and 94 .mu.g,
respectively. The two stents were then coated with an
EVAL-40-O-(2-hydroxy)ethyl-rapamycin blend at a drug:polymer ratio
of 2:1 to produce a reservoir layer. After application, it was
determined that the reservoir layers had weights of 586 .mu.g and
588 .mu.g, respectively. From the total weight of the reservoir
layers and the drug:polymer ratio, it was estimated that the
coatings contained about 391 .mu.g and 392 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin, respectively. Polymeric barrier
layers were also applied to the stents and it was determined that
the weights of the barrier layers were 380 .mu.g and 369 .mu.g,
respectfully.
[0228] The stents from this Example were then sterilized using an
e-beam sterilization process. In particular, the stents were placed
in a stent container which was run through an e-beam chamber. While
moving through the e-beam chamber via a conveyor belt, the stent
container was exposed to an e-beam with a constant energy level so
that the stent container received between 33.11 and 46.24 KGy. The
stent therefore at any point along the length of the stent received
at a minimum 25 KGy.
[0229] After sterilization, the coating was then analyzed using an
HPLC to determine the peak purity of the drug in the stent coating.
It was determined that the 40-O-(2-hydroxy)ethyl-rapamycin in the
coating had a peak purity of about greater than 95%. FIG. 4 is a
chromatograph showing the peak purity the
40-O-(2-hydroxy)ethyl-rapamycin in one of the coatings, labeled
"e-beam," as compared to a reference standard for
40-O-(2-hydroxy)ethyl-rapamycin, labeled "Ref Std."
Example 34
[0230] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0231] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
44.+-.3 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:2, and the measured average drug content was 245 .mu.g
as determined by Example 2. For the barrier layer, the measured
average dry weight was 104 .mu.g.
[0232] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 23.5
.mu.g, or 9.6% of the total.
Example 35
[0233] 13 mm PENTA stents were coated by spraying a 2% (w/w)
solution of EVAL and 98% (w/w) dimethylacetamide. The solvent was
removed by baking at 140.degree. C. for 2 hours. A solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)
dimethylacetamide and 30% (w/w) ethanol was spray coated onto the
stents. The stents were then baked at 50.degree. C. for 2 hours. A
barrier layer was formed by spraying the stents with a solution of
EVAL in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)
pentane. Another 2 hour bake at 50.degree. C. was performed to
remove the solvent.
[0234] A select number of stents were analyzed to quantify the
coating components. For the primer layer, there was a target dry
weight of 40 .mu.g of polymer, and a measured average dry weight of
45.+-.3 .mu.g of polymer. For the reservoir layer, the drug:polymer
ratio was 1:1.5, and the measured average drug content was 337
.mu.g as determined by Example 2. For the barrier layer, the
measured average dry weight was 169 .mu.g.
[0235] After the coatings were formed on the stents, a select
number of stents were tested for the drug release rate from the
coatings according to the procedure described in Example 18. It was
determined that the average drug released in 24 hours was 37.1
.mu.g, or 11.0% of the total.
Example 36
[0236] Stents from Example 34 and stents from Example 35 were
sterilized according to the process described in Example 32. The
released rates of the drug in the stent coatings of sterilized
stents and non-sterilized were then tested according to the process
described in Example 5. The results of the release rate test are
graphically shown in FIG. 5.
Example 37
[0237] A 13 mm PENTA stent can be coated by spraying a solution of
EVAL, 40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent.
The stent is then baked at 50.degree. C. for 2 hours to yield a
reservoir coating with 300 .mu.g of EVAL and 300 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and pentane. A second 2
hour bake at 50.degree. C. can be performed to remove the solvent
to yield a barrier coating with 320 .mu.g of EVAL.
Example 38
[0238] A 13 mm PENTA stent can be coated by spraying a solution of
EVAL and DMAC onto the stent. The solvent is removed by baking at
140.degree. C. for 2 hours to yield a primer coating with 100 .mu.g
of EVAL. A reservoir layer can be applied by spraying a solution of
EVAL, 40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent.
The stent is then baked at 50.degree. C. for 2 hours to yield a
reservoir coating with 200 .mu.g of EVAL and 400 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and pentane. A second 2
hour bake at 50.degree. C. is performed to remove the solvent to
yield a barrier coating with 350 .mu.g of EVAL.
Example 39
[0239] A 13 mm PENTA stent can be coated by spraying a solution of
EVAL, 40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent.
The stent is then baked at 50.degree. C. for 2 hours to yield a
reservoir coating with 500 .mu.g of EVAL and 250 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and pentane. A second 2
hour bake at 50.degree. C. is performed to remove the solvent to
yield a barrier coating with 300 .mu.g of EVAL.
Example 40
[0240] A 13 mm PENTA stent can be coated by spraying a solution of
EVAL, 40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent.
The stent is then baked at 50.degree. C. for 2 hours to yield a
reservoir coating with 475 .mu.g of EVAL and 175 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and pentane. A second 2
hour bake at 50.degree. C. is performed to remove the solvent to
yield a barrier coating with 300 .mu.g of EVAL.
Example 41
[0241] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 400 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 300 .mu.g of EVAL.
Example 42
[0242] An 8 mm Pixel stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 400 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of polybutylmethacrylate
("PBMA") and HFE FLUX REMOVER. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 150 .mu.g of PBMA.
Example 43
[0243] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 200 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 200 .mu.g of EVAL.
Example 44
[0244] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 200 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can formed by
spraying the stent with a solution of PBMA and HFE FLUX REMOVER. A
second 2 hour bake at 50.degree. C. is performed to remove the
solvent to yield a barrier coating with 150 .mu.g of PBMA.
Example 45
[0245] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 200 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 200 .mu.g of EVAL.
Example 46
[0246] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 200 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of PBMA and HFE FLUX REMOVER. A
second 2 hour bake at 50.degree. C. is performed to remove the
solvent to yield a barrier coating with 100 .mu.g of PBMA.
Example 47
[0247] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 270 .mu.g of EVAL and 150 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 150 .mu.g of EVAL.
Example 48
[0248] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 170 .mu.g of EVAL and 150 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of PBMA and HFE FLUX REMOVER. A
second 2 hour bake at 50.degree. C. is performed to remove the
solvent to yield a barrier coating with 75 .mu.g of PBMA.
Example 49
[0249] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 150 .mu.g of EVAL and 150 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 200 .mu.g of EVAL. A finishing layer can then applied by
spraying the stent with a solution of EVAL, polyethyleneoxide
(molecular weight of 17.5 K) ("PEO") and dimethylacetamide. The
stent is baked at 50.degree. C. for 2 hours to remove the solvent
to yield a finishing coating with 83 .mu.g of EVAL and 17 .mu.g of
PEO.
Example 50
[0250] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 270 .mu.g of EVAL and 150 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 150 .mu.g of EVAL. A finishing layer can then applied by
spraying the stent with a solution of EVAL, PEO and
dimethylacetamide. The stent is baked at 50.degree. C. for 2 hours
to remove the solvent to yield a finishing coating with 83 .mu.g of
EVAL and 17 .mu.g of PEO.
Example 51
[0251] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 200 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 100 .mu.g of EVAL.
Example 52
[0252] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 200 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL, KYNAR and HFE FLUX
REMOVER. A second 2 hour bake at 50.degree. C. is performed to
remove the solvent to yield a barrier coating with 50 .mu.g of EVAL
and 50 .mu.g of KYNAR.
Example 53
[0253] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 350 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer is formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 200 .mu.g of EVAL.
Example 54
[0254] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 350 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of PBMA and HFE FLUX REMOVER. A
second 2 hour bake at 50.degree. C. is performed to remove the
solvent to yield a barrier coating with 100 .mu.g of PBMA.
Example 55
[0255] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 350 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 200 .mu.g of EVAL.
Example 56
[0256] An 8 mm PIXEL stent is coated by spraying a solution of EVAL
and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 350 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of EVAL and a mixture of
dimethylacetamide and pentane. A second 2 hour bake at 50.degree.
C. is performed to remove the solvent to yield a barrier coating
with 100 .mu.g of EVAL. A finishing layer can then be applied by
spraying the stent with a solution of EVAL, PEO and
dimethylacetamide. The stent is baked at 50.degree. C. for 2 hours
to remove the solvent to yield a finishing coating with 83 .mu.g of
EVAL and 17 .mu.g of PEO.
Example 57
[0257] An 8 mm PIXEL stent can be coated by spraying a solution of
EVAL and 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of
dimethylacetamide and ethanol onto the stent. The stent is then
baked at 50.degree. C. for 2 hours to yield a reservoir coating
with 350 .mu.g of EVAL and 200 .mu.g of
40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed by
spraying the stent with a solution of PBMA and HFE FLUX REMOVER. A
second 2 hour bake at 50.degree. C. is performed to remove the
solvent to yield a barrier coating with 75 .mu.g of PBMA. A
finishing layer can then be applied by spraying the stent with a
solution of PBMA, PEO and dimethylacetamide. The stent is baked at
50.degree. C. for 2 hours to remove the solvent to yield a
finishing coating with 62.5 .mu.g of PBMA and 12.5 .mu.g of
PEO.
[0258] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects.
* * * * *