U.S. patent application number 13/085623 was filed with the patent office on 2011-08-11 for loading and release of water-insoluble drugs.
This patent application is currently assigned to BOSTON SCIENTIFIC SCIMED, INC.. Invention is credited to James J. Barry, Maria Palasis.
Application Number | 20110196340 13/085623 |
Document ID | / |
Family ID | 22626067 |
Filed Date | 2011-08-11 |
United States Patent
Application |
20110196340 |
Kind Code |
A1 |
Barry; James J. ; et
al. |
August 11, 2011 |
LOADING AND RELEASE OF WATER-INSOLUBLE DRUGS
Abstract
A medical device, polymer composition, and method for delivering
substantially water-insoluble drugs to tissue at desired locations
within the body. At least a portion of the exterior surface of the
medical device is provided with a polymer coating. Incorporated in
the polymer coating is a solution of at least one substantially
water-insoluble drug in a volatile organic solvent. The medical
device is positioned to a desired target location within the body,
whereupon the drug diffuses out of the polymer coating.
Inventors: |
Barry; James J.; (Marlboro,
MA) ; Palasis; Maria; (Wellesley, MA) |
Assignee: |
BOSTON SCIENTIFIC SCIMED,
INC.
Maple Grove
MN
|
Family ID: |
22626067 |
Appl. No.: |
13/085623 |
Filed: |
April 13, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11833717 |
Aug 3, 2007 |
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13085623 |
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11188850 |
Jul 26, 2005 |
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11833717 |
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09978763 |
Oct 18, 2001 |
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11188850 |
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09172026 |
Oct 14, 1998 |
6306166 |
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09978763 |
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09133603 |
Aug 13, 1998 |
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09172026 |
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08910136 |
Aug 13, 1997 |
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09133603 |
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Current U.S.
Class: |
604/509 ;
427/2.3 |
Current CPC
Class: |
A61L 31/10 20130101;
A61M 2025/1081 20130101; A61L 31/10 20130101; A61M 25/10 20130101;
A61L 2300/604 20130101; A61L 27/34 20130101; A61L 31/10 20130101;
A61L 2300/602 20130101; A61L 31/16 20130101; A61M 2025/1088
20130101; A61L 31/10 20130101; A61M 2025/1075 20130101; A61M
2025/0057 20130101; A61M 25/1027 20130101; A61M 2025/105 20130101;
A61L 29/16 20130101; A61F 2/82 20130101; A61L 2300/222 20130101;
A61L 29/085 20130101; A61L 2300/416 20130101; A61L 2300/45
20130101; A61L 2300/606 20130101; A61M 29/02 20130101; C08L 75/04
20130101; C08L 67/04 20130101; A61L 27/54 20130101; C08L 33/08
20130101 |
Class at
Publication: |
604/509 ;
427/2.3 |
International
Class: |
A61M 25/10 20060101
A61M025/10 |
Claims
1. A method of preparing an angioplasty balloon catheter having a
balloon with an exterior surface, the method comprising: mixing at
least one drug with a volatile solvent to create a drug solution,
the at least one drug comprising paclitaxel and the volatile
solvent comprising at least one volatile organic solvent optionally
in mixture with water; applying said drug solution to said exterior
surface of the balloon, and evaporating the volatile solvent.
2. The method of claim 1, wherein said drug mixture is applied by
dipping, or spraying.
3. The method of claim 1 wherein a predetermined amount of said
solution of known concentration is applied to the balloon to
provide a balloon with a predetermined loading of paclitaxel
thereon.
4. The method of claim 3 wherein the solution is applied from a
pipette.
5. The method of claim 1, wherein said volatile solvent comprises
ethanol.
6. The method of claim 1, wherein said volatile solvent is a
mixture of a volatile organic solvent and water.
7. The method of claim 1, wherein said at least one drug consists
of paclitaxel.
8. The method of claim 1, further comprising the step of applying a
modulating layer comprising a polymer to said balloon after
evaporating said solvent.
9. The method of claim 8, wherein the modulating layer has a
thickness of about 50 to about 5000 Angstroms.
10. The method of claim 9, wherein the modulating layer has a
thickness of about 50-2000 Angstroms.
11. The method of claim 8, wherein said modulating layer further
comprises a drug.
12. The method of claim 13 wherein the modulating layer comprises a
silicone.
13. The method of claim 1 wherein said at least one drug comprising
paclitaxel further comprises a second drug selected from the group
consisting of anticoagulants, anti-inflammatory agents,
antimitotics, antithrombogenics, thrombolytics, nitric
oxide-containing polymers, vascular cell promoters, growth factors,
and mixtures thereof.
14. The method of claim 1 wherein the at least one drug further
comprises a member of the group consisting of dexamethasone,
prednisolone, corticosterone, budesonide, estrogen, sulfasalazine,
mesalamine, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, thymidine kinase inhibitors,
lidocaine, bupivacaine, ropivacaine, and mixtures thereof.
15. The method of claim 1 wherein the drug solution is applied to
the balloon while the balloon is in a substantially deflated
state.
16. The method of claim 1 wherein the drug solution is applied to
the balloon while the balloon is in an inflated state.
17. The method of claim 1 wherein total amount of paclitaxel on the
balloon after evaporating said volatile solvent is in the range of
from about 200 to about 1532 .mu.g.
18. A method of preparing an angioplasty balloon catheter having a
balloon with an exterior surface, the method comprising: mixing at
least one drug with a volatile solvent to create a drug solution,
the at least one drug selected from the group consisting of
paclitaxel dexamethasone, prednisolone, corticosterone, budesonide,
estrogen, sulfasalazine, mesalamine, 5-fluorouracil, cisplatin,
vinblastine, vincristine, epothilones, endostatin, angiostatin,
thymidine kinase inhibitors, lidocaine, bupivacaine, ropivacaine,
and mixtures thereof, and the volatile solvent comprising at least
one volatile organic solvent optionally in mixture with water;
applying said drug solution to said exterior surface of the
balloon, and evaporating the volatile solvent.
19. A method of delivering paclitaxel, to an inner wall of a blood
vessel of a patient from an angioplasty catheter having an
expandable balloon with the paclitaxel on an outer surface of the
balloon, the method comprising: providing a balloon of a balloon
catheter having a layer consisting of dried paclitaxel on the outer
surface of the balloon; and employing the catheter for vessel
dilatation.
20. A method of delivering paclitaxel to an inner wall of a blood
vessel the method comprising: providing a balloon catheter having a
balloon an outer surface and a dried layer containing the
paclitaxel on the outer surface of the balloon; advancing the
balloon within the blood vessel to a treatment site within the
blood vessel; inflating the balloon at the treatment site to
contact the balloon with an inner wall of the blood vessel; and
maintaining the inflated balloon in contact with the inner wall of
the blood vessel so as to transfer paclitaxel to the inner wall of
the blood vessel.
21. The method of claim 20, wherein the blood vessel is a coronary
artery.
22. The method of claim 20, wherein at said providing step, the
implantable medical device includes a total of from about 152 to
about 1532 .mu.g of paclitaxel in said dried layer.
23. The method of claim 20, wherein the method is performed without
implanting a stent within the blood vessel.
24. The method of claim 20, wherein the balloon comprises a
material selected from the group consisting of: a polyamide,
polyolefins, polyesters and copolymers thereof.
25. The method of claim 20, wherein the dried layer consists
essentially of about 200 to about 1532 .mu.g of paclitaxel.
26. The method of claim 20, wherein the time the inflated balloon
is in contact with the inner wall of the blood vessel corresponds
to said maintaining step.
