Note: Descriptions are shown in the official language in which they were submitted.
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MEDICAL DEVICE FOR INT'RA-LUMENAL
DELIVERY OF PHARMACEUTICAL AGENTS
FIELD OF THE INVENTION
The present invention relates to devices for infra lumenal drug delivery. The
devices are particularly useful for local delivery of therapeutic substances
such as
chemotherapeutics, platelet inhibitors, smooth muscle inhibitors and
vasodilators.
Such therapeutic substances can be used in treating restenosis, pulmonary
hypertension and other circulatory disorders. The device is coated or
impregnated
with the pharmaceutical substance and can be permanent or biodegradable.
BACKGROUND OF THE INVENTION
Restenosis
Stenosis is the narrowing of the blood vessel lumen. In the case of the heart,
stenosis of cardiac circulation can lead to acute infarction with subsequent
ischemia.
Stenosis is frequently treated with angioplasty. Neoimtimal formation after
stent
implantation can cause luminal narrowing called restenosis. Restenosis is
induced by
initial platelet adhesion and thrombus formation followed by immunocytic
adhesion
on the stent surface and injured vessel wall. The thrombus then releases
factors that
activate the proliferation of smooth muscle cells.
While percutaneous transluminal angioplasty (PTA), a method of expanding a
blood vessel blocked by plaque, presently enjoys wide use, it suffers from two
major
problems. First, the blood vessel may suffer acute occlusion immediately after
or
within the initial hours after the dilation procedure. The second major
problem
encountered in PTA is the re-narrowing of an artery after an initially
successful
angioplasty. This re-narrowing is referred to as "restenosis" and typically
occurs
within the first six months after angioplasty. Restenosis is believed to arise
through
the proliferation and migration of smooth muscle cells arterial wall, as well
as through
geometric changes im the arterial wall referred to as "remodeling." It has
similarly
been postulated that the delivery of appropriate agents directly into the
arterial wall
could interrupt the cellular andlor remodeling events leading to restenosis.
However,
the results of attempts to prevent restenosis in this manner have been mixed.
A device such as an intravascular stent can be a useful adjunct to PTA,
particularly in the case of either acute or threatened closure after
angioplasty. The
stmt is placed in the dilated segment of the artery to mechanically prevent
abrupt
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closure and restenosis. Unfortunately, even when the implantation of the stent
is
acconnpanied by aggressive and precise antiplatelet and anticoagulation
therapy
(typically by systemic administration), the incidence of thrombotic vessel
closure or
other thrombotic complication remains significant, and the prevention of
restenosis is
S not as successful as desired. An undesirable side effect of the systemic
amiplatelet
and anticoagulation therapy is an increased incidence of bleeding
complications,
limiting its use. A suitable device would work locally to deliver a
therapeutic agent
that would prevent thrombus formation and inhibit smooth muscle cell
proliferation
without undesirable side-effects.
Stents
Recent major breakthroughs have made new materials available for
percutaneous peripheral arterial and coronary artery intervention procedures.
Typically, a stmt is an inserted mesh of wires that stretch and mold to the
arterial wall
to prevent reocclusion. The arterial and coronary artery stents have made
progressive
structural improvements leading to the evolution of third generation stems or
coated
stems. Stents are described for instance in US Fatent Nos. 6,23S,OS3;
6,165,209;
6,129,725; 6,241,760; and 6,197,047.
Implantable medical devices capable of delivering medicinal agents have been
described. Several patents are directed to devices utilizing biodegradable or
bioresorbable polymers as drug containing and releasing coatings, including US
Patent Nos. 4,916,193; 4,994,071; and 6,096,070. Other patents are directed to
the
formation of a drug containing hydrogel on the surface of an implantable
medical
device, these include US Patent Nos. 5,221,698; and 5,304,121. Still other
patents
describe methods for preparing coated intravascular scents. US Patent No.
5,464,650
describes coating stents via application of polymer solutions containing
dispersed
therapeutic material to the stent surface followed by evaporation of the
solvent. US
Patent No. 6,099,561 describes stents with ceramic-like coatings. US Patent
No.
6,231,600 describes stems with hybrid coatings including a time released
restenosis
inhibiting coating and a non-thrombogenic coating to prevent clotting on the
device.
US Patent No. 6,214,901 describes a biocompatible polymer suitable for coating
implantable medical devices and delivering therapeutics suspended therein.
Additional coatings for medical devices are described for instance in US
Patent Nos.
6,071,305; 6,179,817; and 6,218,016.
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Several therapeutic agents have been proposed for treating or preventing
restenosis. US Patent No. 6,214,868 describes preventing or treating coronary
restenosis which comprises adW nistering an egective amount of a catechin,
derived
from a green tea extract. US Patent No. describes inhibiting restenosis with a
peptide
S abundant in basic amino acid residues linked via its C-terminus to a peptide
of at least
two consecutive hydrophobic amino acid residues. US Patent No. 6,239,118
describes inhibiting restenosis with a substituted adenine derivative such as
2-chloro-
deoxyadenisine. US Patent No. 6,171,609 describes inhibiting restenosis with
an
inhibitor of vascular smooth muscle cell contraction. US Patent No. 6,241,718
describes inhibiting restenosis by applying cryogenic energy to a treatment
site. US ø ,
Patent No. 6,156,350 describes inhibiting restenosis by flushing with a
solution with a
pH below 4.0 such as a hydrochloric acid.
Pulmonary Hypertension
Pulmonary hypertension has been an enigma to the medical profession both
diagnostically and therapeutically. Its well known "mirror image cousin,"
arterial
hypertension is probably the most diagnosed and treated medical conditioxi,
while this
poor relation remains undiagnosed, untreated and quietly deadly. Unlike
arterial
hypertension, pulmonary hypertension can not be readily diagnosed such as by a
sphygmomanometer.
Pulmonary hypertension is defined when the pressure in the pulmonary artery
exceeds 25 mm of ~rcury at rest or 30 mm of mercury during exercise. There are
two forms or pulmonary hypertension. One is known as primary pulmonary
hypertension where the cause is unknown and second form is referred to as
secondary
pulmonary hyertension, meaning that it is secondary to another identifiable
underlying cause.
Pulmonary hypertension usually occurs in young adults, with a mean age of
45, varying from 15 to 66 years of age. Approximately 62% are female. The
median
survival time after diagnosis is approximately 2.5 years. Secondary pulnonary
hypertension can result from a multitude of diseases including cardiac
problems such
as sever mural stenosis, severe aortic stenosis, left to right shunts (VSD~,
congestive
heart failure, diastolic dysfunction, to list a few of the cardiac causes.
Other causes
are obstructive sleep apnea, chronic pulmonary emboli, pulmonary parenchyma)
disease such as emphysema, pulmonary fibrosis or chest wall deformities. It
also
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occurs in connective tissue disease e.g. lupus erythematosus, polymiositis,
rheumatoid
arthritis, scleroderma and with the CREST syndrome. Secondary pulmonary
hypertension has been associated with portal hypotension, and with the use of
appetite suppressants.
Elevated pulinonary artery pressure has been found to be a specifically
significant prognostic factor in chronic obstructive pulmonary disease
patients
receiving long term oxygen therapy. In a recent study at the University
Hospital in
Strasbourg France, Oswald-Mammosser and co-workers found that the five year
survival in parient's with severe COPD with normal resting pulmonary artery
pressure
was 62% and in patients with elevated pulmonary artery pressure the survival
was
only 36%. The means of treatment for primary or secondary pulmonary
hypertension
are medical or surgical. At present, most of the medical treatments are
experiment
and are primarily related to prostacyclin analogues given either orally,
inhaled or by
infusion. There have also been several studies with inhaled nitrate oxide and
oral
endothelin receptor antagonists. None of these produced any dramatic results.
WO
01/34088 discusses the use of vasoactive intestinal peptide ('SIP) for
treatment of
pulmonary hypertension.
Surgery for treatment of pulmonary hypertension usually consists of lung
transplantation, single, bilateral or heart with bilateral lung. Most patients
have a
waiting period of two to three years for an appropriate donor, obviating the
need for
many who succumb to pulmonary hypertension. Survival at five years post-
transplantation is 37-44%. At present it does not appear to be a viable
treatment. The
lung volume reduction procedure remains a questionable option for COPD.
Cancer
In spite of numerous advances in medical research, cancer remains the second
leading cause of death in the United States. In the industrialized nations,
roughly one
in five persons will die of cancer. Traditional modes of clinical care, such
as surgical
resection, radiotherapy and chemotherapy, have a significant failure rate,
especially
for solid tumors. Failure occurs either because the initial tumor is
unresponsive, or
because of recurrence due to regrowth at the original site and/or nnetastases.
Even in
cancers such as breast cancer where the mortality rate has decreased,
successful
intervention relies on early detection of the cancerous cells. The etiology,
diagnosis
and ablation of cancer remain a central focus for medical research and
development.
