U.S. patent application number 11/282849 was filed with the patent office on 2006-04-06 for therapeutic composition and a method of coating implantable medical devices.
This patent application is currently assigned to Advanced Cardiovascular Systems, Inc.. Invention is credited to Ni Ding.
Application Number | 20060073183 11/282849 |
Document ID | / |
Family ID | 36101905 |
Filed Date | 2006-04-06 |
United States Patent
Application |
20060073183 |
Kind Code |
A1 |
Ding; Ni |
April 6, 2006 |
Therapeutic composition and a method of coating implantable medical
devices
Abstract
A therapeutic composition is provided including a polysaccharide
or a cationic peptide dissolved in an organic substance. The
polysaccharide can be heparin or a derivative of heparin. The
cationic peptide can be L-arginine, oligo-L-arginine or
poly-L-arginine. The organic substance can be formamide. A method
of coating an implantable medical device is also provided,
comprising applying the therapeutic composition to the device and
allowing the organic substance to evaporate. The device can be a
stent.
Inventors: |
Ding; Ni; (San Jose,
CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA
SUITE 300
SAN FRANCISCO
CA
94111
US
|
Assignee: |
Advanced Cardiovascular Systems,
Inc.
|
Family ID: |
36101905 |
Appl. No.: |
11/282849 |
Filed: |
November 17, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10104179 |
Mar 20, 2002 |
|
|
|
11282849 |
Nov 17, 2005 |
|
|
|
Current U.S.
Class: |
424/426 ;
427/2.26; 514/291; 514/449; 514/56 |
Current CPC
Class: |
A61L 31/10 20130101;
C08L 5/10 20130101; C08L 71/02 20130101; C08L 5/08 20130101; A61F
2/82 20130101; A61L 31/16 20130101; A61L 2300/416 20130101; A61L
31/10 20130101; A61L 2300/606 20130101; A61L 31/10 20130101; A61L
31/10 20130101 |
Class at
Publication: |
424/426 ;
427/002.26; 514/056; 514/291; 514/449 |
International
Class: |
A61K 31/727 20060101
A61K031/727; A61K 31/4745 20060101 A61K031/4745; A61K 31/337
20060101 A61K031/337; A61K 6/083 20060101 A61K006/083 |
Claims
1. A therapeutic composition comprising heparin dissolved in an
organic solvent.
2. The therapeutic composition of claim 1, wherein dissolved is
defined as at least 8% by mass of heparin solubility in the organic
solvent.
3. The therapeutic composition of claim 1, wherein the organic
solvent comprises formamide.
4. The therapeutic composition of claim 1, additionally including
one or a combination of a polymer, a therapeutic substance and a
second solvent.
5. The therapeutic composition of claim 4, wherein the therapeutic
substance is paclitaxel, decetaxel, rapamycin, or derivatives
thereof.
6. A method of coating an implantable medical device, comprising
applying the composition of claim 1 to the device and removing the
organic solvent.
7. The method of claim 6, wherein the device is a stent.
8. The method of claim 6, wherein the composition additionally
comprises one or a combination a polymer, a therapeutic substance
and a solvent.
9. The method of claim 8, wherein the device is a stent.
10. The method of claim 8, wherein the therapeutic substance is
paclitaxel, decetaxel, rapamycin, or derivatives thereof.
11. The method of claim 10, wherein the device is a stent.
Description
CROSS REFERENCE
[0001] This application is a continuation of application Ser. No.
10/104,179, filed on Mar. 20, 2002 (which is incorporated herein by
reference).
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to compositions such as those used
for coating implantable medical devices such as stents.
[0004] 2. Description of Related Art
[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 radially compress against
the atherosclerotic plaque of the lesion 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.
Moreover, thrombosis may develop shortly after the procedure and
restenosis of the artery may develop over several months after the
procedure, which may require 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,
a stent is implanted in the lumen to maintain the vascular
patency.
