U.S. patent application number 14/312972 was filed with the patent office on 2014-10-09 for methods and devices for delivering therapeutic agents to target vessels.
This patent application is currently assigned to CORDIS CORPORATION. The applicant listed for this patent is ROBERT FALOTICO, KRISTIN KING, GERARD H. LLANOS, RONALD RAKOS, CAROL WRIGHT. Invention is credited to ROBERT FALOTICO, KRISTIN KING, GERARD H. LLANOS, RONALD RAKOS, CAROL WRIGHT.
Application Number | 20140303717 14/312972 |
Document ID | / |
Family ID | 37525081 |
Filed Date | 2014-10-09 |
United States Patent
Application |
20140303717 |
Kind Code |
A1 |
WRIGHT; CAROL ; et
al. |
October 9, 2014 |
Methods and Devices for Delivering Therapeutic Agents to Target
Vessels
Abstract
The present disclosure pertains to stents having a coating
applied thereto, wherein the coating comprises a biocompatible
polymer/drug mixture, as well as devices comprising a metallic
stent, a biocompatible polymeric carrier and a drug.
Inventors: |
WRIGHT; CAROL; (SOMERSET,
NJ) ; LLANOS; GERARD H.; (STEWARTSVILLE, NJ) ;
RAKOS; RONALD; (MONMOUTH JUNCTION, NJ) ; KING;
KRISTIN; (WEST NEW YORK, NJ) ; FALOTICO; ROBERT;
(BELLE MEADE, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
WRIGHT; CAROL
LLANOS; GERARD H.
RAKOS; RONALD
KING; KRISTIN
FALOTICO; ROBERT |
SOMERSET
STEWARTSVILLE
MONMOUTH JUNCTION
WEST NEW YORK
BELLE MEADE |
NJ
NJ
NJ
NJ
NJ |
US
US
US
US
US |
|
|
Assignee: |
CORDIS CORPORATION
Miami Lakes
FL
|
Family ID: |
37525081 |
Appl. No.: |
14/312972 |
Filed: |
June 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13420959 |
Mar 15, 2012 |
8790391 |
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14312972 |
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12792114 |
Jun 2, 2010 |
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13420959 |
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12204987 |
Sep 5, 2008 |
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12792114 |
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11555420 |
Nov 1, 2006 |
7666222 |
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12204987 |
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10951385 |
Sep 28, 2004 |
7223286 |
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11555420 |
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10408328 |
Apr 7, 2003 |
6808536 |
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10951385 |
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09874117 |
Jun 4, 2001 |
6585764 |
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10408328 |
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09061586 |
Apr 16, 1998 |
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09874117 |
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60044692 |
Apr 18, 1997 |
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Current U.S.
Class: |
623/1.42 |
Current CPC
Class: |
A61F 2002/91541
20130101; A61L 2300/416 20130101; A61L 31/10 20130101; A61F 2/91
20130101; A61F 2250/0068 20130101; A61F 2/915 20130101; A61L 31/16
20130101; A61F 2002/91558 20130101 |
Class at
Publication: |
623/1.42 |
International
Class: |
A61F 2/91 20060101
A61F002/91; A61L 31/16 20060101 A61L031/16 |
Claims
1. A stent comprising a plurality of generally solid struts, at
least one of the struts comprising a micropore formed therein, at
least one of the struts having a coating applied thereto, the
coating comprising a biocompatible polymer/drug mixture, wherein
the polymer is a nonabsorbable polymer and the drug is
sirolimus.
2. The stent according to claim 1 wherein the drug is contained in
the coating in a weight percentage of about 30%.
3. The stent according to claim 1 comprising a generally thin
walled cylinder.
4. The stent according to claim 1 further comprising a channel
formed in at least one of said struts.
5. The stent according to claim 4, wherein said channel has a
closed perimeter on all sides, an open top and a generally
rectangular perimeter, and said channel is smaller in all
dimensions than said strut.
6. The stent according to claim 1 wherein the coating is dip-coated
onto the stent.
7. The stent according to claim 1 wherein the coating is
spray-coated onto the stent.
