Note: Descriptions are shown in the official language in which they were submitted.
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COATED MEDICAL DEVICES FOR THE PREVENTION AND TREATMENT
OF VASCULAR DISEASE
BACKGROUND OF THE INVENTION
15 1. Field of the Invention
The present invention relates to drugs and coated medical devices for
the prevention and treatment of vascular disease, and more particularly to
drugs and drug coated medical devices for the prevention and treatment of
20 neointimal hyperplasia, specifically edge lumen loss and target lesion
restenosis.
2. Discussion of the Related Art
25 Many individuals suffer from circulatory disease caused by a progressive
blockage of the blood vessels that perfuse the heart and other major organs.
More severe blockage of blood vessels in such individuals often leads to
hypertension, ischemic injury, stroke, or myocardial infarction.
Atherosclerotic
lesions, which limit or obstruct coronary blood flow, are the major cause of
30 ischemic heart disease. Percutaneous transluminal coronary angioplasty is a
medical procedure whose purpose is to increase blood flow through an artery.
Percutaneous transluminal coronary angioplasty is the predominant treatment
for coronary vessel stenosis. The increasing use of this procedure is
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attributable to its relatively high success rate and its minimal invasiveness
compared with coronary bypass surgery. A limitation associated with
percutaneous transluminal coronary angioplasty is the abrupt closure of the
vessel which may occur immediately after the procedure, and restenosis which
occurs gradually following the procedure. Additionally, restenosis is a
chronic
problem in patients who have undergone saphenous vein bypass grafting. The
mechanism of acute occlusion appears to involve several factors and may
result from vascular recoil with resultant closure of the artery and/or
deposition
of blood platelets and fibrin along the damaged length of the newly opened
blood vessel.
Restenosis after percutaneous transluminal coronary angioplasty is a
more gradual process initiated by vascular injury. Multiple processes,
including
thrombosis, inflammation, growth factor and cytokine release, cell
proliferation,
cell migration and extracellular matrix synthesis each contribute to the
restenotic process.
While the exact mechanism of restenosis is not completely understood,
the general aspects of the restenosis process have been identified. In the
normal arterial wall, smooth muscle cells proliferate at a low rate,
approximately less than 0.1 percent per day. Smooth muscle cells in the
vessel walls exist in a contractile phenotype characterized by eighty to
ninety
percent of the cell cytoplasmic volume occupied with the contractile
apparatus.
Endoplasmic reticulum, Golgi, and free ribosomes are few and are located in
the perinuclear region. Extracellular matrix surrounds the smooth muscle cells
and is rich in heparin-like glycosylaminoglycans which are believed to be
responsible for maintaining smooth muscle cells in the contractile phenotypic
state (Campbell and Campbell, 1985).
Upon pressure expansion of an intracoronary balloon catheter during
angioplasty, smooth muscle cells within the vessel wail become injured,
initiating a thrombotic and inflammatory response. Cell derived growth factors
such as platelet derived growth factor, basic fibroblast growth factor,
epidermal
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growth factor, thrombin, etc., released from platelets, invading macrophages
and/or leukocytes, or directly from the smooth muscle cells provoke a
proliferative and migratory response in medial smooth muscle cells. These
cells undergo a change from the contractile phenotype to a synthetic
phenotype characterized by only a few contractile filament bundles, extensive
rough endoplasmic reticulum, Golgi and free ribosomes. Proliferation/migration
usually begins within one to two days post-injury and peaks several days
thereafter (Campbell and Campbell, 1987; Clowes and Schwartz, 1985).
Daughter cells migrate to the intimal layer of arterial smooth muscle and
continue to proliferate and secrete significant amounts of extracellular
matrix
proteins. Proliferation, migration and extracellular matrix synthesis continue
until the damaged endothelial layer is repaired at which time proliferation
slows
within the intima, usually within seven to fourteen days post-injury. The
newly
formed tissue is called neointima. The further vascular narrowing that occurs
over the next three to six months is due primarily to negative or constrictive
remodeling.
Simultaneous with local proliferation and migration, inflammatory cells
adhere to the site of vascular injury. Within three to seven days post-injury,
inflammatory cells have migrated to the deeper layers of the vessel wall. In
animal models employing either balloon injury or stent implantation,
inflammatory cells may persist at the site of vascular injury for at least
thirty
days (Tanaka et al., 1993; Edelman et al., 1998). Inflammatory cells therefore
are present and may contribute to both the acute and chronic phases of
restenosis.
Numerous agents have been examined for presumed anti-proliferative
actions in restenosis and have shown some activity in experimental animal
models. Some of the agents which have been shown to successfully reduce
the extent of intimal hyperplasia in animal models include: heparin and
heparin
fragments (Clowes, A.W. and Karnovsky M., Nature 265: 25-26, 1977; Guyton,
J.R. et al., Circ. Res., 46: 625-634, 1980; Clowes, A.W. and Clowes, M.M.,
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Lab. Invest. 52: 611-616, 1985; Clowes, A.W. and Clowes, M.M., Circ. Res. 58:
839-845, 1986; Majesky et al., Circ. Res. 61: 296-300, 1987; Snow et al., Am.
J. Pathol. 137: 313-330, 1990; Okada, T. et at., Neurosurgery 25: 92-98,
1989),
colchicine (Currier, J.W. et al., Circ. 80: 11-66, 1989), taxol (Sollot, S.J.
et al.,
J. Clin. Invest. 95: 1869-1876, 1995), angiotensin converting enzyme (ACE)
inhibitors (Powell, J.S. et al., Science, 245: 186-188, 1989), angiopeptin
(Lundergan, C.F. et al. Am. J. Cardiol. 17(Suppl. B):132B-136B, 1991),
cyclosporin A (Jonasson, L. et at., Proc. Natl., Acad. Sci., 85: 2303, 1988),
goat-anti-rabbit PDGF antibody (Ferns, G.A.A., et al., Science 253: 1129-1132,
1991), terbinafine (Nemecek, G.M. et al., J. Pharmacol. Exp. Thera. 248: 1167-
1174, 1989), trapidil (Liu, M.W. et at., Circ. 81: 1089-1093, 1990), tranilast
(Fukuyama, J. et at., Eur. J. Pharmacol. 318: 327-332, 1996), interferon-
gamma (Hansson, G.K. and Holm, J., Circ. 84:1266-1272,1991), rapamycin
(Marx, S.O. et al., Circ. Res. 76: 412-417, 1995), corticosteroids (Colburn,
M.D.
et at., J. Vasc. Surg. 15: 510-518, 1992), see also Berk, B.C. et at., J. Am.
Coll.
Cardiol. 17: 111 B-1 17B, 1991), ionizing radiation (Weinberger, J. et al.,
Int. J.
Rad. Onc. Biol. Phys. 36: 767-775, 1996), fusion toxins (Farb, A. et al.,
Circ.
Res. 80: 542-550, 1997) antisense oligonucleotides (Simons, M. et al., Nature
359: 67-70, 1992) and gene vectors (Chang, M.W. et at., J. Clin. Invest. 96:
2260-2268, 1995). Anti-proliferative action on smooth muscle cells in vitro
has
been demonstrated for many of these agents, including heparin and heparin
conjugates, taxol, tranilast, colchicine, ACE inhibitors, fusion toxins,
antisense
oligonucleotides, rapamycin and ionizing radiation. Thus, agents with diverse
mechanisms of smooth muscle cell inhibition may have therapeutic utility in
reducing intimal hyperplasia.
However, in contrast to animal models, attempts in human angioplasty
patients to prevent restenosis by systemic pharmacologic means have thus far
been unsuccessful. Neither aspirin-dipyridamole, ticlopidine, anti-coagulant
therapy (acute heparin, chronic warfarin, hirudin or hirulog), thromboxane
receptor antagonism nor steroids have been effective in preventing restenosis,
although platelet inhibitors have been effective in preventing acute
reocclusion
after angioplasty (Mak and Topol, 1997; Lang et al., 1991; Popma et al.,
1991).
