U.S. patent application number 10/882506 was filed with the patent office on 2006-01-05 for anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders.
Invention is credited to Paul Consigny, Stephen Dugan, Christopher Feezor, Syed Faiyaz Ahmed Hossainy, Nancy Kristen, Gene Park, Wouter Roorda, Gordon Stewart, Gina Zhang.
Application Number | 20060002968 10/882506 |
Document ID | / |
Family ID | 35514191 |
Filed Date | 2006-01-05 |
United States Patent
Application |
20060002968 |
Kind Code |
A1 |
Stewart; Gordon ; et
al. |
January 5, 2006 |
Anti-proliferative and anti-inflammatory agent combination for
treatment of vascular disorders
Abstract
Drug-delivery systems such as drug-delivery stents having an
anti-proliferative agent such as everolimus and an anti-flammatory
agent such as clobetasol are provided. Also disclosed are methods
of treating a vascular impairment such as restenosis or vulnerable
plaque.
Inventors: |
Stewart; Gordon; (San
Francisco, CA) ; Zhang; Gina; (Fremont, CA) ;
Kristen; Nancy; (San Carlos, CA) ; Consigny;
Paul; (San Jose, CA) ; Dugan; Stephen; (San
Francisco, CA) ; Park; Gene; (Oakland, CA) ;
Feezor; Christopher; (San Jose, CA) ; Roorda;
Wouter; (Palo Alto, CA) ; Hossainy; Syed Faiyaz
Ahmed; (Fremont, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA
SUITE 300
SAN FRANCISCO
CA
94111
US
|
Family ID: |
35514191 |
Appl. No.: |
10/882506 |
Filed: |
June 30, 2004 |
Current U.S.
Class: |
424/423 ;
514/291 |
Current CPC
Class: |
A61L 2300/45 20130101;
A61K 31/4745 20130101; A61L 31/16 20130101; A61K 31/573 20130101;
A61L 2300/416 20130101; A61K 31/436 20130101; A61L 31/10 20130101;
A61L 2300/41 20130101; A61K 31/436 20130101; A61K 31/4745 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61F 2250/0067 20130101; A61K 31/573 20130101 |
Class at
Publication: |
424/423 ;
514/291 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; A61F 2/00 20060101 A61F002/00 |
Claims
1. A drug-delivery system, comprising an effective amount of
everolimus, or derivatives thereof, and an effective amount of
clobetasol for the treatment or prevention of a vascular disorder
or a related disorder.
2. The drug-delivery system of claim 1, wherein the system is a
stent.
3. The drug-delivery system of claim 1, wherein the disorder is
restenosis.
4. The drug-delivery system of claim 1, wherein the disorder is
restenosis and/or progression of atherosclerosis in patient subsets
including type I diabetics and type II diabetics.
5. The drug-delivery system of claim 1, wherein the disorder is
vulnerable plaque.
6. The drug-delivery system of claim 1, wherein the system is a
polymer or a polymeric coating.
7. A drug-delivery system, comprising an effective amount of
everolimus, rapamycin, or derivatives of everolimus or rapamycin,
and an effective amount of a steroidal anti-inflammatory agent or a
non steroidal anti-inflammatory agent, wherein the combination is
for treatment or prevention of a vascular disorder.
8. The drug-delivery system of claim 7, wherein the
anti-inflammatory agent is clobetasol.
9. The drug-delivery system of claim 7, wherein the system is a
stent.
10. The drug-delivery system of claim 7, wherein the disorder is
restenosis.
11. The drug-delivery system of claim 7, wherein the disorder is
restenosis and/or progression of atherosclerosis in patient subsets
including type I diabetics and type II diabetics.
12. The drug-delivery system of claim 7, wherein the disorder is
vulnerable plaque.
13. The drug-delivery system of claim 7, wherein the system is a
polymer or a polymeric coating.
14. A method of treating restenosis of a blood vessel comprising
administering to a patient an effective amount of everolimus,
rapamycin, or derivatives of everolimus or rapamycin and an
effective amount of a steroidal anti-inflammatory agent or a non
steroidal anti-inflammatory agent, wherein the combination is for
treatment or prevention of the vascular disorder.
15. The method of claim 14, wherein the anti-inflammatory is
clobetasol.
16. The method of claim 14, wherein everolimus, rapamycin, or
derivatives of everolimus or rapamycin is delivered via a stent and
the anti-inflammatory is delivered by other local means or by
systemic means.
17. The method of claim 14, wherein the combination of the drugs
are administered by a drug-delivery stent.
18. A method of treating vulnerable plaque of a blood vessel
comprising administering to a patient an effective amount of
everolimus, rapamycin, or derivatives of everolimus or rapamycin
and an effective amount of a steroidal anti-inflammatory agent or a
non steroidal anti-inflammatory agent, wherein the combination is
for treatment or prevention of the vascular disorder.
19. The method of claim 18, wherein the anti-inflammatory is
clobetasol.
20. The method of claim 18, wherein everolimus, rapamycin, or
derivatives of everolimus or rapamycin is delivered via a stent and
the anti-inflammatory is delivered by local means other than a
stent or by systemic means.
21. The method of claim 18, wherein the combination of the drugs
are administered by a drug-delivery stent.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention generally relates to a drug combination
including an anti-proliferative drug such as everolimus and an
anti-inflammatory agent such as clobetasol for the treatment of a
disorder such as restenosis and vulnerable plaque.
[0003] 2. Description of the Background
[0004] Plaques have been associated with stenosis and restenosis.
While treatments of plaque-induced stenosis and restenosis have
advanced significantly over the last few decades, the morbidity and
mortality associated with vascular plaques have remained
significant. Recent work suggests that plaque may generally fall
into one of two different general types: standard stenotic plaques
and vulnerable plaques. Stenotic plaque, which is sometimes
referred to as thrombosis-resistant plaque, can generally be
treated effectively by the known intravascular lumen opening
techniques. Although plaques induce stenoses, these atherosclerotic
plaques themselves are often a benign and are an effectively
treatable disease.