27. A method of delivering paclitaxel to an inner wall of a blood
vessel from a balloon catheter having an expandable balloon with a
coating on an outer surface of the balloon, the method comprising:
providing a balloon catheter including a balloon with a dried
coating consisting of paclitaxel or a mixture of paclitaxel with
another bioactive agent, the dried coating being free of any
additional coating atop the dried coating; advancing the balloon
within the blood vessel to a treatment site; inflating the balloon
to directly contact the paclitaxel or mixture of paclitaxel with
another bioactive agent with an inner wall of the blood vessel; and
delivering the paclitaxel or mixture of paclitaxel with another
bioactive agent to the inner wall of the blood vessel while
maintaining the paclitaxel or mixture of paclitaxel with another
bioactive agent in direct contact with the inner wall of the blood
vessel while the balloon is inflated.
28. The method of claim 27, where the balloon is attached to a
catheter shaft that includes a guide wire lumen and an inflation
lumen for inflating the balloon.
29. The method of claim 27, where the paclitaxel or mixture of
paclitaxel with another bioactive agent is brought into direct
contact with the vessel wall only while the outer surface of the
inflated balloon is maintained in contact with the inner wall of
the blood vessel.
30. The method of claim 29, where the method is performed without
implanting a stent within the blood vessel.
31. A method of delivering paclitaxel to an interior wall of a
blood vessel from a balloon catheter having an expandable balloon
with a paclitaxel coating on an outer surface of the balloon, the
method comprising: providing a balloon catheter without a stent,
the balloon catheter having a dried coating consisting of about 200
to about 1532 .mu.g micrograms of a single bioactive coating
material consisting of paclitaxel over the outer surface area of
the balloon, the balloon catheter being free of any coating atop
the paclitaxel, where amounts of the paclitaxel are deliverable to
the interior wall upon direct contact of the paclitaxel with the
interior wall, and where the balloon has been coated in an inflated
state; advancing the balloon in a deflated state within the blood
vessel to a treatment site within the blood vessel; and inflating
the balloon at the treatment site to directly contact the
paclitaxel in the coating with the interior wall of the blood
vessel and thereby deliver paclitaxel to the interior wall without
implanting a stent within the blood vessel.
32. A method of delivering paclitaxel to an inner wall of a blood
vessel of a patient from an implantable medical device having an
expandable balloon with the paclitaxel on an outer surface of the
balloon, the method comprising the steps of: providing an
angioplasty balloon having a dried layer of coating material
containing paclitaxel on the outer surface of the balloon, wherein
the dried layer of coating material is the outermost layer on the
balloon, wherein the balloon has folds, and wherein portions of the
dried layer are positioned in the folds; advancing the balloon
within the blood vessel to a treatment site within the blood
vessel; inflating the balloon at the treatment site so as to cause
the folds to open so that portions of the balloon come into contact
with the inner wall of the blood vessel during which amounts of the
coating material containing paclitaxel are transferred to the inner
wall of the blood vessel; maintaining the inflated balloon in
contact with the inner wall of the blood vessel; deflating the
balloon after said maintaining; and removing the deflated balloon
from the blood vessel.
33. The method of claim 32, wherein the coating material consists
essentially of paclitaxel.
Description
[0001] This application is a Division of application Ser. No.
11/833,717, filed Aug. 3, 2007, which is a Division of application
Ser. No. 11/188,850, filed Jul. 26, 2005, now abandoned, which is a
Continuation of application Ser. No. 09/978,763, filed Oct. 18,
2001, now abandoned, which is a Continuation of application Ser.
No. 09/172,026, filed Oct. 14, 1998, now U.S. Pat. No. 6,306,166,
which is a Continuation-in-part of application Ser. No. 09/133,603,
filed Aug. 13, 1998, now abandoned, which is a Continuation-in-part
of application Ser. No. 08/910,136, filed Aug. 13, 1997, now
abandoned, the contents of each or which are hereby incorporated by
reference.
FIELD OF THE INVENTION
[0002] The invention relates to methods and devices for the
localized delivery of substantially water-insoluble drug agents
within the body.
BACKGROUND
[0003] The systemic administration of drug agents, such as by
transoral or intravenous means, treats the body as a whole even
though the disease to be treated may be localized. In such a case,
systemic administration may not be desirable because, for example,
the drug agents may have unwanted effects on parts of the body
which are not to be treated, or because treatment of the diseased
part of the body requires a high concentration of drug agent that
may not be achievable by systemic administration.
[0004] It is therefore often desirable to administer drug agents at
a localized site within the body. Common examples include cases of
localized disease or occluded body lumens. Various methods have
been proposed for such localized drug administration. For example,
U.S. Pat. No. 5,304,121, hereby incorporated by reference,
discloses a method of delivering water-soluble drugs to tissue at
desired locations of a body lumen wall. The method generally
includes the steps of impregnating a hydrogel polymer on an
expandable catheter with an aqueous drug solution, inserting the
catheter into a blood vessel to a desired location, and expanding
the catheter against the surrounding tissue allowing the release of
the drug to the tissue. This method of localized drug delivery
using hydrogel polymer impregnation has a limitation of being
applicable to drug agents which are dissolved in water at
concentrations sufficient for therapeutic gel loading levels. There
thus exists a need for a method and apparatus for the localized
delivery of drug agents within the body, where the drug agents are
substantially water-insoluble. Moreover, there exists a need for a
method and implantable device that provides a sustained release of
such substantially water-insoluble drug agents over a time frame
effective to inhibit proliferative disease.
SUMMARY OF THE INVENTION
[0005] One objective of the present invention is to provide a
method and apparatus for the localized delivery of substantially
water-insoluble drug agents to predetermined locations within the
human body.
[0006] A further objective of the present invention is to provide a
method and apparatus to facilitate gradual, localized release of
drug agents at predetermined locations within the human body.
[0007] A further objective of the invention is to administer drug
agents by diffusion directly into the tissue requiring treatment.
The drug is preferably applied in a manner that does not further
injure the tissue to be treated, and administration is selectively
and evenly distributed over the treated area such that the drug can
be taken up by the tissue, without, for example, being washed away
by body fluids.
[0008] The present invention provides methods and medical devices
for the localized delivery of substantially water-insoluble drugs
agents.
[0009] A particular embodiment of the present invention features a
catheter and method for delivering substantially water-insoluble
drug agents to tissue at a desired location along body lumen walls.
The catheter is constructed for insertion in a body lumen and has a
catheter shaft and an expandable portion mounted on the catheter
shaft. The expandable portion is expandable to fill the
cross-section of the body lumen. At least a portion of the exterior
surface of the expandable portion is defined by a polymer coating.
Incorporated into the polymer coating is at least one substantially
water-insoluble drug. The catheter is positioned to a desired
target location within the body, whereupon the polymer coating
absorbs water, thus dissolving the drug and resulting in the
diffusion of the drug out of the polymer coating. The polymer and
drug are selected to allow controlled release of a desired dosage
of the drug from the polymer.
[0010] Another particular embodiment of the present invention
features a stent for the localized delivery of substantially
water-insoluble drug agents to tissue at a desired location along
body lumen walls. The stent is at least partially coated with a
polymer coating having at least one substantially water-insoluble
drug therein. The stent configuration, polymer and drug are
selected to allow for the controlled release dosage and release
rate of the drug from the polymer.
[0011] In a most preferred embodiment, the stent is a patterned
stent for the localized delivery of paclitaxel to tissue at a
desired location along body lumen walls. The stent is at least
partially coated with a polymer/paclitaxel matrix that provides
sustained release of paclitaxel at the desired site within the
lumen wall.
[0012] In another aspect of the invention, there is provided a
method for preventing or inhibiting proliferative disease in a
patient comprising implanting a patterned stent comprising an outer
coating of polymer/paclitaxel at a site of cellular proliferation,
wherein the paclitaxel is released from the outer coating at a
release rate and for a period of time sufficient to inhibit or
prevent cellular proliferation at the site.
BRIEF DESCRIPTION OF THE DRAWING
[0013] FIG. 1a shows one embodiment of the present invention in
which a drug solution is impregnated into a polymer-coated balloon
catheter.
[0014] FIG. 1b shows the insertion of a polymer-coated balloon
catheter into a body lumen, in accordance with the present
invention.