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The platelet GP II6/llla receptor, antagonist, Reopro is still under study
but has
not shown definitive results for the reduction in restenosis following
angioplasty
and stenting. Other agents, which have also been unsuccessful in the
prevention of restenosis, include the calcium channel antagonists,
prostacyclin
mimetics, angiotensin converting enzyme inhibitors, serotonin receptor
antagonists, and anti-proliferative agents. These agents must be given
systemically, however, and attainment of a therapeutically effective dose may
not be possible; anti-proliferative (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 (Mak and Topol,
1997; Lang et al., 1991; Popma et al., 1991).
Additional clinical trials in which the effectiveness for preventing
restenosis utilizing dietary fish oil supplements or cholesterol lowering
agents
has been examined showing either conflicting or negative results so that no
pharmacological agents are as yet clinically available to prevent post-
angioplasty restenosis (Mak and Topol, 1997; Franklin and Faxon, 1993:
Serruys, P.W. et al., 1993). Recent observations suggest that the
antilipid/antioxidant agent, probucol may be useful in preventing restenosis
but
this work requires confirmation (Tardif et al., 1997; Yokoi, et al., 1997).
Probucol is presently not approved for use in the United States and a thirty-
day
pretreatment period would preclude its use in emergency angioplasty.
Additionally, the application of ionizing radiation has shown significant
promise
in reducing or preventing restenosis after angioplasty in patients with stents
(Teirstein et al., 1997). Currently, however, the most effective treatments
for
restenosis are repeat angioplasty, atherectomy or coronary artery bypass
grafting, because no therapeutic agents currently have Food and Drug
Administration approval for use for the prevention of post-angioplasty
restenosis.
Unlike systemic pharmacologic therapy, stents have proven effective in
significantly reducing restenosis. Typically, stents are balloon-expandable
slotted metal tubes (usually, but not limited to, stainless steel), which,
when
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expanded within the lumen of an angioplastied coronary artery, provide
structural support through rigid scaffolding to the arterial wall. This
support is
helpful in maintaining vessel lumen patency. In two randomized clinical
trials,
stents increased angiographic success after percutaneous transluminal
coronary angioplasty, by increasing minimal lumen diameter and reducing, but
not eliminating, the incidence of restenosis at six months (Serruys et al.,
1994;
Fischman et al., 1994).
Additionally, the heparin coating of stents appears to have the added
benefit of producing a reduction in sub-acute thrombosis after stent
implantation (Serruys et al., 1996). Thus, sustained mechanical expansion of a
stenosed coronary artery with a stent has been shown to provide some
measure of restenosis prevention, and the coating of stents with heparin has
demonstrated both the feasibility and the clinical usefulness of delivering
drugs
locally, at the site of injured tissue.
Accordingly, there exists a need for effective drugs and drug delivery
systems for the effective prevention and treatment of neointimal thickening
that
occurs after percutaneous transluminal coronary angioplasty and stent
implantation, primarily edge lumen loss.
SUMMARY OF THE INVENTION
The drugs and drug delivery systems of the present invention provide a
means for overcoming the difficulties associated with the methods and devices
currently in use as briefly described above.
The drugs and drug delivery systems of the present invention utilize a
stent or graft in combination with rapamycin or other drugs/agents/compounds
to prevent and treat neointimal hyperplasia, i.e. restenosis, following
percutaneous transluminal coronary angioplasty and stent implantation. It has
been determined that rapamycin functions to inhibit smooth muscle cell
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proliferation through a number of mechanisms. It has also been determined that
rapamycin eluting stent coatings produce superior effects in humans, when
compared to animals, with respect to the magnitude and duration of the
reduction
in neointimal hyperplasia. Rapamycin administration from a local delivery
platform
also produces an anti-inflammatory effect in the vessel wall that is distinct
from
and complimentary to its smooth muscle cell anti-proliferative effect. In
addition, it
has also been demonstrated that rapamycin inhibits constrictive vascular
remodeling in humans.
Other drugs, agents or compounds which mimic certain actions of
rapamycin may also be utilized in combination with local delivery systems or
platforms.
The local administration of drugs, agents or compounds to stented vessels
have the additional therapeutic benefit of higher tissue concentration than
that
which would be achievable through the systemic administration of the same
drugs,
agents or compounds. Other benefits include reduced systemic toxicity, single
treatment, and ease of administration. An additional benefit of a local
delivery
device and drug, agent or compound therapy may be to reduce the dose of the
therapeutic drugs, agents or compounds and thus limit their toxicity, while
still
achieving a reduction in restenosis.
In one aspect, there is provided a drug delivery device comprising: an
intraluminal stent; and a therapeutic dosage of one or more compounds
releasably
affixed, in a predetermined profile, to the stent for the treatment of target
lesion
restenosis. The therapeutic dosage of the one or more compounds releasably
affixed, in a predetermined profile, to the stent comprises:
a first concentration of the one or more compounds affixed to a first portion
of the stent; and
a second concentration of the one or more compounds affixed to a second
portion of the stent, wherein the second concentration is greater than the
first
concentration.
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BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other features and advantages of the invention will be
apparent
from the following, more particular description of preferred embodiments of
the
invention, as illustrated in the accompanying drawings.
FIG. 1 is a chart indicating the effectiveness of rapamycin as an anti-
inflammatory
relative to other anti-inflammatories.
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Figure 2 is a view along the length of a stent (ends not shown) prior to
expansion showing the exterior surface of the stent and the characteristic
banding pattern.
Figure 3 is a perspective view of the stent of Figure 1 having reservoirs
in accordance with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The drug/drug combinations and delivery devices of the present
invention may be utilized to effectively prevent and treat vascular disease,
and
in particular, vascular disease caused by injury. Various medical treatment
devices utilized in the treatment of vascular disease may ultimately induce
further complications. For example, balloon angioplasty is a procedure
utilized
to increase blood flow through an artery and is the predominant treatment for
coronary vessel stenosis. However, as stated above, the procedure typically
causes a certain degree of damage to the vessel wall, thereby potentially
exacerbating the problem at a point later in time. Although other procedures
and diseases may cause similar injury, exemplary embodiments of the present
invention will be described with respect to the treatment of restenosis and
related complications following percutaneous transluminal coronary angioplasty
and other similar arterial/venous procedures.
While exemplary embodiments of the invention will be described with
respect to the treatment of restenosis and related complications following
percutaneous transluminal coronary angioplasty, it is important to note that
the
local delivery of drug/drug combinations may be utilized to treat a wide
variety
of conditions utilizing any number of medical devices, or to enhance the
function and/or life of the device. For example, intraocular lenses, placed to
restore vision after cataract surgery is often compromised by the formation of
a
secondary cataract. The latter is often a result of cellular overgrowth on the
lens surface and can be potentially minimized by combining a drug or drugs
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with the device. Other medical devices which often fail due to tissue in-
growth
or accumulation of proteinaceous material in, on and around the device, such
as shunts for hydrocephalus, dialysis grafts, colostomy bag attachment
devices, ear drainage tubes, leads for pace makers and implantable
defibrillators can also benefit from the device-drug combination approach.
Devices which serve to improve the structure and function of tissue or organ
may also show benefits when combined with the appropriate agent or agents.
For example, improved osteointegration of orthopedic devices to enhance
stabilization of the implanted device could potentially be achieved by
combining
it with agents such as bone-morphogenic protein. Similarly, other surgical
devices, sutures, staples, anastomosis devices, vertebral disks, bone pins,
suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular
implants, tissue adhesives and sealants, tissue scaffolds, various types of
dressings, bone substitutes, intraluminal devices, and vascular supports could
also provide enhanced patient benefit using this drug-device combination
approach. Essentially, any type of medical device may be coated in some
fashion with a drug or drug combination which enhances treatment over use of
the singular use of the device or pharmaceutical agent.
In addition to various medical devices, the coatings on these devices
may be used to deliver therapeutic and pharmacaeutic agents including:
antiproliferative/antimitotic agents including natural products such as vinca
alkaloids (i.e. vinblastine, vincristine, and vinorelbine), paclitaxel,
epidipodophyllotoxins (i.e. etoposide, teniposide), antibiotics (dactinomycin
(actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines,
mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes
(L-asparaginase which systemically metabolizes L-asparagine and deprives
cells which do not have the capacity to synthesize their own asparagine);
antiplatelet agents such as G(GP) Ilb/llla inhibitors and vitronectin receptor
antagonists; antiproliferative/antimitotic alkylating agents such as nitrogen
mustards (mechlorethamine, cyclophosphamide and analogs, melphalan,
chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and
thiotepa), alkyl sulfonates-busulfan, nitrosoureas (carmustine (BCNU) and
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analogs, streptozocin), trazanes - dacarbazinine (DTIC);
antiproliferative/antimitotic antimetabolites such as folic acid analogs
(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and
cytarabine),
purine analogs and related inhibitors (mercaptopurine, thioguanine,
pentostatin
and 2-chlorodeoxyadenosine {cladribine}); platinum coordination complexes
(cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane,
aminoglutethimide; hormones (i.e. estrogen); anticoagulants (heparin,
synthetic
heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as
tissue plasminogen activator, streptokinase and urokinase), aspirin,
dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory;
antisecretory
(breveldin); anti-inflammatory; such as adrenocortical steroids (cortisol,
cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylylpredniso
lone,
triamcinolone, betamethasone, and dexamethasone), non-steroidal agents
(salicylic acid derivatives i.e, aspirin; para-aminophenol derivaties i.e.
acetominophen; indole and indene acetic acids (indomethacin, sulindac, and
etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac),
aryipropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic
acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam,
phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds
(auranofin, aurothioglucose, gold sodium thiomalate); immunosuppressives;
(cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine,
mycophenolate mofetil); angiogenic agents; vascular endothelial growth factor
(VEGF), fibroblast growth factor (FGF); angiotensin receptor blockers; nitric
oxide donors; anti-sense oligionucleotides and combinations thereof; cell
cycle
inhibitors, mTOR inhibitors, and growth factor receptor signal transduction
kinase inhibitors; retenoids; cyclin/CDK inhibitors; HMG co-enzyme reductase
inhibitors (statins); and protease inhibitors.
As stated above, the proliferation of vascular smooth muscle cells in
response to mitogenic stimuli that are released during balloon angioplasty and
stent implantation is the primary cause of neointimal hyperplasia. Excessive
neointimal hyperplasia can often lead to impairment of blood flow, cardiac
ischemia and the need for a repeat intervention in selected patients in high
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treatment groups. Yet repeat revascularization incurs risk of patient
morbidity
and mortality while adding significantly to the cost of health care. Given the
widespread use of stents in interventional practice, there is a clear need for
safe and effective inhibitors of neointimal hyperplasia and negative vascular
remodeling.
Rapamycin is a macroyclic triene antibiotic produced by streptomyces
hygroscopicus as disclosed in U.S. Patent No. 3,929,992. It has been found
that rapamycin inhibits the proliferation of vascular smooth muscle cells in
vivo.
Accordingly, rapamycin may be utilized in treating intimal smooth muscle cell
hyperplasia, restenosis and vascular occlusion in a mammal, particularly
following either biologically or mechanically mediated vascular injury, or
under
conditions that would predispose a mammal to suffering such a vascular injury.
Rapamycin functions to inhibit smooth muscle cell proliferation and does not
interfere with the re-endothelialization of the vessel walls.
Rapamycin functions to inhibit smooth muscle cell proliferation through a
number of mechanisms. In addition, rapamycin reduces the other effects
caused by vascular injury, for example, inflammation. The operation and
various functions of rapamycin are described in detail below. Rapamycin as
used throughout this application shall include rapamycin, rapamycin analogs,
derivatives and congeners that bind FKBP12 and possess the same
pharmacologic properties as rapamycin.
Rapamycin reduces vascular hyperplasia by antagonizing smooth
muscle proliferation in response to mitogenic signals that are released during
angioplasty. Inhibition of growth factor and cytokine mediated smooth muscle
proliferation at the late G1 phase of the cell cycle is believed to be the
dominant mechanism of action of rapamycin. However, rapamycin is also
known to prevent T-cell proliferation and differentiation when administered
systemically. This is the basis for its immunosuppresive activity and its
ability
to prevent graft rejection.
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The molecular events that are responsible for the actions of rapamycin,
a known anti-proliferative, which acts to reduce the magnitude and duration of
neointimal hyperplasia, are still being elucidated. It is known, however, that
rapamycin enters cells and binds to a high-affinity cytosolic protein called
FKBP12. The complex of rapamycin and FKPB12 in turn binds to and inhibits
a phosphoinositide (Pl)-3 kinase called the "mammalian Target of Rapamycin"
or mTOR. The mammalian Target of Rapamycin is a protein kinase that plays
a key role in mediating the downstream signaling events associated with
mitogenic growth factors and cytokines in smooth muscle cells and T
lymphocytes. These events include phosphorylation of p27, phosphorylation of
p70 s6 kinase and phosphorylation of 4BP-1, an important regulator of protein
translation.
It is recognized that rapamycin reduces restenosis by inhibiting
neointimal hyperplasia. However, there is evidence that rapamycin may also
inhibit the other major component of restenosis, namely, negative remodeling.
Remodeling is a process whose mechanism is not clearly understood but
which results in shrinkage of the external elastic lamina and reduction in
lumenal area over time, generally a period of approximately three to six
months
in humans.
Negative or constrictive vascular remodeling may be quantified
angiographically as the percent diameter stenosis at the lesion site where
there
is no stent to obstruct the process. If late lumen loss is abolished in-
lesion, it
may be inferred that negative remodeling has been inhibited. Another method
of determining the degree of remodeling involves measuring in-lesion external
elastic lamina area using intravascular ultrasound (IVUS). Intravascular
ultrasound is a technique that can image the external elastic lamina as well
as
the vascular lumen. Changes in the external elastic lamina proximal and distal
to the stent from the post-procedural timepoint to four-month and twelve-month
follow-ups are reflective of remodeling changes.
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Evidence that rapamycin exerts an effect on remodeling comes from
human implant studies with rapamycin coated stents showing a very low
degree of restenosis in-lesion as well as in-stent. In-lesion parameters are
usually measured approximately five millimeters on either side of the stent
i.e.
proximal and distal. Since the stent is not present to control remodeling in
these zones which are still affected by balloon expansion, it may be inferred
that rapamycin is preventing vascular remodeling.
The data in Table 1 below illustrate that in-lesion percent diameter
stenosis remains low in the rapamycin treated groups, even at twelve months.
Accordingly, these results support the hypothesis that rapamycin reduces
remodeling.
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Angiographic In-Lesion Percent Diameter Stenosis
(%, mean SD and "n=") In Patients Who Received a
Rapamycin-Coated Stent
Coating Post 4 - 6 month 12 month
Group Placement Follow Up Follow Up
Brazil 10.6 5.7 (30) 13.6 8.6 (30) 22.3 7.2 (15)
Netherlands 14.7 8.8 22.4 6.4 -
TABLE 1.0
Additional evidence supporting a reduction in negative remodeling with
rapamycin comes from intravascular ultrasound data that was obtained from a
first-in-man clinical program as illustrated in Table 2 below.
Matched IVUS data in Patients Who Received a Rapamycin-Coated Stent
IVUS Parameter Post (n=) 4-Month 12-Month
Follow-Up Follow-Up
n= (n=)
Mean proximal vessel area 16.53+3.53 16.31 +4.36 13.96+2.26
(mm2) (27) (28) (13)
Mean distal vessel area 13.12+3.68 13.53+4.17 12.49+3.25
(mm2) (26) (26) (14)
TABLE 2.0
The data illustrated that there is minimal loss of vessel area proximally
or distally which indicates that inhibition of negative remodeling has
occurred in
vessels treated with rapamycin-coated stents.
Other than the stent itself, there have been no effective solutions to the
problem of vascular remodeling. Accordingly, rapamycin may represent a
biological approach to controlling the vascular remodeling phenomenon.
It may be hypothesized that rapamycin acts to reduce negative
remodeling in several ways. By specifically blocking the proliferation of
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fibroblasts in the vascular wall in response to injury, rapamycin may reduce
the
formation of vascular scar tissue. Rapamycin may also affect the translation
of
key proteins involved in collagen formation or metabolism.
Rapamycin used in this context includes rapamycin and all analogs,
derivatives and congeners that bind FKBP12 and possess the same
pharmacologic properties as rapamycin.
In a preferred exemplary embodiment, the rapamycin is delivered by a
local delivery device to control negative remodeling of an arterial segment
after
balloon angioplasty as a means of reducing or preventing restenosis. While
any delivery device may be utilized, it is preferred that the delivery device
comprises a stent that includes a coating or sheath which elutes or releases
rapamycin. The delivery system for such a device may comprise a local
infusion catheter that delivers rapamycin at a rate controlled by the
administrator.
Rapamycin may also be delivered systemically using an oral dosage
form or a chronic injectible depot form or a patch to deliver rapamycin for a
period ranging from about seven to forty-five days to achieve vascular tissue
levels that are sufficient to inhibit negative remodeling. Such treatment is
to be
used to reduce or prevent restenosis when administered several days prior to
elective angioplasty with or without a stent.
Data generated in porcine and rabbit models show that the release of
rapamycin into the vascular wall from a nonerodible polymeric stent coating in
a range of doses (35-430 g/15-18 mm coronary stent) produces a peak fifty to
fifty-five percent reduction in neointimal hyperplasia as set forth in Table 3
below. This reduction, which is maximal at about twenty-eight to thirty days,
is
typically not sustained in the range of ninety to one hundred eighty days in
the
porcine model as set forth in Table 4 below.
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Animal Studies with Rapamycin-coated stents.
Values are mean Standard Error of Mean
Study Duration Stentr Rapamycin N Neointimal Area 9_ Chan a From
m,W Po a Metal
Porcine
98009 14 days Metal 8 2.04 0.17
1X+ra am in 153 u 8 1.66 0.17` -42% -19%
1X + TC300 + ra m cin 155 u 8 1.51 + 0.19* -47% -26%
99005 28 days Metal 10 2.29 0.21
9 3.91 + 0.60"
1X+TC30+ra am in 130 u 8 2.81+0.34 +23%
1X+TC100+ra am cin 120 Ita 9 2.62 0.21 +14%
99006 28 days Metal 12 4.57 0.46
EVA/BMA 3X 12 5.02 0,62 +10%
1X + raam cin 125 u11 2. +0.31" -43% -38%
3X + ra am in 430 u 12 3.06 0.17* -39% -33%
3X + ra m cin 157 u 12 2.77 0.41' " -45% -39%
99011 28 days Metal 11 3.09 0.27
11 4.52+0.37
1X + ra am cin 189 u 14 3.05 0.35 -1%
3X + ra am cin/dex 182/363 tto 14 2.72 0.71 -12%
99021 60 days Metal 12 2.14+0.25
1 X + ra am cin 181 u 12 2.9 0.38 +38%
99034 28 days Metal 8 5.24 0.58
1 X + ra am in 186 u 8 2.47 0.33** -53%
3X + ra amycin/dex 185/369 6 2.42 0.64" -54%
20001 28 days Metal 6 1.81 +0.09
1 X + ra am cin 172 u 5 1.66 0.44 -8%
20007
30 das Metal 9 2.94+0.43
1 XTC + ra amycin 155 10 1.40+0.11* -52 %
Rabbit
99019 28 days Metal 8 1.20+0.07
EVA/BMA 1X 10 1.26 + 1 +5%
1 X + ra am cin 64 ua 9 0.92+0.14 -27% -23%
1X + ra mvcin 196 Lta 10 0,66 0.12* -48% -45%
99020 28 days Metal 12 1.18+0.10
EVA/BMA 1 X + rapamycin 197 g 8 0.81 0.16 -32%
'Scent nomenclature: EVA/BMA 1 X, 2X, and 3X signifies approx. 500pg, 1000pg,
and 1500pg total mass (polymer + drug), respectively. TC, top coat of 30 g,
100 g, or 300 g drug-free BMA; Biphasic; 2 x IX layers of rapamycin in EVA/BMA
spearated by a 100pg drug-free BMA layer. 20.25mg/kg/d x 14 d preceeded
by a loading dose of 0.5mg/kg/d x 3d prior to scent implantation.
'p<0.05 from EVA/BMA control. "p<0.05 from Metal;
"Inflammation score: (0 = essentially no intimal involvement: 1 = <25% intima
involved2= >_25 % intima involved; 3 = >50% intima involved).
TABLE 3.0
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180 day Porcine Study with Rapamycin-coated stents.
Values are mean Standard Error of Mean
% Change From Inflammation
Ra m cin Neointima/ Area
Study Duration Stent ~ y Al (mom) Polyme Metal
Score #
20007 3 days Metal 10 0.38 0.06
1.0 0.06
ETP-2-002233-P1 1 XTC + ra am cin 155 u 10 0.29 0.03 -24% 1.08+0.04
30 days Metal 9 2.94 0.43 0.11 0.08
1XTC+ra am cin 155 u 10 1.40 0.11 -52%' .25 0.10
90 days Metal 10 3.45 0.34 0.20 0 08
1 XTC + ra am cin 155 u 10 3.03 f 0.29 -12% 0.8 0.23
1X+ra am in 171 u 10 2.86 0.35 -17% 0.60+0.23
180 days Metal 10 3.65 0.39 0.6 .21
1XTC+ra am in 155 u10 2015 1 8% 1.5 + .34
1 X + ra mvcin 171q. 10 3.3487 + +6% 1.6 + .37
TABLE 4.0
The release of rapamycin into the vascular wall of a human from a
nonerodible polymeric stent coating provides superior results with respect to
the magnitude and duration of the reduction in neointimal hyperplasia within
the stent as compared to the vascular walls of animals as set forth above.
Humans implanted with a rapamycin coated stent comprising rapamycin
in the same dose range as studied in animal models using the same polymeric
matrix, as described above, reveal a much more profound reduction in
neointimal hyperplasia than observed in animal models, based on the
magnitude and duration of reduction in neointima. The human clinical
response to rapamycin reveals essentially total abolition of neointimal
hyperplasia inside the stent using both angiographic and intravascular
ultrasound measurements. These results are sustained for at least one year
as set forth in Table 5 below.
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Patients Treated (N=45 patients) with a Ra am cin-coated Stent
Effectiveness Measures Sirolimus FIM 95%
(N=45 Patients, 45 Lesions) Confidence Limit
Procedure Success QCA 100.0% (45/45) 92.1%,100.0%
4-month In-Stent Diameter Stenosis
Mean SD (N) 4.8% 6.1 % (30) [2.6%,7.09/61
Range (min,max) (-8.2%,14.9%)
6-month In-Stent Diameter Stenosis
Mean SD (N) 8.9 /x 7.6% 13 [4.8%,13.0%]
Range (min,max) (-2.9%,20.4%)
12-month In-Stent Diameter Stenosis (%)
Mean SD (N) 8.9% 6.1% (15) [5.8%,12.0%]
Range (min,max) (-3.0%,22.0%)
4-month In-Stent Late Loss (mm)
Mean SD (N) 0.00 0.29 (30) [-0.10,0.10]
Range (min,max) -0.51,0.45
6-month In-Stent Late Loss (mm)
Mean SD (N) 0.25 0.27 (13) [0.10,0.39]
Range (min,max) (-0.51,0.91)
12-month In-Stent Late Loss (mm)
Mean SD (N) 0.11 0.36 (15) [-0.08,0.29]
Range (min,max) -0.51,0.82
4-month Obstruction Volume (%) (IVUS)
Mean SD (N) 10.48x/ 2.78% (28) [9.45%,11.51%)
Range (min,max) 4.60%,16.35x/
6-month Obstruction Volume (%) (IVUS)
Mean SD (N) 7.22x/ 4.60% (13) [4.72%,9.72%],
Range (min,max) 3.82%,19.88x/
12-month Obstruction Volume (%) (IVUS)
Mean SD (N) 2.11% 5.28% (15) [0.00%,4.78%],
Range (min,max) (0.00%,19.89%)
0.0% (0/30) [0.0%,9.5%]
6-month Target Lesion Revascularization (TLR)
0.0% (0/15) [0.0%,18.1%)
12-month Target Lesion Revascularization
(TLR)
QCA = Quantitative Coronary Angiography
SD = Standard Deviation
IVUS = Intravascular Ultrasound
TABLE 5.0
Rapamycin produces an unexpected benefit in humans when delivered
from a stent by causing a profound reduction in in-stent neointimal
hyperplasia
that is sustained for at least one year. The magnitude and duration of this
benefit in humans is not predicted from animal model data. Rapamycin used in
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this context includes rapamycin and all analogs, derivatives and congeners
that
bind FKBP12 and possess the same pharmacologic properties as rapamycin.
These results may be due to a number of factors. For example, the
greater effectiveness of rapamycin in humans is due to greater sensitivity of
its
mechanism(s) of action toward the pathophysiology of human vascular lesions
compared to the pathophysiology of animal models of angioplasty. In addition,
the combination of the dose applied to the stent and the polymer coating that
controls the release of the drug is important in the effectiveness of the
drug.
As stated above, rapamycin reduces vascular hyperplasia by
antagonizing smooth muscle proliferation in response to mitogenic signals that
are released during angioplasty injury. Also, it is known that rapamycin
prevents T-cell proliferation and differentiation when administered
systemically.
It has also been determined that rapamycin exerts a local inflammatory effect
in the vessel wall when administered from a stent in low doses for a sustained
period of time (approximately two to six weeks). The local anti-inflammatory
benefit is profound and unexpected. In combination with the smooth muscle
anti-proliferative effect, this dual mode of action of rapamycin may be
responsible for its exceptional efficacy.
Accordingly, rapamycin delivered from a local device platform, reduces
neointimal hyperplasia by a combination of anti-inflammatory and smooth
muscle anti-proliferative effects. Rapamycin used in this context means
rapamycin and all analogs, derivatives and congeners that bind FKBP1 2 and
possess the same pharmacologic properties as rapamycin. Local device
platforms include stent coatings, stent sheaths, grafts and local drug
infusion
catheters or porous balloons or any other suitable means for the in situ or
local
delivery of drugs, agents or compounds.
The anti-inflammatory effect of rapamycin is evident in data from an
experiment, illustrated in Table 6, in which rapamycin delivered from a stent
was compared with dexamethasone delivered from a stent. Dexamethasone, a
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potent steroidal anti-inflammatory agent, was used as a reference standard.
Although dexamethasone is able to reduce inflammation scores, rapamycin is
far more effective than dexamethasone in reducing inflammation scores. In
addition, rapamycin significantly reduces neointimal hyperplasia, unlike
dexamethasone.
Group Neointimal Area % Area Inflammation
Rapamycin N (mm2) Stenosis Score
Rap
Uncoated 8 5.24 1.65 54 19 0.97 1.00
Dexamethasone 8 4.31 3.02 45 31 0.39 0.24
(Dex)
Rapamycin 7 2.47 0.94* 26 10* 0.13 0.19*
(Rap)
Rap+Dex 6 2.42 1.58* 26 18* 0.17 0.30*
= significance level P< 0.05
TABLE 6.0
Rapamycin has also been found to reduce cytokine levels in vascular
tissue when delivered from a stent. The data in Figure 1 illustrates that
rapamycin is highly effective in reducing monocyte chemotactic protein
(MCP-1) levels in the vascular wall. MCP-1 is an example of a
proinflammatory/chemotactic cytokine that is elaborated during vessel injury.
Reduction in MCP-1 illustrates the beneficial effect of rapamycin in reducing
the expression of proinflammatory mediators and contributing to the anti-
inflammatory effect of rapamycin delivered locally from a stent. It is
recognized
that vascular inflammation in response to injury is a major contributor to the
development of neointimal hyperplasia.
Since rapamycin may be shown to inhibit local inflammatory events in
the vessel it is believed that this could explain the unexpected superiority
of
rapamycin in inhibiting neointima hyperplasia.
As set forth above, rapamycin functions on a number of levels to
produce such desired effects as the prevention of T-cell proliferation, the
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inhibition of negative remodeling, the reduction of inflammation, and the
prevention of smooth muscle cell proliferation. While the exact mechanisms of
these functions are not completely known, the mechanisms that have been
identified may be expanded upon.
Studies with rapamycin suggest that the prevention of smooth muscle
cell proliferation by blockade of the cell cycle is a valid strategy for
reducing
neointimal hyperplasia. Dramatic and sustained reductions in late lumen loss
and neointimal plaque volume have been observed in patients receiving
rapamycin delivered locally from a stent. The present invention expands upon
the mechanism of rapamycin to include additional approaches to inhibit the
cell
cycle and reduce neointimal hyperplasia without producing toxicity.
The cell cycle is a tightly controlled biochemical cascade of events that
regulate the process of cell replication. When cells are stimulated by
appropriate growth factors, they move from Go (quiescence) to the G1 phase of
the cell cycle. Selective inhibition of the cell cycle in the G1 phase, prior
to
DNA replication (S phase), may offer therapeutic advantages of cell
preservation and viability while retaining anti-proliferative efficacy when
compared to therapeutics that act later in the cell cycle i.e. at S, G2 or M
phase.
Accordingly, the prevention of intimal hyperplasia in blood vessels and
other conduit vessels in the body may be achieved using cell cycle inhibitors
that act selectively at the G1 phase of the cell cycle. These inhibitors of
the G1
phase of the cell cycle may be small molecules, peptides, proteins,
oligonucleotides or DNA sequences. More specifically, these drugs or agents
include inhibitors of cyclin dependent kinases (cdk's) involved with the
progression of the cell cycle through the G1 phase, in particular cdk2 and
cdk4.
Examples of drugs, agents or compounds that act selectively at the G1
phase of the cell cycle include small molecules such as flavopiridol and its
structural analogs that have been found to inhibit cell cycle in the late G1
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phase by antagonism of cyclin dependent kinases. Therapeutic agents that
elevate an endogenous kinase inhibitory proteink'p called P27, sometimes
referred to as P27' 1, that selectively inhibits cyclin dependent kinases may
be
utilized. This includes small molecules, peptides and proteins that either
block
the degradation of P27 or enhance the cellular production of P27, including
gene vectors that can transfact the gene to produce P27. Staurosporin and
related small molecules that block the cell cycle by inhibiting protein
kinases
may be utilized. Protein kinase inhibitors, including the class of tyrphostins
that
selectively inhibit protein kinases to antagonize signal transduction in
smooth
muscle in response to a broad range of growth factors such as PDGF and FGF
may also be utilized.
Any of the drugs, agents or compounds discussed above may be
administered either systemically, for example, orally, intravenously,
intramuscularly, subcutaneously, nasally or intradermally, or locally, for
example, stent coating, stent covering or local delivery catheter. In
addition,
the drugs or agents discussed above may be formulated for fast-release or
slow release with the objective of maintaining the drugs or agents in contact
with target tissues for a period ranging from three days to eight weeks.
As set forth above, the complex of rapamycin and FKPB12 binds to and
inhibits a phosphoinositide (PI)-3 kinase called the mammalian Target of
Rapamycin or TOR. An antagonist of the catalytic activity of TOR, functioning
as either an active site inhibitor or as an allosteric modulator, i.e. an
indirect
inhibitor that allosterically modulates, would mimic the actions of rapamycin
but
bypass the requirement for FKBP1 2. The potential advantages of a direct
inhibitor of TOR include better tissue penetration and better
physical/chemical
stability. In addition, other potential advantages include greater selectivity
and
specificity of action due to the specificity of an antagonist for one of
multiple
isoforms of TOR that may exist in different tissues, and a potentially
different
spectrum of downstream effects leading to greater drug efficacy and/or safety.
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The inhibitor may be a small organic molecule (approximate mw<1000),
which is either a synthetic or naturally derived product. Wortmanin may be an
agent which inhibits the function of this class of proteins. It may also be a
peptide or an oligonucleotide sequence. The inhibitor may be administered
either sytemically (orally, intravenously, intramuscularly, subcutaneously,
nasally, or intradermally) or locally (stent coating, stent covering, local
drug
delivery catheter). For example, the inhibitor may be released into the
vascular
wall of a human from a nonerodible polymeric stent coating. In addition, the
inhibitor may be formulated for fast-release or slow release with the
objective of
maintaining the rapamycin or other drug, agent or compound in contact with
target tissues for a period ranging from three days to eight weeks.
As stated previously, the implantation of a coronary stent in conjunction
with balloon angioplasty is highly effective in treating acute vessel closure
and
may reduce the risk of restenosis. Intravascular ultrasound studies (Mintz et
al., 1996) suggest that coronary stenting effectively prevents vessel
constriction
and that most of the late luminal loss after stent implantation is due to
plaque
growth, probably related to neointimal hyperplasia. The late luminal loss
after
coronary stenting is almost two times higher than that observed after
conventional balloon angioplasty. Thus, inasmuch as stents prevent at least a
portion of the restenosis process, the use of drugs, agents or compounds
which prevent inflammation and proliferation, or prevent proliferation by
multiple mechanisms, combined with a stent may provide the most efficacious
treatment for post-angioplasty restenosis.
The local delivery of drugs, agents or compounds from a stent has the
following advantages; namely, the prevention of vessel recoil and remodeling
through the scaffolding action of the stent and the drugs, agents or compounds
and the prevention of multiple components of neointimal hyperplasia. This
local administration of drugs, agents or compounds to stented coronary
arteries
may also have additional therapeutic benefit. For example, higher tissue
concentrations would be achievable than that which would occur with systemic
administration, reduced systemic toxicity, and single treatment and ease of
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administration. An additional benefit of drug therapy may be to reduce the
dose of the therapeutic compounds, thereby limiting their toxicity, while
still
achieving a reduction in restenosis.
There are a multiplicity of different stents that may be utilized following
percutaneous transluminal coronary angioplasty. Although any number of
stents may be utilized in accordance with the present invention, for
simplicity,
one particular stent will be described in exemplary embodiments of the present
invention. The skilled artisan will recognize that any number of stents may be
utilized in connection with the present invention.
A stent is commonly used as a tubular structure left inside the lumen of
a duct to relieve an obstruction. Commonly, stents are inserted into the lumen
in a non-expanded form and are then expanded autonomously, or with the aid
of a second device in situ. A typical method of expansion occurs through the
use of a catheter-mounted angioplasty balloon which is inflated within the
stenosed vessel or body passageway in order to shear and disrupt the
obstructions associated with the wall components of the vessel and to obtain
an enlarged lumen. As set forth below, self-expanding stents may also be
utilized.
Figure 2 illustrates an exemplary stent 100 which may be utilized in
accordance with an exemplary embodiment of the present invention. The
expandable cylindrical stent 100 comprises a fenestrated structure for
placement in a blood vessel, duct or lumen to hold the vessel, duct or lumen
open, more particularly for protecting a segment of artery from restenosis
after
angioplasty. The stent 100 may be expanded circumferentially and maintained
in an expanded configuration, that is circumferentially or radially rigid. The
stent 100 is axially flexible and when flexed at a band, the stent 100 avoids
any
externally-protruding component parts.
The stent 100 generally comprises first and second ends with an
intermediate section therebetween. The stent 100 has a longitudinal axis and
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comprises a plurality of longitudinally disposed bands 102, wherein each band
102 defines a generally continuous wave along a line segment parallel to the
longitudinal axis. A plurality of circumferentially arranged links 104
maintain
the bands 102 in a substantially tubular structure. Essentially, each
longitudinally disposed band 102 is connected at a plurality of periodic
locations, by a short circumferentially arranged link 104 to an adjacent band
102. The wave associated with each of the bands 102 has approximately the
same fundamental spatial frequency in the intermediate section, and the bands
102 are so disposed that the wave associated with them are generally aligned
so as to be generally in phase with one another. As illustrated in the figure,
each longitudinally arranged band 102 undulates through approximately two
cycles before there is a link to an adjacent band.
The stent 100 may be fabricated utilizing any number of methods. For
example, the stent 100 may be fabricated from a hollow or formed stainless
steel tube that may be machined using lasers, electric discharge milling,
chemical etching or other means. The stent 100 is inserted into the body and
placed at the desired site in an unexpanded form. In one embodiment,
expansion may be effected in a blood vessel by a balloon catheter, where the
final diameter of the stent 100 is a function of the diameter of the balloon
catheter used.
It should be appreciated that a stent 100 in accordance with the present
invention may be embodied in a shape-memory material, including, for
example, an appropriate alloy of nickel and titanium. In this embodiment,
after
the stent 100 has been formed it may be compressed so as to occupy a space
sufficiently small as to permit its insertion in a blood vessel or other
tissue by
insertion means, wherein the insertion means include a suitable catheter, or
flexible rod. On emerging from the catheter, the stent 100 may be configured
to expand into the desired configuration where the expansion is automatic or
triggered by a change in pressure, temperature or electrical stimulation.
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Figure 3 illustrates an exemplary embodiment of the present invention
utilizing the stent 100 illustrated in Figure 2. As illustrated, the stent 100
may
be modified to comprise a reservoir 106. Each of the reservoirs may be
opened or closed as desired. These reservoirs 106 may be specifically
designed to hold the drug, agent, compound or combinations thereof to be
delivered. Regardless of the design of the stent 100, it is preferable to have
the drug, agent, compound or combinations thereof dosage applied with
enough specificity and a sufficient concentration to provide an effective
dosage
in the lesion area. In this regard, the reservoir size in the bands 102 is
preferably sized to adequately apply the drug/drug combination dosage at the
desired location and in the desired amount.
In an alternate exemplary embodiment, the entire inner and outer
surface of the stent 100 may be coated with various drug and drug
combinations in therapeutic dosage amounts. A detailed description of
exemplary coating techniques is described below.
Rapamycin or any of the drugs, agents or compounds described above
may be incorporated into or affixed to the stent in a number of ways and
utilizing any number of biocompatible materials. In the exemplary embodiment,
the rapamycin is directly incorporated into a polymeric matrix and sprayed
onto
the outer surface of the stent. The rapamycin elutes from the polymeric matrix
over time and enters the surrounding tissue. The rapamycin preferably
remains on the stent for at least three days up to approximately six months
and
more preferably between seven and thirty days.
Any number of non-erodible polymers may be utilized in conjunction with
rapamycin. In the exemplary embodiment, the polymeric matrix comprises two
layers. The base layer comprises a solution of ethylene-co-vinylacetate and
polybutylmethacrylate. The rapamycin is incorporated into this layer. The
outer layer comprises only polybutylmethacrylate and acts as a diffusion
barrier
to prevent the rapamycin from eluting too quickly and entering the surrounding
tissues. The thickness of the outer layer or top coat determines the rate at
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which the rapamycin elutes from the matrix. Essentially, the rapamycin elutes
from the matrix by diffusion through the polymer molecules. Polymers tend to
move, thereby allowing solids, liquids and gases to escape therefrom. The
total thickness of the polymeric matrix is in the range from about 1 micron to
about 20 microns or greater.
The ethylene-co-vinylacetate, polybutylmethacrylate and rapamycin
solution may be incorporated into or onto the stent in a number of ways. For
example, the solution may be sprayed onto the stent or the stent may be
dipped into the solution. In a preferred embodiment, the solution is sprayed
onto the stent and then allowed to dry. In another exemplary embodiment, the
solution may be electrically charged to one polarity and the stent
electrically
changed to the opposite polarity. In this manner, the solution and stent will
be
attracted to one another. In using this type of spraying process, waste may be
reduced and more control over the thickness of the coat may be achieved.
Since rapamycin acts by entering the surrounding tissue, it is preferably
only affixed to the surface of the stent making contact with one tissue.
Typically, only the outer surface of the stent makes contact with the tissue.
Accordingly, in a preferred embodiment, only the outer surface of the stent is
coated with rapamycin. For other drugs, agents or compounds, the entire stent
may be coated.
It is important to note that different polymers may be utilized for different
stents. For example, in the above-described embodiment, ethylene-co-
vinylacetate and polybutylmethacrylate are utilized to form the polymeric
matrix. This matrix works well with stainless steel stents. Other polymers may
be utilized more effectively with stents formed from other materials,
including
materials that exhibit superelastic properties such as alloys of nickel and
titanium.
In another exemplary embodiment, the rapamycin or other therapeutic
agent may be incorporated into a film-forming polyfluoro copolymer comprising
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an amount of a first moiety selected from the group consisting of polymerized
vinylidenefluoride and polymerized tetrafluoroethylene, and an amount of a
second moiety other than the first moiety and which is copolymerized with the
first moiety, thereby producing the polyfluoro copolymer, the second moiety
being capable of providing toughness or elastomeric properties to the
polyfluoro copolymer, wherein the relative amounts of the first moiety and the
second moiety are effective to provide the coating and film produced therefrom
with properties effective for use in coating implantbale medical devices.
The present invention provides polymeric coatings comprising a
polyfluoro copolymer and implantable medical devices, for example, stents
coated with a film of the polymeric coating in amounts effective to reduce
thrombosis and/or restenosis when such stents are used in, for example,
angioplasty procedures. As used herein, polyfluoro copolymers means those
copolymers comprising an amount of a first moiety selected from the group
consisting of polymerized vinylidenefluoride and polymerized
tetrafluoroethylene, and an amount of a second moiety other than the first
moiety and which is copolymerized with the first moiety to produce the
polyfluoro copolymer, the second moiety being capable of providing toughness
or elastomeric properties to the polyfluoro copolymer, wherein the relative
amounts of the first moiety and the second moiety are effective to provide
coatings and film made from such polyfluoro copolymers with properties
effective for use in coating implantable medical devices.
The film-forming biocompatible polymer coatings generally are applied
to the stent in order to reduce local turbulence in blood flow through the
stent,
as well as adverse tissue reactions. The coatings and films formed therefrom
also may be used to administer a pharmaceutically active material to the site
of
the stent placement. Generally, the amount of polymer coating to be applied to
the stent will vary, depending on, among other possible parameters, the
particular polyfluoro copolymer used to prepare the coating, the stent design
and the desired effect of the coating. Generally, the coated stent will
comprise
from about 0.1 to about fifteen weight percent of the coating, and preferably
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from about 0.4 to about ten weight percent. The polyfluoro copolymer coatings
may be applied in one or more coating steps, depending on the amount of
polyfluoro copolymer to be applied. Different polyfluoro copolymers may be
used for different layers in the stent coating. In fact, in certain exemplary
embodiments, it is highly advantageous to use a diluted first coating solution
comprising a polyfluoro copolymer as a primer to promote adhesion of a
subsequent polyfluoro copolymer coating layer that may include
pharmaceutically active materials. The individual coatings may be prepared
from different polyfluoro copolymers.
Additionally, a top coating may be applied to delay release of the
pharmaceutical agent, or they could be used as the matrix for the delivery of
a
different pharmaceutically active material. Layering of coatings may be used
to
stage release of the drug or to control release of different agents placed in
different layers.
Blends of polyfluoro copolymers may also be used to control the release
rate of different agents or to provide a a desirable balance of coating
properties, i.e., elasticity, toughness, etc., and drug delivery
characteristics, for
example, release profile. Polyfluoro copolymers with different solubilities in
solvents may be used to build up different polymer layers that may be used to
deliver different drugs or to control the release profile of a drug. For
example,
polyfluoro copolymers comprising 85.5/14.5 (wt/wt) of
poly(vinylidinefluoride/HFP) and 60.6/39.4 (wt/wt) of
poly(vinylidinefluoride/HFP) are both soluble in DMAc. However, only the
60.6/39.4 poly(vinylidinefloride) polyfluoro copolymer is soluble in methanol.
So, a first layer of the 85.5/14.5 poly(vinylidinefluoride) polyfluoro
copolymer
comprising a drug could be over coated with a topcoat of the 60.6/39.4
poly(vinylidinefluoride) polyfluoro copolymer made with the methanol solvent.
The top coating may be used to delay the drug delivery of the drug contained
in
the first layer. Alternately, the second layer could comprise a different drug
to
provide for sequential drug delivery. Multiple layers of different drugs could
be
provided by alternating layers of first one polyfluoro copolymer, then the
other.
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As will be readily appreciated by those skilled in the art, numerous layering
approaches may be used to provide the desired drug delivery.
Coatings may be formulated by mixing one or more therapeutic agents
with the coating polyfluoro copolymers in a coating mixture. The therapeutic
agent may be present as a liquid, a finely divided solid, or any other
appropriate physical form. Optionally, the coating mixture may include one or
more additives, for example, nontoxic auxiliary substances such as diluents,
carriers, excipients, stabilizers or the like. Other suitable additives may be
formulated with the polymer and pharmaceutically active agent or compound.
For example, a hydrophilic polymer may be added to a biocompatible
hydrophobic coating to modify the release profile, or a hydrophobic polymer
may be added to a hydrophilic coating to modify the release profile. One
example would be adding a hydrophilic polymer selected from the group
consisting of polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol,
carboxylmethyl cellulose, and hydroxymethyl cellulose to a polyfluoro
copolymer coating to modify the release profile. Appropriate relative amounts
may be determined by monitoring the in ivtro and/or in vivo release profiles
for
the therapeutic agents.
The best conditions for the coating application are when the polyfluoro
copolymer and pharmaceutic agent have a common solvent. This provides a
wet coating that is a true solution. Less desirable, yet still usable, are
coatings
that contain the pharmaceutical agent as a solid dispersion in a solution of
the
polymer in solvent. Under the dispersion conditions, care must be taken to
ensure that the particle size of the dispersed pharmaceutical powder, both the
primary powder size and its aggregates and agglomerates, is small enough not
to cause an irregular coating surface or to clog the slots of the stent that
need
to remain essentially free of coating. In cases where a dispersion is applied
to
the stent and the smoothness of the coating film surface requires improvement,
or to be ensured that all particles of the drug are fully encapsulated in the
polymer, or in cases where the release rate of the drug is to be slowed, a
clear
(polyfluoro copolymer only) topcoat of the same polyfluoro copolymer used to
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provide sustained release of the drug or another polyfluoro copolymer that
further restricts the diffusion to the drug out of the coating may be applied.
The
topcoat may be applied by dip, coating with mandrel to clear the slots. This
method is disclosed in U.S. Patent No. 6,153,252. Other methods for applying
the topcoat include spin coating and spray coating. Dip coating of the topcoat
can be problematic if the drug is very soluble in the coating solvent, which
swells the polyfluoro copolymer, and the clear coating solution acts as a zero
concentration sink and redissolves previously deposited drug. The time spent
in the dip bath may need to be limited so that the drug is not extracted out
into
the drug free bath. Drying should be rapid so that the previously deposited
drug does not completely diffuse into the topcoat.
The amount of therapeutic agent will be dependent upon the particular
drug employed and medical condition being treated. Typically, the amount of
drug represents about 0.001 percent to about seventy percent of the total
coating weight, and more typically about 0.001 percent to about sixty percent
of
the total coating weight. It is possible that the drug may represent as little
as
0.001 percent to the total coating weight.
The quantity and type of polyfluoro copolymers employed in the coating
film comprising the pharmaceutic agent will vary depending on the release
profile desired and the amount of drug employed. The product may contain
blends of the same or different polyfluoro copolymers having different
molecular weights to provide the desired release profile or consistency to a
given formulation.
Polyfluoro copolymers may release dispersed drug by diffusion. This
can result in prolonged delivery (over, say approximately one to two-thousand
hours, preferably two to eight-hundred hours) of effective amounts (0.001
g/cm2 -min to 100 g/cm2-min) of the drug. The dosage may be tailored to the
subject being treated, the severity of the affliction, the judgment of the
prescribing physician, and the like.
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Drug eluting stents, as described above, have demonstrated an ability to
dramatically reduce late lumen loss and restenosis rates in patients with
coronary artery disease based on data from randomized clinical trials.
However, the ability of this technology to substantially eliminate the problem
of
restenosis has only recently been investigated in very large patient cohorts
that
examine longer and more complex lesions, including Type C lesions. Lesions
may be classified as Type A, B or C, which is the American College of
Cardiology/American Heart Association classification system. A Type A lesion
is minimally complex, discrete (length <10 mm), concentric, readily
accessible,
non-angulated segment (<45 ), smoother contour, little or no calcification,
less
than totally occlusive, not ostial in location, no major side branch
involvement,
and an absence of thrombus. A Type B lesion is moderately complex, tubular
(length 10 mm to 20 mm), eccentric, moderate tortuosity of proximal segment,
moderately angulated segment (>45 , <90 ), irregular contour, moderate or
heavy calcification, total occlusions <3 months old, ostial in location,
bifurcation
lesions requiring double guidewires, and some thrombus is present. A Type C
lesion is severely complex, diffuse (length >2cm), excessive tortuosity of
proximal segment, extremely angulated segments (>90 ), total occlusions >3
months old and/or bridging collaterals, inability to protect major side
branches,
and degenerated vein grafts with friable lesions.
Initial quantitative results obtained with rapamycin eluting stents in the
first large (one thousand one hundred patient) randomized multicenter trial
representative of real world stenting conditions, i.e.,Type A, B, C lesions,
reveal a phenomenon that suggests the depth and direction of drug penetration
from the stent struts into the vessel wall may play an important role in
eliminating lumen loss within the treated segment, which incorporates the in-
stent region and the in-lesion region, which as explained above includes a
length of vessel extending five mm past the ends of the stent. More
importantly, the results indicate that drug penetration into the proximal and
distal portions of the vessel beyond the stent edges, i.e., the five mm
boarder
region may be required to substantially eliminate restenosis caused by
aggressive remodeling and neointimal hyperplasia. Essentially, it is
preferable
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that the drug coated stent of the present invention be used for the prevention
of
target lesion restenosis, wherein target lesion includes the stented region
and
areas extending past the stented region.
Angiographic results from the first four hundred patients followed up at
eight months in the above-referenced large randomized multicenter trial
demonstrate that in-stent late lumen loss is dramatically reduced (0.92 +/-
0.69
mm versus 0.14+/- 0.44 mm; bare stent versus rapamycin coated stent,
p<0.0001) as is distal edge lumen loss (0.19+/- 0.61 mm versus 0.04 +/- 0.42
mm; bare stent versus rapamycin coated stent, p<0.05). In contrast, the
proximal edge lumen loss (0.26+/- 0.55 mm versus 0.16 +/- 0.16 mm; bare
stent versus rapamycin coated stent, p=0.22, ns) suggests that there is a
somewhat diminished effect. This unexpected result suggests a need for an
improved design of drug eluting stents to minimize edge lumen loss,
particularly proximal to the stent, in addition to minimizing target lesion
restenosis.
It is important to note that the above-described trials utilized the
EVA/BMA coating described above.
One possible explanation for these results is the direction of blood flow
relative to the stent. It may be possible for the blood to be carrying away a
portion of the rapamycin as it elutes from the stent, thereby effectively
reducing
the concentration available for absorption into the tissue proximal to the
stent.
Accordingly, in a preferred exemplary embodiment, a drug eluting stent
should incorporate an improved drug release profile from the edges of the
stent, particularly the proximal edge, to prevent or substantially reduce edge
restenosis. Improvement in drug release should preferably lead to improved
axial and radial drug distribution from the stent struts into the vessel
segments
outside the stented region or zone. These improvements may take any
number of forms.
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In one exemplary embodiment, the polymer/drug combination coating
may be applied to the stent such that there is a higher concentration of the
drug proximate to the edges of the stent, particularly the proximal two to
three
mm thereof. In other words, it is preferable that there be more drug on the
ends of the stent, for example, from the ends of the stent extending up to
three
mm or more. This tailored or profiled coating technique may be achieved by
increasing the mass of the coating on the edges by a predetermined
percentage of, for example, at least ten percent to about three-hundred
percent, or by increasing the concentration of the drug in the polymer, for
example, from about thirty-three percent to about eighty percent. The increase
in drug concentration depends on the drug and the particular coating selected.
In another alternate exemplary embodiment where a topcoat is utilized as a
diffusion barrier, the thickness of the topcoat in the regions proximate the
edges of the stent may be reduced thereby increasing the rate of drug elution
from the edges of the stent.
In yet another alternate exemplary embodiment, another drug, agent
and/or compound with improved solubility may be used in combination with the
stent. For example, a rapamycin analog having improved solubility and thus
potentially greater tissue penetration may be utilized. A rapamycin analog may
include any structural modification that altered physical and chemical
properties but did not alter the fundamental mechanism of the drug; i.e. the
inhibition of mTOR. It may also be possible to use a combination of drugs. For
example, rapamycin may be utilized on a major portion of the stent and an
analog as just described may be utilized in the remaining end portions.
In yet another alternate exemplary embodiment, another drug, agent
and/or compound may be utilized in combination with rapamycin. This other
drug, agent and/or compound may be utilized to improve drug permeability or
enhance uptake of rapamycin into the vessel wall. The additional drug, agent
and/or compound may simply provide this effect or augment the effect of
rapamycin.
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Although shown and described is what is believed to be the most
pratical and preferred embodiments, it is apparent that departures from
specific
designs and methods described and shown will suggest themselves to those
skilled in the art and may be used without departing from the spirit and scope
of the invention. The present invention is not restricted to the particular
constructions described and illustrated, but should be constructed to cohere
with all modifications that may fall within the scope of the appended claims.