[0005] Unfortunately, as plaque matures, narrowing of a blood
vessel by a proliferation of smooth muscle cells, matrix synthesis,
and lipid accumulation may result in formation of a plaque which is
quite different than a standard stenotic plaque. Such
atherosclerotic plaque becomes thrombosis-prone, and can be highly
dangerous. This thrombosis-prone or vulnerable plaque may be a
frequent cause of acute coronary syndrome.
[0006] While the known procedures for treating plaque have gained
wide acceptance and shown good efficacy for treatment of standard
stenotic plaques, they may be ineffective (and possibly dangerous)
when thrombotic conditions are superimposed on atherosclerotic
plaques. Specifically, mechanical stresses caused by primary
treatments like percutaneous transluminal intervention (PTI), such
as stenting, may actually trigger release of fluids and/or solids
from a vulnerable plaque into the blood stream, thereby potentially
causing a coronary thrombotic occlusion. For example, rupture of
the fibrous cap that overlies the thrombogenic necrotic core is
presently believed to play an important role in acute ischemic
events, such as stroke, transient ischemic attack, myocardial
infarction, and unstable angina (Virmani R, et al. Arterioscler
Thromb Vasc Biol. 20: 1262-1275 (2000)). There is evidence that
fibrous cap can be ruptured during stent deployment. Human data
from various sources have indicated that lipid rich and/or
positively remodeled and/or echolucent lesions in sysmptomatic
coronary atherosclerosis have higher likelihood for restenosis
(See, for example, J. Am. Coll. Cardiol. 21(2):298-307 (1993); Am.
J. Cardiol. 89(5):505 (2002); Circ. 94(12):3098-102 (1996)).
Therefore, there is a need for the treatment of vulnerable plaques
and restenosis.
[0007] The embodiments of the present invention address these and
other needs.
SUMMARY OF THE INVENTION
[0008] Described herein are a drug-delivery system and the method
of using the drug-delivery system. The drug-delivery system has two
or more drugs for treating a vascular disorder or a related
disorder. The drugs can be a combination of at least one
anti-proliferative agent, at least one anti-inflammatory agent, and
optionally a third bioactive agent. In one embodiment, the
anti-proliferative agent can be a drug such as everolimus, and the
anti-inflammatory agent can be a drug such as clobetasol.
[0009] Methods of treating of preventing vascular disorders such as
restenosis and vulnerable plaque are also disclosed by
administering to the patient a combination of at least one
anti-proliferative agent, at least one anti-inflammatory agent, and
optionally a third bioactive agent. The mode of delivery can be
local or systemic.
BRIEF DESCRIPTION OF THE FIGURE
[0010] FIG. 1 shows the results of 28 day quantitative coronary
angioplasty (QCA) of a porcine implant study on drug-delivery
systems described herein.
[0011] FIG. 2 shows 28 day histology data of a porcine implant
study on drug-delivery systems described herein.
[0012] FIG. 3 shows the 28 day morphometry data of a porcine
implant study on drug-delivery systems described herein.
DETAILED DESCRIPTION
Anti-Proliferative Agents and Anti-Inflammatory Agents
[0013] In accordance with one embodiment, described herein are a
drug-delivery system and the method of using the drug-delivery
system. The term "treatment" includes prevention, reduction, delay
or elimination of the vascular disorder. In some embodiments,
treatment also includes repairing damage caused by the dirorder
and/or the mechanical intervention. The drug-delivery system has
two or more drugs for treating a vascular disorder or a related
disorder. The drugs can be a combination of at least one
anti-proliferative agent, at least one anti-inflammatory agent, and
optionally a third bioactive agent.
[0014] In one embodiment, the composition described herein includes
an effective amount of at least one anti-inflammatory agent and an
effective amount of an anti-proliferative agent. In another
embodiment, the composition described herein includes an effective
amount of an agent which is effective both as an anti-inflammatory
agent and as an anti-proliferative agent.
[0015] In some embodiments, the anti-proliferative agent can be
everolimus (available under the trade name Certican.TM., Novartis
Pharma A G, Germany), and the anti-inflammatory agent can be
clobetasol (available under the trade name Temovate.TM.,
Glaxosmithkline, UK).
[0016] The anti-proliferative agent and the anti-inflammatory agent
can be in the form of a coating with and/or without a polymer
matrix on a medical device or at elast one of the agents can be
administered in a separate dose form such as bolus dose of a free
drug, optionally with fluoroscopic dye, or bolus dose of a gel
encapsulating a drug. The drug-delivery system or composition may
further include a third agent such as a high-density lipoproptein
mimetic (HDL-mimetic). For example, an anti-inflammatory agent such
as clobetasol can be delivered along with the catheter based
delivery of a HDL-mimetic while everolimus is administered by a
stent.
[0017] The drug-delivery system or composition disclosed herein can
be used to treat or prevent a disorder such as thrombosis, high
cholesterol, hemorrhage, vascular dissection or perforation,
vascular aneurysm, vulnerable plaque, chronic total occlusion,
claudication, anastomotic proliferation for vein and artificial
grafts, bile duct obstruction, ureter obstruction, tumor
obstruction, restenosis and progression of atherosclerosis in
patient subsets including type I diabetics, type II diabetics,
metabolic syndrome and syndrome X, vulnerable lesions including
those with thin-capped fibroatheromatous lesions, systemic
infections including gingivitis, hellobacteria, and
cytomegalovirus, and combinations thereof.
Inflammation in Stenting a Vessel
[0018] A common disorder in association with mechanical
modification of a vessel, such as by a balloon or stenting is
restenosis. A number of cellular mechanisms have been proposed that
lead to restenosis of a vessel. Two of these mechanisms are (1) the
migration and proliferation of smooth muscle cells to and at the
site of injury, and (2) the acute and chronic inflammatory response
to injury and foreign body presence.
