U.S. patent application number 14/852772 was filed with the patent office on 2016-01-21 for drug composition and coating.
The applicant listed for this patent is W. L. Gore & Associates, Inc.. Invention is credited to Robert L. Cleek, Paul D. Drumheller, Theresa A. Holland, Todd J. Johnson.
Application Number | 20160015870 14/852772 |
Document ID | / |
Family ID | 52682735 |
Filed Date | 2016-01-21 |
United States Patent
Application |
20160015870 |
Kind Code |
A1 |
Drumheller; Paul D. ; et
al. |
January 21, 2016 |
Drug Composition and Coating
Abstract
According to the invention there is provided inter alia a
medical device for delivering a therapeutic agent to a tissue, the
device having a solid surfactant-free particulate coating layer
applied to a surface of the device, the coating layer comprising a
therapeutic agent and at least one non-polymeric organic additive
which is hydrolytically stable; wherein at least a proportion of
the particulate coating layer comprising the therapeutic agent and
the at least one organic additive melts as a single phase at a
lower temperature than the melting point of the therapeutic agent
and the at least one organic additive when in pure form; wherein
the therapeutic agent is paclitaxel; and wherein the therapeutic
agent, when formulated in the coating layer, is stable to
sterilization.
Inventors: |
Drumheller; Paul D.;
(Flagstaff, AZ) ; Cleek; Robert L.; (Flagstaff,
AZ) ; Johnson; Todd J.; (Flagstaff, AZ) ;
Holland; Theresa A.; (Flagstaff, AZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
W. L. Gore & Associates, Inc. |
Newark |
DE |
US |
|
|
Family ID: |
52682735 |
Appl. No.: |
14/852772 |
Filed: |
September 14, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14210118 |
Mar 13, 2014 |
|
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14852772 |
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Current U.S.
Class: |
424/423 ;
514/449 |
Current CPC
Class: |
A61K 31/436 20130101;
A61L 27/54 20130101; A61P 7/02 20180101; A61L 31/16 20130101; A61L
31/10 20130101; A61L 33/0035 20130101; A61F 2002/91575 20130101;
A61L 29/08 20130101; A61K 31/337 20130101; A61L 2420/02 20130101;
A61L 2420/06 20130101; A61P 35/00 20180101; A61F 2/07 20130101;
A61L 31/08 20130101; A61L 33/064 20130101; A61L 2300/416 20130101;
A61K 45/06 20130101; A61L 2300/61 20130101; A61L 33/04 20130101;
A61L 29/16 20130101; A61K 31/727 20130101; A61L 31/048 20130101;
A61F 2/915 20130101; A61L 2300/606 20130101; A61P 9/00 20180101;
A61L 2300/216 20130101; A61L 2300/602 20130101; A61L 33/0076
20130101; A61L 27/28 20130101; A61L 2300/42 20130101; A61L 29/085
20130101; A61K 31/337 20130101; A61K 2300/00 20130101; A61K 31/727
20130101; A61K 2300/00 20130101 |
International
Class: |
A61L 31/16 20060101
A61L031/16; A61L 31/10 20060101 A61L031/10; A61L 29/16 20060101
A61L029/16; A61K 31/337 20060101 A61K031/337; A61L 29/08 20060101
A61L029/08 |
Claims
1. A medical device for delivering a therapeutic agent to a tissue,
the device having a solid surfactant-free particulate coating layer
applied to a surface of the device, the coating layer comprising a
therapeutic agent and at least one non-polymeric organic additive
which is hydrolytically stable; wherein at least a proportion of
the particulate coating layer comprising the therapeutic agent and
the at least one organic additive melts as a single phase at a
lower temperature than the melting point of the therapeutic agent
and the at least one organic additive when in pure form; wherein
the therapeutic agent is paclitaxel; and wherein the therapeutic
agent, when formulated in the coating layer, is stable to
sterilization.
2. A method for the prevention or treatment of stenosis or
restenosis which comprises inserting transiently or permanently
into said blood vessel in the human body a medical device according
to claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to solid paclitaxel
compositions, medical devices with coatings comprising solid
paclitaxel compositions and to methods for making such compositions
and coatings.
BACKGROUND OF THE INVENTION
[0002] It has become increasingly common to treat a variety of
medical conditions by introducing a medical device into the
vascular system within a human. For example, medical devices used
for the treatment of vascular disease include stents, stent-grafts,
grafts, catheters, balloon catheters, guide wires, cannulas and the
like.
[0003] In the case of a localized vascular disease, a systemic
administration of a drug may not be desirable because the drug may
have unwanted effects on parts of the body which are not to be
treated, or because treatment of the diseased vasculature requires
a high concentration of drug that may not be achievable by systemic
administration. It is therefore often desirable to administer drugs
in a localized manner to vascular tissues. Several devices for
localized drug delivery are known, including a stent coated with an
elutable drug, also known as a drug eluting stent (DES), and a
balloon catheter coated with an elutable drug, also known as a drug
eluting balloon (DEB).
[0004] DESs are coated with the drug using a variety of coating
techniques. When the DES is inserted into a vascular organ, the
drug may be slowly released into the surrounding vascular tissue,
to provide a long lasting therapeutic effect. Alternatively, the
drug may be rapidly released from the coating, with minimal drug
remaining on the stent shortly after implantation. Coatings with
fast drug release characteristics are particularly advantageous if
a medical device is not permanently implanted, as it is necessary
in this situation to rapidly deliver drug to the vascular tissue at
the time of treatment. An example of such a device is a DEB.
[0005] Non-stent based local delivery systems, such as DEBs, have
also been effective in the treatment of vascular disease. The DEB
is coated with drug using a variety of coating techniques. Therapy
commences when the DEB is inserted into the patient to a target
site, and inflated at the target site, wherein the DEB is pressed
against the vascular tissue to deliver the drug. When DEBs are
used, it is advantageous for the drug in the coating to be retained
on the balloon surface prior to inflation, and to be rapidly
released and transferred to the vascular tissue upon inflation. One
of the potential drawbacks to the use of a DEB for the localized
treatment of vascular disease, is the unintended release of drug
away from the target site. This unintended release may occur during
removal from the packaging and insertion into the body, tracking to
and placement at the treatment site, during expansion of the
balloon, or occur post-treatment as the device is withdrawn from
the body. Such unintended release may result from physical
dislodgement of the coating and particulation, drug diffusion,
device contact with areas proximate the treatment site, or washing
out of the drug from the surface of the balloon due to blood flow.
Another potential drawback to the use of DEBs for the localized
treatment of vascular disease, is the possibility that the drug
adheres too strongly to the balloon surface during device
inflation, such that the balloon may be deflated and withdrawn
before the drug can be released and absorbed by vascular tissues.
Therefore, the quantity of drug that is delivered to the target
vascular tissue may be too low and difficult to measure or predict,
and the application of drug to the vascular tissue may be
non-uniform.
[0006] A drug commonly used for the localized treatment of vascular
disease is paclitaxel. Paclitaxel can be coated onto a DEB using a
variety of coating techniques. One technique involves combining the
paclitaxel with an excipient, either in dry form using powder
methods, or in solution or in suspension using solvent methods. The
paclitaxel-excipient combination is then applied to the surface of
the DEB, either in the form of a powder or via the application of
the solution or suspension followed by a drying step.
[0007] There are numerous factors that must be considered when
creating a paclitaxel-excipient combination, and when coating the
combination onto a medical device such as a DEB. In general,
combining drugs and excipients, and coating medical devices with
drug-excipient combinations, are complicated areas of technology.
They involve the usual formulation challenges, such as those of
oral or injectable pharmaceuticals, together with the added
challenge of maintaining drug adherence to the medical device until
it reaches the target site and subsequently delivering the drug to
the target tissues with the desired release and absorption
kinetics. DEB coatings generally contain little to no components in
the form of a liquid, which typically are often used to stabilize
drugs. International application WO2009/051614 (Lutonix, Inc.)
discloses a coating comprising a therapeutic agent and an additive
that has both a hydrophilic part and a drug affinity part which is
said to form an effective drug delivery coating on a medical device
without the use of oils and lipids.
[0008] A further key requirement is that the therapeutic agent,
when formulated in the coatings, must survive a sterilization
process essentially intact.
[0009] Thus, there is a need to develop paclitaxel-excipient
combinations that are appropriate for the localized treatment of
vascular disease. In particular there is a need to develop coatings
for DEBs and other similar medical devices comprising
paclitaxel-excipient combinations that can rapidly deliver
paclitaxel in a localized manner to a target vascular tissue to
treat a vascular disease. The coating should have good adherence to
the DEB while in transit but quickly release the paclitaxel in an
effective and efficient manner to the target vascular tissue, where
the paclitaxel should rapidly permeate the vascular tissue. The
therapeutic agent, when formulated in the coating, should also be
stable to sterilization, in particular ethylene oxide
sterilization.