[0007] Stents are used not only as a mechanical intervention but
also as a vehicle for providing biological therapy. As a mechanical
intervention, 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.
Biological therapy for reducing or eliminating thrombosis or
restenosis 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 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.
[0008] Local delivery can be accomplished by coating the stent with
a polymeric carrier containing a biologically active agent. A
polymer dissolved in an organic solvent and the agent added thereto
are applied to the stent and the organic solvent is allowed to
evaporate, leaving a polymeric coating impregnated with the
agent.
[0009] Biologically active agents including polysaccharides, e.g.,
heparin, and polycationic peptides, e.g., poly-L-arginine have
proven to provide beneficial effects in the treatment of thrombosis
and restenosis, more particularly when used in conjunction with a
stent. However, incorporation of these compounds into a polymeric
carrier has proven to be challenging due to such compounds' limited
solubility. To pose the problem more concretely by way of example,
heparin is soluble in water but not in organic solvents, while
conventional polymers used for the sustained release of heparin are
soluble in organic solvents but not water. To avoid the problem of
solubility incompatibility, efforts have been made to fabricate
heparin-polymer coatings from heparin-polymer suspensions. For
example, U.S. Pat. Nos. 5,837,313 and 5,879,697, disclose
micronizing heparin followed by physically blending with a polymer
and solvent to form the suspension. The suspension methods have
drawbacks and disadvantages. The manufacturing process, for
example, requires spraying equipment capable of handling particles.
In addition, heparin-polymer suspensions lack sufficient stability
in the absence of suspension agents and require constant agitation
during the coating process.
[0010] Alternatively, a complex of heparin with a cationic
surfactant can be formed for converting the heparin into an
organically soluble compound. Examples of suitable surfactant
counter ions include benzalkonium and tridodecylmethyl ammonium.
However, a surfactant-bound heparin has lower antithrombotic
activity because the surfactant alters heparin's charge balance and
binding coefficient with coagulation cofactors.
[0011] In view of the foregoing, there is a need to prepare a true
solution of polysaccharides and cationic peptides with organic
solvent compositions commonly used to form polymeric coatings on
implantable medical devices.
SUMMARY
[0012] In accordance with one embodiment of the invention, a
therapeutic composition comprising a polysaccharide or a cationic
peptide dissolved in an organic substance is provided. The
polysaccharide can be heparin, heparin salts, heparinoids,
heparin-based compounds, heparin having a hydrophobic counter-ion,
dermatan sulfate, keratan sulfate, chondroitin sulfate, hyaluronic
acid and hyaluronates. The cationic peptide can be L-arginine,
oligo-L-arginine, poly-L-arginine, or arginine-containing peptide.
The organic substance can be formamide.
[0013] In accordance with another embodiment of the invention, a
method of coating an implantable medical device, for example a
stent, is provided, comprising applying the above mentioned
composition to the device and allowing the organic substance to
evaporate.
[0014] In accordance with another embodiment, a method of coating a
stent is provided. The method includes the acts of preparing a
solution comprising heparin or a heparin derivative in an organic
substance; applying the solution to the stent; and allowing the
organic substance to evaporate. The organic substance can be
formamide. In one embodiment, the method additionally includes
combining the solution with a composition including a polymer and
optionally a biologically active substance. The polymer can be, for
example, poly(ethylene-co-vinyl alcohol), polyacrylates, poly
(ethylene glycol), polyurethanes, polyesters, fluorinated polymers,
and mixtures or combinations thereof. The biologically active
substance can be, for example, actinomycin D, rapamycin, taxol,
estradiol, poly(ethylene glycol)/poly(ethylene oxide), and
derivatives thereof.
[0015] In accordance with another embodiment, a method for coating
a stent is provided, comprising preparing a solution comprising
L-arginine, or polymers or oligomers thereof, in an organic
substance; applying the solution to the stent, and allowing the
organic substance to evaporate. The organic substance can be
formamide. In one embodiment, the method additionally comprises
combining the solution with a composition including a polymer and
optionally a biologically active substance.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 schematically depicts a cross-section of a coating on
a stent in accordance with one embodiment of the present
invention.