[0019] Inflammation is a defensive, biological response to injury,
infection or an abrupt change in tissue homeostasis. Inflammation
can occur anywhere in the body, and most of the time is confined to
that part of the body. Well-known indicators of inflammation are
pain, redness, warmth, swelling, and loss of function. In nature,
inflammatory responses are designed to destroy, dilute and isolate
injurious agents and then lead to recovery and repair of the
affected tissue. The intensity of an inflammatory response can vary
from one that is self-limiting, which requires minor therapeutic
intervention, to one that is life threatening, which requires
intense intervention. One drawback of the inflammatory process is
its ability to become progressive, meaning tissue damage continues
after the stimulus is neutralized or removed.
[0020] Vascular inflammation is the first stage of the inflammatory
response, developing after the initial contact with the stimulus
and continuing sometimes for several days. The presence of a
stimulatory agent in the blood or in the tissue triggers the body's
response through endothelial cells. The endothelial cell layer is
the innermost layer of larger vessels and the only cell layer of
the smallest vessels, the capillaries. Endothelial cells produce
substances called chemokines that attract neutrophils and other
white blood cells to the site of injury. Within the site,
neutrophils and endothelium relay information back and forth across
cell membranes through presentation of adhesion molecules and
cytokines. Cellular cross-talk promotes physical interaction
between the "inflamed" neutrophil and the "inflamed"
endothelium.
[0021] Another important pathological feature of vascular
inflammation is endothelial cell swelling. This action reduces the
functional vessel diameter such that the speed of blood flow falls
significantly and the vessel becomes congested. When these
conditions predominate, inflamed neutrophils are induced to plug
the vessel. As a result, endothelial cells lose their tight
connections allowing neutrophils to transmigrate into the
surrounding tissue.
[0022] Within hours of the initial stimulus, neutrophils begin to
enter the tissue and may continue transmigration for many days. The
appearance of inflammatory cells in the surrounding tissue marks
the beginning of tissue damage. In some inflammatory conditions,
tissue damage is caused by direct injury of the vessels and
amplified by the subsequent recruitment of neutrophils into the
tissue.
[0023] Activated by local mediators, neutrophils and tissue
macrophages are triggered to release agents that destroy toxins and
clean up dead cells in the area. Unfortunately, these same agents
also cause collateral damage to healthy cells, which further
extends the borders of the initial tissue destruction.
[0024] Tissue repair is the third and final stage of inflammation.
It may take several days for tissue destruction to reach full
intensity before tapering off. Until then, the tissue repair
process that consists of growth of new blood vessels and entry of
monocytes to clean up the debris is delayed. Fibroblasts also enter
the local tissue to replace the extracellular matrix and collagen.
The process of tissue repair is stringently controlled within the
tissue site. If the process becomes dysregulated, inappropriate
tissue repair will lead to excessive scarring. Depending on the
tissue and the intensity/duration of the inflammatory condition,
the amount of scarring can be significant.
[0025] An example of disorders that vessel inflammation is involved
is vulnerable plaque (VP) rupture. Previous studies have
demonstrated that inflammation promotes proliferation at sites of
balloon angioplasty and stent placement in pigs (Komowski, et al.,
Coron Artery Dis. 12(6):513-5 (2001)). Since sites of vulnerable
plaque have a higher density of macrophages and lymphocytes than
other types of atherosclerotic lesions, it is expected that these
sites, when stented, will produce elevated amounts of the cytokines
(IL-1, TNF-alpha) that promote smooth muscle cell
proliferation.
[0026] Another example of disorders that vessel inflammation is
involved is diabetes. Studies have shown that patients with type-2
diabetes have higher rates of restenosis than the general
population. The diabetic patient is in pro-inflammatory state that
can amplify restenosis because diabetic lesions contain a large
number of inflammatory cells (e.g., macrophages, lymphocytes,
etc.).
Anti-Proliferative Agents
[0027] Any drugs having anti-proliferative effects can be used in
the present invention. The anti-proliferative agent can be a
natural proteineous agent such as a cytotoxin or a synthetic
molecule. Preferably, the active agents include antiproliferative
substances such as actinomycin D, or derivatives and analogs
thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue,
Milwaukee, Wis. 53233; or COSMEGEN available from Merck) (synonyms
of actinomycin D include dactinomycin, actinomycin IV, actinomycin
I.sub.1, actinomycin X.sub.1, and actinomycin C.sub.1), all taxoids
such as taxols, docetaxel, and paclitaxel, paclitaxel derivatives,
all olimus drugs such as macrolide antibiotics, rapamycin,
everolimus, structural derivatives and functional analogues of
rapamycin, structural derivatives and functional analogues of
everolimus, FKBP-12 mediated mTOR inhibitors, biolimus,
perfenidone, prodrugs thereof, co-drugs thereof, and combinations
thereof. Representative rapamycin derivatives include
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or
40-O-tetrazole-rapamycin, prodrugs thereof, co-drugs thereof, and
combinations thereof.
[0028] In one embodiment, the anti-proliferative agent is
everolimus. Everolimus acts by first binding to FKBP12 to form a
complex (Neuhhaus, P., et al., Liver Transpl. 2001 7(6):473-84
(2001) (Review)). The everolimus /FKBP 12 complex then binds to
mTOR and blocks its activity (Id.). By blocking mTOR activity,
cells are unable to pass through GI of the cell cycle and as a
result, proliferation is inhibited. mTOR inhibition has also been
shown to inhibit vascular smooth muscle migration.
Anti-Inflammatory Agents
[0029] Any drugs having anti-inflammatory effects can be used in
the present invention. The anti-inflammatory drug can be a
steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory
agent, or a combination thereof. In some embodiments,
anti-inflammatory drugs include, but are not limited to,
alclofenac, alclometasone dipropionate, algestone acetonide, alpha
amylase, amcinafal, amcinafide, amfenac sodium, amiprilose
hydrochloride, anakinra, anirolac, anitrazafen, apazone,
balsalazide disodium, bendazac, benoxaprofen, benzydamine
hydrochloride, bromelains, broperamole, budesonide, carprofen,
cicloprofen, cintazone, cliprofen, clobetasol propionate,
clobetasone butyrate, clopirac, cloticasone propionate,
cormethasone acetate, cortodoxone, deflazacort, desonide,
desoximetasone, dexamethasone dipropionate, diclofenac potassium,
diclofenac sodium, diflorasone diacetate, diflumidone sodium,
diflunisal, difluprednate, diftalone, dimethyl sulfoxide,
drocinonide, endrysone, enlimomab, enolicam sodium, epirizole,
etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac,
fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort,
flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin
meglumine, fluocortin butyl, fluorometholone acetate, fluquazone,
flurbiprofen, fluretofen, fluticasone propionate, furaprofen,
furobufen, halcinonide, halobetasol propionate, halopredone
acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen
piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen,
indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam,
ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol
etabonate, meclofenamate sodium, meclofenamic acid, meclorisone
dibutyrate, mefenamic acid, mesalamine, meseclazone,
methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,
naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,
orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,
pentosan polysulfate sodium, phenbutazone sodium glycerate,
pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine,
pirprofen, prednazate, prifelone, prodolic acid, proquazone,
proxazole, proxazole citrate, rimexolone, romazarit, salcolex,
salnacedin, salsalate, sanguinarium chloride, seclazone,
sermetacin, sudoxicam, sulindac, suprofen, talmetacin,
talniflumate, talosalate, tebufelone, tenidap, tenidap sodium,
tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol
pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate,
zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid),
salicylic acid, corticosteroids, glucocorticoids, tacrolimus,
pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations
thereof.
[0030] In one embodiment, the anti-inflammatory agent is
clobetasol. Clobetasol is a corticosteroid that binds to
corticosteroid receptors, a class of nuclear receptor. The binding
of clobetasol to the corticosteroid receptor subsequently alters
gene expression in such a way that inflammation is inhibited. For
example, corticosteroids inhibit the activation of NFkB, the
nuclear factor that is responsible for changes in gene expression
that promote inflammation. The reduction in inflammation may also
inhibit the mechanisms that promote small muscle cell (SMC) hyper
proliferation. This is shown in that dexamethasone, a less potent
glucocorticoid as compared to clobetasol, reduces the production of
PGDF and thus has anti-proliferative properties. Clobetasol acts
through similar pathways and is more potent than dexamethasone.
Dosage
[0031] The dosage or concentration of the anti-proliferative and
anti-inflammatory agents required to produce a favorable
therapeutic effect should be less than the level at which the
bioactive agent produces toxic effects and greater than the level
at which non-therapeutic results are obtained. The dosage or
concentration of the agents required can depend upon factors such
as the particular circumstances of the patient, the nature of the
trauma, the nature of the therapy desired, the time over which the
ingredient administered resides at the vascular site, and if other
active agents are employed, the nature and type of the substance or
combination of substances. Therapeutic effective dosages can be
determined empirically, for example by infusing vessels from
suitable animal model systems and using immunohistochemical,
fluorescent or electron microscopy methods to detect the agent and
its effects, or by conducting suitable in vitro studies.
[0032] In one embodiment, the bioactive agents can be incorporated
into polymeric coating in a percent loading of between about 0.01%
and less than about 100% by weight, more preferably between about
5% and about 50% by weight of the total drug-load that includes
greater than about 0% to about 100% of the anti-proliferative agent
and less than about 100% to greater than about 0% of the
anti-inflammatory agent. The relative amount of the
anti-proliferative agent and anti-inflammatory agent can be
determined by the type of lesions to be treated. For example, where
everolimus is used as the anti-proliferative agent and clobetasol
is used as the anti-inflammatory agent, the relative amount of
everolimus and clobetasol can be varied for different types of
lesions, that is, the relative amount of everolimus can be higher
for more proliferative lesions, and on the other hand, the relative
amount of clobetasol can be higher for more inflammatory
lesions.
Other Bioactive Agents
[0033] In some embodiments, other agents can be used in combination
with the anti-proliferative agent and the anti-inflammatory agents:
These bioactive agents can be any agent which is a therapeutic,
prophylactic, or diagnostic agent. These agents can also have
anti-proliferative and/or anti-inflammmatory properties or can have
other properties such as antineoplastic, antiplatelet,
anti-coagulant, anti-fibrin, antithrombonic, antimitotic,
antibiotic, antiallergic, antioxidant as well as cystostatic
agents. Examples of suitable therapeutic and prophylactic agents
include synthetic inorganic and organic compounds, proteins and
peptides, polysaccharides and other sugars, lipids, and DNA and RNA
nucleic acid sequences having therapeutic, prophylactic or
diagnostic activities. Nucleic acid sequences include genes,
antisense molecules which bind to complementary DNA to inhibit
transcription, and ribozymes. Some other examples of other
bioactive agents include antibodies, receptor ligands, enzymes,
adhesion peptides, blood clotting factors, inhibitors or clot
dissolving agents such as streptokinase and tissue plasminogen
activator, antigens for immunization, hormones and growth factors,
oligonucleotides such as antisense oligonucleotides and ribozymes
and retroviral vectors for use in gene therapy. Examples of
antineoplastics and/or antimitotics include methotrexate,
azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin
hydrochloride (e.g. Adriamycin.RTM. from Pharmacia & Upjohn,
Peapack N.J.), and mitomycin (e.g. Mutamycin.RTM. from
Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such
antiplatelets, anticoagulants, antifibrin, and antithrombins
include sodium heparin, low molecular weight heparins, heparinoids,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa
platelet membrane receptor antagonist antibody, recombinant
hirudin, thrombin inhibitors such as Angiomax a (Biogen, Inc.,
Cambridge, Mass.), calcium channel blockers (such as nifedipine),
colchicine, fibroblast growth factor (FGF) antagonists, fish oil
(omega 3-fatty acid), histamine antagonists, lovastatin (an
inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand
name Mevacor.RTM. from Merck & Co., Inc., Whitehouse Station,
N.J.), monoclonal antibodies (such as those specific for
Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,
phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,
serotonin blockers, steroids, thioprotease inhibitors,
triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric
oxide donors, super oxide dismutases, super oxide dismutase
mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl
(4-amino-TEMPO), estradiol, anticancer agents, dietary supplements
such as various vitamins, and a combination thereof. Examples of
such cytostatic substance include angiopeptin, angiotensin
converting enzyme inhibitors such as captopril (e.g. Capoten.RTM.