[0010] For medical devices in which the paclitaxel-excipient is
combined on a device that is intended to remain within the body for
a period of time, such as stents and stent-grafts, the rapid
delivery of the paclitaxel to the target vascular tissue is not an
essential feature. However, whether the paclitaxel coating is
delivered rapidly, or relatively more slowly, in both cases the
coating of such a device should have the same advantageous
qualities as those for a DEB, such as good adherence in transit and
good paclitaxel stability to sterilization.
SUMMARY OF THE INVENTION
[0011] The present inventors have prepared novel
paclitaxel-excipient solid compositions which exhibit a depressed
melting endotherm. Such paclitaxel-excipient solid compositions
have been coated onto a variety of medical devices and demonstrate
appropriate adherence thereby reducing the extent of unintentional
paclitaxel release during device insertion and tracking, while
providing suitable release characteristics of the paclitaxel to the
target tissue. The paclitaxel present in the compositions and
coatings of the invention is also stable to sterilization, in
particular ethylene oxide sterilization. Furthermore, when a
paclitaxel-excipient coating was over-coated onto a medical device
already coated with immobilized biologically active heparin (as an
example of an additional therapeutic agent), following removal of
the outer paclitaxel-excipient coating, the heparin activity was
preserved.
[0012] In one aspect, the invention provides a medical device for
delivering a therapeutic agent to a tissue, the device having a
solid surfactant-free particulate coating layer applied to an
exterior surface of the device, the coating layer comprising a
therapeutic agent and at least one non-polymeric organic additive
which is hydrolytically stable; wherein at least a proportion of
the particulate coating layer comprising the therapeutic agent and
the at least one organic additive melts as a single phase at a
lower temperature than the melting point of the therapeutic agent
and the at least one organic additive when in pure form; wherein
the therapeutic agent is paclitaxel; and wherein the therapeutic
agent, when formulated in the coating layer, is stable to ethylene
oxide sterilization.
BRIEF DESCRIPTION OF THE FIGURES
[0013] FIGS. 1A through 1C show differential scanning calorimetry
(DSC) thermograms of a paclitaxel-PABA composition (1A), a
paclitaxel-succinic acid composition (1B), and a paclitaxel-adipic
acid composition (1C) respectively prepared according to Example
1;
[0014] FIG. 2 shows the results of an adhesion test (Example 4)
carried out on coatings prepared according to Example 3b;
[0015] FIG. 3 shows the results of an in vitro tissue test (Example
5) carried out on coatings prepared according to Example 3b;
[0016] FIG. 4 shows the % paclitaxel remaining on a coated balloon
prepared according to Example 3b after in vivo deployment (Example
6);
[0017] FIG. 5 shows paclitaxel levels in porcine arterial tissue 7
days after in vivo deployment of a coated balloon prepared
according to Example 3b (Example 6);
[0018] FIG. 6 shows paclitaxel levels in porcine arterial tissue 28
days after in vivo deployment of a coated balloon prepared
according to Example 3b (Example 6);
[0019] FIG. 7 shows a DSC thermogram of a paclitaxel-succinic acid
coated balloon prepared according to Example 13
(paclitaxel:succinic acid=82:18 wt/wt) and compared to the
paclitaxel-succinic acid composition shown in FIG. 1B;
[0020] FIG. 8 shows a DSC thermogram of a paclitaxel-succinic acid
coated balloon prepared according to Example 13
(paclitaxel:succinic acid=18:82 wt/wt) and compared to the
paclitaxel-succinic acid coated balloon (paclitaxel:succinic
acid=82:18 wt/wt), the DSC thermogram of which is shown in FIG.
7;
[0021] FIG. 9 shows a DSC thermogram of a ternary composition of
the invention containing paclitaxel, succinic acid and caffeine
(Example 14).
DETAILED DESCRIPTION OF THE INVENTION
[0022] The present invention relates to novel paclitaxel-excipient
solid compositions which exhibit a depressed melting endotherm.
Such compositions are particularly useful for coating medical
devices.