[0017] FIG. 2 is a scanning electronic micrograph (SEM) showing a
coated stent, where the stent coating included heparin applied in
accordance with one embodiment of the present invention.
DETAILED DESCRIPTION
[0018] FIG. 1 illustrates a partial cross section of a substrate 1
of an implantable medical device, such as a stent, having a
coating. The coating can include, for example, an optional primer
layer 2, a reservoir layer 3, and an optional topcoat layer 4.
According to one embodiment of the present invention, the reservoir
layer 3 can comprise a polymer and a polysaccharide. One example of
a biologically active polysaccharide is heparin or a heparin
derivative. Heparin is known to have an antithrombotic property,
among other biologically active functions, and can be made from a
mixture of sulfated polysaccharide chains based on D-glucosamine
and D-glucoronic or L-iduronic acid.
[0019] "Heparin derivative" or "derivative of heparin" is intended
to include any functional or structural variation of heparin.
Representative variations include alkali metal or alkaline-earth
metal salts of heparin, such as sodium heparin (also known as
hepsal or pularin), potassium heparin (formerly known as clarin),
lithium heparin, calcium heparin (also known as calciparine),
magnesium heparin (also known as cutheparine), and low molecular
weight heparin (also known as ardeparin sodium). Other examples
include heparan sulfate, heparinoids, heparin-based compounds and
heparin having a hydrophobic counter-ion.
[0020] Examples of other polysaccharides include glycosaminoglycans
(or mucopolysaccharides) such as keratan sulfate, chondroitin
sulfate, dermatan sulfate (also known as .beta.-heparin or as
chondroitin sulfate B), hyaluronic acid and hyaluronates.
[0021] According to another aspect of the present invention, the
reservoir layer 3 can comprise highly positively charged peptides
or proteins, such as L-arginine or oligomers and polymers of
L-arginine. These oligomers and polymers are oligo- or polycationic
peptides (or proteins) and are products of self-polycondensation of
an amino acid L-arginine, also known as 2-amino-5-guanidinovaleric
acid having a formula
NH.dbd.C(NH.sub.2)--NH--CH.sub.2--CH.sub.2--CH(NH.sub.2)COOH.
[0022] One example of oligomeric L-arginine that can be used is a
heptamer known as R7. Oligomers and polymers of L-arginine can be
used in a form of a derivative, such as a salt, for example,
hydrochloride, trifluoroacetate, acetate, or sulfate salts.
Oligomers and polymers of L-arginine, including R7, for the
purposes of the present invention are collectively designated as
PArg. A general formula of PArg as a hydrochloride salt can be
represented as H[--NH--CHR--CO--].sub.mOH.HCl, or PArg.HCl, where
"m" can be an integer within a range of between 5 and 1,000 and "R"
is 1-guanidinopropyl radical having the structure
--CH.sub.2--CH.sub.2--CH.sub.2--NH--C(NH.sub.2).dbd.NH. In case of
R7, m equals 7. "L-arginine," "oligomers and polymers of
L-arginine," or "PArg" is intended to include pure L-arginine in
its monomeric, oligomeric or polymeric form as well as derivatives
of L-arginine.
[0023] Formamide (H--CO--NH.sub.2) can be used as a solubilizing
agent for heparin, heparin derivatives, or PArg. Heparin or a
heparin derivative or PArg can be dissolved in formamide. At least
8% by mass of a solution of heparin or a derivative thereof or PArg
in formamide can be prepared.
[0024] A heparin-formamide solution or a PArg-formamide solution
can be mixed with a polymer. Should the polymer not be capable of
dissolving in formamide, the polymer can be first admixed with an
organic solvent or a mixture of organic solvents capable of
dissolving the polymer. The solution can be applied onto the
surface of the stent or onto the primer layer 2 by spraying or
dipping techniques as is well known to one of ordinary skilled in
the art. Alternatively, the heparin-formamide solution or the
PArg-formamide solution can be applied followed by applying the
solution of the polymer in the organic solvent or the mixture of
organic solvents. The process can be repeated to obtain a suitable
weight of the compound on the stent.
