U.S. patent application number 14/599160 was filed with the patent office on 2015-07-16 for coatings with tunable molecular architecture for drug-coated balloon.
This patent application is currently assigned to ABBOTT CARDIOVASCULAR SYSTEMS INC.. The applicant listed for this patent is ABBOTT CARDIOVASCULAR SYSTEMS INC.. Invention is credited to Syed Hossainy, Michael Ngo, Stephen Pacetti, John Stankus, Mikael Trollsas.
Application Number | 20150196690 14/599160 |
Document ID | / |
Family ID | 43640590 |
Filed Date | 2015-07-16 |
United States Patent
Application |
20150196690 |
Kind Code |
A1 |
Stankus; John ; et
al. |
July 16, 2015 |
COATINGS WITH TUNABLE MOLECULAR ARCHITECTURE FOR DRUG-COATED
BALLOON
Abstract
A drug delivery balloon is provided, the a balloon having an
outer surface, and a tunable coating disposed on at least a length
of the balloon surface. The tunable coating includes a first
therapeutic agent and a first excipient, wherein the cytostatic
therapeutic agent and the at least one excipient have a weight
ratio of about 20:1 to about 1:20, and further wherein the coating
provides increased efficiency of therapeutic transfer to a body
lumen.
Inventors: |
Stankus; John; (Campbell,
CA) ; Trollsas; Mikael; (San Jose, CA) ;
Hossainy; Syed; (Hayward, CA) ; Pacetti; Stephen;
(San Jose, CA) ; Ngo; Michael; (San Jose,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABBOTT CARDIOVASCULAR SYSTEMS INC. |
SANTA CLARA |
CA |
US |
|
|
Assignee: |
ABBOTT CARDIOVASCULAR SYSTEMS
INC.
SANTA CLARA
CA
|
Family ID: |
43640590 |
Appl. No.: |
14/599160 |
Filed: |
January 16, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12636079 |
Dec 11, 2009 |
8951595 |
|
|
14599160 |
|
|
|
|
Current U.S.
Class: |
604/509 ;
427/2.24 |
Current CPC
Class: |
A61F 2/958 20130101;
A61M 25/10 20130101; A61F 2250/0067 20130101; A61L 2300/416
20130101; A61L 2300/204 20130101; A61M 25/1029 20130101; A61L
29/085 20130101; A61L 2420/06 20130101; A61L 2420/02 20130101; A61L
29/16 20130101; A61L 2300/606 20130101; A61M 2025/105 20130101;
A61M 2025/1031 20130101 |
International
Class: |
A61L 29/08 20060101
A61L029/08; A61L 29/16 20060101 A61L029/16; A61M 25/10 20060101
A61M025/10 |
Claims
1. A method of coating a medical device having an outer surface,
the method comprising: selecting a cytostatic therapeutic agent;
selecting at least one excipient; blending the cytostatic agent and
excipient to define a coating; and applying the coating to the
outer surface of the medical device, wherein the cytostatic
therapeutic agent and the at least one excipient have a weight
ratio of about 20:1 to about 1:20, and further wherein the coating
provides increased efficiency of therapeutic transfer to a body
lumen.
2. The method of claim 1, further including: blending a plasticizer
with the cytostatic therapeutic agent and the excipient.
3. The method of claim 2, wherein the excipient to plasticizer
weight ratio is from about 20:1 to about 1:20.
4. The method of claim 1, wherein the cytostatic therapeutic agent
and the at least one excipient has a weight ratio of about 2:1 to
about 1:2.
5. The method of claim 1, wherein the cytostatic therapeutic agent
is zotarolimus.
6. The method of claim 1, wherein the excipient is
poly(vinylpyrrolidone).
7. The method of claim 2, wherein the plasticizer is glycerol.
8. The method of claim 1, wherein the coating is applied to the
outer surface of the medical device by direct fluid
application.
9. The method of claim 1, further including applying heat to the
coated medical device to dry the coating.
10. The method of claim 1, wherein the medical device is a balloon
catheter.
11. A method of coating a medical device having an outer surface,
the method comprising: selecting a cytostatic therapeutic agent;
selecting at least one polymeric excipient; blending the cytostatic
therapeutic agent and at least one polymeric excipient to define a
coating; and applying the coating to at least one length of the
outer surface of the medical device, wherein the at least one
polymeric excipient has a polydispersity index from about 1.05 to
about 10 and provides increased efficiency of therapeutic transfer
to a body lumen.
12. The method of claim 11, further including: blending a
plasticizer with the cytostatic therapeutic agent and
excipient.
13. The method of claim 11, wherein cytostatic therapeutic agent is
zotarolimus.
14. The method of claim 11, wherein the excipient is
poly(vinylpyrrolidone).
15. The method of claim 12, wherein the plasticizer is
glycerol.
16. The method of claim 11, wherein the medical device is a balloon
catheter.
17. A method of coating a medical device having an outer surface,
the method comprising: selecting a cytostatic therapeutic agent;
selecting at least one excipient; blending the cytostatic
therapeutic agent and at least one excipient to define a coating;
applying the coating to at least one length of the outer surface of
the medical device; and inserting or implanting the coated medical
device in a body lumen, wherein the coating has a dissolution rate
of about 10 seconds to about 1 hour and provides an increased
efficiency of therapeutic transfer to a body lumen.
18. The method of claim 17, further including: blending a
plasticizer with the cytostatic therapeutic agent and
excipient.
19. The method of claim 17, wherein cytostatic therapeutic agent is
zotarolimus.
20. The method of claim 17, wherein the excipient is
poly(vinylpyrrolidone).
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/636,079 filed on Dec. 11, 2009, the content
of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The disclosed subject matter is related to the delivery of
drugs from an insertable medical device. More particularly, the
disclosed subject matter relates to a medical device including a
balloon for delivery of a therapeutic agent, the balloon having a
tunable, durable coating disposed on its outer surface.
BACKGROUND OF THE INVENTION
[0003] Atherosclerosis is a syndrome affecting arterial blood
vessels. A hallmark of atherosclerosis is a chronic inflammatory
response in the walls of arteries, in large part due to the
accumulation of lipid, cholesterol, leucocytes, and other
inflammatory cells and the formation of plaque on the arterial
wall. Atherosclerosis is commonly referred to as hardening of the
arteries. Angioplasty is a vascular interventional technique
involving mechanically widening an obstructed blood vessel,
typically caused by atherosclerosis.
[0004] During angioplasty, a catheter having a tightly folded
balloon is inserted into the vasculature of the patient and is
passed to the narrowed location of the blood vessel at which point
the balloon is inflated to a fixed size using an inflation fluid,
typically angiographic contrast media. Percutaneous coronary
intervention (PCI), commonly known as coronary angioplasty, is a
therapeutic procedure to treat the stenotic coronary arteries of
the heart, often found in coronary heart disease.
[0005] In contrast, peripheral angioplasty, commonly known as
percutaneous transluminal angioplasty (PTA), refers to the use of
mechanical widening of blood vessels other than the coronary
arteries. PTA is most commonly used to treat narrowing of the leg
arteries, especially, the iliac, external iliac, superficial
femoral and popliteal arteries. PTA can also treat narrowing of
veins, and other blood vessels.
[0006] Although the blood vessel is often successfully widened by
angioplasty, sometimes the treated wall of the blood vessel
experienced abrupt closure after balloon inflation or dilatation
due to acute recoil or vasospasm. One solution to such collapse is
stenting the blood vessel to prevent collapse. A stent is a device,
typically a metal tube or scaffold, that is inserted into the blood
vessel following angioplasty, in order to hold the blood vessel
open.
[0007] While the advent of stents eliminated many of the
complications of abrupt vessel closure after angioplasty
procedures, within about six months of stenting, a re-narrowing of
the blood vessel can form, a condition known as restenosis.
Restenosis was discovered to be a response to the injury of the
angioplasty procedure and is characterized by a growth of smooth
muscle cells--analogous to a scar forming over an injury. As a
solution, drug eluting stents were developed to address the
reoccurrence of the narrowing of blood vessels. One example of a
drug eluting stent is a metal stent that has been coated with a
drug that is known to interfere with the process of restenosis. A
potential drawback of certain drug eluting stents is known as late
stent thrombosis, which is an event in which blood clots inside the
stent.