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Neoplasia resulting in benign tumors can usually be completely cured by
removing the mass surgically. If a tumor becomes malignant, as manifested by
invasion of surrounding tissue, it becomes much more diffcult to eradicate.
Once a
malignant tumor metastasizes, it is much less likely to be eradicated.
The three major cancers, in terms of morbidity and mortality, are colon,
breast
and lung. New surgical procedures offer an increased survival rate for colon
cancer.
Improved screening methods increase the detection of breast cancer, allowing
earlier,
less aggressive therapy. Numerous studies have shown that early detection
increases
survival and treatment options. Lung cancer remains largely refractory to
treatment.
Excluding basal cell carcinoma, there are aver one million new cases of cancer
per year in the United States alone, and cancer accounts for over one half
million
deaths per year in this country. In the world as a whole, the five most common
cancers are those of lung, stomach, breast, colon/rectiun, and uterine cervix,
aad the
total number of new cases per year is over 6 million. Only about half the
number of
people who develop cancer die of it.
Vasodilators
Vasodilators cause vasodilation of or in increased rate of blood flow through
the arteries. Thus, upon administration of VIP and/or NF, vasodilation or rate
of
blood flow would be expected to increase.
Vasoactive Intestinal Peptide
VIP is a basic, linear 28 amino acid polypeptide isolated initially form
porcine
duodenum (Mutt et al. (1974) Eur. J. >3iochern. 42:581-589) and widely found
in the
. central and peripheral nervous systems and digestive tract. VIP has strong
vasodilating properties and hypotensive activity and systemic vasodilatory
activity.
Administered intravenously (IV) or directly into the heart, VIP increases
heart rate
and contractile force. Anderson et al. (1988) J. Cardio. Pharnacol. 12:365-
371; Rigel
et al. (1988) Am J. Physiol. 255:H317-319; Karasawa et al. (1990) Eur. J.
Pharmacol.
187:9-17; and Unverferth et al. (1985) J. Laboratory. Clip. Med. 106:542-550.
The amino acid structure of VIP was clarified in 1974, and since this
structure
is similar to both secretin and glucagons, VIP is considered to be a peptide
hormone
belonging to the glucagons-secretin family. Other members of this family of
structurally related peptides include gastric inhibitory peptide (GIP), growth
hormone
releasing factor (GHRF) and adenylate cyclase-activating peptide (PACAP). Like
all
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secretory peptides, VIP is derived by proteolylic cleavage from a larger
precursor
molecule. The 170 amino acid precursor preproVIP contains histidine
isoleucine,
another biologically active peptide. Itoh et al. (1983) Nature 304:547-549.
VIF
contains at Ieast two functional regions: a region of receptor-specific
binding and a
region involved in biological activity. Gozes et al. (1989) Mol. Neurobiol.
3:201-236.
VIP mediates or modulates several basic cell fiunctions. These include brain
activity, endocrine functions, cardiac activity, respiration, digestion and
sexual
potency. The widespread physiologic distribution of VIP correlates with its
involvement in a broad spectrum of biological activities. The actions of VIP
are of a
complex nature, encompassing receptor modulation, inducting release
ofneurotrophic r
factors, neurotransmission and neuromodulation. VLP occurs widely in the
central
and peripheral nervous systems and digestive tract, and may play a role in
parasympathetic responses in the trachea and gastrointestinal tract.
VIP is an important modulator of cell growth, differentiation and survival
during development of the sympathetic nervous system. VIP acts as a
neuromodulator in several responses. Ferron et al. {1985) Proc. Natl. Acad.
Sci. iJSA
82:8810-8812; and Kawatani et al. {1985) Science 229:879-881. In cholinergic
studies VIP has a selective effect on muscarinie excitation in sympathetic
ganglia with
no apparent effect on nicotinic responses, indicating that VIP has intrinsic
properties
affecting electrical activity and also interacts with other neurotransmitter
systems to
modulate physiologic responses.
VIP has been found in glial cells and appears to be of physiological
importance. VIP mediates communication between neurons and glia, a
relationship of
fundamental importance to neurodevelopment and fimction.
VIP irnmunoreactive fibers are present in and appear to be intrinsic to the
canine heart. Weihe et al. (1981) Neurosei. Let. 26;283-288; and Weihe et al.
(1984)
Cell Tiss. Res. 236:527-540. VIP-containing neurons are present in canine
hearts
where VIP exerts a strong global myocardial effect similar to, but more
sustained
than, the adrenergic effect. The effect is qualitatively similar to other
inotropic drugs
that act through specific cell surface membrane receptors coupled to adenylate
cyclase, for example j3-adrenergic agonists such as proterenol.
VIP receptors are found in both canine and human hearts, thus canines are an
appropriate model for VIP in humans. Vagal, efferent stimulation of ~-blocked,
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atropini~ed dogs increased heart rate and contractile force, an effect that
may be due
to the release of VIP. Rigel et al. (1984) Am J. Physial. 246(heart circ.
physiol.
15)H168-173. VIP is released from dog atria when parasympathetic nerves are
stimulated. Hill et al. (1993) J. Autos. Nerv. Sys. 43:117-122; and Hill et
al. (1995).
Many different potential therapeutic uses of VIP, VIP analogues and VIP-lilee
polypeptides have been proposed. Due to the widespread distribution and
variety of
activities of VIP, VIP analogues and VIP-like peptides have been proposed as
treatment for various conditions including, among others, asthma and erectile
dysfunction.
I O VIP is active when present in amounts of only picograms, and is stable in
solution. This makes it particularly suited for use in a medicinal context.
VIP has isotropic and chronotropic effects due to its vasodilatory properties.
VIP acts as a bronchodilator and a relaxant of pulmonary vascular smooth
muscle.
The isotropic state of the ventricle may be affected by the activation of
several
receptors, some of which are coupled to adenylate cyclase. Foremast among
these is
the (3-adrenergic receptor, which, when activated by its corresponding
neurotransmitter norepinephrine, mediates increased cardiac contractility.
Additional positive isotropic cardiac receptor pathways have been identified
although physiologic roles have not yet been established. These include
pathways
that respond to (3-adrenergic agonists including histamine, serotonin,
enkephalins and
VIP. Of these, VIP is a potentially important agonist because it is present in
nerve
fibers in the heart, is coupled to adenylate cyclase, and, when administered
IV,
mediates both increased contractility and coronary vasodilation. There is some
evidence that VIP has two discrete binding sites specific to the central
nervous
system.
The time-course of chronotropic effects of VIP is dose-dependent; however
the time-course for recovery from isotropic effects is not. This may be due to
variation in neurotransmitter levels in extracellular spaces, occurring due to
heart
movement. At a constant level of sympathetic nerve stimulation, dogs whose
hearts
were paced at different rates showed different recovery times from the
isotropic
response. Thus the recovery from VIP isotropic effects is affected by heart
rate,
which in tum is altered by the chronotropic effects. The isotropic and
chronotropic
effects of VIP are therefore related but do not occur through the same
mechanism
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There may be different receptors for the two responses or the biochemical
cascade
initiated dicers for the two.
Intact endothelium is necessary to achieve vascular relaxation in response to
acetylcholine. The endothelial layer modulates autonomic and hormonal effects
on
the contractility of blood vessels. In response to vasoactive stimuli,
endothelial cells
release short-lived vasodilators called endothelium derived relaxing factor
(EDRf) or
endotheliumderived contracting factor. Endothelial cell~dependent mechanisms
are
important in a variety of vascular beds, including the coronary circulation.
The natural properties of VIP have been improved. The C-terminus holds a
receptor recognition site, and the N-terminus holds the activation site with
minimal
binding capacity. These are essential to VIP function. Peptides non-essential
to
function have been manipulated and altered, resulting in some cases in
increased
levels of activity over natural VIP. These VIP analogues and VIP ldce peptides
can
be utilized in any situation where ViP is effective. Some VIP analogues have
improved storage properties and increased duration of action, and therefore
may be
superior drugs. EP A 0613904; and US Patent Nos. 4,737,487; 5,428,015; and
5,521,157. VIP antagonists alter VIP function. US Patent No. 5,217,953.
VIP inervation has been demonstrated in the airways and pulmonary vessels
(Dey et al. (1981) Cell Tiss. Res. 220:231-238), and the lungs are believed to
be an
important physiological target for VIP. The rat and guinea pig brains have VIP-
specific receptor sites. Taylor et al. (1979) Proc. Nail. Acad. Sei. USA
76:660-664;
Robberecht et al. (1978) Eur. J. Biochem. 90:147-154. The receptor-molecule
complex has been identified in the intestine and lung. Laburthe et al. (1984)
Eur. J.
Biochem. 139:181-187; and Paul et al. (1985) Regul. Peptide 3:552. Two classes
of
receptors with different pharmacological properties have been detected in rat
lung and
in human colonic adenocarcinoma cells. Atthi et al. (1988) J. Biol. Chem.
263:363-
369; and El Baatari et al. (1988) 3. Biol. Chem. 263:685-689.
cDNAs encoding rat and human VIP receptors have been cloned; at least one
of these receptors is structurally related to the secretin receptor; at least
one of these
receptors is structurally related to the secretin receptor. Ish~ara et al.
(1992) Neuron;
Sreedharan et al. (1993) Biochem. Biophys. Res. Comm. 193:546-553; and
Sreedharan et al. (1995) Proc. Natl. Acad. Sci. USA 92:2939-2943. rnRNA for
this
CA 02489282 2004-12-10
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VIP has been found in several tissues including liver, lung, intestine and
brain.
rnRNA for another VIP receptor has been found in stomach, testes and brain.
The VIP receptor or receptors may be coupled to adenylate cyclase, as a VIP-
stimulated adenylate cyclase has been identified in various areas of the
central
S nervous system as well as the liver and pituitary. Quick et al. (1978)
Biochem
Pharn~acol. 27:2209-2213; Deschodt-Lanckman et al. (1977) FEBS Lett. 83:76-80;
and Rostene {1984) Progr. Neurobiol. 22:103-129. Studies of rat sensory
neurons
show that VIP transcription may be increased via activation of cellular
transcription
factors that bind to a cyclic adenosine monophosphate (CAMP) responsive
element.
Dobson et al. (1994) Neurosci. Left. 167:19-23; Tsukada et aL (1987) J. Biol.
Chem.
262:8743-8787; and Giladi et al. {1990) Brain Res. MoL 7:261-267.
VIP action on cAMP may be mediated via G-proteins, signal transducers that
stimulate hydrolysis of GTP to GDP, as GTP and its analogues inhibit VIP-
receptor
binding and potentiate CAMP synthesis in response to VIP. Paul (1989) Biochem
IS Pharmacol. 38:699-702. Ifthe VIP-receptor is coupled to G proteins, this
could
explain the array of VIP effects found, as G-proteins are widespread and
involved in
several signal transduction pathways. VIP induces its own mRNA in PCI2 cells,
probably as a result of its activation of adenylate cyclase. Tsukada et al.
(1995) Mol.
Cell. Endocrinol, i 07:231-239. Regulation of VIP expression occurs also at a
translational or post-translational level. Agoston et al. (1992). VIP may act
as an
autocrine regulator of its own synthesis.
VIP treatment produces a loss of responsiveness to subsequent rechallenges; a
short-term exposure to VIP results in internalization of the receptor-peptide
complex,
a feature that may be tissue-specific. Rosselin et al. (1988) Ann. NY Acad.
Sci.
527:220-237; Boissard et al. (1986) Cancer Res. 46:4406-4413; and Anteunis ~t
al.
(1989) Am J. Physiol. 256:6689-697. After internalization, VIP is degraded in
lysosymes and may serve as an intracellular effector, while the receptors are
recycled
to the cell surface.
VIP binding sites and VIP-stimulated adenylate cyclase can be reduced by
preincubation with different agents, although the different agents appear to
function
by different mechanisms. Tamer et al. (1988) J. Pharmacol. Exp. Ther. 247:417-
423.
The VIP receptor appears to be translocated to a light vesicle fraction alter
such
exposure. In some cell lines, the half life of the receptor was around 2 days,
and N-
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glycosylation was necessary for translocation. An internalized VIP receptor is
dissociated from adenylate cyclase activity, although the internalization
process is not
completely independent of CAMP accumulation. Hejblum et al. (1988) Cancer Res.
48:6201-6210. VIP signal transduction thus relies on multiple pathways other
than
S elevation of CAMP.
Neuropentide
Neuropeptide Y (NPY) is a 36-amino acid peptide neurotransmitter that is
located throughout the central and peripheral nervous systems. Tatemoto (1982)
Proc. Nail. Acad. Sci. USA 79:5485; and Hazlewood (1993) Proc. Soc. Exp. Biol.
Med. 202:44. It affects a broad range of phenomena, including blood pressure
regulation, memory, am~iolysis/sedation, food and water appetite, vascular and
other
smooth muscle activity, intestinal electrolyte secretion, and urinary sodium
excretion.
Cohners and Wahlestedt, The Biology of Neuropeptide Y and Related Peptides
(Humana Press, Totowa, NJ 1993).
Peptide YY (PYY) is also a 36 amino acid peptide and has significant
sequence homology (70%) to NPY. Tatemoto et at. (1982) Nature 296:659. Its
anatomical distribution is similar to that of NPY, although it is located
mainly in the
endocrine cells ofthe lower gastrointestinal tract. Bottcher et al. (1984)
Regul. Pept.
8:261 {1984). Like NPX, PYY stimulates feeding in rats. Morley et aI. (i985)
Brain
Res. 341:200. Along with the pancreatic polypeptide (PP), NPY and PYY have a
common tertiary structure, characterized by the so-called PP-fold. Glover
{1985) Eur.
J. Biochem 142:379. Both NPY and PYY show about a SO% sequence homology
with PP.
Because of their structural similarities, NPY and PYY have a number of
common receptors. At least four receptor subtypes, Yl, Y2, Y3, and Y4IPP, have
been identified. The amity for NPY, PYY, and various fragments thereof varies
among the subtypes. WO 95117906. As used herein, NP encompasses all forms of
neuropeptides with stenosis-inhibiting activity.
OBJECTS AND SLfMMARY OF THE INVENTION
The present invention encompasses a device containing a delivery system for
implantation in a blood vessel or other biological lumen and a therapeutically
effective amount a pharmaceutical agent. The device is particularly useful for
delivery of a pharmaceutical agent locally for instance of vasoactive
intestinal peptide
CA 02489282 2004-12-10
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e~'ective to treat stenosis in the blood vessel or proximal to a solid tumor
to deliver
chemotherapy directly to the vasculature of the tumor. The delivery system can
be
any known in the art including, but not limited to, a stmt. The device need
only be
the general shape of a scent however in that it has a lumen and can be placed
in a
biologic lumen. The device need not provide the rigidity of a stent as it is
not
necessarily provided to maintain the lumen size of an angioplasty stmt.
The device can be, and preferably, is biodegradable or bioresorbable. In the
case of such stents, replacement as needed is provided. For instance, in the
case of
prevention of restenosis, a single scent with a drug delivery life of 3-6
months should
be sufficient to treat restenosis. A scent or similar device that is resorbed
or degraded w ,
within this time would be sufficient. In treating pulmonary hypertension,
however,
replacement stems would ensure continuous treatment ofthe disease. A device
that
could be resorbed or degraded and replaced every few months would greatly
improve
the treatment profile of these patient. Methods of placing stents are well
known in the
I5 art and the preferred locations of placement are likewise known in the art.
In some circumstances, a biodegradable or bioresorbable catheter or stmt
provides the properties necessary for drug delivery according to the
invention. If the
stmt is permanent, the pharmaceutical agent can be coated onto or impregnated
into
the stmt. Numerous stems are known in the art, including, but not limited to,
those
discussed in the Background of the Invention. Additional suitable scents are
mentioned for instance in US Patent Nos. 6,3$7,124; 6,387,035; 6,383,215;
6,378,382; 6,372,723; 6,368,356; 6,358,989; 6,55,640; 6,352,682; 6,350,764;
6,344,486; 6,399,072; 6,338,739; 6,338,709; 6,306,074; 6,290,949; 6,287,332;
6,273,913; 6273,908; 6,261,630; 6,261,320; 6,258,121; 6,254,628; 6,251,920;
6,248,12; 6,235,778; 6,176,871; 6,176,871; 5,593,974; and US Patent
Application
Serial Nos. 2002/0065552; 2002/0061326; 2002/0055710; 2002/0055666;
20p2/0052572; 2002/0049162; 200210042645; 2002/0032414; 2002/0029052;
2002/0002353; 200110034352; and 200110009911.
In one embodiment, the device provided herein provides a drug eluting stmt
that inhibits intimal cell proliferation, reverses endothelial dysfunction,
enhances the
microcirculation and prevents or inhibits negative remodeling. The device is
suitable
for use in treatment of decreased blood flow through a blood vessel such as is
found
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in pulmonary hypertension, restenosis and diabetes. Thus, the device is
suitable for
use in treating each of these indications.
It has been demonstrated in multiple clinical studies that angioplasty is more
effective than thrombolytic therapy in reestablishing flow in acute/subacute
myocardial infarction. The device is suitable for use in treating pulmonary
hypertension, acutelsubacute infarction, or severe stenosis causing ischemia,
the so-
called rescue angioplasty. The stmt is suitable for use in treating any
patient in
danger of suffering stenosis of a blood vessel or pulmonary hypertension.
Where used for heating restenosis, the device has mad advantages over
30 ordinary stents in ameliorating stenosis. Restenosis is induced by initial
platelet
adhesion and thrombus formation followed by immunocyte adhesions on the stent
surface and injured vessel wall. The thrombus then releases factors that
activate
proliferation of smooth muscle cells. The pharmaceutical agents employed with
the
device of the present invention elevate platelet cAMP levels and inhibit the
platelet
activation induced by platelet activating factor. By administering the
pharmaceutical
agent directly to the site of stenosis, the device decreases side effects and
allows for
use of much lower drug concentrations than would be used in systemic
administration. Due to the nature of vasodilators such as VIP and NP, systemic
administration would be contra-indicated in treating or preventing stenosis.
In another embodiment, the device is suitable for use in delivering a
chemotheXapeutic agent to a tumor. The device can be implanted in an artery
that
feeds the vasculature of the tumor. Thus, the device is implanted proximal to
a tumor.
This decreases systemic levels of chemotherapeutic agents and increases the
concentration of agent delivered directly to the tumor. .Any suitable tumor
can be
treated including, but not limited to, astrocytoma, oligodendroglioma,
ependymoma,
medulloblastoma, primitive neural ectodermal tumor (PNET), pancreatic ductal
adenocarcinoma, small and large cell lung aclenocarcinomas, squamous cell
carcinoma, bronchoalveolarcareinoma, epithelial adenocarcinoma, and fiver
metastases thereola hepatoma, cholangiocarcinoma, breast tumors such as ductal
and
lobular adenocarcinoma, squamous and adenocarcinomas of the uterine cervix,
uterine and ovarian epithelial carcinomas, prostatic adenocarcimomas,
transitional
squamous cell carcinoma. of the bladder, soft tissue sarcomas and
leiomyosarcomas.
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The device is also useful for treating pancreatic disorders and can be placed
in
the pancreatic duct. In this instance, a biodegradable or bioresorbable device
is
preferred. The device is also suitable for use when placed in other lumens
including,
but not limited to, ureter, urethra, bile duct and spinal column for deliver
of
pharmaceutical agents to these sites.
The dose of the pharmaceutical agent required to be administered to achieve
the desired effect of improvement in the patient's condition will vary
depending on
several factors, including the severity of symptoms, size and health of the
patient and
elapsed time since onset of infarction, ischemia or at~gioplasty. The
preferred amount
to be administered depends on the pharmaceutical agent, patient and the M ,
circumstances.
The appropriate dosage range is that which is large enough to produce
amelioration but not so large as to induce unwanted side effects. The required
dosage
can be determined by one of skill in the art. Preferably, when the
pharmaceutical
agent is VIP, it is present in the range of from about 0.001 pg to 500 pg.
More
preferably, the VIP is present in an amount of from about 1 pg to 250 pg.
Preferably,
when the pharmaceutical agent is NP, it is present in the range of from about
0.001 pg
to 500 pg. More preferably, the NP is present in an amount of from about i pg
to 250
pg. if VIP and NP are used in combination, the concentrations of one or both
are
adjusted accordingly. Any concentration ofthe named pharmaceutical agents
effective to ameliorate (prevent, inhibit or treat) restenosis is encompassed
by the
invention.
As used herein, "VIP" and 'DTI'" refer to the native molecules and derivatives
thereof. VIP and NP encompass any natural or synthetic peptide that is
substantially
similar to the native peptide and retains native activity even though the
peptide may
have been manipulated, genetically or otherwise, to alter or enhance that
activity.
"Substantially similar" means a peptide in which amino acid residues non-
essential to
the stenosis-inhibition activity of the peptide have been altered in an
attempt to alter
or enhance that activity, but the peptide still retains a high level of amino
acid residue
sequence similarity to the native peptide. VIP is advantageous because it is a
vasodilator; a vasorelaxant (it decreases systemic vascular resistance (SVR));
an anti-
inflammatory, it inhibits mitogen induced T lymphocyte proliferation; inhibits
cytokine release; decreases Interleukin-2 production; inhibits vascular smooth
muscle
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cell growth; and enhances endothelial constitutive nitric oxide synthetase
(ecNOS) an
enzyme for generating nitric oxide (NO) in endothelial cells. NP is
advantageous
because it is a potent vasodilator (200 times more than prostacyclin); a
vasorelaxant;
an anti-inflammatory, and inhibits mitogen induced The lymphocyte
proliferation;
inhibits cytokine release; decreases Interleukin-2 production; enhances ecNOS;
inhibits platelet aggregation increasing cAMP in platelets and therefore
lessens
platelet aggregation. It also lessens platelet aggregation by inhibiting
phospholipase
A2 activity.
Suitable chemotherapeutic agents include, without limitation, vinca allcaloids
such as the vinblastine, vincristine and vindesine sulfates, adriamycin,
bleomycin
sulfate, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine,
dactinomycin, duanorubicin hydrochloride, doxozubicin hydrochloride,
etoposide,
fluorouracil, lomustine, mechlororethamine hydrochloride, rnelphalari,
mercaptopurine, methotrexate, mitomycin, mitotane, pentostatin, pipobroman,
procarbaze hydrochloride, streptozotocin, taxol, thioguanine, uracil mustard
and anti-
cancer antibodies.
"Amelioration" means any improvement in the condition of the patient that
has occurred as a result of administration of treatment with the claimed
invention.
This includes any increase in survival time over what would have previously
been
expected. In a patient responding particularly well there should be some
restoration
of effective cardiac function. It does not mean a complete cure or prevention
of all
restenosis although this is what is aimed far.
A "patient" is a vertebrate, preferably mammal, more preferably human.
Mammals including, but not limited to, humans, farm animals, sport animals and
pets.
Preferably, the patient is human. Suitable patients for treatment with this
invention
are those suffering from arterial stenosis arising by any means.
The pharmaceutical agents can be delivered by the delivery system by any
method known in the art. For instance, the agent can be coated or adsorbed on
the
delivery system Any biocompatible coating known in the art, including, but not
limited to, those discussed in the Background of the Invention, can be used
provided it
releases the pharmaceutical agent in a therapeutically effective manner. The
biocompatible coatings are typically polymers with their tertiary structure
acting as a
depot for a drug to be held and released by the characteristics of the coating
or elution
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WO 03/103743 PCT/US03/18059
of the drug from a coating. Suitable coatings also include saccharides and
polysaccharides. Numerous coatings and solid dose delivery compositions are
provided by Roser et al. WO 96/03978. Preferably, the device is biodegradable
or
bioresorbable and allows for near zero order release rate of the agent.
Suitable materials for use in making or coating the device include, without
limitation, reducing, non-reducing and hydrophobically derivatized
carbohydrates.
Reducing carbohydrates include, without limitation glucose, maltose, lactose,
fructose, galactose, mannose, maltulose, iso-maltulose and lactulose. Non-
reducing
carbohydrates include, without limitation, trehalose, ramose, stachyose,
sucrose and
dextran. Other useful carbohydrates include non-reducing glycosides of
polyhydroxy
compounds selected from sugar alcohols and other straight chain polyalcohols.
The
sugar alcohol glycosides are preferably monoglycosides, in particular the
compounds
obtained by reduction of disaccharides such as lactose, maltose, la~ctulose
and
maltulose. Hydrophobically derivatized carbohydrates refer to a wide variety
of
carbohydrates where at least one hydroxyl group is substituted with a
hydrophobic
moiety including, but not limited to, esters and ethers. Numerous examples of
suitable carbohydrates and their syntheses are described in Developments in
Food
Carbohydrate -2 ed. C.K Lee, Applied Science Publishers, London (1980). Other
syntheses are described for instance, in Akoh et al. (1987) 3. Food. Sci.
52:1570;
Khan et al. (1993) Tetra. Lefts 34:7767 Khan (1984) Pure & Appl. Chem. 56:833-
844; and Khan et al. (1990) Carb. Res. 198:275-283. Such carbohydrates
include,
without limitation, sorbitol hexaacetate, a-glucose pentaacetate, ~i-glucose
pentaacetate, 1-0-Octyl-~-D-glucose tetraacetate, trehalose octaacetate, and
di-0-
methyl-hexa-0-acetyl sucrose.
Whichever method is used coating or impregnation of pharmaceutical agent, it
should allow slow release of a therapeutically effective amount of the
pharmaceutical
agent for a therapeutically effective length of time. For instance, slow
release by
diffusion into the lumen of a local artery or duct is effective. Of course,
drug
dissolution into the wall of the lumen will occur and account for some of the
therapeutic affect. The pharmaceutical agents can also be bonded onto the
surface of
the delivery system and released by chemical interaction with the blood and
its
components or other physiologic fluids.
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The pharmaceutical agent can be formulated with other physiologically
acceptable components. Such formulations can contain appropriate non-toxic and
non-interfering components. Such components including, but not limited to,
liquid
excipients, medicinal agents, pharmaceutical agents, carriers and substances
such as
S wetting or emulsifying agents and pH buffering agents. Liquid excipients
including,
but not limited to, water, saline glycerol or ethanol.
All references cited herein, both supra and infra, are hereby incorporated
herein by reference. Although the foregoing invention has been described in
some
detail by way of illustration and example for the purposes of clarity and
IO understanding, it will be apparent to those skilled in the art that certain
changes and
modifications can be practiced. Therefore, the description and examples should
not
be construed as limiting the scope of the invention, which is delineated by
the
appended claims.
16