[0025] FIG. 2 is a SEM of a stent coating which includes heparin
applied according to one embodiment of the present invention. The
coating shown on FIG. 2 was comprised of:
[0026] (a) a reservoir 3 having about 740 .mu.g of total solids
which included poly(ethylene-co-vinyl alcohol) (EVAL) and heparin
in a 2:1 mass ratio; and
[0027] (b) a topcoat layer (about 54 .mu.g of EVAL).
[0028] As evidenced by the micrograph, a very smooth coating was
obtained.
[0029] The above-mentioned poly(ethylene-co-vinyl alcohol) (EVAL)
is one example of a suitable polymer than can be employed to
prepare the drug-polymer layer 3, the optional primer layer 2
and/or the optional topcoat layer 4. EVAL has the general formula
--[CH.sub.2--CH.sub.2].sub.m--[CH.sub.2--H(OH)].sub.n--. EVAL is a
product of hydrolysis of ethylene-vinyl acetate copolymers. EVAL
can also be a terpolymer including up to, for example, 5 molar % of
units derived from styrene, propylene and other suitable
unsaturated monomers. Other suitable polymers that can be used
include 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), co-poly(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, such as poly(alkyl)(meth) acrylates, for
example, poly(butyl methacrylate) and copolymers of butyl
methacrylate, for instance, with hydroxymethyl methacrylate; 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 and its derivatives, cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellophane,
cellulose nitrate, cellulose propionate, cellulose ethers, soluble
fluorinated polymers and carboxymethyl cellulose.
[0030] The topcoat layer 4 may also contain a small amount of
Na-heparin and/or PArg. The reservoir layer 3 can optionally
include a therapeutic agent with or without heparin or PArg. If
such an agent is to be used, the agent can be either incorporated
into the heparin or PArg composition, the polymer composition, or
added subsequent to the combination of these compositions. Examples
such of suitable therapeutic agents include actinomycin D or
derivatives and analogs thereof. Synonyms of actinomycin D include
dactinomycin, actinomycin IV, actinomycin I.sub.1, actinomycin
X.sub.1, and actinomycin C.sub.1. The active agent can also fall
under the genus of antineoplastic, anti-inflammatory, antiplatelet,
anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,
anfiallergic and antioxidant substances. Examples of such
antineoplastics and/or antimitotics include paclitaxel (e.g.
Taxol.RTM. by Bristol-Myers Squibb Co. of Stamford, Conn.),
docetaxel (e.g. Taxotere.RTM., from Aventis S. A. of Frankfurt,
Germany) methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin.RTM. from
Pharmacia & Upjohn, of Peapack N.J.), and mitomycin (e.g.
Mutamycin.RTM. from Bristol-Myers Squibb Co. of Stamford). Examples
of such antiplatelets, anticoagulants, antifibrin, and
antithrombins include hirudin, argatroban, forskolin, vapiprost,
prostacyclin and prostacyclin analogues, dextran,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor
antagonist antibody, recombinant hirudin, and thrombin inhibitors
such as Angiomax.RTM. made by Biogen, Inc., of Cambridge, Mass.).
Examples of such cytostatic or antiproliferative agents include
angiopeptin, angiotensin converting enzyme inhibitors such as
captopril (e.g. Capoten.RTM. and Capozide.RTM. from Bristol-Myers
Squibb Co. of Stamford), cilazapril or lisinopril (e.g.