[0008] Drug eluting balloons are believed to be a viable
alternative to drug eluting stents in the treatment of
atherosclerosis. In a study which evaluated restenosis and the rate
of major adverse cardiac events such as heart attack, bypass,
repeat stenosis, or death in patients treated with drug eluting
balloons and drug eluting stents, the patients treated with drug
eluting balloons experienced only 3.7 percent restenosis and 4.8%
MACE (major adverse coronary events) as compared to patients
treated with drug eluting stents, in which restenosis was 20.8
percent and 22.0 percent MACE rate. (See, PEPCAD II study,
Rotenburg, Germany).
[0009] Although drug eluting balloons are a viable alternative, and
in some cases appear to have greater efficacy than drug eluting
stents as suggested by the PEPCAD II study, drug eluting balloons
present challenges due to the very short period of contact between
the drug coated balloon surface and the blood vessel wall. In
particular, the balloon can only be inflated for less than one
minute, and is often inflated for only thirty seconds. Therefore,
an efficacious, therapeutic amount of drug must be transferred to
the vessel wall within a thirty-second to one-minute time period.
For the peripheral vasculature, the allowable inflation times can
be greater than one minute, but are still measured in minutes.
Thus, there are challenges specific to drug delivery via a drug
coated balloon because of the necessity of a short inflation time,
and therefore time for drug or coating transfer--a challenge not
presented by a drug eluting stent, which remains in the patient's
vasculature once implanted.
[0010] Other considerations are the current theories about the
mechanism by which a drug coated balloon transfers drug to the
vessel wall. One theory, for example, is that upon balloon
expansion, drug mechanically fractures or dissolves from the
coating, diffuses to the vessel wall and then permeates into the
vessel wall. A second theory is that upon balloon expansion the
balloon coating is transferred to the vessel wall, and then drug
permeates into the vessel wall from the coating adhered to the
vessel wall. Another theory is that the balloon expansion creates
tears and microfissures in the vessel wall, and a portion of the
coating inserts into the tears and microfissures. Drug then
permeates into the vessel wall from the coating within the tears
and fissures. Yet another theory is that upon balloon expansion, a
layer of dissolved drug and coating excipients is formed at a high
concentration on the vessel wall as a boundary layer. The drug
diffuses and permeates from this boundary layer into the vessel
wall. In most of these theories, the drug transfers from the
balloon to the circulation or the vascular wall tissue upon
fracture of the coating due to inflation of the balloon and occurs
within one minute, and preferably within 30 seconds. Therefore, a
need exists for a drug coated balloon having efficient drug
transfer to a vessel wall.
[0011] Various embodiments of drug-coated balloons have been
proposed, including balloons with a therapeutic agent disposed
directly on the balloon surface and balloons having various
protective sheaths. However, not all embodiments result in an
efficacious response in reducing restenosis after balloon and bare
metal stent trauma.
[0012] Therefore, a need exists for a drug eluting balloon and more
particularly, a balloon coated with a therapeutic agent that
provides for effective delivery kinetics of the therapeutic agent
from the surface of the balloon.
SUMMARY OF INVENTION
[0013] The purpose and advantages of the disclosed subject matter
will be set forth in and apparent from the description that
follows, as well as will be learned by practice of the disclosed
subject matter. Additional advantages of the disclosed subject
matter will be realized and attained by the methods and systems
particularly pointed out in the written description and claims
hereof, as well as from the appended drawings.
[0014] In accordance with an aspect of the disclosed subject
matter, a method is provided for coating a medical device including
a body having an outer surface. For example, the medical device is
a drug delivery balloon or a balloon catheter. The method includes
selecting a cytostatic therapeutic agent, selecting at least one
excipient, and blending the cytostatic agent and excipient to
define a coating. In one embodiment, the cytostatic therapeutic
agent and at least one excipient has a weight ratio of about 20:1
to about 1:20, and defines a coating, which provides increased
efficiency of therapeutic transfer to a body lumen. In another
embodiment, the cytostatic therapeutic agent and polymeric
excipient define a coating in which at least one polymeric
excipient has a polydispersity index from about 1.05 to about 10,
and provides increased efficiency of therapeutic transfer to a body
lumen.
[0015] The method can include adding or blending a plasticizer with
the cytostatic therapeutic agent and the excipient. For example,
but not limitation, the plasticizer includes glycerol. In one
embodiment, the excipient to plasticizer weight ratio is from about
20:1 to about 1:20 and the cytostatic therapeutic agent and the at
least one excipient have a weight ratio of about 20:1 to about
1:20.
[0016] In another embodiment, the medical device is a drug delivery
balloon having a coating tuned to have a dissolution rate of about
10 seconds to about 1 h. For the therapeutic agent, delivery with
balloon inflation occurs in less than 60 seconds and preferably
less than 30 seconds.
[0017] In yet another aspect of the disclosed subject matter, a
method is provided for tuning the solubility of a coating for
application to a medical device. In one embodiment, the excipient
is modified prior to blending the cytostatic therapeutic agent and
excipient to achieve desired delivery kinetics. In one embodiment,
the excipient is modified by positively charging the excipient. In
another embodiment, the excipient includes a cyclic and aliphatic
carbon chain and the excipient is modified by adjusting the ratio
of cyclic chain to aliphatic chain. Advantageously, the adjusted
chain ratio results in reduced elasticity and/or reduced release
rate of the therapeutic agent. For example but not limitation, the
excipient can be poly(vinylpyrrolidone), poly(ethylene glycol), or
poly(ester amide) polymer.
[0018] The excipient can be modified by grafting a low molecular
weight polyethylene glycol molecule to the excipient. In this
regard, the modified excipient exhibits increased adhesion to a
vessel wall. In another embodiment, the excipient is modified by
increasing the crystallinity of the excipient. For example and not
limitation, the excipient is
poly(L-lactide-co-caprolactone)polyester, and the crystallinity of
the excipient is modified by adjusting the content of L-lactide. In
this regard, the content of L-lactide can be increased, thereby
defining a coating having greater storage stability
[0019] The coatings of the disclosed subject matter can be applied
to any surface of the medical device. In one embodiment, it is
applied to the outer surface of the medical device. In accordance
with one embodiment, the coating is applied to the surface of the
medical device by direct fluid application. The method can further
include applying heat to the coated medical device to dry the
coating.
[0020] It is to be understood that both the foregoing description
is exemplary and is intended to provide further explanation of the
disclosed subject matter claimed to a person of ordinary skill in
the art. The accompanying drawings are included to illustrate
various embodiments of the disclosed subject matter to provide a
further understanding of the disclosed subject matter. The
exemplified embodiments of the disclosed subject matter are not
intended to limit the scope of the claims.
BRIEF DESCRIPTION OF DRAWINGS
[0021] The disclosed subject matter will now be described in
conjunction with the accompanying drawings in which:
[0022] FIG. 1A depicts a representative planar view of a medical
device of the disclosed subject matter, which is shown as a balloon
catheter for illustration and not limitation.
[0023] FIG. 1B is a cross-sectional view taken along lines A-A in
FIG. 1A in accordance with one embodiment of the disclosed subject
matter.
[0024] FIG. 2 is a graph illustrating percent drug release as a
function of drug, excipient and plasticizer ratio (D:E:P) in
accordance with one embodiment of the disclosed subject matter.
[0025] FIG. 3 are optical micrographs (100.times. magnification)
demonstrating the results of scratch tests of
zotarolimus:PVP:glycerol coatings on glass slides at 10:1:0.4 (left
panel) and 2:1:0.4 (right panel) in accordance with one embodiment
of the disclosed subject matter.
[0026] FIG. 4 are optical micrographs (100.times. magnification)
demonstrating the results of scratch tests of glass slide coatings
of zotarolimus:PVP:Tween 20, 2:1:0.67 (left panel) and
zotarolimus:PVP:Tween 80, 2:1:0.4 (right panel) in accordance with
one embodiment of the disclosed subject matter.
[0027] FIG. 5 are optical micrographs (50.times. magnification)
demonstrating the results of scratch tests of glass slide coatings
of zotarolimus:PEG-PE, 2:1 (left panel) and zotarolimus:PEG-PE, 1:1
(right panel) in accordance with one embodiment of the disclosed
subject matter.
[0028] FIG. 6 are optical micrographs demonstrating the results of
scratch tests of glass slide coatings of zotarolimus:PEG-PE, 1:2
under brightfield (left panel, 50.times. magnification) or crossed
polarizers (right panel, 200.times. magnification) in accordance
with one embodiment of the disclosed subject matter.
DETAILED DESCRIPTION
[0029] Reference will now be made in detail to the various aspects
of the disclosed subject matter. The method of the disclosed
subject matter will be described in conjunction with the detailed
description of the device, the figures and examples provided
herein.
