U.S. patent application number 17/550538 was filed with the patent office on 2022-03-31 for treatment of restenosis using temsirolimus.
The applicant listed for this patent is MERCATOR MEDSYSTEMS, INC.. Invention is credited to Kirk Patrick SEWARD.
Application Number | 20220096447 17/550538 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-31 |
View All Diagrams
United States Patent
Application |
20220096447 |
Kind Code |
A1 |
SEWARD; Kirk Patrick |
March 31, 2022 |
TREATMENT OF RESTENOSIS USING TEMSIROLIMUS
Abstract
Described herein are methods for distributing temsirolimus to a
tissue surrounding a blood vessel for treating vascular diseases.
Also disclosed are injectable compositions of temsirolimus for
delivery into the tissue surrounding a blood vessel for treating
vascular diseases.
Inventors: |
SEWARD; Kirk Patrick;
(Brooklyn, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MERCATOR MEDSYSTEMS, INC. |
Emeryville |
CA |
US |
|
|
Appl. No.: |
17/550538 |
Filed: |
December 14, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16809298 |
Mar 4, 2020 |
|
|
|
17550538 |
|
|
|
|
15890857 |
Feb 7, 2018 |
10617678 |
|
|
16809298 |
|
|
|
|
PCT/US2017/052790 |
Sep 21, 2017 |
|
|
|
15890857 |
|
|
|
|
62398471 |
Sep 22, 2016 |
|
|
|
International
Class: |
A61K 31/436 20060101
A61K031/436; A61P 9/00 20060101 A61P009/00; A61K 9/00 20060101
A61K009/00; A61P 9/14 20060101 A61P009/14 |
Claims
1. An injectable composition comprising temsirolimus or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient for use in treating restenosis in a peripheral
artery of a human subject, wherein the composition is suitable for
adventitial delivery to the peripheral artery, wherein the
composition is suitable for direct injection to a vascular disease
site in a tissue surrounding a wall of the peripheral artery or in
the wall of the peripheral artery via a laterally extending needle
from a catheter advanced through vasculature of the human subject
in a therapeutically effective amount effective to cause patency at
the disease site after administration to increase or minimally
decrease when compared to patency at the disease site at the time
of administration.
2. The injectable composition for use of claim 1, wherein the
composition is suitable for adventitial delivery in the leg.
3. The injectable composition for use of claim 2, wherein the
composition is suitable for adventitial delivery below the
knee.
4. The injectable composition for use of claim 2, wherein the
composition is suitable for adventitial delivery in the leg above
the knee.
5. The injectable composition for use of claim 2, wherein the
composition is suitable for adventitial delivery to a below-knee
popliteal or tibial vessel.
6. The injectable composition of claim 1, wherein the
therapeutically effective amount of temsirolimus is about 1 .mu.g
to 50 mg.
7. The injectable composition of claim 6, wherein the
therapeutically effective amount of temsirolimus is about 10 .mu.g
to 20 mg.
8. The injectable composition of claim 7, wherein the
therapeutically effective amount of temsirolimus is about 25 .mu.g
to 10 mg.
9. The injectable composition of claim 1, wherein an injection
volume of the composition is about 0.01 ml to about 50 ml.
10. The injectable composition of claim 9, wherein the injection
volume of the composition is about 0.5 ml to about 20 ml.
11. The injectable composition of claim 1, wherein the
therapeutically effective amount of temsirolimus is about 0.005 mg
to 5 mg per cm of longitudinal length of the disease site in the
blood vessel.
12. The injectable composition of claim 11, wherein the
therapeutically effective amount of temsirolimus is about 0.025 mg
to 1 mg per cm of longitudinal length of the disease site in the
blood vessel.
13. The injectable composition of claim 1, wherein a concentration
of temsirolimus is about 0.01 mg/mL to about 2.0 mg/mL.
14. The injectable composition of claim 13, wherein the
concentration of temsirolimus is about 0.1 mg/mL to about 0.5
mg/mL.
15. The injectable composition of claim 14, wherein the
concentration of temsirolimus is about 0.1 mg/mL to about 0.4
mg/mL.
16. The injectable composition for use of claim 1, wherein the
pharmaceutically acceptable excipient is 0.9% sodium chloride
injection USP, dehydrated alcohol, dl-alpha tocopherol, anhydrous
citric acid, polysorbate 80, polyethylene glycol 400, propylene
glycol, or a combination thereof.
17. The injectable composition of claim 1, wherein the tissue
comprises an adventitia tissue around the peripheral artery.
18. The injectable composition of claim 1, wherein the tissue
comprises the perivascular tissue around the peripheral artery.
19. The injectable composition of claim 1, wherein the vascular
disease site comprises the site of tissue damage or sites within
100 mm of the tissue damage.
20. The injectable composition of claim 1, wherein a
cross-sectional area at the disease site decreased no more than 60%
when compared to cross-sectional area at the disease site at the
time of administration.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 16/809,298, filed Mar. 4, 2020, which is a divisional of U.S.
application Ser. No. 15/890,857, filed Feb. 7, 2018, now U.S. Pat.
No. 10,617,678, issued Apr. 14, 2020, which is a continuation of
International Application No. PCT/US2017/052790, filed Sep. 21,
2017, which claims the benefit of U.S. Provisional Application No.
62/398,471, filed Sep. 22, 2016, the content of each of which is
incorporated herein by reference in their entirety.
BACKGROUND
[0002] The present disclosure relates generally to medical methods
and devices. More particularly, the present disclosure relates to
medical methods and kits for distributing temsirolimus in the
tissue surrounding a blood vessel.
[0003] Blockages can form in blood vessels under various disease
conditions. In atherosclerosis, the narrowing of arteries in the
body, particularly in the heart, legs, carotid and renal anatomy,
can lead to tissue ischemia from lack of blood flow. Mechanical
revascularization methods, such as balloon angioplasty,
atherectomy, stenting, or surgical endarterectomy, may be used to
open the blood vessel and to improve blood flow to downstream
tissues. Unfortunately, mechanical revascularization can lead to an
injury cascade that causes the blood vessel to stiffen and vessel
walls to thicken with a scar-like tissue, which can reduce the
blood flow and necessitate another revascularization procedure.
There is a great desire to reduce the vessel stiffening and
thickening following mechanical revascularization to maintain or
improve the patency of the blood vessel.
SUMMARY
[0004] There is a great desire to reduce the vessel stiffening and
thickening following mechanical revascularization of narrowed blood
vessel to maintain or improve the patency of the blood vessel. The
present disclosure provides methods and injectable composition for
distributing temsirolimus to a tissue surrounding a blood vessel
for treating vascular diseases.
[0005] In a certain aspect, described herein, is a method of
treating a vascular disease in a subject. The method of treating
the vascular disease in the subject comprises administering to the
subject a therapeutically effective amount of a pharmaceutical
composition comprising temsirolimus or its pharmaceutically
acceptable salts. In certain embodiments, the composition is
administered by direct injection to a disease site. In a certain
embodiment, the composition is injected though a catheter with a
needle. In a certain embodiment, the composition is injected distal
or proximal to the disease site. In a certain embodiment, the
composition is injected at least about 2 cm away from the disease
site. In a certain embodiment, the composition is injected at or
adjacent to the disease site. In a certain embodiment, the
composition is administered by injection into a blood vessel. In a
certain embodiment, the composition is injected into an adventitial
tissue surrounding a blood vessel. In a certain embodiment, the
composition is injected into a perivascular tissue surrounding a
blood vessel. In a certain embodiment, the blood vessel is an
artery. In a certain embodiment, the blood vessel is a vein. In a
certain embodiment, the artery is a coronary artery or a peripheral
artery. In a certain embodiment, the artery is selected from the
group consisting of renal artery, cerebral artery, pulmonary
artery, and artery in the leg. In a certain embodiment, the artery
is below the knee. In a certain embodiment, the artery is in the
leg above the knee. In a certain embodiment, the blood vessel is
below-knee popliteal vessel or tibial vessel. In a certain
embodiment, the composition is injected into a blood vessel wall.
In a certain embodiment, the composition is injected into a tissue
surrounding the blood vessel wall.
[0006] In certain embodiments, the therapeutically effective amount
of temsirolimus is about 1 .mu.g to 50 mg, about 10 .mu.g to 20 mg,
or about 25 .mu.g to 10 mg. In certain embodiments, the
therapeutically effective amount of temsirolimus is about 0.005 mg
to 5 mg per cm, or about 0.025 mg to 1 mg per cm of longitudinal
length of the disease site in the blood vessel. In certain
embodiments, the injection volume of the composition is about 0.01
ml to about 50 ml, or about 0.5 ml to about 20 ml. In certain
embodiments, the injection concentration of temsirolimus is 0.01
mg/mL to 2.0 mg/mL, 0.1 mg/mL to 0.5 mg/mL, or 0.1 mg/mL to 0.4
mg/mL. In certain embodiments, 12 months after administration of
the pharmaceutical composition, vessel cross-sectional area at the
disease site has decreased no more than 60%, 50%, or 30%, when
compared to vessel cross-sectional area at the disease site at the
time of administration. In a certain embodiment, the composition
further comprises a contrast medium for visualizing the injection.
In a certain embodiment, the subject is human.
[0007] In certain embodiments, the vascular disease is angina,
myocardial infarction, congestive heart failure, cardiac
arrhythmia, peripheral artery disease, claudication, or critical
limb ischemia. In certain embodiments, the vascular disease is
atherosclerosis, bypass graft failure, transplant vasculopathy,
vascular restenosis, or in-stent restenosis.
[0008] In another aspect, described herein, is an injectable
composition comprising temsirolimus or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient for use in treating a vascular disease. In a certain
embodiment, the composition is suitable for adventitial delivery.
In a certain embodiment, the composition is suitable for
adventitial delivery in the leg. In a certain embodiment, the
composition is suitable for adventitial delivery below the knee. In
a certain embodiment, the composition is suitable for adventitial
delivery in the leg above the knee. In a certain embodiment, the
composition is suitable for adventitial delivery to a below-knee
popliteal or tibial vessel. In a certain embodiment, the
composition is suitable for direct injection to the vascular
disease site. In certain embodiments, the therapeutically effective
amount of temsirolimus is about 1 .mu.g to 50 mg, about 10 .mu.g to
20 mg, or about 25 .mu.g to 10 mg. In certain embodiments, the
injection volume of the composition is about 0.01 ml to about 50
ml, or about 0.5 ml to about 20 ml. In certain embodiments, the
therapeutically effective amount of temsirolimus is about 0.005 mg
to 5 mg per cm, or about 0.025 mg to 1 mg per cm of longitudinal
length of the disease site in the blood vessel. In certain
embodiments, the concentration of temsirolimus is 0.01 mg/mL to 2.0
mg/mL, about 0.1 to 0.5 mg/mL, or about 0.1 mg/mL to about 0.4
mg/mL. In a certain embodiment, the injectable composition is for
use in treating, preventing, or inhibiting restenosis in the leg.
In a certain embodiment, the injectable composition is for use in
treating, preventing, or inhibiting restenosis below the knee. In a
certain embodiment, the injectable composition is for use in
treating, preventing, or inhibiting restenosis in the leg above the
knee. In a certain embodiment, the injectable composition is for
use in treating, preventing, or inhibiting restenosis in a
below-knee popliteal vessel or tibial vessel. In a certain
embodiment, the injectable composition is for use in treating,
preventing, or inhibiting restenosis in a femoral vessel. In a
certain embodiment, the pharmaceutically acceptable excipient of
the injectable composition is 0.9% sodium chloride injection USP,
dehydrated alcohol, dl-alpha tocopherol, anhydrous citric acid,
polysorbate 80, polyethylene glycol 400, propylene glycol, or a
combination thereof.
[0009] In another aspect, described herein, is a method of treating
a peripheral artery disease in a human subject in need thereof, the
method comprising administering to the subject a therapeutically
effective amount of a pharmaceutical composition comprising
temsirolimus or its pharmaceutically acceptable salts thereof,
wherein the composition is administered by direct injection to or
near a disease site in a tissue surrounding a wall of a peripheral
artery or in the wall of the peripheral artery via a laterally
extending injection needle of a catheter advanced through
vasculature of the human subject, wherein the amount of the
pharmaceutical composition is therapeutically effective to cause
patency at the disease site after administration to only minimally
decrease or to increase when compared to patency at the disease
site at the time of administration. In certain embodiments, the
therapeutically effective amount of temsirolimus is about 1 .mu.g
to 50 mg, about 10 .mu.g to 20 mg, or about 25 .mu.g to 10 mg. In
certain embodiments, the therapeutically effective amount of
temsirolimus is about 0.005 mg to 5 mg per cm, or about 0.025 mg to
1 mg per cm of longitudinal length of the disease site in the
peripheral artery. In certain embodiments, the injection volume of
the composition is about 0.01 ml to about 50 ml, or about 0.5 ml to
about 20 ml. In certain embodiments, the injection concentration of
temsirolimus is 0.01 mg/mL to 2.0 mg/mL, 0.1 mg/mL to 0.5 mg/mL, or
0.1 mg/mL to 0.4 mg/mL. In certain embodiments, 12 months after
administration of the pharmaceutical composition, vessel
cross-sectional area at the disease site has decreased no more than
60%, 50%, or 30%, when compared to vessel cross-sectional area at
the disease site at the time of administration. In a certain
embodiment, the composition further comprises a contrast medium for
visualizing the injection. In a certain embodiment, the artery is
below the knee. In a certain embodiment, the artery is in the leg
above the knee. In a certain embodiment, the blood vessel is
below-knee popliteal vessel or tibial vessel.
[0010] In another aspect, described herein, is an injectable
composition comprising temsirolimus or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient for use in treating restenosis in a peripheral artery of
a human subject, wherein the composition is suitable for
adventitial delivery to the peripheral artery, wherein the
composition is suitable for direct injection to a vascular disease
site in a tissue surrounding a wall of the peripheral artery or in
the wall of the peripheral artery via a laterally extending needle
from a catheter advanced through vasculature of the human subject
in a therapeutically effective amount effective to cause patency at
the disease site after administration to increase or minimally
decrease when compared to patency at the disease site at the time
of administration. In a certain embodiment, the composition is
suitable for adventitial delivery in the leg. In a certain
embodiment, the composition is suitable for adventitial delivery
below the knee. In a certain embodiment, the composition is
suitable for adventitial delivery in the leg above the knee. In a
certain embodiment, the composition is suitable for adventitial
delivery to a below-knee popliteal or tibial vessel. In certain
embodiments, the therapeutically effective amount of temsirolimus
is about 1 .mu.g to 50 mg, about 10 .mu.g to 20 mg, or about 25
.mu.g to 10 mg. In certain embodiments, the injection volume of the
composition is about 0.01 ml to about 50 ml, or about 0.5 ml to
about 20 ml. In certain embodiments, the therapeutically effective
amount of temsirolimus is about 0.005 mg to 5 mg per cm, or about
0.025 mg to 1 mg per cm of longitudinal length of the disease site
in the blood vessel. In certain embodiments, the concentration of
temsirolimus is about 0.01 mg/mL to about 2.0 mg/mL, about 0.1
mg/mL to about 0.5 mg/mL, or about 0.1 mg/mL to about 0.4 mg/mL. In
a certain embodiment, the pharmaceutically acceptable excipient is
0.9% sodium chloride injection USP, dehydrated alcohol, dl-alpha
tocopherol, anhydrous citric acid, polysorbate 80, polyethylene
glycol 400, propylene glycol, or a combination thereof.
INCORPORATION BY REFERENCE
[0011] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The novel features of the present disclosure are set forth
with particularity in the appended claims. A better understanding
of the features and advantages of the present disclosure will be
obtained by reference to the following detailed description that
sets forth illustrative embodiments, in which the principles of the
present disclosure are utilized, and the accompanying drawings of
which:
[0013] FIG. 1A is a schematic, perspective view of an intraluminal
injection catheter suitable for use in the methods and systems of
the present disclosure.
[0014] FIG. 1B is a cross-sectional view along line 1B-1B of FIG.
1A.
[0015] FIG. 1C is a cross-sectional view along line 1C-1C of FIG.
1A.
[0016] FIG. 2A is a schematic, perspective view of the catheter of
FIGS. 1A-1C shown with the injection needle deployed.
[0017] FIG. 2B is a cross-sectional view along line 2B-2B of FIG.
2A.
[0018] FIG. 3 is a schematic, perspective view of the intraluminal
catheter of FIGS. 1A-1C injecting therapeutic agents into an
adventitial space surrounding a body lumen in accordance with the
methods of the present disclosure.
[0019] FIG. 4 is a schematic, perspective view of another
embodiment of an intraluminal injection catheter useful in the
methods of the present disclosure.
[0020] FIG. 5 is a schematic, perspective view of still another
embodiment of an intraluminal injection catheter useful in the
methods of the present disclosure, as inserted into one of a
patient's body lumens.
[0021] FIG. 6 is a perspective view of a needle injection catheter
useful in the methods and systems of the present disclosure.
[0022] FIG. 7 is a cross-sectional view of the catheter FIG. 6
shown with the injection needle in a retracted configuration.
[0023] FIG. 8 is a cross-sectional view similar to FIG. 7, shown
with the injection needle laterally advanced into luminal tissue
for the delivery of therapeutic or diagnostic agents according to
the present disclosure.
[0024] FIGS. 9A-9E are cross-sectional views of an exemplary
fabrication process employed to create a free-standing low-modulus
patch within a higher modulus anchor, framework or substrate.
[0025] FIGS. 10A-10D are cross-sectional views of the inflation
process of an intraluminal injection catheter useful in the methods
of the present disclosure.
[0026] FIGS. 11A-11C are cross-sectional views of the inflated
intraluminal injection catheter useful in the methods of the
present disclosure, illustrating the ability to treat multiple
lumen diameters.
[0027] FIGS. 12A-F show schematic views of treating a blood vessel
affected by atherosclerosis with delivery of a pharmaceutical
composition by injection by a needle through a catheter.
[0028] FIG. 13 shows a flow chart of a method of treating vascular
disease in a subject.
[0029] FIGS. 14A-14B are graphs showing the levels of temsirolimus
and sirolimus circulating in whole blood at 1 hour, and 3, 7, and
28 days post-procedure.
[0030] FIG. 15 includes graphs showing the levels of temsirolimus
and sirolimus at 1 hour, and 3, 7, and 28 days post-procedure at
various locations along the injection site (2.5 cm).
DETAILED DESCRIPTION
[0031] The present disclosure describes methods of treating a
vascular disease in a subject comprising administering a
therapeutically effective amount of a pharmaceutical composition
comprising temsirolimus or its pharmaceutically acceptable salts,
wherein the composition is administered by direct injection to a
disease site.
[0032] Blockages can form in blood vessels under various disease
conditions. Atherosclerosis, which causes the narrowing, or
stenosis, of arteries in the body, particularly in the heart, legs,
carotid, and renal anatomy, can lead to tissue ischemia from lack
of blood flow. Atherosclerosis in the coronary arteries can cause
myocardial infarction, commonly referred to as a heart attack,
which can be immediately fatal or, even if survived, can cause
damage to the heart which can incapacitate the patient. Other
coronary diseases include congestive heart failure, vulnerable or
unstable plaque, and cardiac arrhythmias, which cause death and
incapacitation. In addition, peripheral artery disease (PAD), where
the arteries in peripheral tissues narrow, most commonly affects
the leg, renal, and carotid arteries. Blood clots and thrombus in
the peripheral vasculature may occlude peripheral blood flow,
leading to tissue and organ necrosis. Some patients with PAD
experience critical limb ischemia that can result in ulcers and can
require amputation in the worst cases. PAD in renal artery can
cause renovascular hypertension, and clots in the carotid artery
can embolize and travel to the brain, potentially causing ischemic
stroke.
[0033] To improve blood flow to downstream tissues, various
revascularization methods may be used to bypass or open the artery.
Artery bypass surgery can be an effective treatment for stenosed,
or narrowed, arteries resulting from atherosclerosis and other
causes, but it is a highly invasive procedure which is also
expensive and requires substantial hospital and recovery time.
Mechanical revascularization methods with balloon angioplasty,
atherectomy, stenting, or surgical endarterectomy may be used to
open, or dilate, the artery. For example, percutaneous transluminal
angioplasty (PTA), commonly referred to as balloon angioplasty, is
less invasive, less traumatic, and significantly less expensive
than bypass surgery. In addition, the effectiveness of balloon
angioplasty has improved with the introduction of stenting which
involves the placement of a scaffold structure within the artery
which has been treated by balloon angioplasty. The stent inhibits
abrupt re-closure of the artery and has some benefit in reducing
subsequent restenosis resulting from hyperplasia. By salvaging
blood vessels rather than bypassing them, more options are left
available to physicians in the further treatment of the
disease.
[0034] Unfortunately, mechanical revascularization procedure can
lead to an injury cascade that causes the artery to stiffen and
arterial walls to thicken with a scar-like tissue, known as
neointimal hyperplasia. Not only can the inner wall of the artery,
also known as the intima, thicken and stiffen in response to the
injury cascade, but the media, or the middle tissue layer of the
wall, and the adventitia, the outer layer of the wall, can thicken
and stiffen as well. The thickening, also known as hyperplasia, and
the stiffening, also known as sclerosis, can reduce the blood flow
to tissues distal to the affected site. As a result, patients who
have undergone mechanical revascularization procedure procedures
may suffer from a high incidence of restenosis resulting from
hyperplasia. Restenosis, or recurrence of stenosis or narrowing, of
the blood vessel may necessitate another revascularization
procedure to the affected area again.
[0035] There is a great desire to reduce the buildup of sclerosis
and hyperplasia following mechanical revascularization. Recently,
experimental trials have demonstrated that the implanting of stents
which have been coated with anti-proliferative drugs can reduce the
occurrence of hyperplasia. Mechanical endovascular
revascularization alone leads to patency (the binary measure of
vessel openness, typically greater than 50% in diameter compared to
adjacent non-diseased vessel) rates of 33-55% at one year and
20-50% at two years, while drug-coated balloons and adventitial
drug delivery have shown an ability to improve patency to better
than 80% at one year and 65-70% at 2 years.
[0036] Mechanistic target of rapamycin (mTOR) inhibitors have been
identified as promising drugs for coating stents. A member of
phosphatidylinositol-3 kinase-related kinase (PIKK) family, mTOR is
involved in regulating cell growth, proliferation, cell survival,
and angiogenesis. In response to physical insult of
revascularization procedure, smooth muscle and endothelial cells in
blood vessels can activate stress response pathways, which can lead
to cell proliferation, secretion of pro-inflammatory mediators and
extracellular matrix components, and ultimately to restenosis.
Drugs successful in blocking one or more of the stress response
pathways can decrease the degree of restenosis. mTOR inhibitors may
reduce cellular proliferation and inflammation and have been used
successfully in graft-versus-host disease, in organ transplant and
in some cancers by blocking mTOR activation in response to insulin,
growth factors and amino acids.
[0037] mTOR inhibitors have been generally given names including
-limus as their suffix. mTOR inhibitors include the original mTOR
inhibitor, sirolimus, also known as rapamycin, and the analogs of
sirolimus. These analogs include everolimus, zotarolimus,
deforolimus, biolimus and temsirolimus. The -limus drugs were
originally approved as immunosuppressants and subsequently, several
of the -limus analogs including sirolimus have been approved to
treat various cancers. Temsirolimus is approved for the treatment
of renal cell carcinoma (RCC), but it is not approved for the
treatment of vascular restenosis
[0038] Temsirolimus, also known as CCI-779, is the only sirolimus
analog that is approved in an injectable form. Temsirolimus has a
higher water solubility than sirolimus, which allows for
intravenous administration. Temsirolimus is a pro-drug for
sirolimus, where temsirolimus is metabolized to sirolimus, the
active form. Temsirolimus can also be active as an analog and as a
prodrug, and can inhibit mTOR and disrupt cell mitosis without
being metabolized. This can be important for local delivery for
treatment of vascular disease, because there are fewer metabolic
reactions in the vascular tissue than in the liver, where the drug
is metabolized when administered systemically.
[0039] Vascular treatment devices coated with mTOR inhibitors have
been in development. Sirolimus, everolimus, and zotarolimus have
been coated onto stents. Sirolimus has also been in development for
release from a drug-coated balloon in nanoparticle formulation.
Other -limus drugs are also being developed for drug-coated balloon
release into the inner surface of the endothelial wall of blood
vessels.
[0040] As an alternative to stent-based luminal drug delivery, the
direct delivery of drug into vascular and other luminal walls has
been proposed. It would be beneficial to provide methods which
enhance the therapeutic concentrations of the pharmaceutical agents
in targeted tissues. For example, it would be particularly
desirable if the methods could provide for an extended volumetric
distribution of the delivered pharmaceutical agent including both
longitudinal and radial spreading from the injection site(s) in
order to provide therapeutic dosage levels of the agent within the
targeted tissue region. It would be further beneficial if the
methods could efficiently deliver the drugs into the targeted
tissue and limit or avoid the loss of drugs into the luminal blood
flow. It would be still beneficial if the persistence of such
therapeutic concentrations of the pharmaceutical agent in the
tissue were also increased, particularly in targeted tissues away
from the blood vessel wall, including the adventitial tissue
surrounding the blood vessel wall. Additionally, it would be
beneficial to increase the uniformity and extent of pharmaceutical
agent delivery over remote, extended, and distributed regions of
the adventitia and other tissues surrounding the blood vessels. In
some instances, it would be beneficial to provide methods which
permit the delivery of pharmaceutical agents through the blood
vessel walls at non-diseased sites within the blood vessel, where
the agent would then be able to migrate through the adventitia or
other tissues to the diseased site(s). Still further, it would be
desirable if such intravascular delivery of pharmaceutical agents
would be useful for treating diseases and conditions of the tissues
and organs in addition to those directly related to the
vasculature.
[0041] Subjects treated by the methods disclosed herein can exhibit
a vascular disease. In one example, the vascular disease may be
atherosclerosis in the heart, legs, carotid, or renal blood
vessels. In another example, the vascular disease may be peripheral
artery disease (PAD). In another example, the vascular disease may
be angina, myocardial infarction, congestive heart failure, cardiac
arrhythmia, peripheral artery disease, claudication, or critical
limb ischemia. In another example, the vascular disease may be
atherosclerosis, bypass graft failure, transplant vasculopathy,
in-stent restenosis, or restenosis. In one example, the vascular
disease may be blood clots, thrombus, or other blockages in a blood
vessel that may occlude peripheral blood flow, leading to tissue
and organ necrosis. In one example, the vascular disease may be PAD
in renal artery or carotid artery. In some examples, the subject
with restenosis may have had a procedure to improve the patency of
the blood vessel or a revascularization procedure previously.
[0042] The disease site of the vascular disease may include blood
vessels and the tissues surrounding the blood vessel. The
vasculature of a subject refers to the circulatory system and may
comprise arterial system, venous systems, or both arterial and
venous systems and the blood vessels within those systems. In some
examples, the blood vessel may be an artery, arteriole, or other
blood vessels of the arterial system. In some examples, the blood
vessel may be a vein, venule, or other blood vessels of the venous
system. In one example, the artery may be a coronary artery or a
peripheral artery. In one example, the artery may be below the
knee. In another example, the artery may be in the leg above the
knee. In another example, the blood vessel may be below-knee
popliteal vessel or tibial vessel. In some examples, the blood
vessel may be a femoral vessel. In some examples, the artery may be
renal artery, carotid artery, cerebral artery, pulmonary artery, or
artery in the leg. In some examples, the artery may be a femoral
artery.
[0043] Restenosis may be in various tissues and blood vessels in
the body. In some instances, the restenosis may be in a peripheral
artery. In some instances, the restenosis may be in the leg. In
other instances, the restenosis may be below the knee or in the leg
above the knee. In some instances, the restenosis may be in a
below-knee popliteal vessel or tibial vessel. In some instances,
the restenosis may be in a femoral vessel. In other instances, the
restenosis may be in a femoral artery.
[0044] In some instances, the tissue surrounding a blood vessel may
refer to any tissues outside the endothelial cell wall of the blood
vessel that is radially away from the lumen of the blood vessel in
a cross section and may include plaque and calcification. In some
instances, the tissue surrounding a blood vessel may comprise
adventitial tissue, perivascular tissue, or any tissue surrounding
the endothelial wall of a blood vessel. In some instances,
adventitial tissue is also known as adventitia or tunica adventitia
or tunica externa. In some instances, adventitial tissue may be
outside of the external elastic membrane. In some instances, the
tissue surrounding a blood vessel may be tissues outside the tunica
intima of the blood vessel. In some instances, the tissue
surrounding a blood vessel may be tissues outside the tunica media
of the blood vessel. In some instances, the tissue surrounding a
blood vessel may be tissues outside the internal elastic membrane.
In some instances, the tissue may be a connective tissue. In some
instances, the tissue may be diseased tissue such as plaque,
fibrosis, calcification, or combinations of diseased and healthy
tissues.
[0045] In some instances, patency may refer to blood vessel
openness. In some instances, patency at the disease site may refer
to patency of the blood vessel, or blood vessel openness, at the
disease site. In some instances, vessel cross-sectional area at the
disease site may refer to patency of the blood vessel at the
disease site. In some instances, vessel cross-sectional area may be
determined by angiography. In some instances, the angiography may
be quantitative vascular angiography (QVA). In other instances,
vessel cross-sectional area may be determined by intravascular
ultrasound (IVUS). In some instances, patency may be described as
percent of diameter of the lumen of the blood vessel that is open
and unobstructed. In some instances, patency may be described as
percent of cross sectional area of the lumen of the blood vessel,
or vessel cross-sectional area, that is open and unobstructed. In
other instances, patency may percent of luminal volume that is open
and unobstructed. In some instances, patency may require
determination of the boundaries of the endothelial wall of the
blood vessel. In some instances, a blood vessel that is completely
open and unobstructed may have 100% patency; i.e., the blood vessel
has a cross-sectional area that is healthy and typical of a normal,
healthy blood vessel in the same part of the body. In some
instances, a blood vessel that is completely blocked and obstructed
may have 0% patency. In some instances, patency is the binary
measure of openness greater than 50% in diameter compared to
adjacent non-diseased vessel. In some instances, patency is the
binary measure of openness greater than 50% in cross-sectional area
compared to adjacent non-diseased vessel. In some instances,
patency is the binary measure of openness greater than 50% in
luminal volume compared to adjacent non-diseased vessel.
[0046] In some instances, therapeutically effective may refer to
increasing vessel cross-sectional area at the disease site. In some
instances, therapeutically effective may refer to increasing the
vessel cross-sectional area at the disease site after
administration of a pharmaceutical composition. In some instances,
therapeutically effective may refer to minimally decreasing the
vessel cross-sectional area at the disease site after
administration when compared to the vessel cross-sectional area at
the disease site at the time of administration. In some instances,
therapeutically effective may refer to increasing the vessel
cross-sectional area at the disease site. In some instances,
therapeutically effective may refer to increasing minimally the
vessel cross-sectional area at the disease site after
administration when compared to the vessel cross-sectional area at
the disease site at the time of administration. In some instances,
therapeutically effective may refer to decreasing the vessel
cross-sectional area at the disease site no more than 30%, 20%,
10%, or 0% when compared to the vessel cross-sectional area at the
disease site at the time of administration; in other words the
patency may decrease no more than 30%, 20%, 10%, or 0% when
compared to the patency at the disease site at the time of
administration. In some instances, the vessel cross-sectional area
at the disease site may decrease no more than 60%, 50%, 40%, 30%,
20%, or 10% when compared to vessel cross-sectional area at the
disease site at the time of administration. In some instances, the
vessel cross-sectional area at the disease site may increase at
least 60%, 50%, 40%, 30%, 20%, or 10% when compared to vessel
cross-sectional area at the disease site at the time of
administration.
[0047] The pharmaceutical composition to treat the vascular disease
may comprise temsirolimus or its pharmaceutically acceptable salts
thereof. In some instances, temsirolimus may be Torisel.RTM.. In
some instances, the pharmaceutical compositions may further
comprise 0.9% sodium chloride injection USP, dehydrated alcohol,
dl-alpha tocopherol, anhydrous citric acid, polysorbate 80,
polyethylene glycol 400, propylene glycol, or a combination
thereof. In some instances, the pharmaceutical compositions may
comprise pharmaceutically acceptable excipients. In some instances,
the pharmaceutical compositions may comprise other excipients
commonly used in injectable compositions. In some instances, the
pharmaceutical compositions may comprise a contrast agent to aid in
visualization of the delivery of the pharmaceutical composition. In
some instances, the pharmaceutical compositions may be injectable.
In some instances, the pharmaceutical compositions may be a liquid,
a suspension, a solution, or a gel.
[0048] In some instances, the pharmaceutical composition may be
injected at various locations at or near the disease site. In some
instances, the disease site may refer to a blood vessel affected by
a vascular disease. In some instances, the disease site may refer
to a blood vessel with a partial or complete blockage of the lumen.
In some instances, the disease site may refer to a blood vessel
with a vessel cross-sectional area of less than 100%, 90%, 80%,
70%, 60%, 50%, 40%, 30%, 20%, or 10% of vessel cross-sectional area
of an unobstructed vessel as determined from the vessel wall. In
some instances, the pharmaceutical composition may be injected
distal or proximal to the disease site. In some instances, the
pharmaceutical composition may be injected at least about 2 cm away
from the disease site. In some instances, the pharmaceutical
composition may be injected at or adjacent to the disease site. In
some instances, the pharmaceutical composition may be injected into
a blood vessel. In some instances, the pharmaceutical composition
may be injected into an adventitial tissue surrounding a blood
vessel. In some instances, the pharmaceutical composition may be
injected into a perivascular tissue surrounding a blood vessel.
[0049] Temsirolimus may have a range of doses that are
therapeutically effective for treating the vascular disease. In
some instances, the therapeutically effective amount of
temsirolimus may be about 1 .mu.g to 50 mg, about 10 .mu.g to 20
mg, about 25 .mu.g to 10 mg, about 1 .mu.g to 2 mg, about 10 .mu.g
to 500 .mu.g, about 100 .mu.g to 1 mg, or about 100 .mu.g to 500
.mu.g. In some instances, the therapeutically effective amount of
temsirolimus may be about 10 .mu.g, about 25 .mu.g, about 50 .mu.g,
about 100 .mu.g, about 500 .mu.g, about 1.0 mg, about 5.0 mg, about
10.0 mg, or about 15.0 mg. In some instances, the therapeutically
effective volume of temsirolimus may be about 0.01 ml to about 50
ml, about 0.5 ml to about 20 ml, about 0.5 ml to about 25 ml, about
0.5 ml to about 5 ml, or about 1 ml to about 5 ml. In some
instances, the therapeutically effective concentration of
temsirolimus may be about 0.1 mg/mL to about 0.4 mg/mL, about 0.1
mg/mL to about 0.5 mg/mL, or about 0.01 mg/mL to about 2.0 mg/mL.
In some instances, the therapeutically effective concentration of
temsirolimus may be about 0.1 mg/mL, about 0.2 mg/mL, about 0.3
mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 1.0 mg/ml, about 1.5
mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, or 3.0 mg/ml. In some
instances, the therapeutically effective amount of temsirolimus may
be about 0.005 mg to 5 mg per cm of longitudinal length of the
disease site in the blood vessel, about 0.025 mg to 1 mg per cm of
longitudinal length of the disease site in the blood vessel, about
0.05 mg to 2 mg per cm of longitudinal length of the disease site
in the blood vessel, or about 0.1 mg to 1 mg per cm of longitudinal
length of the disease site in the blood vessel. The longitudinal
length of the disease site in the blood vessel, also known as the
longitudinal length of the lesion, may be about 1 cm, 5 cm, 10 cm,
20 cm, 30 cm, 40 cm, or 50 cm.
[0050] Drug injection or infusion catheters and devices may be
suitable for use with the methods described herein to inject
pharmaceutical compositions into blood vessels the treat
restenosis. An example of a device includes the Mercator
Bullfrog.RTM. Micro-Infusion Device available from Mercator
MedSystems of Emeryville, Calif. Other examples include the devices
described in U.S. patent application Ser. No. 14/605,865 (Attorney
Docket No. 34634-703.505) and Ser. No. 15/691,138 (Attorney Docket
No. 34634-721.302), the entire disclosures of which are
incorporated herein by reference. Examples of suitable devices and
their use are described as follows.
[0051] A pharmaceutical composition to treat the vascular disease
may be delivered to the tissue surrounding a blood vessel using a
drug injection or infusion catheter. In one example of a drug
injection or infusion catheter as shown in FIGS. 1A-2B, a
microfabricated intraluminal catheter 10 includes an actuator 12
having an actuator body 12a and central longitudinal axis 12b. The
actuator body more or less forms a C-shaped outline having an
opening or slit 12d extending substantially along its length. A
microneedle 14 is located within the actuator body, as discussed in
more detail below, when the actuator is in its unactuated condition
(furled state) (FIG. 1B). The microneedle is moved outside the
actuator body when the actuator is operated to be in its actuated
condition (unfurled state) (FIG. 2B). The actuator may be capped at
its proximal end 12e and distal end 12f by a lead end 16 and a tip
end 18, respectively, of a therapeutic catheter 20. The catheter
tip end serves as a means of locating the actuator inside a body
lumen by use of a radio opaque coatings or markers. The catheter
tip also forms a seal at the distal end 12f of the actuator. The
lead end of the catheter provides the necessary interconnects
(fluidic, mechanical, electrical or optical) at the proximal end
12e of the actuator.
[0052] Retaining rings 22a and 22b are located at the distal and
proximal ends, respectively, of the actuator. The catheter tip is
joined to the retaining ring 22a, while the catheter lead is joined
to retaining ring 22b. The retaining rings are made of a thin, on
the order of 10 to 100 microns (.mu.m), substantially flexible but
relatively non-distensible material, such as Parylene (types C, D
or N), or a metal, for example, aluminum, stainless steel, gold,
titanium or tungsten. The retaining rings form a flexible but
relatively non-distensible substantially "C"-shaped structure at
each end of the actuator. The catheter may be joined to the
retaining rings by, for example, a butt-weld, an ultra sonic weld,
integral polymer encapsulation or an adhesive such as an epoxy.
[0053] The actuator body further comprises a central, expandable
section 24 located between retaining rings 22a and 22b. The
expandable section 24 includes an interior open area 26 for rapid
expansion when an activating fluid is supplied to that area. The
central section 24 is made of a thin, semi-flexible but relatively
non-distensible or flexible but relatively non-distensible,
expandable material, such as a polymer, for instance, Parylene
(types C, D or N), silicone, polyurethane or polyimide. The central
section 24, upon actuation, is expandable somewhat like a
balloon-device.
[0054] The central section is capable of withstanding pressures of
up to about 200 psi upon application of the activating fluid to the
open area 26. The material from which the central section is made
of is flexible but relatively non-distensible or semi-flexible but
relatively non-distensible in that the central section returns
substantially to its original configuration and orientation (the
unactuated condition) when the activating fluid is removed from the
open area 26. Thus, in this sense, the central section is very much
unlike a balloon which has no inherently stable structure.
[0055] The open area 26 of the actuator is connected to a delivery
conduit, tube or fluid pathway 28 that extends from the catheter's
lead end to the actuator's proximal end. The activating fluid is
supplied to the open area via the delivery tube. The delivery tube
may be constructed of Teflon.COPYRGT. or other inert plastics. The
activating fluid may be a saline solution or a radio-opaque
dye.
[0056] The microneedle 14 may be located approximately in the
middle of the central section 24. However, as discussed below, this
is not necessary, especially when multiple microneedles are used.
The microneedle is affixed to an exterior surface 24a of the
central section. The microneedle is affixed to the surface 24a by
an adhesive, such as cyanoacrylate. Alternatively, the microneedle
may be joined to the surface 24a by a metallic or polymer mesh-like
structure 30 (See FIG. 4), which is itself affixed to the surface
24a by an adhesive. The mesh-like structure may be-made of, for
instance, steel or nylon.
[0057] The microneedle includes a sharp tip 14a and a shaft 14b.
The microneedle tip can provide an insertion edge or point. The
shaft 14b can be hollow and the tip can have an outlet port 14c,
permitting the injection of a pharmaceutical or drug into a
patient. The microneedle, however, does not need to be hollow, as
it may be configured like a neural probe to accomplish other
tasks.
[0058] As shown, the microneedle extends approximately
perpendicularly from surface 24a. Thus, as described, the
microneedle will move substantially perpendicularly to an axis of a
lumen into which has been inserted, to allow direct puncture or
breach of body lumen walls.
[0059] The microneedle further includes a pharmaceutical or drug
supply conduit, tube or fluid pathway 14d which places the
microneedle in fluid communication with the appropriate fluid
interconnect at the catheter lead end. This supply tube may be
formed integrally with the shaft 14b, or it may be formed as a
separate piece that is later joined to the shaft by, for example,
an adhesive such as an epoxy.
[0060] The needle 14 may be a 30-gauge, or smaller, steel needle.
Alternatively, the microneedle may be microfabricated from
polymers, other metals, metal alloys or semiconductor materials.
The needle, for example, may be made of Parylene, silicon or glass.
Microneedles and methods of fabrication are described in U.S.
application Ser. No. 09/877,653, filed Jun. 8, 2001, entitled
"Microfabricated Surgical Device", assigned to the assignee of the
subject application, the entire disclosure of which is incorporated
herein by reference.
[0061] The catheter 20, in use, is inserted through an opening in
the body (e.g. for bronchial or sinus treatment) or through a
percutaneous puncture site (e.g. for artery or venous treatment)
and moved within a patient's body passageways 32, until a specific,
targeted region 34 is reached (see FIG. 3). The targeted region 34
may be the site of tissue damage or more usually will be adjacent
the sites typically being within 100 mm or less to allow migration
of the therapeutic or diagnostic agent. As is well known in
catheter-based interventional procedures, the catheter 20 may
follow a guide wire 36 that has previously been inserted into the
patient. Optionally, the catheter 20 may also follow the path of a
previously-inserted guide catheter (not shown) that encompasses the
guide wire.
[0062] During maneuvering of the catheter 20, well-known methods of
fluoroscopy or magnetic resonance imaging (MRI) can be used to
image the catheter and assist in positioning the actuator 12 and
the microneedle 14 at the target region. As the catheter is guided
inside the patient's body, the microneedle remains unfurled or held
inside the actuator body so that no trauma is caused to the body
lumen walls.
[0063] After being positioned at the target region 34, movement of
the catheter is terminated and the activating fluid is supplied to
the open area 26 of the actuator, causing the expandable section 24
to rapidly unfurl, moving the microneedle 14 in a substantially
perpendicular direction, relative to the longitudinal central axis
12b of the actuator body 12a, to puncture a body lumen wall 32a. It
may take only between approximately 100 milliseconds and five
seconds for the microneedle to move from its furled state to its
unfurled state.
[0064] The ends of the actuator at the retaining rings 22a and 22b
remain fixed to the catheter 20. Thus, they do not deform during
actuation. Since the actuator begins as a furled structure, its
so-called pregnant shape may exist as an unstable buckling mode.
This instability, upon actuation, may produce a large-scale motion
of the microneedle approximately perpendicular to the central axis
of the actuator body, causing a rapid puncture of the body lumen
wall without a large momentum transfer. As a result, a microscale
opening is produced with very minimal damage to the surrounding
tissue. Also, since the momentum transfer is relatively small, only
a negligible bias force is required to hold the catheter and
actuator in place during actuation and puncture.
[0065] The microneedle aperture, in fact, travels with such force
that it can enter body lumen tissue 32b as well as the adventitia,
media, or intima surrounding body lumens. Additionally, since the
actuator is "parked" or stopped prior to actuation, more precise
placement and control over penetration of the body lumen wall are
obtained.
[0066] After actuation of the microneedle and delivery of the
agents to the target region via the microneedle, the activating
fluid is exhausted from the open area 26 of the actuator, causing
the expandable section 24 to return to its original, furled state.
This also causes the microneedle to be withdrawn from the body
lumen wall. The microneedle, being withdrawn, is once again
sheathed by the actuator.
[0067] Various microfabricated devices can be integrated into the
needle, actuator and catheter for metering flows, capturing samples
of biological tissue, and measuring pH. The device 10, for
instance, could include electrical sensors for measuring the flow
through the microneedle as well as the pH of the pharmaceutical
being deployed. The device 10 could also include an intravascular
ultrasonic sensor (IVUS) for locating vessel walls, and fiber
optics, as is well known in the art, for viewing the target region.
For such complete systems, high integrity electrical, mechanical
and fluid connections are provided to transfer power, energy, and
pharmaceuticals or biological agents with reliability.
[0068] By way of example, the microneedle may have an overall
length of between about 200 and 3,000 microns (.mu.m). The interior
cross-sectional dimension of the shaft 14b and supply tube 14d may
be on the order of 20 to 250 um, while the tube's and shaft's
exterior cross-sectional dimension may be between about 100 and 500
.mu.m. The overall length of the actuator body may be between about
5 and 50 millimeters (mm), while the exterior and interior
cross-sectional dimensions of the actuator body can be between
about 0.4 and 4 mm, and 0.5 and 5 mm, respectively. The gap or slit
through which the central section of the actuator unfurls may have
a length of about 4-40 mm, and a cross-sectional dimension of about
50-500 .mu.m. The diameter of the delivery tube for the activating
fluid may be about 100 .mu.m. The catheter size may be between 1.5
and 15 French (Fr).
[0069] Variations of the present disclosure include a
multiple-buckling actuator with a single supply tube for the
activating fluid. The multiple-buckling actuator includes multiple
needles that can be inserted into or through a lumen wall for
providing injection at different locations or times.
[0070] For instance, as shown in FIG. 4, the actuator 120 includes
microneedles 140 and 142 located at different points along a length
or longitudinal dimension of the central, expandable section 240.
The operating pressure of the activating fluid is selected so that
the microneedles move at the same time. Alternatively, the pressure
of the activating fluid may be selected so that the microneedle 140
moves before the microneedle 142.
[0071] Specifically, the microneedle 140 is located at a portion of
the expandable section 240 (lower activation pressure) that, for
the same activating fluid pressure, will buckle outwardly before
that portion of the expandable section (higher activation pressure)
where the microneedle 142 is located. Thus, for example, if the
operating pressure of the activating fluid within the open area of
the expandable section 240 is two pounds per square inch (psi), the
microneedle 140 will move before the microneedle 142. It is only
when the operating pressure is increased to four psi, for instance,
that the microneedle 142 will move. Thus, this mode of operation
provides staged buckling with the microneedle 140 moving at time
t.sub.1, and pressure p.sub.1, and the microneedle 142 moving at
time t.sub.2 and p.sub.2, with t.sub.1, and p.sub.1, being less
than t.sub.2 and p.sub.2, respectively.
[0072] This sort of staged buckling can also be provided with
different pneumatic or hydraulic connections at different parts of
the central section 240 in which each part includes an individual
microneedle.
[0073] Also, as shown in FIG. 5, an actuator 220 could be
constructed such that its needles 222 and 224A move in different
directions. As shown, upon actuation, the needles move at angle of
approximately 90.degree. to each other to puncture different parts
of a lumen wall. A needle 224B (as shown in phantom) could
alternatively be arranged to move at angle of about 180.degree. to
the needle 224A.
[0074] Referring now to FIG. 6, a needle injection catheter 310
constructed in accordance with the principles of the present
disclosure comprises a catheter body 312 having a distal end 314
and a proximal 316. Usually, a guide wire lumen 313 will be
provided in a distal nose 352 of the catheter, although
over-the-wire and embodiments which do not require guide wire
placement will also be within the scope of the present disclosure.
A two-port hub 320 is attached to the proximal end 316 of the
catheter body 312 and includes a first port 322 for delivery of a
hydraulic fluid, e.g., using a syringe 324, and a second port 326
for delivering the pharmaceutical agent, e.g., using a syringe 328.
A reciprocatable, deflectable needle 330 is mounted near the distal
end of the catheter body 312 and is shown in its laterally advanced
configuration in FIG. 6.
[0075] Referring now to FIG. 7, the proximal end 314 of the
catheter body 312 has a main lumen 336 which holds the needle 330,
a reciprocatable piston 338, and a hydraulic fluid delivery tube
340. The piston 338 is mounted to slide over a rail 342 and is
fixedly attached to the needle 330. Thus, by delivering a
pressurized hydraulic fluid through a lumen 341 tube 340 into a
bellows structure 344, the piston 338 may be advanced axially
toward the distal tip in order to cause the needle to pass through
a deflection path 350 formed in a catheter nose 352.
[0076] As can be seen in FIG. 8, the catheter 310 may be positioned
in a coronary blood vessel BV, over a guide wire GW in a
conventional manner. Distal advancement of the piston 338 causes
the needle 330 to advance into luminal tissue T adjacent to the
catheter when it is present in the blood vessel. The therapeutic or
diagnostic agents may then be introduced through the port 326 using
syringe 328 in order to introduce a plume P of agent in the cardiac
tissue, as illustrated in FIG. 8. The plume P will be within or
adjacent to the region of tissue damage as described above.
[0077] The needle 330 may extend the entire length of the catheter
body 312 or, more usually, will extend only partially into the
therapeutic or diagnostic agents delivery lumen 337 in the tube
340. A proximal end of the needle can form a sliding seal with the
lumen 337 to permit pressurized delivery of the agent through the
needle.
[0078] The needle 330 will be composed of an elastic material,
typically an elastic or super elastic metal, typically being
nitinol or other super elastic metal. Alternatively, the needle 330
could be formed from a non-elastically deformable or malleable
metal which is shaped as it passes through a deflection path. The
use of non-elastically deformable metals, however, is less
preferred since such metals will generally not retain their
straightened configuration after they pass through the deflection
path.
[0079] The bellows structure 344 may be made by depositing parylene
or another conformal polymer layer onto a mandrel and then
dissolving the mandrel from within the polymer shell structure.
Alternatively, the bellows 344 could be made from an elastomeric
material to form a balloon structure. In a still further
alternative, a spring structure can be utilized in, on, or over the
bellows in order to drive the bellows to a closed position in the
absence of pressurized hydraulic fluid therein.
[0080] After the therapeutic material is delivered through the
needle 330, as shown in FIG. 8, the needle is retracted and the
catheter either repositioned for further agent delivery or
withdrawn. In some embodiments, the needle will be retracted simply
by aspirating the hydraulic fluid from the bellows 344. In other
embodiments, needle retraction may be assisted by a return spring,
e.g., locked between a distal face of the piston 338 and a proximal
wall of the distal tip 352 (not shown) and/or by a pull wire
attached to the piston and running through lumen 341.
[0081] FIGS. 9A-9E illustrate an exemplary process for fabricating
a dual modulus balloon structure or anchored membrane structure in
accordance with the principles of the present disclosure. The first
step of the fabrication process is seen in FIG. 9A, in which a low
modulus "patch", or membrane, material 400 is layered between
removable (e.g. dissolvable) substrates 401 and 402. The substrate
401 covers one entire face of the patch 400, while the substrate
402 covers only a portion of the opposite face, leaving an exposed
edge or border region about the periphery.
[0082] In FIG. 9B, a layer of a "flexible but relatively
non-distensible" material 403 is deposited onto one side of the
sandwich structure from FIG. 9A to provide a frame to which the
low-modulus patch is attached. This material may be, for example,
parylene N, C, or D, though it can be one of many other polymers or
metals. When the flexible but relatively non-distensible material
is parylene and the patch material is a silicone or siloxane
polymer, a chemomechanical bond is formed between the layers,
creating a strong and leak-free joint between the two materials.
The joint formed between the two materials usually has a peel
strength or interfacial strength of at least 0.05 N/mm.sup.2,
typically at least 0.1 N/mm.sup.2, and often at least 0.2
N/mm.sup.2.
[0083] In FIG. 9C, the "flexible but relatively non-distensible"
frame or anchor material 403 has been trimmed or etched to expose
the substrate material 402 so that it can be removed. Materials 401
and 402 may be dissolvable polymers that can be removed by one of
many chemical solvents. In FIG. 9D, the materials 401 and 402 have
been removed by dissolution, leaving materials 400 and 403 joined
edge-to-edge to form the low modulus, or elastomeric, patch 400
within a frame of generally flexible but relatively non-distensible
material 403.
[0084] As shown in FIG. 9E, when positive pressure+.DELTA.P is
applied to one side 405 of the structure, the non-distensible frame
403 deforms only slightly, while the elastomeric patch 400 deforms
much more. The low modulus material may have a material modulus
which is always lower than that of the high modulus material and is
typically in the range from 0.1 to 1,000 MPa, more typically in the
range from 1 to 250 MPa. The high modulus material may have a
material modulus in the range from 1 to 50,000 MPa, more typically
in the range from 10 to 10,000 MPa. The material thicknesses may
range in both cases from approximately 1 micron to several
millimeters, depending on the ultimate size of the intended
product. For the treatment of most body lumens, the thicknesses of
both material layers 402 and 403 are in the range from 10 microns
to 2 mm.
[0085] Referring to FIGS. 10A-10D, the elastomeric patch of FIGS.
9A-9D is integrated into the intraluminal catheter of FIG. 1-5. In
FIG. 10A-D, the progressive pressurization of such a structure is
displayed in order of increasing pressure. In FIG. 10A, the balloon
is placed within a body lumen L. The lumen wall W divides the lumen
from periluminal tissue T, or adventitia A*, depending on the
anatomy of the particular lumen. The pressure is neutral, and the
non-distensible structure forms a U-shaped involuted balloon 12
similar to that in FIG. 1 in which a needle 14 is sheathed. While a
needle is displayed in this diagram, other working elements
including cutting blades, laser or fiber optic tips, radiofrequency
transmitters, or other structures could be substituted for the
needle. For all such structures, however, the elastomeric patch 400
will usually be disposed on the opposite side of the involuted
balloon 12 from the needle 14.
[0086] Actuation of the balloon 12 occurs with positive
pressurization. In FIG. 10B, pressure (+.DELTA.P.sub.1) is added,
which begins to deform the flexible but relatively non-distensible
structure, causing the balloon involution to begin its reversal
toward the lower energy state of a round pressure vessel. At higher
pressure +.DELTA.P.sub.2 in FIG. 10C, the flexible but relatively
non-distensible balloon material has reached its rounded shape and
the elastomeric patch has begun to stretch. Finally, in FIG. 10D at
still higher pressure +.DELTA.P.sub.3, the elastomeric patch has
stretched out to accommodate the full lumen diameter, providing an
opposing force to the needle tip and sliding the needle through the
lumen wall and into the adventitia. Typical dimensions for the body
lumens contemplated in this figure are between 0.1 mm and 50 mm,
more often between 0.5 mm and 20 mm, and most often between 1 mm
and 10 mm. The thickness of the tissue between the lumen and
adventitia is typically between 0.001 mm and 5 mm, more often
between 0.01 mm and 2 mm and most often between 0.05 mm and 1 mm.
The pressure +.DELTA.P useful to cause actuation of the balloon is
typically in the range from 0.1 atmospheres to 20 atmospheres, more
typically in the range from 0.5 to 20 atmospheres, and often in the
range from 1 to 10 atmospheres.
[0087] As illustrated in FIGS. 11A-11C, the dual modulus structure
formed herein provides for low-pressure (i.e., below pressures that
may damage body tissues) actuation of an intraluminal medical
device to place working elements such as needles in contact with or
through lumen walls. By inflation of a constant pressure, and the
elastomeric material will conform to the lumen diameter to provide
full apposition. Dual modulus balloon 12 is inflated to a pressure
+.DELTA.P.sub.3 in three different lumen diameters in FIGS. 11A,
11B, and 11C. for the progressively larger inflation of patch 400
provides optimal apposition of the needle through the vessel wall
regardless of diameter. Thus, a variable diameter system is created
in which the same catheter may be employed in lumens throughout the
body that are within a range of diameters. This is useful because
most medical products are limited to very tight constraints
(typically within 0.5 mm) in which lumens they may be used. A
system as described in this disclosure may accommodate several
millimeters of variability in the luminal diameters for which they
are useful.
[0088] FIGS. 12A-12F show schematics of an exemplary treating
vascular disease in a subject. FIG. 12A shows a blood vessel 1210
in the lower limb that may be affected by atherosclerosis or a
plaque 1220 of lumen of the blood vessel. FIG. 12B shows the
affected blood vessel 1210 after a revascularization procedure to
increase the lumen diameter of the blood vessel. The target region
of the tissue surrounding the affected blood vessel may have had a
revascularization procedure previously. FIG. 12C shows the delivery
of the treatment catheter 10 into the target region through the
vasculature of the subject. FIG. 12D shows the expansion of the
expandable element 12 of the treatment catheter to puncture into
the target tissue 1260 surrounding the blood vessel with the needle
14 of the treatment catheter. The expandable element 12 may be also
known as an actuator. FIG. 12E shows the delivery of the
pharmaceutical composition comprising temsirolimus 1270 into the
target tissue surrounding the blood vessel 1260. FIG. 12F shows the
withdrawal of the treatment catheter 10 after the collapse of the
expandable element 12 and withdrawal of the needle 14 from the
target tissue 1260 surrounding the blood vessel.
[0089] FIG. 13 shows a flow chart of a method 1300 of treating
vascular disease in a subject. In a step 1305, a subject suitable
for treating a vascular disease may be identified. The vascular
disease may be any vascular disease described above and herein. In
exemplary embodiments, the vascular disease is post-angioplasty
restenosis. In a step 1310, a blood vessel or blood vessels in the
subject to target for treatment may be identified. The blood vessel
may be any blood vessel described above and herein, such as a
femoral artery. In a step 1315, a treatment catheter may be
prepared with a pharmaceutical composition comprising temsirolimus.
Alternative pharmaceutical compositions may be used as well; and
the treatment catheter may comprise any of the drug injection and
infusion devices described herein and above. In a step 1320, the
catheter may be advanced through the vasculature of the subject to
the target region(s), such as target region(s) in the blood vessel
where plaque has been compressed by angioplasty. In a step 1325,
the catheter may be positioned at or near the target region(s) of
the blood vessel. In a step 1330, an expandable element of the
catheter may be expanded to puncture the target region with a
needle on the balloon. The expandable element may be an expandable
segment, an expandable section, or a balloon of the treatment
catheter. The needle may be a microneedle. In a step 1335, the
needle of the treatment catheter may be positioned into the tissue
surrounding the blood vessel so that the aperture of the needle may
be positioned at the target tissue. In a step 1340, a therapeutic
amount of the pharmaceutical composition comprising temsirolimus
may be injected into the target tissue surrounding the blood
vessel. The target tissue may be adventitial tissue, perivascular
tissue, or connective tissue surrounding a blood vessel. In a step
1345, the needle may be withdrawn from the tissue and the
expandable element may be collapsed. In a step 1350, the treatment
catheter with the collapsed expandable element and the needle may
be removed from the vasculature of the subject.
[0090] Although the above steps show FIG. 12 and method 1300 of
treating a vascular disease in FIG. 13 in accordance with
embodiments, a person of ordinary skill in the art will recognize
many variations based on the teaching described herein. The steps
may be completed in a different order. Steps may be added or
deleted. Some of the steps may comprise sub-steps. Many of the
steps may be repeated as often as beneficial to the treatment.
EXAMPLES
Example 1: Porcine Model of Femoral Vessel Injury
[0091] In a porcine model of femoral artery injury, a dose of
temsirolimus was administered directly into the tissue around an
injured artery through a catheter with a needle. Porcine vascular
anatomy is similar to human anatomy, allowing the study of medical
equipment intended for use in humans. Porcine vascular pathology
allows for the development of stenotic arteries for the study of
anti-stenotic or anti-restenotic therapies intended for use in
humans.
[0092] In eleven Yorkshire pigs, the femoral artery in each leg
(hindleg) were injured by angioplasty overstretch and followed with
either temsirolimus or control saline injection, for bilateral
injury and injection. The angioplasty balloon was selected to be
40-60% larger than the reference diameter of the artery to be
injured and delivered by a catheter to the target injury site by
carotid artery access. The angioplasty balloon was inflated to
10-20 atmosphere of pressure three times for 30 seconds each
inflation at the target injury site. After the balloon was removed,
the Mercator MedSystems Bullfrog.RTM. Micro-Infusion Device
catheter with a needle was used to deliver either temsirolimus or
control saline by injection into the adventitia and perivascular
tissue around the injured artery at the center of each target
injury site. The injections were administered under and verified by
fluoroscopy. The animals were monitored before, during, and after
the procedure, and all animals survived without adverse incidents
until sacrifice.
[0093] Temsirolimus preparation. The 25 mg/ml of Torisel.RTM.
(temsirolimus) was diluted to 10 mg/ml with the supplied diluent
and further diluted to 476 .mu.g/ml in 0.9% sodium chloride
solution. Then, the 476 .mu.g/ml temsirolimus was mixed at 1:1
ratio with a contrast medium, Isovue-370, for a final temsirolimus
concentration of 238 .mu.g/ml. This temsirolimus preparation was
subsequently administered in temsirolimus-treated group pigs.
Similarly, a control solution was prepared by mixing 0.9% sodium
chloride solution at 1:1 ratio with a contrast medium, Isovue-370.
This control solution was administered in control group pigs.
[0094] Temsirolimus-treated group. Eight pigs received a single
dose of temsirolimus (1.5 ml of 238 .mu.g/ml temsirolimus) in the
tissue around each injured femoral artery, for a total of two doses
per animal. In each case, all temsirolimus treated animals
underwent perivascular infusion into the femoral artery adventitia.
Two pigs were sacrificed at each time point of 1 hour, 3 days, 7
days, and 28 days post-procedure, and each pig was analyzed for
histopathology, pharmacokinetics, and safety evaluation.
[0095] Control group. Three pigs served as control animals. Two of
the pigs received 2 injuries per femoral vessel in multiple
vessels, for a total up to 6 injury sites per animal. There were a
total of 12 femoral vessels amongst the three pigs. Each injury
site received 1.5 ml of 0.9% sodium chloride (saline) diluted 1:1
ratio with contrast medium (Isovue-370). One pig was sacrificed at
each time point of 3 days, 7 days, and 28 days post-procedure, and
each pig was analyzed for histopathology, pharmacokinetics, and
safety evaluation.
[0096] All temsirolimus-treated and control group animals
successfully received the respective injection administered
directly to the adventitia and perivascular tissues of the femoral
arteries. All injection sites except two control sites had complete
or partial circumferential and longitudinal coverage of the target
site by the injection.
[0097] Histopathology. There was no or minor structural injury
ascribable to the overstretch angioplasty procedure at 0, 3, and 7
days. By day 28, the observed injuries were healed and produced no
adverse consequences on the patency or healing of treated vessels.
The temsirolimus-treated vessels were fully or nearly fully healed
as early as day 7, generally showing a normal wall and occasionally
displaying minimal to mild perivascular or adventitial fibrosis and
low severity non-specific and localized mural inflammation
considered to be of no pathological significance. There was
complete or near complete re-endothelialization and no or minimal
to mild and non-stenosing neointima formation.
[0098] Ki-67 staining indicated that cellular proliferation
increased on day 3 in the vessel wall and adventitia and peaked on
day 7 before decreasing slightly thereafter. In
temsirolimus-treated vessels, a moderate to marked decrease in cell
proliferation throughout the vessel wall was observed at all time
periods (day 3, 7 and 28) compared to the respective controls. The
decrease was substantial and consistent along the vessel
length.
[0099] Pharmacokinetics. Whole blood samples were taken following
each injection at 5 minutes, 20 minutes, 1 hour, and then 24 hours
and upon sacrifice. Whole blood samples were analyzed for
circulating temsirolimus and sirolimus concentrations. FIG. 14A and
FIG. 14B show the levels of temsirolimus and sirolimus,
respectively, circulating in whole blood at 1 hour, and 3, 7, and
28 days post-procedure. The mean temsirolimus level in whole blood
was highest at 1 hour after the first injection (32.1.+-.11.0
ng/mL) and decreased by an order of magnitude within 24 hours
(2.4.+-.1.0 ng/mL). Temsirolimus concentrations continued to
decrease between 24 hours and 3 days and were below the limit of
quantitation at 7 and 28 days post-procedure. FIG. 15 shows the
levels of temsirolimus and sirolimus at 1 hour, and 3, 7, and 28
days post-procedure at various locations along the injection site
(2.5 cm). In analysis of the harvested vessel tissues, similar
trends were observed in the sirolimus concentration in the local
vascular tissue, but presence of temsirolimus was much more
persistent and measured in the tissue up to 28 days post-dosing.
Sirolimus remained stable for three days and decreased
significantly by day 7.
[0100] Safety Evaluation. There was no evidence of local or
systemic toxicity assessed by clinical observations and clinical
pathology either during the survival duration or by analysis of
tissues post mortem. Overall injection of temsirolimus directly
into the adventitia of femoral arteries with the Mercator
Bullfrog.RTM. device appeared safe in this model.
[0101] This study shows that temsirolimus can be delivered safely
to the adventitia and perivascular tissue in porcine models after
balloon angioplasty injury of the vessel by catheter-based needle
injection. In comparison to the control group, temsirolimus-treated
group had reduced cellular proliferation as measured by Ki-67
expression. This may be critical for reducing restenosis in
vascular disease after angioplasty or atherectomy procedures to
open the blood vessel. The result of temsirolimus having inhibitory
capability on vascular smooth muscle cells at and near the delivery
site in a vascular disease model appears to be novel. This result
suggests that temsirolimus, which has been described as a pro-drug,
may be active locally to the delivery site and not only when
delivered systemically and thus metabolized into the active form of
sirolimus.
[0102] While preferred embodiments of the present disclosure have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
present disclosure. It should be understood that various
alternatives to the embodiments of the present disclosure described
herein may be employed in practicing the present disclosure. It is
intended that the following claims define the scope of the
invention and that methods and structures within the scope of these
claims and their equivalents be covered thereby.
* * * * *