Prinivil.RTM. and Prinzide.RTM. from Merck & Co., Inc. of
Whitehouse Station, N.J.); calcium channel blockers (such as
nifedipine), colchicine, fibroblast growth factor (FGF)
antagonists, fish oil (omega 3-fatty acid), histamine antagonists,
lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol
lowering drug, brand name Mevacor.RTM. from Merck & Co., Inc.,
of Whitehouse Station, N.J.), monoclonal antibodies (such as those
specific for Platelet-Derived Growth Factor (PDGF) receptors),
nitroprusside, phosphodiesterase inhibitors, prostaglandin
inhibitors, suramin, serotonin blockers, steroids, thioprotease
inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric
oxide. An example of an antiallergic agent is permirolast
potassium. Other therapeutic substances or agents which may be
appropriate include alpha-interferon, genetically engineered
epithelial cells, rapamycin and its derivatives, estradiol and its
derivatives, poly(ethylene glycol)/poly(ethylene oxide) and
dexamethasone.
[0031] The embodiments of the present invention are described with
reference to a stent, such as a self-expandable or a balloon
expandable stent. Other suitable implantable medical device can
also be similarly coated. Examples of such implantable devices
include, but are not limited to, 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 Corp.). 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), "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. of
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.
[0032] Embodiments of the present invention are further illustrated
by the following examples:
EXAMPLE 1
[0033] About 1 milliliter (1.133 gram) of formamide was added to
0.1 gram of sodium heparin (NaHep) obtained from Aldrich Chemical
Co. of Milwaukee, Wis. The suspension was heated at a temperature
about 70.degree. C. After about 5 minutes of heating, sodium
heparin was fully dissolved in formamide to form about 8.1 mass %
NaHep solution. About 0.15 gram of EVAL was dissolved in about 0.85
gram of dimethylacetamide (DMAC) to form 15% (mass) solution of
EVAL. About 1 gram of the 15% EVAL solution was further dissolved
in a mixture of about 2 grams of DMAC and about 1 gram of methyl
alcohol. This final EVAL solution was added to the NaHep-formamide
solution prepared above. The two solutions were thoroughly mixed to
form a clear heparin-polymer (NaHep-EVAL) solution. The NaHep-EVAL
solution had a solid content of about 4.8 mass % and the mass ratio
of NaHep to EVAL of about 2:3.
[0034] At room temperature, the NaHep-EVAL solution was not
sufficiently stable and developed substantial turbidity within
about 15 minutes after the mixing of the NaHep-formamide solution
and the EVAL solution. In order to avoid the phase separation, the
NaHep-EVAL solution was heated at about 70.degree. C. for several
minutes until the solution had become clear again. When kept at a
temperature of about 40.degree. C, the NaHep-EVAL solution was
clear and stable.
[0035] Prior to application, the NaHep-EVAL solution was filtered
through 0.45 micron filter. The NaHep-EVAL solution was then
applied to a stent using a spray apparatus, such as an EFD 780S
spray nozzle with a VALVEMATE 7040 control system, manufactured by
EFD, Inc. of East Providence, R.I. The EFD 780S spray nozzle is an
air-assisted external mixing atomizer. The composition was atomized
by air and applied to the stent surfaces at a pressure of about
103.4 kPa (15 psi or 1.03 atm). The distance between the spray
nozzle and the stent surface was about 105 mm. The NaHep-EVAL
solution was fed to the spray block at a pressure of about 23.3 kPa
(3.35 psi or 0.23 atm).
[0036] The container with NaHep-EVAL solution was maintained at a
temperature of about 40.degree. C., in order to avoid possible
precipitation of the polymer or the drug. The spray block
temperature was kept at about 60.degree. C. During the process of
applying the composition, the stent can be optionally rotated about
its longitudinal axis, at a speed of 50 to about 150 rpm. The stent
can also be linearly moved along the same axis during the
application.
[0037] The NaHep-EVAL solution was applied to a 18-mm TETRA stent
(available from Guidant Corp.) in a series of 10-second passes, to
deposit about 45 .mu.g of coating per spray pass. Between the spray
passes, the stent was dried for 10 seconds using flowing air with a
temperature of about 80.degree. C. to 100.degree. C. A total of
about 1.2 milligram of solid mass was applied. The coated stent was
partially dried overnight at room temperature. Upon visual
inspection, no pool webs were observed.