[0030] As disclosed herein, the devices and methods presented can
be used for delivery within and/or treating of the lumen of a
patient. In particular, the disclosed subject matter is
particularly suited for treatment of the cardiovascular system of a
patient, such as performance of angioplasty and delivery of a
balloon expandable medical device, such as a stent, filter and
coil.
[0031] As disclosed herein, a balloon catheter is provided for
delivery of a therapeutic agent, the balloon including an outer
surface having a tunable and durable coating disposed on at least a
length of the outer surface. The tunable and durable coating
includes a therapeutic agent and an excipient. The solubility of
the coating in vivo, the biosolubility, of the coating is tunable
based on the substances and concentrations chosen for the
therapeutic agent and excipient.
[0032] Referring to FIG. 1, for purposes of illustration and not
limitation, an exemplary embodiment of balloon catheter device in
accordance with the disclosed subject matter is shown schematically
in FIGS. 1A and 1B. As depicted in FIGS. 1A and 1B, the balloon
catheter device 10 generally includes an elongated catheter shaft
12 having a proximal end and having a distal end and an expandable
balloon 30 located proximate to the distal end of the catheter
shaft. The expandable balloon has an outer surface and an inner
surface disposed at the distal end portion of the catheter shaft.
In accordance with the disclosed subject matter, a tunable coating
40 is applied to at least one length of the balloon catheter, the
tunable coating including a first therapeutic agent and a first
excipient, and can include a second therapeutic agent and a second
excipient, wherein the first and second therapeutic agents have
different dissolution rates during balloon inflation. In accordance
with a preferred embodiment, as illustrated by way of example and
not limitation in FIG. 1A, the coating is applied to at least one
length of the outer surface of the balloon catheter.
[0033] The elongated catheter shaft 12 comprises an outer tubular
member 14 and an inner tubular member 16. The outer tubular member
14 defines an inflation lumen 20 that can be disposed between the
proximal end portion and the distal end portion of the catheter
shaft 12. Specifically, as illustrated in FIG. 1B, the coaxial
relationship between the inner tubular member 16 and the outer
tubular member 14 defines an annular inflation lumen 20. The
expandable member 30 is placed in fluid communication with the
inflation lumen 20. The inflation lumen can supply fluid under
pressure, and establish negative pressure to the expandable member.
The expandable member 30 can thus be inflated and deflated. The
elongated catheter is sized and configured for delivery through a
tortuous anatomy, and can further include a guidewire lumen 22 that
permits it to be delivered over a guidewire 18. As illustrated in
FIG. 1B, the inner tubular member 16 defines the guidewire lumen 22
for the guidewire 18. Although FIGS. 1A and 1B illustrate the
guidewire lumen as having an over-the-wire (OTW) construction, the
guidewire lumen can be configured as a rapid-exchange (RX)
construction, as is well known in the art.
[0034] As disclosed herein, the coating is tunable with respect to
its solubility. Therefore, the drug delivery balloon is able to
provide the desired delivery kinetics as a result of its
tunability. The choice of excipient is key in determining efficacy
factors such as, retaining of the therapeutic agent during
delivery, releasing of the therapeutic agent during deployment,
minimizing systemic dosing, maximizing agent delivery efficiency
and therapeutic effect, and preventing particulate generation and
related thromboses, among other factors.
[0035] As used in accordance with the disclosed subject matter,
"tunable" refers to the ability to be tuned or adjusted for desired
functioning. Accordingly, a tunable coating refers to a coating
that can be adjusted according to various parameter discussed
herein.
[0036] As disclosed herein, the balloon includes a tunable coating
that comprises a therapeutic agent and an excipient. In accordance
with one embodiment, the tunable coating includes a first
therapeutic agent and a first excipient, and a second therapeutic
agent and a second excipient. The coating has a biosolubility that
is tunable based on the substances and concentrations chosen for
each of the therapeutic agent and excipient. Preferably, the
therapeutic agents have different dissolution rates. The coating
can include additional therapeutic agents and excipients.
[0037] In accordance with the disclosed subject matter, the
solubility of the coating can be adjusted by modifying a number of
factors, including excipient type, composition and molecular weight
of the excipient, modulation of excipient or polymer properties
such as aqueous solubility, octanol/water partition coefficient,
HLB (hydrophile-lipophile balance) number, glass transition
temperature, degree of amorphous versus crystalline polymer, and
orientation. Furthermore, the solubility or dissolution rates of
the coating can be adjusted by varying the therapeutic agent
concentration, therapeutic agent to excipient ratio, or coating
thickness. Accordingly, these factors can be varied in order to
provide a coating with the desired solubility and drug delivery
kinetics.
[0038] The tunable coating provides for dissolution rates during
balloon inflation that can be characterized generally as ranging
from fast, soluble, intermediate, slow, extra slow, and
non-soluble. Depending on the target tissue or vasculature where
the therapeutic agent is to be delivered, the coating can be tuned
such that the dissolution rate provides for effective drug delivery
and uptake. A "fast" coating dissolution rate will typically have a
dissolution time of less than 1 minute. A "soluble" coating
dissolution rate will typically have a dissolution time ranging
from about 1 minute to about 1 hour. An "intermediate" coating
dissolution rate will typically have a dissolution time ranging
from about 1 hour to about 2 weeks. A "slow" coating dissolution
rate will typically have a dissolution time ranging from about 2
weeks to about 3 months. An "extra slow" coating dissolution rate
will typically have a dissolution time ranging from about 3 months
to 2 years. A "non-soluble" coating dissolution rate will typically
have a dissolution time greater than 2 years. However, it shall be
noted that the specific dissolution of a coating composition is
dependent upon an interplay between input factors and that the
dissolution rates provided herein are, therefore, recited as
ranges.
[0039] The excipients include various oil-based, biosoluble, and
durable or biodurable substances that are suitable for the delivery
of a therapeutic agent. Biosolubility indicates solubility in a
relevant biological media, such as blood. A substance which is not
intended to degrade in the body, or which degrades only very
slowly, is biodurable.
[0040] In accordance with a preferred embodiment, the excipients of
the disclosed subject matter are water soluble. The excipients can
include non-ionic hydrophilic polymers. Non-ionic hydrophilic
polymers include, but are not limited to, poly(vinyl pyrrolidone)
(PVP, povidone), silk-elastin like polymer, poly(vinyl alcohol),
poly(ethylene glycol) (PEG), pluronics (PEO-PPO-PEO), poly(vinyl
acetate), poly(ethylene oxide) (PEO), PVP-vinyl acetate
(copovidone), polysorbate 80 (Tween 80), and polysorbate 20 (Tween
20). Preferably, the molecular weight of non-ionic hydrophilic
polymers can be less than 50 kDa for fast solubility. The excipient
can also include fatty acids. Further, the excipient can be a
lubricious material which improves spreading and uniformity of
coating.
[0041] In accordance with one embodiment, the excipient consists of
a biocompatible plasticizer. Alternatively, the plasticizer can be
added to the excipient to keep it soft and pliable. Plasticizers
can allow for greater coating flexibility and elongation to prevent
coating cracking during inflation or brittleness. Plasticizers
include, but are not limited to, glycerol, ethanol,
dimethylsulfoxide, ethyl lactate, benzyl alcohol, benzyl benzoate,
Cremophor EL, Vitamin E, tocopherol, liquid PEG (MW<1000),
triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyl
triethyl citrate, dibutyl phthalate, dibutyl sebacate, dimethyl
phthalate, triacetin, propylene glycol, glycerin, 2-pyrridone, and
combinations thereof. Preferably, a biocompatible plasticizer is
used.
[0042] In accordance with yet another embodiment, sugars,
polysaccharides or cellulosics, can be used as binders for the
particles. Polysaccharides include, but are not limited to,
dextran, sulfonated dextran, hydrogenated dextran, chondroitin
sulfate, sodium hyaluronate, hyaluronic acid, hyaluronan, chitosan,
sodium alginate, sucrose, pectin, mannitol, carboxymethyl cellulose
(CMC) sodium, methyl cellulose, ethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, and
hydroxypropylmethylcellulose. Certain negative charged
polysaccharides will provide a mucoadhesive effect to enhance
tissue drug retention. Furthermore, sugars such as mannitol will
provide a decreased hygroscopic effect when blended with more
moisture-sensitive active ingredients such as cytostatic drugs or
moisture sensitive excipients. Water soluble cellulosic materials
can enhance coating strength or brittleness.
[0043] In accordance with yet another embodiment, anti-coagulants
can be used as an excipient. For example, heparin based
polysaccharides can provide a minimally thrombogenic surface to
prevent blood clotting on the balloon surface or minimize platelet
activation induced by the procedure. Heparin based polysaccharides
include, but are not limited to, heparin, heparin sulfate, heparin
disaccharides, heparin fraction 1, heparin fraction 2, low
molecular weight heparin, heparin ammonium, heparin calcium,
heparin lithium, heparin lithium, and heparin zinc lithium. Low
molecular weight heparin includes centaxarin, periodate-oxidized
heparin, heparin sodium end-amidated, heparin sodium, and nitrous
acid delaminated.
[0044] In accordance with a preferred embodiment of the disclosed
subject matter, the excipient possesses a mucoadhesive property.
This mucoadhesive property of the binder will lead to longer drug
retention within the coating adhered to the vessel wall. In
particular, positively charged excipients such as chitosan,
negatively charged excipients such as some polysaccharides (e.g.
carboxymethylcellulose, sodium hyaluronate, sodium alginate) and
some non-ionic hydrophilic polymers exhibit mucoadhesive
properties. Any of the above carboxylated materials can also be
lightly activated with esters such as nitrophenolate or NHS-esters
(N-hydroxy succinimide) for increased mucoadhesiveness.
Alternatively, any above materials can be lightly thiolated for
increased mucoadhesiveness and continued solubility.
[0045] Additionally or alternatively, the excipient is or includes
a contrast agent, including but not limited to, Iopromide
(Ultravist), Ioxaglate (Hexabrix), Ioversol (Optiray), Iopamidol
(Isovue), Diatrixoate (Conray), Iodixanol (Visipaque), Iohexol
(Omnipaque), and Iotrolan. At an intermediate coating thickness, a
lower molecular weight (<1 kDa) hydrophilic contrast agent such
as Iopromide (Ultravist) would enable faster therapeutic release
and a slightly higher viscous coating of the vessel wall as
compared with drug alone. The contrast agents are lipophilic and
can aid in drug uptake and retention into the tissue wall. In
accordance with one embodiment, Ultravist and Optiray can be used
given their more benign history of effects to smooth muscle and
endothelial cells.
[0046] In accordance with yet another embodiment, excipients can
consist of carboxylated aromatics similar in molecular structure to
the structure used in contrast agents but without iodide
substituents. These negatively charged carboxylated aromatic
structures can be alkylated (C2-C12) to optimize drug tissue
uptake, or halogenated with fluoride, chloride or bromide for the
same reason. The negatively charged structures are beneficial for
tissue adhesiveness.
[0047] Table 1 provides non-limiting examples of the solubility
data for excipients that can be used in accordance with the
disclosed subject matter:
TABLE-US-00001 TABLE 1 Solubility Enhancement of a Therapeutic
Agent with Select Excipients Zotarolimus Solubility Solution (5%
w/w) (.mu.g/ml, n = 3) Phosphate buffered saline 0.53 PVP C-17 5.6
.+-. 1.6 Hydroxypropyl-.beta.-cyclodextrin 11.6 .+-. 3.1 PEG 400
31.5 .+-. 3.5 Glycerol 43.2 .+-. 30.1 5% .gamma.-Cyclodextrin 55.3
.+-. 34.3 Vitamin E TPGS 512 .+-. 49.5 Tween 20 732 .+-. 94.7 18:0
PEG2000 PE (PEG-PE)* 1020 .+-. 417
*1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneg-
lycol)-2000] (ammonium salt)
[0048] As illustrated in Table 1, the excipients provide for
increased solubility for the cytostatic drug, zotarolimus, as
compared to saline alone. The excipients Vitamin E TPGS, Tween 20,
and PEG-PE demonstrate the largest increase in zotarolimus
solubility.
[0049] Table 2 provides non-limiting examples of coating
dissolution rates during balloon inflation and representative
excipient examples.
TABLE-US-00002 TABLE 2 Examples of Delivery Kinetics and Expected
Variable Ranges for Balloon Coatings Coating Dissolution Rate
(during Coating balloon Dissolution Representative Excipient
inflation) Time Example Fast <1 minute Poly(vinylpyrrolidone)
(PVP) (MW <60 kDa) or Poly(ethylene glycol) (PEG) (lower MW
<35 kDa) Soluble 1 min to 1 hour Poly(vinylpyrrolidone) (PVP)
(MW >60 kDa) or Polyethylene oxide (PEO) (higher MW >100 kDa)
Intermediate 1 hour to 2 Silk-elastin like protein polymers weeks
Slow 2 weeks-3 Biodegradable polymer such as months
Poly(D,L-lactide-co-glycolide) (PLGA) (50:50) Extra Slow 3 months-2
Biodegradable polymer such as years
Poly(L-lactide-co-.epsilon.-caprolactone) (PLLA:PCL) (70:30)
Non-Soluble >2 years Durable polymer such as Poly(vinylidene
fluoride-co- hexafluoropropylene)
[0050] As illustrated in Table 2 above, for a "fast" coating
dissolution rate, representative excipient examples include,
without limitation, polyvinylpyrrolidone (PVP) with a molecular
weight less than about 60 kDa, or polyethylene glycol (PEG) having
a molecular weight less than about 35 kDa. The drug delivery
mechanism and kinetics expected with this representative example
include the release of the therapeutic agent with the coating
during inflation. Further, the potential mucoadhesive polymer
increases drug retention time on tissue or vasculature.
Alternatively, or additionally, the lipophilic additive increases
drug uptake in tissue.
[0051] As illustrated in Table 2 above, for a "soluble" coating
dissolution rate, representative excipient examples include,
without limitation, poly(vinylpyrrolidone) (PVP) having a molecular
weight greater than about 60 kDa, or poly(ethylene glycol) (PEG)
having a molecular weight greater than about 100 kDa. The drug
delivery mechanism and kinetics expected with this representative
example are similar to that of the "fast" coating dissolution rate,
however, the slightly slower dissolution time allows for less drug
wash off during balloon delivery before inflation.
[0052] As illustrated in Table 2 above, for an "intermediate"
coating dissolution rate, representative excipient examples
include, without limitation, silk-elastin like protein polymers.
The drug delivery mechanism and kinetics expected with this
representative example provides for enhanced systemic drug loss
protection and absence of short-term solubility, therefore allowing
for enhanced particulate safety. For an "intermediate" dissolution
rate, the therapeutic agent is not released together with the
coating but from the coating. The therapeutic agent release
kinetics and transfer to tissue are significantly enhanced by
mechanical action during balloon inflation. Typically, these type
of coating materials can by hydrophilic and can swell to some
extent upon hydration to aid in fast drug release.
[0053] As illustrated in Table 2 above, for a "slow" coating
dissolution rate, representative excipient examples include,
without limitation, biodegradable polymers such as
Poly(D,L-lactide-co-glycolide) (PLGA) (50:50). The coatings from
biodegradable hydrophobic polymers will offer enhanced systemic
drug loss protection and a better particulate safety profile. The
therapeutic agent is not released together with the coating but
from the coating. Drug release kinetics and transfer to tissue are
significantly enhanced by mechanical action during balloon
inflation. Techniques such as using a thin coating, a polymer with
a low glass transition temperature (Tg), and amorphous material or
low crystalline material can provide for a more rapid drug release
profile when using a biodegradable polymer.
[0054] As illustrated in Table 2 above, for an "extra slow" coating
dissolution rate, representative excipient examples include,
without limitation, biodegradable polymers such as
poly(L-lactide-co-.epsilon.-caprolactone) (PLLA:PCL) (70:30). The
drug delivery mechanism and kinetics are similar to a "slow"
coating dissolution rate, however the degradation time is
significantly extended. These coatings will have more long term
degradation and mechanical stability under storage.
[0055] As illustrated above, for a "non-soluble" coating
dissolution rate, representative excipient examples include,
without limitation, durable polymers such as poly(vinylidene
fluoride-co-hexafluoropropylene). The drug delivery mechanism and
kinetics are similar to both a "slow" and "extra slow" coating
dissolution rate, however the material is non-biodegradable. These
non-soluble coatings will have the most chemical and mechanical
stability under storage than other types.
[0056] In accordance with one embodiment, the excipient is a
durable or biodurable excipient. Certain representative examples of
durable excipients are provided in Table 3.
TABLE-US-00003 TABLE 3 Examples of durable excipients Excipient
Specific Description Hydroxypropylmethylcellulose phthalate Coating
agent, can improve coating strength and be combined with
plasticizer to reduce brittleness PVP/PEO + acrylates +
photoinitiator + PVP UV curable coating would retain drug during
crosslinker delivery and rapidly release drug after balloon
expansion, lubricious Polyethylene vinyl acetate phthalate Coating
agent, can improve coating strength and be combined with
plasticizer to reduce brittleness Poly(.epsilon.-caprolactone)
(PCL); flexible material, low Tg and low crystallinity Poly
(caprolactone) co-polymerized with material can provide for rapid
drug release lactide and/or glycolide Poly(DL-lactide) Flexible
material, soluble in various solvents for spray processing, can
improve coating strength and be combined with plasticizer to reduce
brittleness Poly(L-lactide-co-e-caprolactone)(PLCL) Flexible
material, soluble in various solvents (50:50) for spray processing,
can improve coating strength and be combined with plasticizer to
reduce brittleness PCL-PEG (di and tri-block copolymers); Flexible
material, can modulate PEG length for Poly(trimethylenecarbonate)
copolymerized varying degrees of water absorption and with
caprolactone, lactide, glycolide and/or release rates other
comonomoers; Poly(lactide)-PEG(di- and tri-block copolymers)lactide
copolymerized with caprolactone, glycolide and/or other comonomers
Polyethylene vinyl acetate Flexible material; biocompatible PVDF
and PVDF copolymers (e.g., Solef) Blood compatible, low
thrombogenicity, flexible materials with good temperature
stability, soluble in acetone for spray processing PEA based on
leucine, alanine, phenylalanine, Polymer structure can be fine
tuned to any other amino acid, or combinations thereof modulate
drug miscibility and release profile, soluble in various solvents
for spray processing Phosphorylcholine derivatized polymers
Non-thrombogenic polymer structure that can including acrylates,
methacrylates, PEA and be fine tuned to modulate drug miscibility
and aliphatic polyesters release profile, soluble in various
solvents for spray processing Silk-elastin like polymers Thermally
crosslinked, biocompatible PEG-based thol-ene crosslinked gels
Enhanced mucoadhesiveness, low thrombogenicity Polyacrylic acid
(Carbomer) Mucoadhesive, swells but does not dissolve in aqueous
media PBMA copolymers; Good adhesion HPMA; PHEMA-co-PAAm
Hydrophilic polyurethane containing a PEO or Blood compatible,
flexible material, can other hydrophilic soft segment modulate
water absorption and drug release rate with soft segment MW and
content
[0057] The durable excipients in accordance with the disclosed
subject matter bind the therapeutic agent to the balloon or device
surface and protect the agent during delivery to a treatment
location. For example, after expansion of the balloon at the
treatment site, the balloon will contact the vessel wall and the
therapeutic agent will be rapidly released to cause the desired
beneficial effect. During and after inflation, the biodurable
excipient will remain on the balloon with no particulate loss. To
release the drug at a sufficient rate from these polymers, it is
necessary to have high drug concentrations above perculation, with
drug to polymer ratios at about 1:1 or higher.
[0058] In accordance with one embodiment, a primer coating is
necessary to allow for good and adequate adhesion such that, for
example, a stent and coating can be removed in a safe manner.
[0059] In accordance with the disclosed subject matter, the outer
surface of the balloon has a tunable coating that is disposed on at
least a length of the outer surface. Preferably, the tunable
coating includes a first therapeutic agent and a first excipient
and a second therapeutic agent and a second excipient. In
accordance with a preferred embodiment, the first and second
therapeutic agents have different dissolution rates during balloon
inflation. Thus, the desired coating dissolution rates can be
tunable and achieved as desired for either drug kinetics or safety
profile. The delivery of the therapeutic agents can be modified and
optimized to meet the therapeutic need. Furthermore, depending on
the excipients used, the therapeutic agents can be released from
the excipient or coating or with the excipient or coating. In
accordance with one embodiment, the first therapeutic agent is
released from the coating, and the second therapeutic agent is
released with the coating.
[0060] In one embodiment, the first therapeutic agent is different
than the second therapeutic agent. Alternatively, however, the
therapeutic agents can be the same.
[0061] In accordance with another embodiment, the coating can also
include a third therapeutic agent and a third excipient. The
therapeutic agents and excipients can be applied simultaneously to
the balloon surface or they can be applied separately.
[0062] In accordance with yet another embodiment, the disclosed
subject matter includes a balloon having a the tunable coating
including a cytostatic drug and at least one excipient, wherein in
the coating at least one polymeric component has a polydispersity
index from about 1.05 to about 10, more preferably from 1.05 to 5.
The polydispersity index (PDI), is a measure of the distribution of
molecular mass in a given polymer sample. The PDI calculated is the
weight average molecular weight divided by the number average
molecular weight. It indicates the distribution of individual
molecular masses in a batch of polymers. A smaller PDI value
provides a more consistent dissolution rate among the polymeric
excipient molecules.
[0063] It has been found that coatings can be tunable to achieve
desirable dissolution and drug delivery kinetics. In this regard,
the choice of an excipient or modified excipient can be important
to define coatings exhibiting efficacy factors such as but not
limited to: how the therapeutic agent is retained during delivery,
how the agent is released during balloon inflation, minimizing
systemic drug dosing, maximizing agent delivery efficiency and
therapeutic effect, and preventing particulate loss, related
thromboses and embolic events.
[0064] Accordingly, in one aspect of the disclosed subject matter,
a method is provided for coating a medical device, such as a drug
coated balloon. The coating includes a cytostatic therapeutic agent
and an excipient having a tunable molecular architecture. As used
herein the phrase "tunable molecular architecture" means selection
of an appropriate excipient composition, molecular structure,
functionality, and morphology including appropriate modifications
to yield the desired coating dissolution and drug delivery
kinetics. The molecular architecture can be tuned through the
design of input variables such as monomer/polymer composition,
aromaticity, hydrophilicity, molecular charge, neutrality,
aliphatic chain length, density of functional groups, molecular
weight, aqueous solubility, octanol/water partition coefficient,
HLB number, glass transition temperature, and percent
crystallinity. The method of the disclosed subject matter
advantageously is capable of providing desired delivery kinetics as
a result of its tunability.
[0065] In accordance with the disclosed subject matter, the method
includes selecting a cytostatic therapeutic agent and an excipient,
and blending or mixing the cytostatic agent and excipient to define
a coating. The method can further include tuning the molecular
structure of the coating such that specific characteristics of the
coating that are important to product performance can be adjusted
and optimized. Some of these characteristics include coating
solubility, coating hydrophilicity, coating adhesion and cohesion,
coating stability under sterilization and storage, drug release
kinetics, drug solubility and stability, and safety profile
including particulate hazard and re-endothelialization.
[0066] For example and not limitation, the molecular architecture
of the excipient can be modified and tuned through the adjustment
of several input parameters, as described in Table 4 below.
TABLE-US-00004 TABLE 4 Inputs that Affect Molecular Architecture
and Excipient or Coating Characteristics Excipient Effect(s) of
Effect(s) of Modification Increase Decrease Example Monomer/Polymer
Choice of excipient or coating composition Poly(vinylpyrrolidone)
Composition has a large effect on all coating (PVP) or contrast
agent for characteristics. soluble coating agent. Thin
poly(vinylidene fluoride-co- hexafluoropropylene) (PVDF-HFP) for
durable coating. Monomer/Polymer A high interaction More spacing
Increased L-lactide content Composition - between polymer between
chains can in poly(L-lactide-co- Intramolecular chains can provide
provide more caprolactone) copolymers attraction: H for increased
coating amorphous content can lead to higher Bonding versus
mechanical stability, and lower crystallinity. Polyurethane Steric
Hindrance cohesion, higher crystallinity for ureas exhibit
increased H- crystallinity and faster solubility and bonding and
mechanical greater molecular decreased stability stability. packing
density. of material. Hydrophilicity Will provide faster Slower
water Non-ionic hydrophilic water absorption, absorption, slower
polymers such as PVP and faster drug release, drug release, and
polyethylene glycol (PEG) and faster coating slower coating are
water soluble and dissolution. dissolution. provide for fast
coating dissolution and drug delivery. Can increase or decrease PEG
content as a soft segment in polyurethanes to increase or decrease
hydrophilicity. Non-ionic hydrophobic polymers such as PVDF- HFP or
PCL are non-water soluble. Molecular Charge Charged molecules Lower
charge or Charged polysaccharides or Neutrality tend to possess
more neutral species such as mucoadhesive can exhibit less
carboxymethylcellulose, properties. mucoadhesive sodium
hyaluronate, properties. chitosan, and sodium alginate can exhibit
mucoadhesive properties as well as complex and/or physically bind
negatively charged molecules. Cyclic Chain Cyclic chain will Lower
chain rigidity Adjusting the ratio of cyclic increase chain (lower
Tg), faster to aliphatic chain in rigidity (higher Tg), release
rate and poly(ester amide) (PEA) therefore slow down higher %
polymers. the release rate. The elongation. elasticity will also be
reduced as a result. Aliphatic Chain Increased carbon Decreased
carbon Adjusting length of Length chain length will chain lengths
will hydrocarbon chains in lend towards lend towards poly(ester
amide) (PEA) increased flexibility increased stiffness polymers.
(lower Tg) of (higher Tg) of material for higher material for lower
% elongation and % elongation and slower drug release. faster drug
release. Density of Increase density of Lower density of RGD
grafted low MW PEG Functional Groups grafted signaling or
functional groups can provide for increased other molecules such
and attached ligands adhesion of released coating as RGD sequences
can allow for to the vascular endothelial for cell attachment.
decreased steric cell wall. hindrance and increased
bioavailability. Molecular Weight Higher molecular Lower molecular
Lower molecular weight weight material will weight will tend
(<60 kDa). tend towards higher towards lower spray
poly(vinylpyrrolidone) is spray viscosity and viscosity and easily
spray coated due to lower solubility in increased solubility its
low spray viscosity and various spray in various spray high
solubility in aqueous solvents and in solvents and in and organic
media. aqueous media. In aqueous media. general, a higher Lower Mw
will also molecular weight for translate to faster provide for
release rate. increased mechanical strength and cohesion of a
coating to a certain cut-off value. Higher MW will also translate
to slower release rate. Glass Transition Increased EtO Decreased
EtO Certain low Tg Poly(e- Temperature sterilization stability
sterilization stability caprolactone) based and slower drug leading
to coating materials can provide a very release. Less flow and
faster drug fast burst release of drug up flexible coating for
release. More to 99% + release at 1 day. decreased handling
flexible coating for Adding a plasticizer such as and catheter
enhanced catheter glycerol to non-ionic processing processing
hydrophilic polymers such performance. performance. as
polyvinylpyrrolidone) can lower the dry coating Tg to increase
coating flexibility. % Crystallinity Higher storage Lower storage
Increasing or decreasing L- stability, slower drug stability,
faster lactide) content in poly(L- release, less flexible
solubility, faster lactide-co-caprolactone) coating. drug release,
more polyester copolymers. flexible coating. Adding HFP to PVDF
copolymer to increase coating flexibility and drug release.
[0067] In accordance with the disclosed subject matter, the coating
can be applied to the medical device by processes such as
dip-coating, pipette coating, syringe coating, air assisted
spraying, electrostatic spraying, piezoelectric spraying, spray
drying, pneumatic spray, ultrasonic spray, spray with patterning,
electrospinning, direct fluid application, or other means as known
to those skilled in the art. The coating can be applied over at
least a length or the entirety of the balloon or medical device. By
way of example, and not limitation, certain coating processes that
can be used with the instant disclosed subject matter are described
in U.S. Pat. No. 6,669,980 to Hansen; U.S. Pat. No. 7,241,344 to
Worsham; and U.S. Publication No. 20040234748 to Stenzel, the
entire disclosures of which are hereby incorporated by reference.
In accordance with one embodiment of the disclosed subject matter,
the medical device is a balloon catheter and the coating can be
applied to either a folded or inflated balloon. Furthermore, the
coating can be directly applied into the folds of the folded
balloons. The coating characteristics are affected by process
variables. For example, for dip-coating process, coating quality
and thickness can vary as an effect of variables such as number,
rate, and depth of dips along with drying time and temperature.
[0068] In accordance with one embodiment, the balloon can be
sprayed with therapeutic agent encapsulated in the durable
excipient solution. Spray solvents can consist of the following
class III solvents including but not limited to acetone, anisole,
1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether,
cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether,
ethyl formate, heptane, hexane, cyclohexane, isobutyl acetate,
isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl
ketone, methylisobutyl ketone, cyclohexanone, 2-methyl-1-propanol,
pentanel, 1-pentanol, 1-propanol, and propyl acetate, or blends
thereof.
[0069] Additional spray solvents that can be used or blended with
class III solvents include class II spray solvents. The class II
spray solvents include but are not limited to, acetonitrile,
chloroform, 1,2-dichloroethane, dichloromethane,
1,2-dimethyloxyethene, N,N-dimethylacetamide,
N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene
glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl
ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane,
pyridine, sulfolane, tetrahydrofuran, tetralin, toluene,
1,1,2-trichloroethene, and xylene.
[0070] In accordance with the disclosed subject matter, the
excipient and therapeutic agent coating process can occur
aseptically or be followed with terminal sterilization methods such
as E-beam, gamma irradiation, or ethylene oxide sterilization.
[0071] In accordance with the disclosed subject matter, excipients
are utilized together with the therapeutic agent in the coating at
ratios ranging from 1:20 to 20:1 excipient:drug by weight,
preferably from 1:10 to 10:1, more preferably from 1:2 to 2:1.
Preferably, the coating includes a plasticizer. In this regards,
the excipient to plasticizer weight ratio is from about 20:1 to
about 1:20, more preferably from 10:1 to 1:1.
[0072] In accordance with another embodiment of the disclosed
subject matter, the coating includes various layers. In one
embodiment, the coating includes first and second layers adsorbed
to the surface of the balloon. The first layer typically consists
of one therapeutic agent and one excipient and the second layer
typically consists of a second therapeutic agent and second
excipient. The drug coated balloon is designed such that the first
and second layers each have a dissolution rate. Preferably, the
dissolution profile of the first layer is different than the
dissolution profile of the second layer. Providing layers with
various dissolution profiles allows the coating to be tuned to an
optimized range.
[0073] In accordance with yet another embodiment, the disclosed
subject matter includes a method of increasing the efficiency of
therapeutic transfer to a body lumen by implanting or inserting a
medical device in a body lumen. The medical device includes an
expandable member having an outer surface and a coating disposed on
the outer surface of the medical device, the coating including a
therapeutic agent and an excipient.
[0074] For example and not limitation, the therapeutic agent or
drug can include anti-proliferative, anti-inflammatory,
antineoplastic, antiplatelet, anti-coagulant, anti-fibrin,
antithrombotic, antimitotic, antibiotic, antiallergic and
antioxidant compounds. Thus, the therapeutic agent can be, again
without limitation, a synthetic inorganic or organic compound, a
protein, a peptide, a polysaccharides and other sugars, a lipid,
DNA and RNA nucleic acid sequences, an antisense oligonucleotide,
an antibody, a receptor ligands, an enzyme, an adhesion peptide, a
blood clot agent including streptokinase and tissue plasminogen
activator, an antigen, a hormone, a growth factor, a ribozyme, and
a retroviral vector. Preferably, however, the therapeutic agents
include a cytostatic drug. The term "cytostatic" as used herein
means a drug that mitigates cell proliferation, allows cell
migration, and does not induce cell toxicity. These cytostatic
drugs, include for the purpose of illustration and without
limitation, macrolide antibiotics, rapamycin, everolimus,
zotarolimus, biolimus, novolimus, myolimus, temsirolimus,
deforolimus, structural derivatives and functional analogues of
rapamycin, structural derivatives and functional analogues of
everolimus, structural derivatives and functional analogues of
zotarolimus and any macrolide immunosuppressive drugs. The term
"antiproliferative" as used herein means a drug used to inhibit
cell growth, such as chemotherapeutic drugs. Some non-limiting
examples of antiproliferative drugs include taxanes, paclitaxel,
and protaxel.
[0075] Therefore, in accordance with a preferred embodiment, a
balloon for delivery of a cytostatic drug is provided. The outer
surface of the balloon includes a tunable coating, the tunable
coating including a first cytostatic drug and a first excipient and
a second cytostatic drug and a second excipient. The first and
second cytostatic drugs preferably have different dissolution rates
during balloon inflation. The various dissolution rates allow for
more effective and efficient delivery of the therapeutic agent.
[0076] With reference to the balloon construction, a polymeric
expandable balloon material is preferred. For example, the
polymeric material utilized to form the balloon body can be
compliant, non-compliant or semi-compliant polymeric material or
polymeric blends.
[0077] In one embodiment, the polymeric material is compliant such
as but not limited to a polyamide/polyether block copolymer
(commonly referred to as PEBA or polyether-block-amide).
Preferably, the polyamide and polyether segments of the block
copolymers can be linked through amide or ester linkages. The
polyamide block can be selected from various aliphatic or aromatic
polyamides known in the art. Preferably, the polyamide is
aliphatic. Some non-limiting examples include nylon 12, nylon 11,
nylon 9, nylon 6, nylon 6/12, nylon 6/11, nylon 6/9, and nylon 6/6.
Preferably, the polyamide is nylon 12. The polyether block can be
selected from various polyethers known in the art. Some
non-limiting examples of polyether segments include
poly(tetramethylene ether), tetramethylene ether, polyethylene
glycol, polypropylene glycol, poly(pentamethylene ether) and
poly(hexamethylene ether). Commercially available PEBA material can
also be utilized such as for example, PEBAX.RTM. materials supplied
by Arkema (France). Various techniques for forming a balloon from
polyamide/polyether block copolymer is known in the art. One such
example is disclosed in U.S. Pat. No. 6,406,457 to Wang, the
disclosure of which is incorporated by reference.
[0078] In another embodiment, the balloon material is formed from
polyamides. Preferably, the polyamide has substantial tensile
strength, be resistant to pin-holing even after folding and
unfolding, and be generally scratch resistant, such as those
disclosed in U.S. Pat. No. 6,500,148 to Pinchuk, the disclosure of
which is incorporated herein by reference. Some non-limiting
examples of polyamide materials suitable for the balloon include
nylon 12, nylon 11, nylon 9, nylon 69 and nylon 66. Preferably, the
polyamide is nylon 12. Other suitable materials for constructing
non-compliant balloons are polyesters such as poly(ethylene
terephthalate) (PET), Hytrel thermoplastic polyester, and
polyethylene.
[0079] In another embodiment, the balloon is formed of a
polyurethane material, such as TECOTHANE.RTM. (Thermedics).
TECOTHANE.RTM. is a thermoplastic, aromatic, polyether polyurethane
synthesized from methylene disocyanate (MDI), polytetramethylene
ether glycol (PTMEG) and 1,4 butanediol chain extender.
TECOTHANE.RTM. grade 1065D is presently preferred, and has a Shore
durometer of 65D, an elongation at break of about 300%, and a high
tensile strength at yield of about 10,000 psi. However, other
suitable grades can be used, including TECOTHANE.RTM. 1075D, having
a Shore D hardness of 75. Other suitable compliant polymeric
materials include ENGAGE.RTM. (DuPont Dow Elastomers (an ethylene
alpha-olefin polymer) and EXACT.RTM. (Exxon Chemical), both of
which are thermoplastic polymers. Other suitable compliant
materials include, but are not limited to, elastomeric silicones,
latexes, and urethanes.
[0080] The compliant material can be cross linked or uncrosslinked,
depending upon the balloon material and characteristics required
for a particular application. The presently preferred polyurethane
balloon materials are not crosslinked. However, other suitable
materials, such as the polyolefinic polymers ENGAGE.RTM. and
EXACT.RTM., are preferably crosslinked. By crosslinking the balloon
compliant material, the final inflated balloon size can be
controlled. Conventional crosslinking techniques can be used
including thermal treatment and E-beam exposure. After
crosslinking, initial pressurization, expansion, and preshrinking,
the balloon will thereafter expand in a controlled manner to a
reproducible diameter in response to a given inflation pressure,
and thereby avoid overexpanding the stent (if used in a stent
delivery system) to an undesirably large diameter.
[0081] In one embodiment, the balloon is formed from a low tensile
set polymer such as a silicone-polyurethane copolymer. Preferably,
the silicone-polyurethane is an ether urethane and more
specifically an aliphatic ether urethane such as PURSIL AL 575A and
PURSIL AL10, (Polymer Technology Group), and ELAST-EON 3-70A,
(Elastomedics), which are silicone polyether urethane copolymers,
and more specifically, aliphatic ether urethane cosiloxanes. In an
alternative embodiment, the low tensile set polymer is a diene
polymer. A variety of suitable diene polymers can be used such as,
but not limited to, an isoprene such as an AB and ABA
poly(styrene-block-isoprene), a neoprene, an AB and ABA
poly(styrene-block-butadiene) such as styrene butadiene styrene
(SBS) and styrene butadiene rubber (SBR), and 1,4-polybutadiene.
Preferably, the diene polymer is an isoprene including isoprene
copolymers and isoprene block copolymers such as
poly(styrene-block-isoprene). A presently preferred isoprene is a
styrene-isoprene-styrene block copolymer, such as Kraton 1161K
available from Kraton, Inc. However, a variety of suitable
isoprenes can be used including HT 200 available from Apex Medical,
Kraton R 310 available from Kraton, and isoprene (i.e.,
2-methyl-1,3-butadiene) available from Dupont Elastomers. Neoprene
grades useful in the disclosed subject matter include HT 501
available from Apex Medical, and neoprene (i.e., polychloroprene)
available from Dupont Elastomers, including Neoprene G, W, T and A
types available from Dupont Elastomers.
[0082] In accordance with another aspect of the disclosed subject
matter, the outer surface of the balloon is modified. In this
regard, the balloon surface can include a textured surface,
roughened surface, voids, spines, channels, dimples, pores, or
microcapsules or a combination thereof, as will be described
below.
[0083] In accordance with the disclosed subject matter, the balloon
does not include a stent or is free of a stent. However, a stent
can be mounted onto the coated balloon. The stent will not
detrimentally affect coating integrity or drug delivery. The type
of stent that can be used includes, but is not limited to, bare
metal stent, balloon expandable stent, self expanding stent, drug
eluting stent, prohealing stent, and self-expanding vulnerable
plaque implant. The balloon can be coated independently of the
stent or in conjunction with the stent coating process. The stent
coating can contain the same or different therapeutic agents from
the balloon catheter or expandable member. However, the particular
coating on the balloon catheter or expandable member preferably has
distinct release kinetics from the therapeutic coating on the
stent.
[0084] In one embodiment of the disclosed subject matter, the
balloon is formed of a porous elastomeric material having at least
one void formed in the wall of the balloon surface. For example,
the entire cross section of the balloon can contain a plurality of
voids. Alternatively, the plurality of void can be distributed
along select lengths of the balloon outer surface. For example and
not limitation, the plurality of voids can be distributed only
along only the working section of the balloon. The voids define an
open space within the outer surface of the balloon. Preferably, the
therapeutic agent is dispersed within the space defined by the
plurality of voids across the cross section of the balloon outer
surface.
[0085] In operation, the therapeutic agent is released or is
expelled from the pores upon inflation of the balloon. In this
regard, the durometer of the polymeric material of the balloon
surface and in particular the depression of the void is
sufficiently flexible to allow for expulsion of the therapeutic
agent and/or coating contained within the plurality of voids upon
inflation of the balloon. The expelled coating with therapeutic
agent is released into the vessel lumen or into the tissue
surrounding and contacting the inflated balloon.
[0086] In another embodiment, the balloon includes protrusions
configured to contact or penetrate the arterial wall of a vessel
upon inflation of the balloon. A coating containing therapeutic
agent is disposed on the protrusions and when inflated the coating
and/or therapeutic agent coats the tissue of the arterial wall.
Alternatively, the balloon can include two concentric balloons in a
nesting configuration. The coating with therapeutic agent is
disposed between the two concentric balloons. Thus, the space
between the two concentric balloons; one being an interior balloon
and the other being an exterior balloon, acts as a reservoir. In
this regard, the protrusions can include apertures for expulsion of
the coating and/or therapeutic agent upon inflation of the interior
and exterior concentric balloons. For example, as described in U.S.
Pat. No. 6,991,617 to Hektner, the disclosure of which is
incorporated herein by reference thereto. In another embodiment,
the balloon can include longitudinal protrusions configured to form
ridges on the balloon surface. As described in U.S. Pat. No.
7,273,417 to Wang, the entire disclosure of which is incorporated
herein by reference, the ridges can be formed of filaments spaced
equidistantly apart around the circumference of the balloon.
However, a larger or smaller number of ridges can alternatively be
used. The longitudinal ridges can be fully or partially enveloped
by the polymeric material of the balloon.
[0087] In yet another embodiment of the disclosed subject matter,
the balloon can include microcapsules on its outer surface. In this
regard, the microcapsules are configured to encompass the coating
and/or therapeutic agent. Upon inflation of the balloon the
microcapsules located on the surface of the balloon contact the
tissue of the arterial wall. Alternatively, the microcapsules can
be formed in the wall of the balloon surface. The coating and/or
therapeutic agent can be released from the microcapsules by
fracturing of the microcapsules and/or diffusion from the
microcapsule into the arterial wall. The microcapsules can be
fabricated in accordance with the methods disclosed in U.S. Pat.
No. 5,1023,402 to Dror or U.S. Pat. No. 6,129,705 to Grantz and the
patents referenced therein, each of which is incorporated herein by
reference in its entirety.
[0088] In accordance with another aspect of the disclosed subject
matter, if desired, a protective sheath can be utilized to protect
the coating from being rubbed off of the balloon during the
movement of the coated balloon through the body lumen. The sheath
is preferably made from an elastic and resilient material which
conforms to the shape of the balloon and in particular is capable
of expanding upon inflation of the balloon. The sheath preferably
includes apertures along a length thereof. In operation, the
inflation of the balloon causes the apertures of the sheath to
widen for release of the coating and/or therapeutic agent to the
tissue of the arterial wall. Preferably, the sheath has a thickness
less than 10 mils. However, other thicknesses are possible.
[0089] In another embodiment, the sheath has at least one
longitudinal line of weakness allowing the sheath to rupture upon
inflation of the balloon and the release of the coating and/or
therapeutic agent onto the tissue of the arterial wall of the
vessel. Preferably, the sheath is formed from polymeric material
known to be suitable for use in balloon catheters. Preferably, the
sheath material is an elastomeric material which will also spring
back when it splits to expose more of the body lumen to the
coating. The line of weakness could be provided by various
techniques known in the art. However, one non-limiting examples
include perforating the sheath material. In operation, the sheath
is placed over the coated balloon while in the deflated state. When
the coated balloon is inflated, the sheath is expanded to the
extent that it exceeds its elastic limit at the line of weakness
and bursts to expose and therefore release the coating and/or
therapeutic agent to the tissue of the arterial wall or vessel
lumen. For example, see U.S. Pat. No. 5,370,614 to Amundson, the
entire disclosure of which is incorporated by reference.
[0090] In accordance with another embodiment, an outer fibrous
coating can be electrospun or stretched onto the medical device or
balloon catheter to prevent drug loss during delivery. During
balloon inflation, the coating is stretched and allows for coating
dissolution and release. The fiber diameters and material
properties can be fine tuned for optimal pore size and to release
the particles containing the therapeutic agent. Fibrous coatings on
expandable members are described in U.S. patent application Ser.
No. 12/237,998 to R. von Oepen and U.S. patent application Ser. No.
12/238,026 to K. Ehrenreich, the disclosures of which are
incorporated by reference in their entirety.
[0091] It is to be noted that the term "a" entity or "an" entity
refers to one or more of that entity. For example, a protein refers
to one or more proteins or at least one protein. As such, the terms
"a", "an", "one or more", and "at least one" can be used
interchangeably herein. The terms "comprising," "including," and
"having" can also be used interchangeably. In addition, the terms
"amount" and "level" are also interchangeable and can be used to
describe a concentration or a specific quantity. Furthermore, the
term "selected from the group consisting of" refers to one or more
members of the group in the list that follows, including mixtures
(i.e. combinations) of two or more members.
[0092] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within 3 or more
than 3 standard deviations, per the practice in the art.
Alternatively, "about" can mean a range of up to +/-20%, preferably
up to +/-10%, more preferably up to +/-5%, and more preferably
still up to +/-1% of a given value. Alternatively, particularly
with respect to biological systems or processes, the term can mean
within an order of magnitude, preferably within 5-fold, and more
preferably within 2-fold, of a value. With reference to
pharmaceutical compositions, the term "about" refers to a range
that is acceptable for quality control standards of a product
approved by regulatory authorities.
EXAMPLES
[0093] The present application is further described by means of the
examples, presented below. The use of such examples is illustrative
only and in no way limits the scope and meaning of the disclosed
subject matter or of any exemplified term.
Example A
[0094] To simulate drug release from a drug coated balloon, a three
step in-vitro release method was developed. This method consists of
a sequential dip release in 37.degree. C. porcine serum for 1 min,
inflation release in 37.degree. C. porcine serum for 1 min and
extraction release in 50% acetonitrile solution designed to mimic
the balloon release during delivery to the lesion, drug delivery on
inflation and the remaining drug on the balloon respectively. The
resulting zotarolimus concentrations in the porcine serum
supernatant are measured by liquid chromatography mass spectrometry
(LCMS) and drug from the extraction measured by high performance
liquid chromatography (HPLC).
[0095] This in-vitro release method was used to evaluate the drug
release from zotarolimus (Zot):poly(vinylpyrrolidone)
(PVP):glycerol drug coated balloons as a function of
drug:excipient:plasticizer ratio (D:E:P) and PVP K-value. For the
combined dip release and inflation release that simulates coating
dissolution rate and drug delivery from a drug coated balloon, it
is shown in FIG. 2 that a higher drug to excipient ratio such as
D:E:P, 20:1:0.4 (w/w) resulted in a "soluble" coating dissolution
rate with a dissolution time in the range of 1 min to 1 h releasing
less than 5% of drug in 2 min. For lower D:E:P ratios and
increasing amounts of plasticizer, the Zot:PVP:glycerol formulation
demonstrated a "fast" dissolution rate, i.e. less than 1 min
releasing up to 90% of drug in 2 min. For a lower molecular weight
or PVP K-value such as PVP C-15, the coating dissolution rate and
drug release during the dip release was further increased to 30% as
compared to the PVP C-30 coating at the same 1:1:0.4, D:E:P ratio
which demonstrated less than 5% dip release. The K-Values of C-15
and C-30 designate PVP K value for low endotoxin grade.
Example B
[0096] Scratch tests of coatings on glass slides were used to
qualitatively evaluate coating mechanical properties in terms of
hardness and tackiness. FIGS. 3 through 6 are optical micrographs
of drug delivery balloon coating formulations coated onto glass
slides. To produce the optical micrographs, the coating
formulations were pipetted onto glass slides, and then the slides
were baked at 50.degree. C. for one hour. While observing under an
optical microscope, the coatings were scratched with a steel
mandrel to assess their hardness, brittleness, and resistance to
fracture in the dry state. Stickiness was assessed by placing
another clean glass slide onto the coatings, pressing them together
and noting the force, if any, required to pull them apart.
[0097] It was observed that increasing the drug to excipient ratio
for zotarolimus:PVP:glycerol to 10:1:0.4 (FIG. 3 left panel) from
2:1:0.4 (FIG. 3 right panel) resulted in increased hardness and
reduced tackiness. Representative optical micrographs of these
coatings after scratching are shown in FIG. 3. Coating with the
10:1:0.4 ratio (left panel) is much harder than the 2:1:0.4 ratio
(right panel), which was waxy.
Example C
[0098] The qualitative mechanical properties of
zotarolimus:PVP:tween 20 coatings were evaluated by scratch tests
of coatings deposited on glass slides. It was shown with
representative optical micrographs in FIG. 4 (left panel) that
zotarolimus:PVP:tween 20 at a ratio of 2:1:0.67 exhibited a soft
and waxy coating. With zotarolimus:PVP:tween 80 at a ratio of
2:1:0.4 as shown in FIG. 4 (right panel) a slightly brittle, weak
and chunky coating resulted.
Example D
[0099] The qualitative mechanical properties of zotarolimus:PEG-PE
coatings were evaluated by scratch tests of coatings deposited on
glass slides. It was shown with representative optical micrographs
in FIG. 5 (left panel) that zotarolimus:PEG-PE, 2:1 exhibited a
soft and waxy coating. With zotarolimus:PEG-PE, 1:1 as shown in
FIG. 5 (right panel) a soft, waxy and tacky coating resulted. This
coating underwent visible flow after scratching.
Zotarolimus:PEG-PE, 1:2 as shown in FIG. 6 (left panel) exhibited a
hard and waxy coating and was birefringence when observed under
polarized light (right panel). This drug:excipient system exhibited
eutectic behavior with the 1:1 ratio coating being the softest and
compositions greater in either component being harder. Furthermore,
at the lower drug:excipient ratio of 1:2 the birefringence
indicates crystallization of the PEG-PE component.
[0100] The disclosed subject matter can be embodied in other
specific forms without departing from its spirit or essential
characteristics. The described embodiments are to be considered in
all respects only as illustrative and not restrictive. Thus, it is
intended that the disclosed subject matter include modifications
and variations that are within the scope of the appended claims and
their equivalents. All references recited herein are incorporated
herein in their entirety by specific reference.
* * * * *