[0015] FIG. 1c shows the expansion of a polymer-coated balloon
catheter at an occlusion site within a body lumen, in accordance
with the present invention.
[0016] FIG. 2 shows a drug delivery balloon catheter embodiment of
the present invention including a sheath for covering the catheter
as it is being moved through a vessel toward the occlusion to be
treated.
[0017] FIGS. 3a and 3b show the release profile of paclitaxel from
a balloon catheter having a polyacrylic acid-based coating for up
to 50 and 5000 minutes, respectively, in accordance with the
present invention.
[0018] FIGS. 4a and 4b show the release profile of dexamethasone
from a balloon catheter having a polyacrylic acid-based coating for
up to 30 and 400 minutes, respectively, in accordance with the
present invention.
[0019] FIG. 5 shows the release profiles of molsidomine from
various balloon catheters having a polyacrylic acid-based coating
for up to 5 minutes, in accordance with the present invention.
[0020] FIG. 6 shows the release profiles of dexamethasone from
various balloon catheters having a polyacrylic acid-based coating
for up to 450 minutes, in accordance with the present
invention.
[0021] FIGS. 7a and 7b show the release profiles of water-soluble
and substantially water-insoluble estradiol from balloon catheters
having a polyacrylic acid-based coatings for up to 10 and 200
minutes, respectively, in accordance with the present
invention.
[0022] FIG. 8 shows the release profile of paclitaxel for up to 10
days from polyurethane coated stents dipped in 30 mg/ml paclitaxel
in ethanol for 3 days, in accordance with the present
invention.
[0023] FIG. 9 shows the release profiles of paclitaxel from various
polyurethane-coated balloon catheters for up to 2 hours, in
accordance with the present invention.
[0024] FIG. 10 shows the cumulative release profile of paclitaxel
over a time frame of days. This figure shows the cumulative release
of paclitaxel for delivery rates of 5 .mu.g/day and 0.5
.mu.g/day.
DETAILED DESCRIPTION
[0025] The present invention provides methods and medical devices
for the localized delivery of one or more substantially
water-insoluble drug agents to predetermined locations within the
human body, such as within the vascular system, urinary tract,
prostate, esophagus, colon, brain, etc.
[0026] In accordance with an embodiment of the invention, a
substantially water-insoluble drug agent is dissolved in a volatile
organic solvent. "Organic solvent" is intended to mean a singular
organic solvent or a solvent mixture having at least one organic
component. The solvent mixture also includes mixtures of water with
miscible organic solvents. The drug solution is then applied to a
polymer coating on a medical device that is adapted for insertion
into the body. Examples of such medical devices include catheters,
guide wires, balloons, filters (e.g., vena cava filters), stents,
stent grafts, vascular grafts, intraluminal paving systems,
implants and other devices used in connection with drug-loaded
polymer coatings. Such devices are implanted or otherwise utilized
in body lumina and organs such as the coronary vasculature,
esophagus, trachea, colon, biliary tract, urinary tract, prostate,
brain, and the like. Examples of suitable vascular grafts are
described in U.S. Pat. Nos. 5,509,931, 5,527,353, and 5,556,426.
Vena cava filters such as those described in WO 96/12448 and WO
96/17634 may also be used in the present invention. All of
foregoing documents identified by number are incorporated herein in
their entireties.
[0027] The filters that can be provided with a polymeric
material/drug-agent matrix in accordance with the present invention
include, for example, thrombus filters that can be placed at a
selected location within the vascular system and removed when no
longer required. A preferred location for placement of these
filters is the vena cava. Filters placed in the vascular system can
intercept blood clots that may otherwise travel to the lungs and
result in a pulmonary embolism, a life-threatening emergency that
has become increasingly common. In one embodiment of the present
invention there is provided such an implanted vascular filter
having a polymeric material/drug outer coating thereon. In a most
preferred embodiment, the filter has a polymeric
material/paclitaxel outer coating, and most preferably, a
polylactic acid/polycaprolactone copolymer/paclitaxel coating. The
polymeric coating may also have incorporated therein or thereon any
other therapeutic agent that is used for reducing the formation of,
or complications due to, clot formation or neointima formation.
Such agents, include, but are not limited to antithrombogenic
agents and thrombolytic agents and other antiproliferative
agents.
[0028] Further examples of filters that may be provided with the
polymeric material/drug coating in accordance with present
invention include, e.g., those described in International
Application No. WO 96/17634 and International Application No. WO
96/12448, both of which are herein incorporated by reference.
[0029] The grafts, including stent grafts, that can be provided
with a polymeric material/drug agent matrix in accordance with the
present invention include synthetic vascular grafts that can be
used for replacement of blood vessels in part or in whole. A
typical vascular graft is a synthetic tube with each end thereof
sutured to the remaining ends of a blood vessel from which a
diseased or otherwise damaged portion has been removed. In a
typical stent graft, each end of the synthetic tube portion
includes a stent that is affixed to each of the remaining ends of a
blood vessel from which a diseased or otherwise damaged portion has
been removed. Alternatively, in a stent graft, the replacement
vessel may be segment of a vessel removed from another location in
the patient, such as a portion of a femoral artery or the like. In
the case of a synthetic graft, the graft is typically tubular and
may be, e.g., of a woven, knit or velour construction. Preferred
materials for the grafts and covering material for the stent grafts
include polyethylene terephthalate and polytetrafluoroethylene. The
vascular grafts may be reinforced with, for example, helices,
rings, etc. in order to provide uniform strength over the entire
surface of the graft tubing. The materials of which such grafts are
constructed are biologically compatible materials including, but
not limited to, thermoplastic materials such as polyester,
polytetrafluoroethylene (PTFE), silicone and polyurethanes. The
preferred materials include polyester fibers and PTFE.
[0030] Examples of other suitable grafts are described in U.S. Pat.
Nos. 5,509,931, 5,527,353, and 5,556,426, all of which are herein
incorporated by reference. In a most preferred embodiment of the
invention, the graft is provided with a coating of polymeric
material/paclitaxel, and most preferably, the polymeric material is
a copolymer of polycaprolactone and polylactic acid. This
paclitaxel-coated graft, when positioned at a desired site in the
body provides an extended release of paclitaxel to the site.
[0031] A polymeric material/drug agent matrix in accordance with
the present invention may be used as an intraluminal paving system.
In such intraluminal paving systems as are known in the art, the
polymeric material/drug agent matrix will typically be applied
directly to an interior surface of vascular or non-vascular lumina.
An intraluminal paving system is formed, for example, by admixing a
drug agent with a liquid polymer, in the absence of a solvent, to
form a liquid polymer/drug agent mixture. The mixture is then
applied directly to a luminal surface by any conventional method,
such as by injecting the mixture against the luminal surface.
Curing of the mixture typically occurs in-situ. To facilitate
curing, a cross-linking or curing agent may be added to the mixture
prior to application thereof to the luminal surface. Addition of
the cross-linking or curing agent to the polymer/drug agent liquid
mixture must not occur too far in advance of the application of the
mixture to the luminal surface in order to avoid over-curing of the
mixture prior to application thereof to the luminal surface. Curing
may also occur in-situ by exposing the polymer/drug agent mixture,
after application to the luminal surface, to radiation such as
ultraviolet radiation or laser light, heat, or by contact with
metabolic fluids such as water at the site where the mixture has
been applied to the luminal surface. In a preferred intraluminal
paving system in accordance with the invention, the drug agent is
paclitaxel and the paclitaxel may be incorporated in the polymeric
material alone or in combination with another drug agent. In
intraluminal paving systems in accordance with a preferred
embodiment of the present invention, the polymeric material
incorporating the paclitaxel and, if desired, any additional
therapeutic agent(s), may be either bioabsorbable or biostable. Any
of the polymers described herein that may be formulated as a liquid
may be used to form the polymer/drug agent mixture for use as an
intraluminal paving system.
[0032] In a preferred embodiment, the polymer used to coat the
medical device is provided in the form of a coating on an
expandable portion of a medical device. After applying the drug
solution to the polymer and evaporating the volatile solvent from
the polymer, the medical device is inserted into a body lumen where
it is positioned to a target location. In the case of a balloon
catheter, the expandable portion of the catheter is subsequently
expanded to bring the drug-impregnated polymer coating into contact
with the lumen wall. The drug is released from the polymer as it
slowly dissolves into the aqueous bodily fluids and diffuses out of
the polymer. This enables administration of the drug to be
site-specific, limiting the exposure of the rest of the body to the
drug.
[0033] The polymer used in the present invention is preferably
capable of absorbing a substantial amount of drug solution. When
applied as a coating on a medical device in accordance with the
present invention, the dry polymer is typically on the order of
from about 1 to about 50 microns thick. In the case of a balloon
catheter, the thickness is preferably about 1 to 10 microns thick,
and more preferably about 2 to 5 microns. Very thin polymer
coatings, e.g., of about 0.2-0.3 microns and much thicker coatings,
e.g., more than 10 microns, are also possible. It is also within
the scope of the present invention to apply multiple layers of
polymer coating onto a medical device. Such multiple layers are of
the same or different polymer materials.
[0034] The polymer of the present invention is hydrophilic or
hydrophobic, and is selected from the group consisting of
polycarboxylic acids, cellulosic polymers, including cellulose
acetate and cellulose nitrate, gelatin, polyvinylpyrrolidone,
cross-linked polyvinylpyrrolidone, polyanhydrides including maleic
anhydride polymers, polyamides, polyvinyl alcohols, copolymers of
vinyl monomers such as EVA, polyvinyl ethers, polyvinyl aromatics,
polyethylene oxides, glycosaminoglycans, polysaccharides,
polyesters including polyethylene terephthalate, polyacrylamides,
polyethers, polyether sulfone, polycarbonate, polyalkylenes
including polypropylene, polyethylene and high molecular weight
polyethylene, halogenated polyalkylenes including
polytetrafluoroethylene, polyurethanes, polyorthoesters, proteins,
polypeptides, silicones, siloxane polymers, polylactic acid,
polyglycolic acid, polycaprolactone, polyhydroxybutyrate valerate
and blends and copolymers thereof as well as other biodegradable,
bioabsorbable and biostable polymers and copolymers. Coatings from
polymer dispersions such as polyurethane dispersions
(BAYHDROL.RTM., etc.) and acrylic latex dispersions are also within
the scope of the present invention. The polymer may be a protein
polymer, fibrin, collage and derivatives thereof, polysaccharides
such as celluloses, starches, dextrans, alginates and derivatives
of these polysaccharides, an extracellular matrix component,
hyaluronic acid, or another biologic agent or a suitable mixture of
any of these, for example. In one embodiment of the invention, the
preferred polymer is polyacrylic acid, available as HYDROPLUS.RTM.
(Boston Scientific Corporation, Natick, Mass.), and described in
U.S. Pat. No. 5,091,205, the disclosure of which is hereby
incorporated herein by reference. U.S. Pat. No. 5,091,205 describes
medical devices coated with one or more polyisocyanates such that
the devices become instantly lubricious when exposed to body
fluids. In a most preferred embodiment of the invention, the
polymer is a copolymer of polylactic acid and polycaprolactone.
[0035] By "substantially water-insoluble drug" is meant any
therapeutic agent having a greater solubility in organics than in
water. More specifically, such drugs have a water solubility of no
greater than 1 part drug to 30 parts water, more typically no
greater than 1 part drug to 1,000 parts water. Such solubilities
are described as "sparingly soluble" to "very slightly soluble" in
the art.
[0036] The drug agents used in the present invention are selected
from a number of drug types depending on the desired application.
For example, these drugs include anti-inflammatory agents such as
dexamethasone, prednisolone, corticosterone, budesonide, estrogen,
sulfasalazine, mesalamine, and analogues thereof;
antineoplastic/antiproliferative/anti-miotic agents such as
paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,
epothilones, endostatin, angiostatin, thymidine kinase inhibitors,
and analogues thereof; anesthetic agents such as lidocaine,
bupivacaine, ropivacaine, and analogues thereof; anti-coagulants;
and growth factors.
[0037] The drug agents useful in accordance with the present
invention may be used singly or in combination. For example, an
anti-proliferative agent such as paclitaxel may be used in
combination with another drug agent, such as an anticoagulant,
anti-inflammatory, antithrombogenic, thrombolytic, nitric
oxide-containing polymer, or a vascular cell promoter such as VEGF,
for example.
[0038] Paclitaxel is a preferred drug agent for use in accordance
with the present invention either alone or in combination with
another drug agent, as described above. Paclitaxel is a complex
alkaloid extracted from the Pacific Yew Taxusbrevifolia Family
(Family Taxacea) which has been demonstrated to have
antiproliferative activity. As used herein, paclitaxel includes the
alkaloid and any pharmacologically active derivative or analog
thereof. Thus paclitaxel includes naturally occurring forms and
derivatives thereof and synthetic and semi-synthetic forms thereof
TAXOL.RTM. is a commercially available form of paclitaxel.
[0039] In accordance with the present invention, the drug agents
are dissolved in a volatile organic solvent such as, for example,
ethanol, isopropanol, chloroform, acetone, pentane, hexane, or
methylene chloride, to produce a drug solution. In the case of
paclitaxel the preferred solvent is chloroform. The drug solution
is then applied to the polymer. A volatile organic solvent
typically is selected to provide drug solubilities much greater
than the corresponding aqueous solubility for the substantially
water-insoluble drug. Accordingly, application of the drug solution
to the polymer often results in drug loadings that are orders of
magnitude greater than loadings that can be achieved by application
of a saturated aqueous solution of the drug to the polymer.
[0040] The drug solution is applied to the polymer coating by any
suitable means, including dipping the polymer coating into the drug
solution or by applying the solution onto the coating such as by
pipet or by spraying, for example. In the former method, the amount
of drug loading is controlled by regulating the time the polymer is
immersed in the drug solution, the extent of polymer cross-linking,
the concentration of the drug in the solution and/or the amount of
polymer coating. In another embodiment of the invention, the drug
is incorporated directly into the polymer prior to the application
of the polymer topcoat as a coating onto a medical device.
[0041] After applying the drug solution to the polymer coating, the
volatile solvent is evaporated from the coating, for example, by
drying in air or in an oven.
[0042] The release profile of the drug from the polymer coating is
determined by many factors including the drug solubility, amount of
drug applied and the thickness and porosity of the polymer
coating.
[0043] In a preferred embodiment of the present invention, one or
more additional layers may be applied over at least a portion of a
medical device previously coated with a polymer/drug agent in
accordance with the present invention. Desirably, such an
additional layer will be provided to modify or modulate the release
of one or more of the drug agents in the underlying layer. For
example, a polymeric coating may be applied over the previously
applied polymer/drug agent coating to modulate the release rate of
the drug agent in that layer. This additional release
rate-modifying or modulating layer may be applied in a subsequent
coating step in a manner similar to that disclosed herein, for
example by spraying a polymer solution onto the previously applied
coating layer or by dipping the previously coated medical device
into a solution of the polymer selected to form the modifying or
modulating layer. However, other methods for applying polymeric
materials to substrates, including, for example, in-situ
polymerization methods such as plasma polymerization may also be
used to provide the additional release rate-modifying or modulating
polymeric layer. Such other application processes included within
the scope of the present invention are those that will not
detrimentally affect the previously applied layer, including the
drug agent(s) incorporated therein or thereon. The additional layer
may also include one or more additional drug agents including any
of the drug agents incorporated into the underlying polymer/drug
agent coating layer. Prior to application of the modifying or
modulating layer, any conventional adhesion promotion agent may be
applied to the previously applied coating, or other treatment
thereof may be conducted, in order to promote adhesion of the
modifying or modulating layer to the previously applied coating.
Where the modifying or modulating layer is applied in a manner
similar to the underlying layer, the polymeric material used for
the modifying or modulating layer can be any of the polymers
described herein. Where such polymeric material is applied, for
example, by plasma polymerization, the polymers are those that can
be formed by monomers in a gas phase that can be activated for
example by radio frequency waves. Such monomers include, for
example, silicone-based monomers such as cyclic or acyclic
siloxanes, silanes, silylimidazoles; fluorine-based monomers such
as hydrofluorocarbons; aliphatic or aromatic hydrocarbons; acrylic
monomers; and combinations thereof. The monomer gas may have
functional groups that facilitate later attachment of drug agents
thereto by covalent bonding, for example. Any appropriate polymer
for the modifying or modulating layer is preferably selected to
have a porosity that provides the modifying or modulating effect as
described above. The porosity of this polymeric material may also
be modified by addition of porosigens or other porosity-effecting
adjuvants that are conventionally added to polymers for this
purpose. Other factors guiding the selection of a modulating or
modifying polymer include, but are not limited to, the thickness of
coating layer, the tortuosity of the polymeric material affecting
the path of resistance to drug mobility within the polymeric
material, the cross-linking density, drug solubility in the
modulating or modifying layer, etc. The thickness of the modifying
or modulating layer will preferably be less than 5,000 .ANG., and
more preferably in the range of from about 50-2000 .ANG.. A
preferred modifying or modulating polymer in accordance with the
present invention is a siloxane polymer formed, for example, by a
plasma polymerization process. This siloxane modifying or
modulating polymer is preferably applied to a medical device that
has a polyurethane/drug agent coating previously applied thereto in
accordance with the present invention.
[0044] When an expandable member such as a balloon catheter is used
to administer the drug, pressure can be used to increase the rate
of drug transfer to the tissue. An increase in pressure increases
the diameter of the balloon and therefore the diameter of the
surrounding tissue, thereby increasing the surface area for drug
transfer. The amount of drug that is delivered per unit time is
therefore increased.
[0045] When an expandable catheter is chosen as the medical device
of the present invention, the expandable portion is preferably a
balloon, in which case the drug is placed in the polymer for
controlled release of the drug upon expansion of the balloon
against a body lumen. The expandable portion optionally includes a
stent, mountable in a body lumen by expansion thereof. The catheter
also optionally comprises a sheath member which is extendable over
the expandable portion to inhibit release of the drug into body
fluids during placement of the catheter.
[0046] Referring now to FIGS. 1a-1c, an embodiment for the
localized delivery of substantially water-insoluble drugs to a
predetermined location within the body is described. The drug
administration method shown in FIGS. 1a-1c illustrates the use of
the present invention in conjunction with an angioplasty process.
Catheter device 1 comprises a body 3 having a balloon 4 attached at
its distal end. The balloon 4 on the catheter 3 includes a polymer
coating 6. As shown in FIG. 1a, drug solution 8 is impregnated into
the polymer coating with the balloon in its substantially deflated
state prior to insertion into the patient. As shown in FIG. 1b,
after the volatile solvent is evaporated, the device 1 is inserted
into a body lumen 2 having a region to be treated, such as an
occlusion due to a deposition of plaque 5 on the lumen wall tissue
9. The device 1 is moved along the vessel to position the balloon 4
at the occlusion site, as shown in FIG. 1c. The lumen may be, for
example, a narrow, tortuous opening through which the catheter is
passed by torquing or other known techniques. As shown in FIG. 1c,
the balloon is inflated to provide close contact between the
drug-impregnated polymer coating 6 and the surrounding plaque and
tissue. As water from the body penetrates into the polymer coating
6, it begins to dissolve the drug agent, which subsequently
diffuses out of the polymer coating 6 and into the surrounding
plaque and tissue.
[0047] During drug administration, a substantial amount of the drug
contained in the polymer coating is diffused into the affected
area. The inflation pressure needed to expand the balloon catheter
and dilate the lumen, if necessary, is typically in the range of
about 1 to 20 atm. The balloon is formed of any suitable materials
such as vinyl polymers such as polyethylene; polyesters such as
polyethylene terephthalate; polyamides such as nylon; polyolefins
and copolymers thereof (e.g., Selar, Pebax, Surlyn, Hytrel, etc.).
The balloon is optionally a perfusion balloon, which allows blood
to perfuse the catheter to prevent ischemia during delivery. A
perfusion balloon is particularly preferred for long arterial
delivery times and when the delivery drug is only very slightly
soluble in water.
[0048] Referring to the embodiment of the invention illustrated in
FIG. 2, the balloon portion 4 of catheter 3 is optionally covered
by a protective sheath 7 while the instrument 1 is inserted into a
body lumen 2 and positioned at a treatment region. As the coated
balloon 4 is positioned at occluded site 5, the protective sheath 7
is drawn back to expose the balloon 4. In an alternative
embodiment, the sheath remains stationary while the catheter moves
the coated balloon forward into the occluded region. The sheath 7
protects the coating and inhibits premature release of the drug.
Such a sheath might be particularly advantageous when using drugs
which are not sufficiently water-insoluble or if even minor
delivery to tissue during catheter placement is a problem, e.g. for
extremely toxic drugs.
[0049] Although FIGS. 1 and 2 illustrate the application of the
present invention to an angioplasty process, the present invention
is also used to administer drug agents to target locations where
there is no occlusive formation.
[0050] In other embodiments, the medical device of the present
invention is an implantable medical device such as a stent, covered
stent, stent graft, intraluminal paving system, wire guide,
cannulae, artificial limbs, joints, and other prosthetic devices.
Where a stent is used it may either balloon- or self-expandable,
and is constructed of any biocompatible material. The grafts and
covering materials for the stent grafts are made of any
biocompatible material such as, for example, polyurethane,
polyesters, silicone, or polytetrafluoroethylene.
[0051] Stents are generally configured in one of two
configurations: patterned or coil. Coil-type stents include, for
example, wire stents in the form of coils, spirals or the like,
with or without spines, an example of which is the subject of U.S.
Pat. No. 4,886,062 (incorporated herein by reference), another
example of which is the GR-II.RTM. (Cook Inc.) stent. Patterned
stents used in accordance with a most preferred embodiment of the
invention include all stents other than coil-type stents such as,
for example, slotted tube stents, criss-cross tubular stents,
braided stents, hexagonal stents, nets, articulated stents, and the
like. Patterned stents are also generally preferred over coil
stents because they provide more radial support for surrounding
body lumina. Preferred patterned stents for use in the present
invention include the NIR.TM. and RADIUS.TM. stents (SCIMED Life
Systems, Inc.) as described in U.S. Pat. No. 5,733,303 and WO
96/26689 (both of which are incorporated herein by reference); the
WALLSTENT.RTM. (Schneider Inc.) as described in U.S. Pat. Nos.
4,655,771 and 5,061,275 (both of which are incorporated herein by
reference); and the SYMPHONY.RTM. stent (Boston Scientific Corp.)
as described in U.S. Pat. No. 5,540,712 (incorporated herein by
reference). The stents and stent grafts described in U.S. Pat. Nos.
5,766,237, 5,681,356, 5,522,881 and 5,776,180 (each of which is
incorporated herein by reference) and the polymer stents described
in U.S. Pat. No. 5,769,883 (incorporated herein by reference) are
also within the scope of the present invention.
[0052] The implantation of a stent, stent graft, vascular graft or
filter in accordance with the present invention can be conducted by
any medical procedure conventionally used for such implantation. In
the case of a stent, a polymer/paclitaxel coated stent in
accordance with the present invention can be fitted over the
inflatable element of a balloon catheter and expanded by the
balloon to force the stent into contact with the body lumen at or
near a site of injury such as, for example, within an injured blood
vessel.
[0053] Where the medical device in accordance with the present
invention is, e.g., a catheter, stent, graft, filter, etc., or any
other device used in the vascular system, any blood vessel
including arteries, veins and capillaries may be treated in
accordance with the present invention. These blood vessels may be
in or near any organ in the human or mammalian body.