EXAMPLE 2
[0038] About 1 milliliter (1.133 gram) of formamide was added to
about 0.1 gram of poly-L-arginine sulfate. The suspension was
heated at a temperature of 50.degree. C. After a few minutes of
heating, PArg was fully dissolved in formamide to form about 8.1
mass % PArg solution. About 0.15 gram of EVAL was dissolved in
about 0.85 gram of DMAC to form 15% (mass) solution of EVAL. About
1 gram of the 15% EVAL solution was further dissolved in a mixture
of about 2 grams of DMAC and about 1 gram of methyl alcohol. This
final EVAL solution was added to the PArg-formamide solution. The
two solutions were thoroughly mixed to form the PArg-EVAL solution.
The PArg-EVAL solution had a solid content of about 4.8 mass % and
the mass ratio of PArg to EVAL of about 2:3.
[0039] At room temperature, the PArg-EVAL solution was not
sufficiently stable and developed substantial turbidity within
about 15 minutes after the mixing of the PArg-formamide solution
with the EVAL solution. In order to avoid phase separation, the
PArg-EVAL solution was heated at about 70.degree. C. for several
minutes until the solution became clear again. When kept at a
temperature of about 40.degree. C., the PArg-EVAL solution was
clear and stable.
[0040] Using the process and equipment described in Example 1, the
PArg-EVAL solution was applied to an 8-mm TETRA stent. 10 .mu.g of
coating per spray pass was applied. Between the spray passes, the
stent was dried for 10 seconds using flowing air with a temperature
of about 80.degree. C. to 100.degree. C. A total of about 500
milligram of solid mass was applied. Upon visual inspection, no
pool webs were observed.
EXAMPLE 3
[0041] A drug-polymer layer containing NaHep-EVAL was formed on a
stent according to the procedure described in Example 1. A 2%
(mass) solution of EVAL in DMAC was prepared by mixing about 2
grams of EVAL and about 98 grams of DMAC. Using the process and
equipment described in Example 1, the 2% EVAL solution was applied
to an 8-mm TETRA stent coated with the NaHep-EVAL drug-polymer
layer to form a topcoat layer. About 10 .mu.g of coating per spray
pass was deposited. A total of about 33 .mu.g of solid mass was
applied as a topcoat layer followed by drying in a convection oven
at about 70.degree. C. for about 2 hours.
[0042] Using the process and equipment described in Example 1, the
2% EVAL solution was also applied to an 18-mm TETRA stent coated
with the NaHep-EVAL drug-polymer. layer to form a topcoat layer.
About 20 .mu.g of coating per spray pass was deposited. A total of
about 120 .mu.g of solid mass was applied as a topcoat layer
followed by drying in a convection oven at about 70.degree. C. for
about 2 hours.
EXAMPLE 4
[0043] A drug-polymer layer containing PArg-EVAL was formed on a
stent according to the procedure described in Example 1. A 2%
(mass) solution of EVAL in DMAC was prepared by mixing about 2
grams of EVAL and about 98 grams of DMAC. Using the process and
equipment described in Example 1, the 2% EVAL solution was applied
on an 8-mm TETRA stent coated with the PArg-EVAL drug-polymer layer
to form a topcoat layer. About 10 .mu.g of coating per spray pass
was deposited. A total of about 40 .mu.g of solid mass was applied
as a topcoat layer followed by drying in a convection oven at about
70.degree. C. for about 2 hours.
[0044] Using the process and equipment described in Example 1, the
2% EVAL solution was also applied to an 18-mm TETRA stent coated
with the PArg-EVAL drug-polymer layer to form a topcoat layer.
About 20 .mu.g of coating per spray pass was deposited. A total of
about 400 .mu.g of solid mass was applied as a topcoat followed by
drying in a convection oven at about 70.degree. C. for about 2
hours.
[0045] 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. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *