U.S. patent application number 13/911962 was filed with the patent office on 2014-01-23 for coatings with tunable solubility profile 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, John J. Stankus, Mikael Trollsas.
Application Number | 20140025005 13/911962 |
Document ID | / |
Family ID | 43402229 |
Filed Date | 2014-01-23 |
United States Patent
Application |
20140025005 |
Kind Code |
A1 |
Stankus; John J. ; et
al. |
January 23, 2014 |
COATINGS WITH TUNABLE SOLUBILITY PROFILE 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, and a second therapeutic
agent and a second excipient. The first and second therapeutic
agents have different dissolution rates during balloon inflation
and therefore provide a coating that is tunable.
Inventors: |
Stankus; John J.; (Campbell,
CA) ; Trollsas; Mikael; (San Jose, CA) ;
Hossainy; Syed; (Hayward, 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: |
43402229 |
Appl. No.: |
13/911962 |
Filed: |
June 6, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12636124 |
Dec 11, 2009 |
8480620 |
|
|
13911962 |
|
|
|
|
Current U.S.
Class: |
604/103.02 |
Current CPC
Class: |
A61L 29/16 20130101;
A61L 2300/416 20130101; A61L 2300/608 20130101; A61L 2300/61
20130101; A61L 29/085 20130101 |
Class at
Publication: |
604/103.02 |
International
Class: |
A61L 29/08 20060101
A61L029/08 |
Claims
1. A balloon for delivery of a drug, the balloon comprising: a body
having an outer surface; and a coating disposed on at least a
length of the outer surface, the tunable coating including
zotarolimus and at least one excipient including
polyvinylpyrrolidone or polyethylene glycol, the coating having a
dissolution time of about 10 seconds to about 1 hour, wherein the
at least one excipient increases the solubility of the zotarolimus
to between about 4 ug/ml to about 1437 ug/ml.
2. The balloon of claim 1, wherein the at least one excipient is
blended with a contrast agent.
3. The balloon of claim 1, wherein the at least one excipient
includes a polymer having a molecular weight of less than about 35
kDalton.
4. The balloon of claim 1, wherein the at least one excipient
includes a polymer having a molecular weight greater than about 100
kDalton.
5. The balloon of claim 1, wherein the coating further includes a
plasticizer.
6. The balloon of claim 5, wherein the plasticizer is glycerol.
7. The balloon of claim 1, wherein the dissolution rate is about 10
seconds to 10 minutes.
8. A balloon for delivery of a therapeutic agent, the balloon
comprising: a body having an outer surface; and a coating disposed
on at least a length of the outer surface, the coating including a
first therapeutic agent and a first excipient having a first
dissolution rate, and a second therapeutic agent and a second
excipient having a second dissolution rate, wherein the first
therapeutic agent is zotarolimus, the first excipient is
polyvinylpyrrolidone or polyethylene glycol, and the weight ratio
of zotarolimus to the first excipient is from about 20:1, to about
1:20, and wherein the first excipient increases the solubility of
the zotarolimus to between 4 .mu.g/ml to 1437 .mu.g/ml.
9. The balloon of claim 8, wherein the first therapeutic agent is
different than the second therapeutic agent.
10. The balloon of claim 8, wherein the first excipient has a
molecular weight of less than about 35 kDalton.
11. The balloon of claim 8, wherein the second excipient is a
polymer having a molecular weight greater than about 100
kDalton.
12. The balloon of claim 8, wherein the second excipient is
polyvinylpyrrolidone or polyethylene glycol.
13. The balloon of claim 8, wherein the second excipient is a
biodegradable polymer.
14. The balloon of claim 13, wherein the biodegradable polymer is
Poly(D, L-lactide-co-glycolide) or
Poly(L-lactide-co-.epsilon.-caprolactone).
15. The balloon of claim 8, wherein the second excipient is a
protein polymer.
16. The balloon of claim 8, wherein the second therapeutic agent is
paclitaxel.
17. The balloon of claim 8, wherein both the first and second
therapeutic agents are zotarolimus.
18. The balloon of claim 8, wherein the second therapeutic agent is
sirolimus.
19. The balloon of claim 8, wherein the coating includes a third
therapeutic agent and a third excipient.
20. The balloon of claim 8, wherein the coating includes first and
second layers adsorbed to the surface of the balloon.
21. The balloon of claim 20, wherein the first layer consists of
the first therapeutic agent and first excipient and the second
layer consists of the second therapeutic agent and the second
excipient.
22. The balloon of claim 20, wherein the first and second layers
each has a dissolution time, the dissolution time of the first
layer being different than the dissolution time of the second
layer.
23. The balloon of claim 8, wherein at least one of the first or
second excipients is a carboxylated aromatic compound.
24. The balloon of claim 8, wherein at least one of the first or
second excipients is halogenated.
25. The balloon of claim 8, wherein at least one of the first or
second excipients is alkylated.
26. The balloon of claim 8, wherein the first therapeutic agent is
released from the coating, and the second therapeutic agent is
released with the coating.
27. The balloon of claim 8, wherein at least one excipient is
blended with a contrast agent.
28. The balloon of claim 27, wherein the contrast agent is
Ultravist
29. The balloon of claim 8, wherein the balloon is free of a stent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of Ser. No. 12/636,124,
filed Dec. 11, 2009, the contents of which are 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 coating disposed on its outer surface.
BACKGROUND OF THE INVENTION
[0003] Atherosclerosis is a syndrome affecting arterial blood
vessels. It is a chronic inflammatory response in the walls of
arteries, which is in large part due to the accumulation of lipid,
macrophages, foam cells and the formation of plaque in the arterial
wall. Atherosclerosis is commonly referred to as hardening of the
arteries although the pathophysiology of the disease manifests
itself with several different types of lesions ranging from
fibrotic to lipid laden to calcific. 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 desired size and pressure 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. Interventional cardiologists
addressed this problem by stenting the blood vessel to prevent
acute recoil and vasospasm. A stent is a device, typically a metal
tube or scaffold, that was 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 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 one embodiment of the disclosed subject
matter, a drug delivery balloon is provided for delivering at least
one therapeutic agent to a vasculature or tissue. The balloon
catheter has an elongate tubular member having a proximal end, a
distal end and a lumen therebetween. An expandable balloon is
attached to the distal end of the elongate tubular member. The
balloon has an outer surface having a tunable coating disposed on
at least a length of the outer surface, the tunable coating
including a first therapeutic agent and a first excipient, and a
second therapeutic agent and a second excipient. In accordance with
the present subject matter, the first and second therapeutic agents
have different dissolution rates during balloon inflation. The
different dissolution rates define the tunable solubility. The
coating has a biosolubility that is tunable based on the
therapeutic agents and excipients that are selected.
[0015] In accordance with one embodiment, the first therapeutic
agent is different than the second therapeutic agent. In accordance
with the disclosed subject matter, the solubility of the coating
can be modified depending on the molecular weight of the excipient.
In accordance with one embodiment, the excipient is a polymer
having a molecular weight of less than about 35 kDalton. In
accordance with yet another embodiment, the excipient is a polymer
having a molecular weight greater than about 100 kDalton. In
accordance with another embodiment, the coating includes a third
therapeutic agent and a third excipient.
[0016] In accordance with the disclosed subject matter, the
solubility of the coating can be tuned by selecting a certain type
of excipient. In accordance with a preferred embodiment of the
disclosed subject matter, the excipient includes
polyvinylpyrrolidone, silk-elastin like protein polymers,
biodegradable polymers, and polyvinylidene fluoride, carboxylated
aromatic compound. In accordance with one embodiment, the first
excipient is the same as the second excipient. Alternatively, the
first excipient is different from the second excipient.
[0017] The therapeutic agent can include anti-proliferative,
anti-inflammatory, antineoplastic, antiplatelet, anti-coagulant,
anti-fibrin, antithrombotic, antimitotic, antibiotic, antiallergic
and antioxidant compounds. In accordance with a preferred
embodiment, the therapeutic agent is a cytostatic drug, such as for
example, zotaroliums.
[0018] In accordance with another embodiment, the coating includes
first and second layers adsorbed to the surface of the balloon. The
first layer consists of the first therapeutic agent and first
excipient and the second layer consists of the second therapeutic
agent and the second excipient. In this regard, the first and
second layers each have a dissolution rate, the dissolution profile
of the first layer being different than the dissolution profile of
the second layer.
[0019] In accordance with another embodiment, the disclosed subject
matter includes a balloon for delivery of a drug. The balloon
includes an outer surface having a tunable coating disposed on at
least a length of the outer surface, the tunable coating including
a cytostatic drug and at least one excipient, the tunable coating
having a dissolution rate of about 10 seconds to about 1 hour.
Preferably, the dissolution rate consists of 10 seconds to 10
minutes and the excipient is hydrophilic.
[0020] In accordance with yet another embodiment, the disclosed
subject matter includes a balloon for delivery of a drug. The
balloon includes an outer surface having a tunable coating disposed
on at least a length of the outer surface, the tunable coating
including a cytostatic drug and at least one excipient, wherein the
cytostatic drug to excipient weight ratio is from about 20:1 to
about 1:20. In accordance with one embodiment, the coating further
includes a plasticizer and the excipient to plasticizer weight
ratio is from about 20:1 to about 1:20.
[0021] In accordance with yet another embodiment, the disclosed
subject matter includes a balloon for delivery of a drug. The
balloon includes an outer surface having a tunable coating disposed
on at least a length of the outer surface, the tunable coating
including a cytostatic drug and at least one excipient, wherein the
at least one polymeric excipient has a polydispersity index from
about 1.05 to about 10, more preferably from 1.05 to 5.
[0022] 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
[0023] The disclosed subject matter will now be described in
conjunction with the accompanying drawings in which:
[0024] FIG. 1A is a representative embodiment of a planar view of a
medical device in accordance with the disclosed subject matter; and
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
for illustration and not limitations.
[0025] FIG. 2 is a graph illustrating percent drug release as a
function of drug, excipient and plasticizer ratio (D:E:P) and
polyvinylpyrrolidone) K value in accordance with one embodiment of
the disclosed subject matter.
[0026] FIG. 3 is a graph illustrating the amount of released
everoliums as a function of release type and excipient in
accordance with one embodiment of the disclosed subject matter.
DETAILED DESCRIPTION
[0027] 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.
[0028] 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.
[0029] As disclosed herein, a balloon catheter is provided for
delivery of a therapeutic agent, the balloon including an outer
surface having a tunable coating disposed on at least a length of
the outer surface. The tunable 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.
[0030] 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 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.
[0031] 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.
[0032] 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
tenability. 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.
[0033] As disclosed herein, "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.
[0034] 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 can include 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.
[0035] 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.
[0036] 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.
[0037] The excipients include various oil-based, biosoluble, and
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. 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), PEG-phosphoethanolamine (PEGPE), 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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 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.
[0042] 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), Iohexyl
(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.
[0043] 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.
[0044] 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) (ug/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)
[0045] 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.
[0046] 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 Polyethylene 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)
[0047] 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 kDalton, 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.
[0048] As illustrated in Table 2 above, for a "soluble" coating
dissolution rate, representative excipient examples include,
without limitation, polyvinylpyrrolidone (PVP) having a molecular
weight greater than about 60 kDa, or polyethylene 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] In one embodiment, the first therapeutic agent is different
than the second therapeutic agent. Alternatively, however, the
therapeutic agents can be the same.
[0055] 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.
[0056] 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 the
coating includes at least one polymeric component having a
polydispersity index from about 1.05 to about 10, more preferably
from 1.05 to 5. The polydispersity index (PDT), 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 should provide a more consistent dissolution rate among the
polymeric excipient molecules.
[0057] 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.
[0058] 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.
[0059] Additional spray solvents that can be used or blended with
class HI 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.
[0060] In accordance with the disclosed subject matter, the
excipient and therapeutic agent coating process can occur
aseptically or be followed with terminal sterilization method such
as E-beam, gamma irradiation, or ethylene oxide sterilization.
[0061] 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.
[0062] 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.
[0063] 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.
[0064] For example and not limitation, the at least one therapeutic
agent 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 antibodies, 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.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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 1065 D is presently preferred, and has a Shore
durometer of 65 D, 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. 1075 D,
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.
[0070] 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.
[0071] 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
polystyrene-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.
[0072] 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.
[0073] In accordance with in 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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.
[0078] 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.
[0079] 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 air 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.
[0080] In accordance with an 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.
[0081] 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.
[0082] 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
[0083] 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
[0084] 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 supernatant are
measured by liquid chromatography mass spectrometry (LCMS) and drug
from the extraction measured by high performance liquid
chromatography (HPLC).
[0085] This in vitro release method was used to evaluate the drug
release from zotarolimus (Zot):polyvinylpyrrolidone (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 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 demonstated a "fast" dissolution rate,
that is, 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
[0086] To provide an intermediate coating dissolution time,
silk-elastin like protein polymers can be used to formulate the
cytostatic drug and coat the balloon from an organic aqueous blend
solvent. For example everolimus can be formulated with a physically
cross-linked silk-elastin like protein polymer at a 1:1 D:E ratio.
As demonstrated in FIG. 3, for 1:1 everolimus:silk-elastin, an
intermediate coating dissolution and drug release can be obtained
with approximately one-third of everolimus dissolved on delivery,
an additional one third delivered on expansion and the remaining
one-third of everolimus remaining on the balloon within the
hydrated coating. The physically cross-linked silk-elastin like
protein polymer would swell on delivery over a few minutes of
hydration but ultimately dissolves over weeks for an intermediate
coating dissolution time.
Example C
[0087] To provide for a slow coating dissolution time and reduced
drug loss on delivery, a bioabsorbable elastomeric polymer such as
poly(L-lactide-co-glycolide) (PLLA-PCL) 50-50 can be formulated
together with everolimus at a 2:1 D:E ratio from organic solvent.
As shown in FIG. 3, less than 2 ug or 1% of the everolimus loading
is released upon dip release for the PLLA-PCL formulation. This
slow dissolution coating would be expected to ultimately bioabsorb
over months.
[0088] 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.
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