[0054] In a most preferred embodiment of the invention, a patterned
stent having a polymer/paclitaxel coating is used to prevent or
inhibit proliferative disease. As used herein, "proliferative
disease" means any disease or disorder including cancers,
malignancies, benign growths and other conditions that result from
hyperactivity or hyperplasia of somatic cells, and includes
restenosis and vascular hyperplasia such as neointimal hyperplasia.
Such proliferative diseases may occur in vascular and other luminal
or non-luminal regions of the body.
[0055] The inventors have surprisingly found that extended drug
release of paclitaxel from a polymer coating on a patterned stent
is obtained and consequently, a significant reduction in neointima
formation results. The reduction in neointima formation obtained
with patterned stents used in accordance with the present invention
is surprisingly superior to that obtained using a coiled stent
coated with a polymer/paclitaxel matrix. FIG. 10 shows the release
rate of paclitaxel obtained with a stent in accordance with the
present invention. In a preferred embodiment, paclitaxel is
released from a polymer/paclitaxel coated stent for a time period
of at least about 28 days after implantation of stent at the
desired location within the body. The patterned stent is coated
with an outer coating of polymer/paclitaxel such that the amount of
paclitaxel is sufficient to prevent, decrease, eliminate or modify
cellular proliferation associated with proliferative disease or
disorder. The amount of paclitaxel sufficient to inhibit or prevent
proliferative disease will vary according to the size of the
patterned stents, but is generally in the range of from about 50
.mu.g to 500 .mu.g per stent.
[0056] Procedures for preparing a drug delivery medical device with
a polymer coating are presented in the following non-limiting
examples.
Example 1
Release Kinetics of Paclitaxel from Polyacrylic Acid-Based
Coating
[0057] A 2 mg/ml solution of paclitaxel is prepared in chloroform.
The solution is gently agitated until the paclitaxel is completely
dissolved. The solution is applied via pipet to a balloon catheter
having a polyacrylic acid-based coating and inflated to 2 atm. A
total of 100 .mu.l of solution, and hence 200 .mu.g of paclitaxel,
is applied to the catheter. The balloon catheter is then dried in
air for 30 minutes and in a vacuum oven for 48 hours at 50.degree.
C. to evaporate the chloroform. The catheter is then immersed in a
solution of 1% dimethyl sulfoxide (DMSO) and phosphate buffered
saline (PBS) having a pH of 7.4 for in-vitro drug release. The
cumulative amount of paclitaxel released from the catheter coating
yields the data shown in FIGS. 3a and 3b.
Example 2
Release Kinetics of Dexamethasone from Polyacrylic Acid-Based
Coating
[0058] Solutions containing 1.5 mg/ml and 200 .mu.g/ml of
dexamethasone in chloroform, are prepared by gently agitating until
the dexamethasone is completely dissolved. The solutions are
separately applied via dripping to separate balloon catheters
having polyacrylic acid-based coatings and inflated to 2 atm. A
total of 100 .mu.l of each solution is applied to each respective
catheter, corresponding to dexamethasone loadings of 1.5 mg and 200
.mu.g, respectively. These results can be contrasted with the
inability to apply substantial amounts of dexamethasone to
polyacrylic acid-based coatings using aqueous solutions, in which
case only about 1 .mu.g of dexamethasone can be loaded into such
coatings. The balloon catheters are then dried in a vacuum oven for
2 hours at 50.degree. C. to evaporate the chloroform solvent. The
catheters are thereafter immersed in PBS (pH=7.4) to track the
release of dexamethasone over time. The cumulative amount of
dexamethasone released from each catheter yields the data shown in
FIGS. 4a and 4b.
Example 3
Release Kinetic of Molsidomine from Polyacrylic Acid-Based
Coating
[0059] Various solutions of molsidomine in volatile solvents are
prepared and applied to balloon catheters by the methods indicated
in Table I. In the "dip" application technique, each balloon
catheter having a polyacrylic acid-based coating is dipped into its
respective solution for 10 minutes. In the "pipet" application
technique, 200 .mu.l of solution is pipetted onto its respective
coated balloon catheter while slowly turning. All samples are dried
in an oven for 30 minutes at 50.degree. C. and thereafter immersed
in PBS (pH=7.4) to track the release of molsidomine over time. The
cumulative amount of molsidomine released from each catheter yields
the data shown in FIGS. 5a and 5b.
TABLE-US-00001 TABLE I Molsidomine solution characterization, and
methods of applying molsidomine solution to polymer coated
catheters. Concentration (mg Molsidomine per Application Sample
Solvent ml solvent) technique 1 chloroform 150 dip 2 chloroform 30
pipet 3 chloroform 150 pipet 4 ethanol 30 pipet 5 ethanol 30
dip
Example 4
Release Kinetics of Dexamethasone Added to Polyacrylic Acid-Based
Topcoat Formulation
[0060] Rather than forming a solution of dexamethasone in an
organic solvent and then applying this solution to polymer-coated
balloon catheters as in Example 2, dexamethasone is added directly
to the polymer used to coat the balloon catheters. Dexamethasone is
weighed out into 0.05 g, 0.1 g, and 0.2 g samples, each of which is
each added to 1 ml lots of polymer topcoat solution containing
polyacrylic acid, methyl ethyl ketone, dimethyl formamide, and
t-butyl alcohol. The dexamethasone samples are mixed with the
polymer topcoat solutions until completely dissolved. The
dexamethasone-containing polymer topcoat solutions are separately
applied via dripping to separate, uncoated balloon catheters
inflated to 2 atm. After drying in a vacuum oven for 2 hours at
50.degree. C., the catheters are immersed in PBS (pH=7.4) to track
the release of dexamethasone over time. The cumulative amount of
dexamethasone released from each catheter yields the data shown in
FIG. 6.
Example 5
Comparative Release Kinetics for Water-Soluble and Water-Insoluble
Estradiol
[0061] Estradiol is provided in both water-soluble and
substantially water-insoluble forms. Water-soluble estradiol is
applied to a balloon catheter coated with a polyacrylic acid-based
coating by i) preparing a 10 mg/ml solution of water-soluble
estradiol in deionized, ultra-filtered water; and ii) placing the
balloon catheter, inflated to 2 atm, into 200 .mu.l of the solution
for 20 minutes. Water-insoluble estradiol is applied to a balloon
catheter coated with a polyacrylic-acid based coating by i)
preparing a 10 mg/ml solution of substantially water-insoluble
estradiol in methanol; and ii) dripping 100 .mu.l of the solution
onto the balloon catheter. The catheters are thereafter immersed in
PBS (pH=7.4) to track the release of both water-soluble and
water-insoluble estradiol over time. Greater release is observed
for the substantially water-insoluble form of estradiol when
compared to the water-soluble form. The cumulative amount of
estradiol released from each catheter yields the data shown in
FIGS. 7a and 7b.
Example 6
In Vivo Delivery of Paclitaxel from Polyacrylic Acid Based
Coating
[0062] A 9.8 mg/ml solution of radio-labeled paclitaxel in
chloroform is prepared. A total of 50 .mu.l of the solution is
applied via pipet to a balloon catheter having a polyacrylic
acid-based coating. The paclitaxel from the coated balloon catheter
is then released in-vivo to porcine arteries. After release for a
predetermined amount of time, the paclitaxel remaining in the
coating is extracted using two sequential ethanol washes. The
amount of paclitaxel released in the pig bloodstream, as calculated
from the amount of paclitaxel loaded into the coating minus that
extracted from the coating after delivery, is shown in Table
II.
TABLE-US-00002 TABLE II Amount of paclitaxel released into pig
bloodstream from an impregnated, polyacrylic acid-based coated
balloon catheter, as a function of delivery time. Amount of pacli-
Amount of pacli- % of Amount of taxal extracted taxel released in
paclitaxel time in from balloon after bloodstream released in
bloodstream delivery (.mu.g) (.mu.g) bloodstream 1 minute.sup. 182
.+-. 1 307 63 5 minutes 160 .+-. 30 330 68
Example 7
Delivery of Paclitaxel to Explanted Porcine Arteries from
Polyacrylic Acid-Based Coating
[0063] A 9.8 mg/ml solution of radio-labeled paclitaxel in
chloroform is prepared. A total of 50 .mu.l of the solution is
applied via pipet to a balloon catheter having a polyacrylic
acid-based coating. The coated balloon catheter is then delivered
to an explanted porcine artery for 15 minutes. After delivery, the
paclitaxel remaining in the coating is extracted using two
sequential ethanol washes. The delivered paclitaxel is extracted
from the vessel, also by using two sequential ethanol washes. In
addition, the vessel is placed in tissue solvent and counted for
paclitaxel. Using these extraction methods, at least 80% of the
paclitaxel loaded onto the balloon catheter is recovered, as shown
in Table III.
TABLE-US-00003 TABLE III Paclitaxel recovery from ex vivo delivery
to porcine artery. Amount paclitaxel loaded onto balloon 489 .mu.g
Amount paclitaxel extracted from the balloon 360 .mu.g after
delivery Amount paclitaxel extracted from artery 30 .mu.g Amount
paclitaxel counted from tissue solution 1 .mu.g Total paclitaxel
measured 391 .mu.g Percentage of paclitaxel recovered 80%
Example 8
Release Kinetics of Paclitaxel Polyurethane Based Stent Coating
[0064] Slotted tube stainless steel stents are coated with
polyurethane by spraying a 1 wt % solution of CHRONOFLEX.RTM.
polyurethane (made by CT Biomaterials) in tetrahydrofuran directly
onto the stent surface. The coated stents are dried in a vacuum
oven for three hours at 70.degree. C.
[0065] Each polyurethane coated stent is placed in a vial, which is
filled to maximum volume (1.5 ml) with a solution of paclitaxel in
ethanol, and sealed. The stent is stored in the vial for three days
at room temperature. The stent is then removed from the vial and
dried for one hour at 65.degree. C.
[0066] The above procedure is conducted using solutions of varying
concentrations. Each stent is analyzed for paclitaxel content by
extraction in dichloromethane solvent. The results are presented in
Table IV below. Samples 1 and 2 were obtained using a paclitaxel
concentration of 10 mg/ml, samples 3 and 4 using a 20 mg/ml
solution and sample 5 and 6 using a 30 mg/ml solution.
TABLE-US-00004 TABLE IV Paclitaxel content. Paclitaxel Paclitaxel
Coating .mu.g Paclitaxel Sample conc. content Wt. per # (mg/ml)
(.mu.g) (.mu.g) .mu.g coating 1 10 44.8 796 0.06 2 10 88.2 859 0.10
3 20 151.2 718 0.21 4 20 127.6 702 0.18 5 30 157.1 736 0.21 6 30
144.3 629 0.23
[0067] These results suggest that paclitaxel loading is relatively
independent of paclitaxel concentration above 20 mg/ml, assuming
equilibrium is attained in the three-day period. Nevertheless, the
30 mg/ml paclitaxel concentration is chosen for release studies as
it produces the maximum paclitaxel loading (21-23%), while still
being sufficiently below the saturation concentration for
paclitaxel in ethanol (39 mg/ml).
[0068] Seven polyurethane coated stents are loaded using a 30 mg/ml
paclitaxel solution, removed and dried as set forth above.
Paclitaxel from four of the stents is extracted in dichloromethane
solvent. The results of this extraction are presented in Table V
below:
TABLE-US-00005 TABLE V Paclitaxel content. Paclitaxel Paclitaxel
Coating .mu.g Paclitaxel Sample conc. content Wt. per # (mg/ml)
(.mu.g) (.mu.g) .mu.g coating 1 30 111.7 676 0.17 2 30 50 627 0.08
3 30 45.3 612 0.07 4 30 37.4 602 0.06
[0069] The remaining three stents are immersed in a solution of
phosphate buffered saline solution having pH 7.4 at 37.degree. C.
Cumulative release as a function of time is presented in FIG.
8.
Example 9
Release Kinetics of Paclitaxel from Polyurethane-Based Balloon
Catheter Coating
[0070] Nylon balloons are coated with polyurethane by dipping into
a 9 wt % solution of CHRONOFLEX.RTM. polyurethane in
dimethylacetamide. The balloons are dried in a vacuum oven
overnight at 50.degree. C.
[0071] Each polyurethane coated balloon is loaded with paclitaxel
either by dipping the coated balloon into a paclitaxel and ethanol
solution or by dripping a known volume of a paclitaxel and ethanol
solution onto the balloon surface.
[0072] In the first instance, a stock saturated solution of
paclitaxel in ethanol is prepared. Then the polyurethane-coated
balloon is inflated and submerged in the paclitaxel stock solution
in a tube. The tube and balloon are well-sealed to prevent solvent
evaporation. After remaining in the tube overnight, the ethanol is
evaporated from the balloon over a suitable time period, such as
about fifteen minutes. Five "dip-coated" balloons are prepared in
this fashion.
[0073] In the second instance, a stock solution of paclitaxel
having a concentration of 10 mg/ml prepared. Twenty ml of this
paclitaxel stock solution are then pipetted onto an inflated
polyurethane-coated balloon, providing a total mass of 200 mg of
paclitaxel per balloon. Afterwards, ethanol is evaporated from the
balloon over a suitable time period, such as about fifteen minutes.
Five "drip-coated" balloons are prepared in this fashion.
[0074] Two drip-loaded balloons and two dip-loaded balloons are
taken and the paclitaxel extracted in dichloromethane to determine
total paclitaxel content. The paclitaxel content of the dip-coated
balloons is found to be 1093+/-439 mg, while the drip-coated
balloons are found to have 215+/-11 .mu.g paclitaxel.
[0075] For comparison, nylon balloons are coated with
paclitaxel/polyurethane by dipping the balloons into a dispersion
of 14.5 wt % BAHYDROL.RTM. polyurethane (made by Bayer) and 2.6 wt
% paclitaxel in a mixture of 73.6 vol % N-methylpyrrolidinone and
26.4 vol % water. Balloons are dried in a vacuum oven overnight at
50.degree. C. The dried coatings contain 15% paclitaxel by weight.
Nine balloons are formed. Seven balloons are tested for paclitaxel
loading yielding an average of 196
[0076] +/-44 .mu.g paclitaxel after extraction in
dichloromethane.
[0077] The remaining three drip-loaded balloons from above, the
remaining three dip-loaded balloons from above, and the remaining
two balloons with the 15% paclitaxel formulated coating are placed
in a solution of phosphate buffered saline solution having pH 7.4
at 37.degree. C., and cumulative paclitaxel release is measured as
a function of time. The results of this study are presented in FIG.
9.
Example 10
Preparation of a Stent-Coated with a Polylactic
Acid/Polycaprolactone (PLA/PCL) Copolymer/Paclitaxel Matrix
[0078] PLA/PCL copolymer obtained from Birmingham Polymers, Inc.,
Birmingham, Ala., was dissolved in chloroform. Paclitaxel obtained
from Hauser, Inc. was then dissolved in the chloroform to form a
solution having a 70/30 weight ratio of copolymer/paclitaxel. The
solution was then sprayed onto the surface of a 9 mm long
balloon-expandable stainless steel NIR.RTM. stent obtained from
Medinol, Inc., Tel Aviv, Israel. Substantially all exposed surfaces
of the stent were covered with the solution. The stent was then
dried in a vacuum oven at 50.degree. C. for approximately 2 hr. and
a matrix of PLA/PCL copolymer having 200 .mu.g of paclitaxel
incorporated therein was thus formed as a coating on the stent. The
paclitaxel component of the matrix comprised approximately 30% by
weight of the matrix.
Example 11
In-Vitro Delivery of Paclitaxel to Porcine Coronary Arteries
[0079] A stent prepared as set forth in Example 10 was inserted via
a balloon catheter and expanded into contact with a porcine
coronary artery. In vitro, the stent delivered 2-3 .mu.g/day of
paclitaxel over a period of 28 days. In comparison to the same
stent having no coating, after 28 days, a 50% reduction in the
occurrence of neointimal hyperplasia was observed.
Example 12
In-Vitro Delivery of Paclitaxel to Rabbit Iliac
[0080] A stent prepared as set forth in Example 10 was inserted via
a balloon catheter and expanded into contact with a rabbit iliac.
In vitro, the stent delivered 2-3 .mu.g/day of paclitaxel over a
period of 28 days. In comparison to the same stent having no
coating, after 28 days, a 70% reduction in the occurrence of
neointimal hyperplasia was observed.
Example 13
In-Vitro Delivery of Paclitaxel to Rabbit Iliac
[0081] A stent prepared as set forth in Example 10 was inserted via
a balloon catheter and expanded into contact with a rabbit iliac.
In vitro, the stent delivered 2-3 .mu.g/day of paclitaxel over a
period of 56 days. In comparison to the same stent having no
coating, after 56 days, a 60% reduction in the occurrence of
neointimal hyperplasia was observed.
Comparative Example 14
Coil Stents with Biocompatible Polymeric Material/TAXOL.RTM.
Coating
[0082] The results presented in Table VI below were obtained by
Leon et al., "TAXOL.RTM.-Coated Coronary Stents: Potential to
Reduce Proliferation," European Society of Cardiology, Vienna,
Austria 1998. GR-II.RTM. coil stents, available from Cook Inc.,
Bloomington, Ind., were coated with a biocompatible polymeric
coating incorporating 175-200 .mu.g of TAXOL.RTM. and exhibiting in
vitro release kinetics of 0.75 .mu.g/day for the first 30 days. The
stents were placed in porcine coronary arteries and the effect on
neointima formation compared to that seen with control stents was
analyzed. The results are shown in Table VI below:
TABLE-US-00006 TABLE VI TAXOL .RTM.-Coated Stents versus Control
Control TAXOL .RTM.-coated (N = 10) Stent (N = 9) Reference Vessel
2.9 .+-. 0.3 3.0 .+-. 0.2 Diameter (mm) Stent/Artery 1.1 .+-. 0.1
1.1 .+-. 0.1 Diameter Stenosis (%) 51 .+-. 27 27 .+-. 27* Neointima
Area (.mu.m) 669 .+-. 357 403 .+-. 197* *p < 0.05 versus
control
[0083] In contrast to the results obtained in Example 11 above
using the NIR.RTM. non-coiled stent in a porcine coronary artery
(neointimal hyperplasia reduction of 50%), the results obtained
with a coil stent and paclitaxel (placed in a porcine coronary
artery) show a neointimal hyperplasia reduction of only 40%
calculated as follows: [(669-403)/669].times.100=40%.
Comparative Example 15
Comparison of Low-dose and High Dose TAXOL.RTM.-Coated Stents
Versus Control
[0084] The results of another study by Leon et al.,
"TAXOL.RTM.-Coated Coronary Stents: Potential to Reduce
Proliferation," European Society of Cardiology, Vienna, Austria
1998 on the effect of coated coil stents on neointima formation
using 2 doses of "fast-release" TAXOL.RTM. are shown in Table VII
below: The results for both "low-dose" and "high-dose"
TAXOL.RTM.-coated stents are shown in Table VII below:
TABLE-US-00007 TABLE VII Low-Dose and High Dose TAXOL .RTM.-Coated
Stents versus Control Low-Dose High-Dose Control TAXOL .RTM. TAXOL
.RTM. (N = 12) (N = 10) (N = 11) Reference 2.8 .+-. 0.2 2.8 .+-.
0.7 3.0 .+-. 0.3 Vessel Diameter (mm) Stent/Artery 1.16 .+-. 0.09
1.15 .+-. 0.07 1.14 .+-. 0.05 Diameter 34.8 .+-. 15.6 19.3 .+-.
9.45* .sup. 15.1 .+-. 6.61*.sup..dagger. Stenosis (%) Neointima
1.52 .+-. 0.78 1.07 .+-. 0.53 .sup. 0.93 .+-. 0.5*.sup..dagger.
Area (.mu.m) *p < 0.05 versus control .sup..dagger.p = not
significant versus low-dose TAXOL .RTM.
[0085] In contrast to the results obtained in Examples 11-13 above
using the NIR.RTM. non-coiled stent (neointimal hyperplasia
reduction of from 50-70%), the above results obtained with a coated
coil stent show a neointimal hyperplasia reduction of only 30% and
39%, respectively, calculated as follows:
[(1.52-1.07)/1.52].times.100=30% (low-dose TAXOL.RTM.) and
[(1.52-0.93)/1.52)].times.100=39% (high-dose TAXOL.RTM.).
Example 16
Preparation of a Vena Cava Filter Coated with a Polylactic
Acid/Polycaprolactone (PLA/PCL) Copolymer/Paclitaxel Matrix
[0086] A filter for placement in the vena cava for capturing blood
clots is coated with a PLA/PCL copolymer/paclitaxel matrix in the
manner substantially as set forth in Example 10. The filter is
sized and constructed to be compressed and passed through the
vasculature of a patient to be anchored against an inner wall
surface of a blood vessel for capturing blood clots in a blood
stream passing therethrough. The filter is described in
International Application No. WO 96/17634.
Example 17
Preparation of a Vena Cava Filter Coated with a Polylactic
Acid/Polycaprolactone (PLA/PCL) Copolymer/Paclitaxel Matrix
[0087] A filter for placement in the vena cava for capturing blood
clots is coated with a PLA/PCL copolymer/paclitaxel matrix in the
manner substantially as set forth in Example 10. The filter is also
adapted for placement in a blood vessel for capturing blood clots
in a blood stream passing therethrough. This filter is provided
with struts that minimize the risk of vessel damage if the vessel
is compressed asymmetrically. The filter is described in
International Application No. WO 96/12448.
Example 18
Preparation of a Vascular Graft Coated with a Polylactic
Acid/Polycaprolactone (PLA/PCL) Copolymer/Paclitaxel Matrix
[0088] A woven synthetic vascular graft for replacement of a
segment a blood vessel is coated with a PLA/PCL
copolymer/paclitaxel matrix in a manner substantially as set forth
in Example 10. The vascular graft is ravel-resistant due to
inclusion of a fusible component and self-supporting due to
inclusion of a stiffening component. The vascular graft is
described in U.S. Pat. No. 5,509,931.
[0089] It is to be appreciated that the parameters described in the
above examples are merely illustrative and that the present
invention is not so limited. For example, in each of the examples
provided, any suitable polymer may be used for the polymer coating,
any suitable drying time periods and temperatures may be used, any
suitable organic solvent may be used, any suitable method for
applying the polymer coatings to the medical devices may be used,
any suitable method for applying the drugs to the polymer coatings
may be used, any suitable water-insoluble analogue of the disclosed
drugs may be used, and any suitable drug loading concentrations may
be used.
[0090] The present invention provides a previously unknown method
and medical device for the localized delivery of substantially
water-insoluble drugs. The present invention provides, in one
embodiment, a paclitaxel/polymer coated stent which has an extended
release rate of from about 0.2 to about 7 .mu.g per day, preferably
in the range of from about 0.5 to about 5 .mu.g per lay over an
extended period of at least about 28 days. In a preferred
embodiment of the invention, there is provided a polymer/paclitaxel
coated non-coiled stent which has an extended release rate of
paclitaxel and which reduces neointima formation in injured blood
vessels and other body lumens into which it is placed. The extended
release rate is effective to prevent, decrease, eliminate, or
modify cellular proliferation associated with neointima formation
and/or other proliferative disease or disorder.
[0091] Those with skill in the art may recognize various
modifications to the embodiments of the invention described and
illustrated herein. Such modifications are meant to be covered by
the spirit and scope of the appended claims.
* * * * *