8. The stent according to claim 1 wherein the coating comprises a
polydimethylsiloxane; a poly(ethylene)vinylacetate; a
poly(hydroxy)ethylmethylmethacrylate; an acrylate based polymer; an
acrylate based copolymer; a polyvinyl pyrrolidone; a cellulose
ester; a fluorinated polymer; or a blend thereof.
9. The stent according to claim 8 wherein the coating comprises a
fluorinated polymer.
10. The stent according to claim 1 that provides a controlled
release of said sirolimus over a period of several weeks.
11. The stent according to claim 1 wherein said sirolimus is
present in a therapeutically beneficial amount to inhibit
neointimal proliferation.
12. A device comprising: a metallic stent that comprises a
plurality of struts, at least one of the struts having a micropore
formed therein; and, a biocompatible polymeric carrier and a drug
that are present in a weight ratio of about 7:3, wherein the
polymer is a nonabsorbable polymer, and the drug is sirolimus and
is present in an amount effective to inhibit neointimal
proliferation.
13. The device according to claim 12 wherein said polymeric carrier
and drug are mixed together.
14. The device according to claim 12 wherein said polymeric carrier
is bound to the drug.
15. The device according to claim 12 wherein the drug is entrapped
on the surface of the stent by said polymeric carrier.
16. The device according to claim 12 wherein the polymeric carrier
and drug are applied to at least one of the struts.
17. The device according to claim 12 further comprising a channel
formed in at least one of said struts.
18. The device according to claim 17, wherein said channel has a
closed perimeter on all sides, an open top and a generally
rectangular perimeter, and said channel is smaller in all
dimensions than said strut.
19. The device according to claim 12 wherein the polymeric carrier
and drug are dip-coated onto the stent.
20. The device according to claim 12 wherein the polymeric carrier
and drug are spray-coated onto the stent.
21. The device according to claim 12 wherein the polymeric carrier
comprises-a polydimethylsiloxane; a poly(ethylene)vinylacetate; a
poly(hydroxy)ethylmethylmethacrylate; an acrylate based polymer; an
acrylate based copolymer; a polyvinyl pyrrolidone; a cellulose
ester; a fluorinated polymer; or a blend thereof
22. The device according to claim 12 wherein the polymeric carrier
comprises a fluorinated polymer.
23. The device according to claim 12 that provides a controlled
release of said sirolimus over a period of several weeks.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is continuation of U.S. application Ser.
No. 13/420,959, filed Mar. 15, 2012 (now allowed), which is a
continuation of U.S. application Ser. No. 12/792,114, filed Jun. 2,
2010 (abandoned), which is a divisional of U.S. application Ser.
No. 12/204,987, filed Sep. 5, 2008 (abandoned), which is a
continuation of U.S. application Ser. No. 11/555,420, filed Nov. 1,
2006, now U.S. Pat. No. 7,666,222, which in turn is a continuation
of Ser. No. 10/951,385, filed Sep. 28, 2004, now U.S. Pat. No.
7,223,286, which is a continuation of Ser. No. 10/408,328, filed
Apr. 7, 2003, now issued as U.S. Pat. No. 6,808,536, which is a
continuation of application Ser. No. 09/874,117, filed Jun. 4,
2001, now issued as U.S. Pat. No. 6,585,764, which is a
continuation of application Ser. No. 09/061,568, filed Apr. 16,
1998, now issued as U.S. Pat. No. 6,273,913, which in turn claims
benefit of provisional application Ser. No. 60/044,692, filed Apr.
18, 1997. The disclosures of each of these prior applications are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] Delivery of rapamycin locally, particularly from an
intravascular stent, directly from micropores in the stent body or
mixed or bound to a polymer coating applied on stent, to inhibit
neointimal tissue proliferation and thereby prevent restenosis.
This invention also facilitates the performance of the stent in
inhibiting restenosis.
BACKGROUND OF THE INVENTION
[0003] Re-narrowing (restenosis) of an artherosclerotic coronary
artery after percutaneous transluminal coronary angioplasty (PTCA)
occurs in 10-50% of patients undergoing this procedure and
subsequently requires either further angioplasty or coronary artery
bypass graft. While the exact hormonal and cellular processes
promoting restenosis are still being determined, our present
understanding is that the process of PTCA, besides opening the
artherosclerotically obstructed artery, also injures resident
coronary arterial smooth muscle cells (SMC). In response to this
injury, adhering platelets, infiltrating macrophages, leukocytes,
or the smooth muscle cells (SMC) themselves release cell derived
growth factors with subsequent proliferation and migration of
medial SMC through the internal elastic lamina to the area of the
vessel intima. Further proliferation and hyperplasia of intimal SMC
and, most significantly, production of large amounts of
extracellular matrix over a period of 3-6 months results in the
filling in and narrowing of the vascular space sufficient to
significantly obstruct coronary blood flow.
[0004] Several recent experimental approaches to preventing SMC
proliferation have shown promise although the mechanisms for most
agents employed are still unclear. Heparin is the best known and
characterized agent causing inhibition of SMC proliferation both in
vitro and in animal models of balloon angioplasty-mediated injury.
The mechanism of SMC inhibition with heparin is still not known but
may be due to any or all of the following: 1) reduced expression of
the growth regulatory protooncogenes c-fos and c-myc, 2) reduced
cellular production of tissue plasminogen activator; are 3) binding
and dequestration of growth regulatory factors such as fibrovalent
growth factor (FGF).
[0005] Other agents which have demonstrated the ability to reduce
myointimal thickening in animal models of balloon vascular injury
are angiopeptin (a somatostatin analog), calcium channel blockers,
angiotensin converting enzyme inhibitors (captopril, cilazapril),
cyclosporin A, trapidil (an antianginal, antiplatelet agent),
terbinafine (antifungal), colchicine and taxol (antitubulin
antiproliferatives), and c-myc and c-myb antinsense
oligonucleotides.
[0006] Additionally, a goat antibody to the SMC mitogen platelet
derived growth factor (PDGF) has been shown to be effective in
reducing myointimal thickening in a rat model of balloon
angioplasty injury, thereby implicating PDGF directly in the
etiology of restenosis. Thus, while no therapy has as yet proven
successful clinically in preventing restenosis after angioplasty,
the in vivo experimental success of several agents known to inhibit
SMC growth suggests that these agents as a class have the capacity
to prevent clinical restenosis and deserve careful evaluation in
humans.
[0007] Coronary heart disease is the major cause of death in men
over the age of 40 and in women over the age of fifty in the
western world. Most coronary artery-related deaths are due to
atherosclerosis. Atherosclerotic lesions which limit or obstruct
coronary blood flow are the major cause of ischemic heart disease
related mortality and result in 500,000-600,000 deaths in the
United States annually. To arrest the disease process and prevent
the more advanced disease states in which the cardiac muscle itself
is compromised, direct intervention has been employed via
percutaneous transluminal coronary angioplasty (PTCA) or coronary
artery bypass graft (CABG).
[0008] PTCA is a procedure in which a small balloon-tipped catheter
is passed down a narrowed coronary artery and then expanded to
re-open the artery. It is currently performed in approximately
250,000-300,000 patients each year. The major advantage of this
therapy is that patients in which the procedure is successful need
not undergo the more invasive surgical procedure of coronary artery
bypass graft. A major difficulty with PTCA is the problem of
post-angioplasty closure of the vessel, both immediately after PTCA
(acute reocclusion) and in the long term (restenosis).
[0009] The mechanism of acute reocclusion appears to involve
several factors and may result from vascular recoil with resultant
closure of the artery and/or deposition of blood platelets along
the damaged length of the newly opened blood vessel followed by
formation of a fibrin/red blood cell thrombus. Recently,
intravascular stents have been examined as a means of preventing
acute reclosure after PTCA.
[0010] Restenosis (chronic reclosure) after angioplasty is a more
gradual process than acute reocclusion: 30% of patients with
subtotal lesions and 50% of patients with chronic total lesions
will go on to restenosis after angioplasty. While the exact
mechanism for restenosis is still under active investigation, the
general aspects of the restenosis process have been identified.
[0011] In the normal arterial will, smooth muscle cells (SMC)
proliferate at a low rate (<0.1%/day; ref). SMC in vessel wall
exists in a `contractile` phenotype characterized by 80-90% of the
cell cytoplasmic volume occupied with the contractile apparatus.
Endoplasmic reticulum, golgi bodies, and free ribosomes are few and
located in the perinuclear region. Extracellular matrix surrounds
SMC and is rich in heparin-like glycosylaminoglycans which are
believed to be responsible for maintaining SMC in the contractile
phenotypic state.
[0012] Upon pressure expansion of an intracoronary balloon catheter
during angioplasty, smooth muscle cells within the arterial wall
become injured. Cell derived growth factors such as platelet
derived growth factor (PDGF), basic fibroblast growth factor
(bFGF), epidermal growth factor (EGF), etc. released from platelets
(i.e., PDGF) adhering to the damaged arterial luminal surface,
invading macrophages and/or leukocytes, or directly from SMC (i.e.,
BFGF) provoke a proliferation and migratory response in medial SMC.
These cells undergo a phenotypic change from the contractile
phenotyope to a `synthetic` phenotype characterized by only few
contractile filament bundles but extensive rough endoplasmic
reticulum, golgi and free ribosomes. Proliferation/migration
usually begins within 1-2 days post-injury and peaks at 2 days in
the media, rapidly declining thereafter (Campbell et al., In:
Vascular Smooth Muscle Cells in Culture, Campbell, J. H. and
Campbell, G. R., Eds, CRC Press, Boca.Raton, 1987, pp. 39-55);
Clowes, A. W. and Schwartz, S. M., Circ. Res. 56:139-145,
1985).
[0013] Finally, daughter synthetic cells migrate to the intimal
layer of arterial smooth muscle and continue to proliferate.
Proliferation and migration continues until the damaged luminal
endothelial layer regenerates at which time proliferation ceases
within the intima, usually within 7-14 days postinjury. The
remaining increase in intimal thickening which occurs over the next
3-6 months is due to an increase in extracellular matrix rather
than cell number. Thus, SMC migration and proliferation is an acute
response to vessel injury while intimal hyperplasia is a more
chronic response. (Liu et al., Circulation, 79:1374-1387,
1989).
[0014] Patients with symptomatic reocclusion require either repeat
PTCA or CABG. Because 30-50% of patients undergoing PTCA will
experience restenosis, restenosis has clearly limited the success
of PTCA as a therapeutic approach to coronary artery disease.
Because SMC proliferation and migration are intimately involved
with the pathophysiological response to arterial injury, prevention
of SMC proliferation and migration represents a target for
pharmacological intervention in the prevention of restenosis.
SUMMARY OF THE INVENTION
Novel Features and Applications to Stent Technology
[0015] Currently, attempts to improve the clinical performance of
stents have involved some variation of either applying a coating to
the metal, attaching a covering or membrane, or embedding material
on the surface via ion bombardment. A stent designed to include
reservoirs is a new approach which offers several important
advantages over existing technologies.
Local Drug Delivery from a Stent to Inhibit Restenosis
[0016] In this application, it is desired to deliver a therapeutic
agent to the site of arterial injury. The conventional approach has
been to incorporate the therapeutic agent into a polymer material
which is then coated on the stent. The ideal coating material must
be able to adhere strongly to the metal stent both before and after
expansion, be capable of retaining the drug at a sufficient load
level to obtain the required dose, be able to release the drug in a
controlled way over a period of several weeks, and be as thin as
possible so as to minimize the increase in profile. In addition,
the coating material should not contribute to any adverse response
by the body (i.e., should be non-thrombogenic, non-inflammatory,
etc.). To date, the ideal coating material has not been developed
for this application.
[0017] An alternative would be to design the stent to contain
reservoirs which could be loaded with the drug. A coating or
membrane of biocompatable material could be applied over the
reservoirs which would control the diffusion of the drug from the
reservoirs to the artery wall.
[0018] One advantage of this system is that the properties of the
coating can be optimized for achieving superior biocompatibility
and adhesion properties, without the addition requirement of being
able to load and release the drug. The size, shape, position, and
number of reservoirs can be used to control the amount of drug, and
therefore the dose delivered.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The invention will be better understood in connection with
the following figures in which FIGS. 1 and 1a are top views and
section views of a stent containing reservoirs as described in the
present invention;
[0020] FIGS. 2a and 2b are similar views of an alternate embodiment
of the stent with open ends;
[0021] FIGS. 3a and 3b are further alternate figures of a device
containing a grooved reservoir; and
[0022] FIG. 4 is a layout view of a device containing a reservoir
as in FIG. 3.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0023] Pharmacological attempts to prevent restenosis by
pharmacologic means have thus far been unsuccessful and all involve
systemic administration of the trial agents. Neither
aspirin-dipyridamole, ticlopidine, acute heparin administration,
chronic warfarin (6 months) nor methylprednisolone have been
effective in preventing restenosis although platelet inhibitors
have been effective in preventing acute reocclusion after
angioplasty. The calcium antagonists have also been unsuccessful in
preventing restenosis, although they are still under study. Other
agents currently under study include thromboxane inhibitors,
prostacyclin mimetics, platelet membrane receptor blockers,
thrombin inhibitors and angiotensin converting enzyme inhibitors.
These agents must be given systemically, however, and attainment of
a therapeutically effective dose may not be possible;
antiproliferative (or anti-restenosis) concentrations may exceed
the known toxic concentrations of these agents so that levels
sufficient to produce smooth muscle inhibition may not be reached
(Lang et al., 42 Ann. Rev. Med., 127-132 (1991); Popma et al., 84
Circulation, 1426-1436 (1991)).
[0024] Additional clinical trials in which the effectiveness for
preventing restenosis of dietary fish oil supplements, thromboxane
receptor antagonists, cholesterol lowering agents, and serotonin
antagonists has been examined have shown either conflicting or
negative results so that no pharmacological agents are as yet
clinically available to prevent post-angioplasty restenosis
(Franklin, S. M. and Faxon, D. P., 4 Coronary Artery Disease,
2-32-242 (1993); Serruys, P. W. et al., 88 Circulation, (part 1)
1588-1601, (1993).
[0025] Conversely, stents have proven useful in preventing reducing
the proliferation of restenosis. Stents, such as the stent 10 seen
in layout in FIG. 4, balloon-expandable slotted metal tubes
(usually but not limited to stainless steel), which when expanded
within the lumen of an angioplastied coronary artery, provide
structural support to the arterial wall. This support is helpful in
maintaining an open path for blood flow. In two randomized clinical
trials, stents were shown to increase angiographic success after
PTCA, increase the stenosed blood vessel lumen and to reduce the
lesion recurrence at 6 months (Serruys et al., 331 New Eng Jour.
Med, 495, (1994); Fischman et al., 331 New Eng Jour. Med, 496-501
(1994). Additionally, in a preliminary trial, heparin coated stents
appear to possess the same benefit of reduction in stenosis
diameter at follow-up as was observed with non-heparin coated
stents. Additionally, heparin coating appears to have the added
benefit of producing a reduction in sub-acute thrombosis after
stent implantation (Serruys et al., 93 Circulation, 412-422,
(1996). Thus, 1) sustained mechanical expansion of a stenosed
coronary artery has been shown to provide some measure of
restenosis prevention, and 2) coating of stents with heparin has
demonstrated both the feasibility and the clinical usefulness of
delivering drugs to local, injured tissue off the surface of the
stent.
[0026] Numerous agents are being actively studied as
antiproliferative agents for use in restenosis and have shown some
activity in experimental animal models. These include: heparin and
heparin fragments (Clowes and Karnovsky, 265 Nature, 25-626,
(1977); Guyton, J. R. et al. 46 Circ. Res., 625-634, (1980);
Clowes, A. W. and Clowes, M. M., 52 Lab. Invest., 611-616, (1985);
Clowes, A. W. and Clowes, M. M., 58 Circ. Res., 839-845 (1986);.
Majesky et al., 61 Circ Res., 296-300, (1987); Snow et al., 137 Am.
J. Pathol., 313-330 (1990); Okada, T. et al., 25 Neurosurgery,
92-898, (1989) colchicine (Currier, J. W. et al., 80 Circulation,
11-66, (1989), taxol (ref), agiotensin converting enzyme (ACE)
inhibitors (Powell, J. S. et al., 245 Science, 186-188 (1989),
angiopeptin (Lundergan, C. F. et al., 17 Am. J. Cardiol. (Suppl.
B); 132B-136B (1991), Cyclosporin A (Jonasson, L. et. al., 85 Proc.
Natl. Acad. Sci., 2303 (1988), goat-anti-rabbit PDGF antibody
(Ferns, G. A. A., et al., 253 Science, 1129-1132 (1991),
terbinafine (Nemecek, G. M. et al., 248 J. Pharmacol. Exp. Thera.,
1167-11747 (1989), trapidil (Liu, M. W. et al., 81 Circulation,
1089-1093 (1990), interferon-gamma (Hansson, G. K. and Holm, 84 J.
Circulation, 1266-1272 (1991), steroids (Colburn, M. D. et al., 15
J. Vasc. Surg., 510-518 (1992), see also Berk, B. C. et al., 17 J.
Am. Coll. Cardiol., 111B-1 17B (1991), ionizing radiation (ref),
fusion toxins (ref) antisense oligonucleotides (ref), gene vectors
(ref), and rapamycin (see below).
[0027] Of particular interest in rapamycin. Rapamycin is a
macrolide antibiotic which blocks IL-2-mediated T-cell
proliferation and possesses antiinflammatory activity. While the
precise mechanism of rapamycin is still under active investigation,
rapamycin has been shown to prevent the G.sub.1 to 5 phase
progression of T-cells through the cell cycle by inhibiting
specific cell cyclins and cyclin-dependent protein kinases
(Siekierka, Immunol. Res. 13: 110-116, 1994). The antiproliferative
action of rapamycin is not limited to T-cells; Marx et al. (Circ
Res 76:412-417, 1995) have demonstrated that rapamycin prevents
proliferation of both rat and human SMC in vitro while Poon et al.
have shown the rat, porcine, and human SMC migratin can also be
inhibited by rapamycin (J Clin Invest 98: 2277-2283, 1996). Thus,
rapamycin is capable of inhibiting both the inflammatory response
known to occur after arterial injury and stent implantation, as
well as the SMC hyperproliferative response. In fact, the combined
effects of rapamycin have been demonstrated to result in a
diminished SMC hyperproliferative response in a rat femoral artery
graft model and in both rat and porcine arterial balloon injury
models (Gregory et al., Transplantation 55:1409-1418, 1993; Gallo
et al., in press, (1997)). These observations clearly support the
potential use of rapamycin in the clinical setting of
post-angioplasty restenosis.
[0028] Although the ideal agent for restenosis has not yet been
identified, some desired properties are clear: inhibition of local
thrombosis without the risk systemic bleeding complications and
continuous and prevention of the dequale of arterial injury,
including local inflammation and sustained prevention smooth muscle
proliferation at the site of angioplasty without serious systemic
complications. Inasmuch as stents prevent at least a portion of the
restenosis process, an agent which prevents inflammation and the
proliferation of SMC combined with a stent may provide the most
efficacious treatment for post-angioplasty restenosis.
Experiments
[0029] Agents: Rapamycin (sirolimus) structural analogs
(macrocyclic lactones) and inhibitors of cell-cycle
progression.
[0030] Delivery Methods:
[0031] These can vary: [0032] Local delivery of such agents
(rapamycin) from the struts of a stent, from a stent graft, grafts,
stent cover or sheath. [0033] Involving comixture with polymers
(both degradable and nondegrading) to hold the drug to the stent or
graft. [0034] or entrapping the drug into the metal of the stent or
graft body which has been modified to contain micropores or
channels, as will be explained further herein. [0035] or including
covalent binding of the drug to the stent via solution chemistry
techniques (such as via the Carmeda process) or dry chemistry
techniques (e.g. vapour deposition methods such as rf-plasma
polymerization) and combinations thereof. [0036] Catheter delivery
intravascularly from a tandem balloon or a porous balloon for
intramural uptake. [0037] Extravascular delivery by the pericardial
route. [0038] Extravascular delivery by the advential application
of sustained release formulations.
[0039] Uses: [0040] for inhibition of cell proliferation to prevent
neointimal proliferation and restenosis. [0041] prevention of tumor
expansion from stents. [0042] prevent ingrowth of tissue into
catheters and shunts inducing their failure. 1. Experimental Stent
Delivery Method--Delivery from Polymer Matrix:
[0043] Solution of Rapamycin, prepared in a solvent miscible with
polymer carrier solution, is mixed with solution of polymer at
final concentration range 0.001 weight % to 30 weight % of drug.
Polymers are biocompatible (i.e., not elicit any negative tissue
reaction or promote mural thrombus formation) and degradable, such
as lactone-based polyesters or copolyesters, e.g., polylactide,
polycaprolacton-glycolide, polyorthoesters, polyanhydrides;
poly-amino acids; polysaccharides; polyphosphazenes;
poly(ether-ester) copolymers, e.g., PEO-PLLA, or blends thereof.
Nonabsorbable biocompatible polymers are also suitable candidates.
Polymers such as polydimethylsiolxane;
poly(ethylene-vingylacetate); acrylate based polymers or
copolymers, e.g., poly(hydroxyethyl methylmethacrylate, polyvinyl
pyrrolidinone; fluorinated polymers such as
polytetrafluoroethylene; cellulose esters.
[0044] Polymer/drug mixture is applied to the surfaces of the stent
by either dip-coating, or spray coating, or brush coating or
dip/spin coating or combinations thereof, and the solvent allowed
to evaporate to leave a film with entrapped rapamycin.
2. Experimental Stent Delivery Method--Delivery from Microporous
Depots in Stent Through a Polymer Membrane Coating:
[0045] Stent, whose body has been modified to contain micropores or
channels is dipped into a solution of Rapamycin, range 0.001 wt %
to saturated, in organic solvent such as acetone or methylene
chloride, for sufficient time to allow solution to permeate into
the pores. (The dipping solution can also be compressed to improve
the loading efficiency.) After solvent has been allowed to
evaporate, the stent is dipped briefly in fresh solvent to remove
excess surface bound drug. A solution of polymer, chosen from any
identified in the first experimental method, is applied to the
stent as detailed above. This outer layer of polymer will act as
diffusion-controller for release of drug.
3. Experimental Stent Delivery Method--Delivery via Lysis of a
Covalent Drug Tether:
[0046] Rapamycin is modified to contain a hydrolytically or
enzymatically labile covalent bond for attaching to the surface of
the stent which itself has been chemically derivatized to allow
covalent immobilization. Covalent bonds such as ester, amides or
anhydrides may be suitable for this.
4. Experimental Method--Pericardial Delivery:
[0047] A: Polymeric Sheet
[0048] Rapamycin is combined at concentration range previously
highlighted, with a degradable polymer such as
poly(caprolactone-gylcolid-e) or non-degradable polymer, e.g.,
polydimethylsiloxane, and mixture cast as a thin sheet, thickness
range 10.mu. to 1000.mu. The resulting sheet can be wrapped
perivascularly on the target vessel. Preference would be for the
absorbable polymer.
[0049] B: Conformal Coating:
[0050] Rapamycin is combined with a polymer that has a melting
temperature just above 37.degree. C., range 40.degree.-45.degree.
C. Mixture is applied in a molten state to the external side of the
target vessel. Upon cooling to body temperature the mixture
solidifies conformably to the vessel wall. Both non-degradable and
absorbable biocompatible polymers are suitable.
[0051] As seen in the figures it is also possible to modify
currently manufactured stents in order to adequately provide the
drug dosages such as rapamycin. As seen in FIGS. 1a, 2a and 3a, any
stent strut 10, 20, 30 can be modified to have a certain reservoir
or channel 11, 21, 31.
[0052] Each of these reservoirs can be open or closed as desired.
These reservoirs can hold the drug to be delivered. FIG. 4 shows a
stent 40 with a reservoir 45 created at the apex of a flexible
strut. Of course, this reservoir 45 is intended to be useful to
deliver rapamycin or any other drug at a specific point of
flexibility of the stent. Accordingly, this concept can be useful
for "second generation" type stents.
[0053] In any of the foregoing devices, however, it is useful to
have the drug dosage applied with enough specificity and enough
concentration to provide an effective dosage in the lesion area. In
this regard, the reservoir size in the stent struts must be kept at
a size of about 0.0005'' to about 0.003''. Then, it should be
possible to adequately apply the drug dosage at the desired
location and in the desired amount.
[0054] These and other concepts will are disclosed herein. It would
be apparent to the reader that modifications are possible to the
stent or the drug dosage applied. In any event, however, the any
obvious modifications should be perceived to fall within the scope
of the invention which is to be realized from the attached claims
and their equivalents.
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