and Capozide.RTM. from Bristol-Myers Squibb Co., Stamford, Conn.),
cilazapril or lisinopril (e.g. Prinivil.RTM. and Prinzide.RTM. from
Merck & Co., Inc., Whitehouse Station, N.J.). An example of an
antiallergic agent is permirolast potassium. Other therapeutic
substances or agents which may be appropriate include
alpha-interferon, and genetically engineered epithelial cells. The
foregoing substances are listed by way of example and are not meant
to be limiting. Other active agents which are currently available
or that may be developed in the future are equally applicable.
Delivery Formulations
[0034] The composition comprising both anti-proliferative agent and
the anti-inflammatory agent can be formulated into any formulation
suitable for delivery by any mode of delivery. For example, the
composition can be formed into a coating on an implantable medical
device to provide controlled release of the anti-proliferative
agent and the anti-inflammatory agent. The composition can also be
formulated into other suitable formulations for example, bolus dose
of free drug, optionally with a fluoroscopic dye, bolus dose of
gel-encapsulated drug.
[0035] The gel can be formed of a gel-forming material or polymer
such as hyaluronic acid, carboxymethyl cellulose, pectin,
hydroxypropyl methylcellulose, hydroxypropyl cellulose,
methylcellulose, sodium carboxymethylcellulose,
hydroxyethylcellulose, polyethylene oxide, acacia, tragacanth, guar
gum, xanthan gum, locust bean gum, Carbopol.TM. acidic carboxy
polymer, polycarbophil, polyethylene oxide, poly(hydroxyalkyl
methacrylate), poly(electrolyte complexes), poly(vinyl acetate)
cross-linked with hydrolyzable bonds, water-swellable N-vinyl
lactams polysaccharides, natural gum, agar, agarose, sodium
alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea,
eucheuma, gum arabic, gum ghatti, gum karaya, arbinoglactan,
amylopectin, gelatin, hydrophilic colloids such as carboxylmethyl
cellulose gum or alginate gum, including both non-crosslinked and
crosslinked alginate gums, where the crosslinked alginate gums may
be crosslinked with di- or trivalent ions, polyols such as
propylene glycol, or other crosslinking agents, Cyanamer.TM.
polyacrylamides, Good-rite.TM. polyacrylic acid, starch graft
copolymers, Aqua-Keeps.TM. acrylate polymer, ester crosslinked
polyglucan, and the like, and combinations thereof. Some of the
gel-forming materials are discussed in U.S. patents, U.S. Pat. Nos.
3,640,741, 3,865,108, 3,992,562, 4,002,173, 4,014,335, and
4,207,893. Hydrogels also are discussed in the Handbook of Common
Polymers, by Scott and Roff, published by the Chemical Rubber
Company, Cleveland, Ohio. For any given gel-forming material or
polymer, use of a material with higher average molecular weight
provides higher viscosity in aqueous solution of any given
concentration. Therefore, using a higher molecular weight generally
enables use of a lesser quantity of polymer to accomplish the
required retardation of dissolution. In some embodiments, the
gel-forming material or polymer can be hydropropyl methylcellulose
having 19-24% methoxyl substitution and 7-12% hydroxypropyl
substitution and a number average molecular weight of at least
20,000. Such polymers include those sold by Dow Chemical Co. under
the tradenames Methocel K4M, Methocel K15M and Methocel K100M.
Modes of Delivery
[0036] In one embodiment, the anti-inflammatory drug such as
clobetasol is formulated into a bolus dose of free drug with,
optionally, a fluoroscopic dye. The anti-proliferative drug such as
everolimus can be formulated into a coating composition with a
polymeric material and then coated onto an implantable device
(e.g., stent). The bolus dose of anti-inflammatory drug is
administered first and then the anti-proliferative drug is
delivered by release from the implantable device such as a
drug-delivery stent. The composition may further include a third
agent such as a HDL (high density lipoprotein)-mimic as described
in U.S. Pat. No. 6,367,479. Alternatively, HDL-mimic can be
delivered by the stent.
[0037] In another embodiment, the anti-inflammatory drug such as
clobetasol is formulated into a bolus dose of gel. The
anti-proliferative drug such as everolimus can be formulated into a
coating composition with a polymeric material and then coated onto
an implantable device. The bolus dose of the anti-inflammatory drug
is administered first and then the anti-proliferative drug is
delivered by release from the implantable device such as a
drug-delivery stent.
[0038] In a further embodiment, the anti-inflammatory drug and the
anti-proliferative drug can be included in a polymeric matrix and
then coated onto a medical device such as a stent. The medical
device coating can be designed to have a variety of different
release parameters for each of the drugs included in the coating.
For example, the anti-inflammatory can have one or a combination of
release profiles that include a pulse release, fast or burst
release, and a sustained release. Similarly, the anti-proliferative
drug can have one or a combination of release profiles that include
a pulse release, fast or burst release, and a sustained release
from the stent. In some embodiments, the combination can be
delivered simultaneously or at least during the drug treatment
period there is at lease some overlap between the release of the
drugs. In some embodiments, the anti-inflammatory can be completely
released prior to the release to the anti-proliferative or can be
partially released with some or significant overlap between the
release of both drugs. "Pulse release" generally refers to a
release profile of a drug that features a sudden surge of the
release rate of the drug. The release rate surge of the drug would
then disappear within a period. A more detailed definition of the
term can be found in Encyclopedia of Controlled Drug Delivery,
Edith Mathiowitz, Ed., Culinary and Hospitality Industry
Publications Services.
[0039] As used herein, the term "fast release" in one embodiment
refers to a release profile of a drug that features a release rate
in the range between about 15 to about 40 .mu.g per day for a 18 mm
stent, about 10 .mu.g to about 27 .mu.g per day for a 13 mm stent,
and about 6.7 .mu.g to about 17.2 .mu.g per day for a 8 mm stent.
Equivalent profiles can be derived by one having ordinary skill in
the art for stents having other sizes. In another embodiment, the
term "fast release" refers to an approximately 20% release in 24
hours of a drug. The term "fast release" is used interchangeably
with the term "burst release."
[0040] As used herein, the term "sustained release" generally
refers to a release profile of a drug that can include zero-order
release, exponential decay, step-function release or other release
profiles that carry over a period of time, for example, ranging
from several days to several years. The terms "zero-order release",
"exponential decay" and "step-function release" as well as other
sustained release profiles are well known in the art (see, for
example, Encyclopedia of Controlled D rug Delivery, Edith
Mathiowitz, Ed., Culinary and Hospitality Industry Publications
Services).
[0041] In one embodiment, at least one of the anti-inflammatory
agent (e.g., clobetasol) and anti-proliferative agent (e.g.,
everolimus) is administered via a stent while the other is
administered by other local means of administration or
alternatively, the other is administered systemically. In other
embodiments, both are administered locally, by means other than a
stent, or alternatively systemically. Systemic administration can
be accomplished orally or parenterally including intravascularly,
rectally, intranasally, intrabronchially, or transdermally. Liquid
carriers which are sterile solutions or suspensions can be injected
intramuscularly, intraperitoneally, subcutaneously, and
intravenously. Rectal administration can be in the form of
conventional suppository. For adminsitration by intranasal or
intrabronchial inhalation or insufflation, the drug can be
formulated into an aqueous or partially aqueous solution, which can
then be utilized in the form of an aerosol. The drug can be
administered transdermally through the used of a transdermal patch
and a carrier that is inert to and mutually compatible with the
active component, is non-toxic to the skin, and allows for the
delivery of the drug for systemic absorption into the blood stream
via the skin. The carrier may take any number of forms such as
creams, ointments, pastes, and gels. The creams and ointments may
be viscous liquids or semisolid emulsions of either the
oil-in-water or water-in-oil type. Pastes made of absorptive
powders dispersed in petroleum or hydrophilic petroleum containing
the active component may also be suitable. Other devices capable of
releasing the drug into the blood stream include semi-permeable
membranes covering a reservoir containing the drug, with or without
a carrier.
[0042] Local administration can be accomplished by a variety of
techniques which administer the active component at or near the
target site. The following examples of local delivery techniques
are provided for illustrative purposes and are not intended to be
limiting. Examples include local delivery catheters, site specific
carriers, implants, direct application, or direct injection. Local
delivery by a catheter allows for the administration of the drug
directly to the target site.
[0043] Local delivery by site specific carriers is conducted by
attaching the drug to a carrier which will direct or link the drug
to the target cells. Examples of this delivery technique include
the use of carrier such as a protein ligand, a monoclonal antibody
or a membrane anchored linker.
[0044] Local delivery by an implant (other than a stent) is the
placement of a matrix carrying the drug at the site. The matrix can
release the active component by, for example, diffusion,
degradation, chemical reaction, solvent activators, etc. One
example of local delivery by an implant can include direct
injection of vesicles or micro-particles. These micro-particles may
be composed of substances such as proteins, lipids, carbohydrates
or synthetic polymers. The micro-particles can have the drug
impregnated therein and/or coated thereon. Application via implants
is not limited to the above described routes and other techniques
such as grafts, micropumps or application of a fibrin glue or
hydrogel containing the active component around the exterior of a
designated region of the vessel can also be implemented by one of
ordinary skill in the art.
[0045] Local delivery by direct injection describes injecting a
liquid carrier containing the drug directly into the site. The
liquid carrier should be inert to and mutually compatible with the
drug. The component can be in true solution or suspended in fine
particles in the carrier. A suitable example of an inert carrier
includes a sterile saline solution.
Biocompatible Polymers
[0046] Any biocompatible polymers can be used to form a coating on
a stent or to provide a drug delivery particle with the
anti-proliferative drug and/or anti-inflammatory drug. Such
biocompatible, bioabsorbable polymers include, but not limited to,
poly(ester amide), poly(ester amide) that may contain alkyl groups,
amino acid groups, or poly(ethylene glycol) (PEG) groups,
polyethylene glycol (PEG), polylakanoates (PHA),
poly(2-hydroxyalkanoates), poly(3-hydroxyalkanoates) such as
poly(3-hydroxypropanoate), poly(3-hydroxybutyrate),
poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),
poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate),
poly(4-hydroxyalknaote) such as poly(4-hydroxybutyrate),
poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),
poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymers
comprising any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate
monomers described herein or blends thereof, polyesters,
poly(D,L-lactide), poly(L-lactide), polyglycolide,
poly(D,L-lactide-co-glycolide), polycaprolactone,
poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(dioxanone), poly(ortho esters), poly(anhydrides),
poly(tyrosine carbonates) and derivatives thereof, poly(tyrosine
ester) and derivatives thereof, poly(imino carbonates),
poly(phosphoesters), polyphosphazenes, poly(amino acids),
polysaccharides, collagen, chitosan, alginate, polyethers,
polyamides, polyurethanes, polyalkylenes, polyalkylene oxides,
polyethylene oxide, polypropylene oxide, polyethylene glycol (PEG),
PHA-PEG, polyvinylpyrrolidone (PVP), alkylene vinyl acetate
copolymers such as ethylene vinyl acetate (EVA), alkylene vinyl
alcohol copolymers such as ethylene vinyl alcohol (EVOH or EVAL),
poly(n-butyl methacrylate) (PBMA), SOLEF.TM. polymers such as
poly(vinylidene fluoride-co-hexafluoropropene) (PVDF-co-HFP) and
poly(vinylidene fluoride) (PVDF) and combinations thereof.
Method of Coating A Device
[0047] The coating described herein can be formed by spray coating
or any other coating process available in the art. Generally, the
coating involves dissolving or suspending the composition, or one
or more components thereof, in a solvent or solvent mixture to form
a solution, suspension, or dispersion of the composition or one or
more components thereof, applying the solution or suspension to an
implantable device, and removing the solvent or solvent mixture to
form a coating or a layer of coating. Suspensions or dispersions of
the composition described herein can be in the form of latex or
emulsion of microparticles having a size between 1 nanometer and
100 microns, preferably between 1 nanometer and 10 microns. Heat
and/or pressure treatment can be applied to any of the steps
involved herein. In addition, if desirable, the coating described
here can be subjected to further heat and/or pressure treatment.
Some additional exemplary processes of coating an implantable
device that may be used are described in, for example, Lambert T L,
et al. Circulation, 1994, 90: 1003-1011; Hwang C W, et al.
Circulation, 2001; 104: 600-605; Van der Giessen W J, et al.
Circulation, 1996; 94: 1690-1697; Lincoff A M, et al. J Am Coll
Cardiol 1997; 29: 808-816; Grube E. et al, J American College
Cardiology Meeting, Mar. 6, 2002, ACCIS2002, poster 1174-15; Grube
E, et al, Circulation, 2003, 107: 1, 38-42; Bullesfeld L, et al. Z
Kardiol, 2003, 92: 10, 825-832; and Tanabe K, et al. Circulation
2003, 107: 4, 559-64.
[0048] As used herein, the term "solvent" refers to a liquid
substance or composition that is compatible with the polymer and is
capable of dissolving or suspending the polymeric composition or
one or more components thereof at a desired concentration.
Representative examples of solvents include chloroform, acetone,
water (buffered saline), dimethylsulfoxide (DMSO), propylene glycol
monomethyl ether (PM,) iso-propylalcohol (IPA), n-propyl alcohol,
methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF),
dimethyl acetamide (DMAC), benzene, toluene, xylene, hexane,
cyclohexane, heptane, octane, nonane, decane, decalin, ethyl
acetate, butyl acetate, isobutyl acetate, isopropyl acetate,
butanol, diacetone alcohol, benzyl alcohol, 2-butanone,
cyclohexanone, dioxane, methylene chloride, carbon tetrachloride,
tetrachloroethylene, tetrachloro ethane, chlorobenzene,
1,1,1-trichloroethane, 1,1,2-trichloroethane, formamide,
hexafluoroisopropanol, 1,1,1-trifluoroethanol, and hexamethyl
phosphoramide and a combination thereof.
[0049] Examples of such implantable devices include self-expandable
stents, balloon-expandable stents, stent-grafts, grafts (e.g.,
aortic grafts), artificial heart valves, cerebrospinal fluid
shunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE
and ENDOTAK, available from Guidant Corporation, Santa Clara,
Calif.). The underlying structure of the device can be of virtually
any design. The device can be made of a metallic material or an
alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),
stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR
108, cobalt chrome alloy L-605, "MP35N," "MP20N," ELASTINITE
(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,
gold, magnesium, or combinations thereof. "MP35N" and "MP20N" are
trade names for alloys of cobalt, nickel, chromium and molybdenum
available from Standard Press Steel Co., Jenkintown, Pa. "MP35N"
consists of 35% cobalt, 35% nickel, 20% chromium, and 10%
molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20%
chromium, and 10% molybdenum. Devices made from bioabsorbable or
biostable polymers could also be used with the embodiments of the
present invention. In one embodiment, the implantable device is a
stent, which can be degradable stents, biodurable stents, depot
stents, and metallic stens such as stents made of stainless steel
or nitinol. The stents can be balloon expandable or self
expanding.
Method of Use
[0050] In accordance with embodiments of the invention, a coating
of the various described embodiments can be formed on an
implantable device or prosthesis, e.g., a stent. For coatings
including one or more active agents, the agent will be retained on
the medical device such as a stent during delivery and expansion of
the device, and released at a desired rate and for a predetermined
duration of time at the site of implantation. Preferably, the
medical device is a stent. A stent having the above-described
coating is useful for a variety of medical procedures, including,
by way of example, treatment of obstructions caused by tumors in
bile ducts, esophagus, trachea/bronchi and other biological
passageways. A stent having the above-described coating is
particularly useful for treating occluded regions of blood vessels
caused by abnormal or inappropriate migration and proliferation of
smooth muscle cells, thrombosis, and restenosis. Stents may be
placed in a wide array of blood vessels, both arteries and veins.
Representative examples of sites include the iliac, renal, and
coronary arteries.
[0051] For implantation of a stent, an angiogram is first performed
to determine the appropriate positioning for stent therapy. An
angiogram is typically accomplished by injecting a radiopaque
contrasting agent through a catheter inserted into an artery or
vein as an x-ray is taken. A guidewire is then advanced through the
lesion or proposed site of treatment. Over the guidewire is passed
a delivery catheter which allows a stent in its collapsed
configuration to be inserted into the passageway. The delivery
catheter is inserted either percutaneously or by surgery into the
femoral artery, brachial artery, femoral vein, or brachial vein,
and advanced into the appropriate blood vessel by steering the
catheter through the vascular system under fluoroscopic guidance. A
stent having the above-described coating may then be expanded at
the desired area of treatment. A post-insertion angiogram may also
be utilized to confirm appropriate positioning.
[0052] The implantable device comprising a coating described herein
can be used to treat an animal having a condition or disorder that
requires a treatment. Such an animal can be treated by, for
example, implanting a device described herein in the animal.
Preferably, the animal is a human being. Exemplary disorders or
conditions that can be treated by the method disclosed herein
include, but not limited to, thrombosis, high cholesterol,
hemorrhage, vascular dissection or perforation, vascular aneurysm,
vulnerable plaque, chronic total occlusion, claudication,
anastomotic proliferation for vein and artificial grafts, bile duct
obstruction, ureter obstruction, tumor obstruction, restenosis and
progression of atherosclerosis in patient subsets including type I
diabetics, type II diabetics, metabolic syndrome and syndrome X,
vulnerable lesions including those with thin-capped
fibroatheromatous lesions, systemic infections including
gingivitis, hellobacteria, and cytomegalovirus, and combinations
thereof.
EXAMPLES
[0053] The embodiments of the present invention will be illustrated
by the following set forth examples. All parameters and data are
not to be construed to unduly limit the scope of the embodiments of
the invention.
Example 1
Porcine Implant Study
[0054] Described in this example is a 28 day porcine implant study
that compared the 200 .mu.g/cm.sup.2 dose Lemans with a
clobetasol-only delivery stent, an everolimus-only stent, and an
everolimus-clobetasol combination drug delivery stent. The study
was performed using three different drug delivery stents, Arm 1,
Arm 2, and Arm 3. Arm 1 is Lemans stent (a stent available from
Guidant based on PVDF-co-HFP) that included 105 .mu.g everolimus
and used as a control. Arm 2 was loaded with 185 .mu.g clobetasol
only, with no everolimus. Arm 3 is loaded with 105 .mu.g everolimus
and 80 .mu.g clobetasol.
[0055] The Arm 1, Arm 2, and Arm 3 stents were implanted in a 30%
overstretch model. Nine samples of each Arm stent were implanted,
one for each coronary artery. 24 hr Release in porcine serum data
were gathered. 3, 7 and 28 day in vivo release data were gathered
(from the mammary arteries), as was 28 day quantitative coronary
angioplasty (QCA), histology and morphometry.
[0056] In this study, 12 mm Vision Small stents (available from
Guidant) were used. All drug solutions were sprayed in a 2%
Solef.TM. in acetone/cyclohexanone formulation. All stents had a
100 .mu.g PBMA primer. Table 1 shows the coating design of the
stents used in this study. TABLE-US-00001 TABLE 1 Coating design
Polymer Evererolimus Clobetasol Solid Target Drug (D) (P) D:P Drug
% Target (.mu.g) Target (.mu.g) (.mu.g) Arm 1 Everolimus Solef .TM.
1:3 25.0 105 -- 420 Arm 2 Clobetasol Solef .TM. 1:4.2 19.2 -- 185
962 Arm 3 Ever & Clob Solef .TM. 1:3.49 22.2 105 80 833
[0057] The release rate data are shown in Table 2. As can be seen
from Table 2, a coating based on Solef.TM. is capable of
simultaneous release of both everolimus and clobetasol.
TABLE-US-00002 TABLE 2 Release rate data In vivo In vivo In vivo In
vitro In vivo In vivo In vivo In vitro Day 3 Day 7 Day 28 24 hr Day
3 Day 7 Day 28 24 hr % % % % % % % % Clobetasol Clobetasol
Clobetasol Clobetasol Everolimus Everolimus Everolimus Everolimus
Release Release Release Release in Release Release Release Release
in Arm (n = 2) (n = 3) (n = 4) PS (n = 3) (n = 2) (n = 3) (n = 4)
PS (n = 3) 1 - Everolimus 37.6% 49.3% 66.7% 30.0% 2 - Clobetasol
32.5% 43.1% 60.6% 26.7% 3 - Everolimus + Clobetasol 40.9% 50.2%
71.9% 30.1% 35.1% 43.6% 60.4% 24.8%
[0058] The results of 28 day QCA are shown in FIG. 1, the 28 day
histology data are in FIG. 2, and the 28 day morphometry data are
shown in FIG. 3 and summarized in Table 3 below. TABLE-US-00003
TABLE 3 28 Day morphometry data from FIG. 3 AVERAGE STANDARD
DEVIATION Media Neointimal Media Neointimal Neointimal Area
Neointimal % Thickness Injury Area Area % Thickness Injury
(mm{circumflex over ( )}2) Area (mm{circumflex over ( )}2) Stenosis
(mm) Score (mm{circumflex over ( )}2) (mm{circumflex over ( )}2)
Stenosis (mm) Score Everolimus 1.21 1.81 27.83 0.28 1.83 Everolimus
0.23 0.72 13.18 0.11 0.23 Clobetasol 1.09 1.73 24.86 0.29 1.79
Clobetasol 0.18 1.57 23.27 0.23 0.22 Clobetasol/ 0.97 0.82 12.39
0.14 1.62 Clobetasol/ 0.18 0.39 7.54 0.04 0.29 Everolimus
Everolimus
[0059] The p values from a t-test of the data from FIG. 3 are
summarized in Table 4. A "t-test" returns the probability
associated with a Student's t-Test that determines whether two
samples are likely to have come from the same two underlying
populations that have the same mean. The value returned from the
test, "p", is the probability that the two groups of data come from
the same population. p Values less than or equal to 0.10 or 0.05
are generally considered significant (Zar, J H. Biostatistical
Analysis. Englewood Cliffs, N.J.: Prentice-Hall Inc, 1974. pp
101-108). TABLE-US-00004 TABLE 4 p Values from a t-test of the data
from FIG. 3 Neointi- Neointi- Media mal % mal Injury Arm Comparison
Area Area Stenosis Thickness Score EVER COMBO 0.05 0.01 0.02 0.01
0.18 EVER CLOB 0.29 0.90 0.77 0.93 0.78 COMBO CLOB 0.24 0.18 0.22
0.14 0.25
[0060] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
* * * * *