Medical Devices and Materials
[0023] The medical devices of the present invention are suitable
for a wide range of applications including, for example, a range of
medical treatment applications within the body. Exemplary
applications include use as a catheter balloon for transferring
drug to, or placement of, or "touch-up" of implanted vascular
grafts, use as stents, stent-grafts, catheters, a permanent or
temporary prosthesis, or other type of medical implant, treating a
targeted tissue within the body, and treating any body cavity,
space, or hollow organ passage(s) such as blood vessels, the
urinary tract, the intestinal tract, nasal or sinus cavities,
neural sheaths, intervertebral regions, bone cavities, the
esophagus, intrauterine spaces, pancreatic and bile ducts, rectum,
and those previously intervened body spaces that have implanted
vascular grafts, stents, prosthesis, or other type of medical
implants.
[0024] Additional examples of medical devices of the present
invention include indwelling monitoring devices, artificial heart
valves (leaflet, frame, and/or cuff), pacemaker or defibrillator
electrodes, guidewires, cardiac leads, sutures, embolic filters,
cardiopulmonary bypass circuits, cannulae, plugs, drug delivery
devices, tissue patch devices, blood pumps, patches,
osteoprostheses, chronic infusion lines, arterial lines, devices
for continuous subarachnoid infusions, feeding tubes, CNS shunts
(e.g., a ventriculopleural shunt, a ventriculo-atrial (VA) shunt,
or a ventriculoperitoneal (VP) shunt), ventricular peritoneal
shunts, ventricular atrial shunts, portosystemic shunts and shunts
for ascites, devices for the filtering or removal of obstructions
such as emboli and thrombi from blood vessels, as a dilation device
to restore patency to an occluded body passage, as an occlusion
device to selectively deliver a means to obstruct or fill a passage
or space, and as a centering mechanism for transluminal instruments
like catheters. In one embodiment, the medical devices of the
present invention can be used to treat stent restenosis or treat
tissue sites where previously placed drug eluting constructs have
failed. In another embodiment, medical devices as described herein
can be used to establish, connect to, or maintain arteriovenous
access sites, e.g., those used during kidney dialysis.
[0025] Further examples of medical devices of the present invention
which can be permanent or temporary are catheters. Examples of
catheters include, but are not limited to, central venous
catheters, peripheral intravenous catheters, haemodialysis
catheters, catheters such as coated catheters include implantable
venous catheters, tunnelled venous catheters, coronary catheters
useful for angiography, angioplasty, or ultrasound procedures in
the heart or in peripheral veins and arteries, hepatic artery
infusion catheters, CVC (central venous catheters), peripheral
intravenous catheters, peripherally inserted central venous
catheters (PIC lines), flow-directed balloon-tipped pulmonary
artery catheters, total parenteral nutrition catheters, chronic
dwelling catheters (e.g., chronic dwelling gastrointestinal
catheters and chronic dwelling genitourinary catheters), peritoneal
dialysis catheters, CPB catheters (cardiopulmonary bypass), urinary
catheters and microcatheters (e.g. for intracranial
application).
[0026] In one embodiment, the medical device is an expandable
member which, according to the present invention, can be a balloon,
expandable catheter, stent, stent-graft, a self-expanding
construct, a balloon expandable construct, a combination
self-expanding and balloon expandable construct, a graft or a
mechanical, radially expanding device which may be expanded, for
example, via application of a torsional or longitudinal force.
Expandable members can also include those which expand due to
pneumatic or hydraulic pressure, those which expand due to magnetic
forces, those which expand due to the application of energy (for
example thermal, electrical, or ultrasonic (piezoelectric) energy).
Expandable members can be placed temporarily in any lumen (e.g. a
vessel) by expanding said device and then removed by collapsing
said device by a torsional or longitudinal force.
[0027] In one embodiment, the medical device is a stent such as a
bifurcated stent, balloon expandable stent or a self-expanding
stent. Stents are configured as braids, wound wire forms, laser-cut
forms, deposited materials, 3-D printed constructs, or combinations
thereof, or take other structural forms, including those with
length-adjustability, which provide support to a luminal wall or
region. Stents are constructed of biocompatible materials including
metals, metal alloys, such as stainless steel and nickel-titanium
alloy (NiTi), polymers, ceramics, biodegradable materials (such as
biodegradable polymers, ceramics, metals and metal alloys), or
combinations thereof. Stents can be of substantially unitary form
or comprise separate components, e.g., rings. Whether unitary or
made up of components, stent structures can be joined together by
struts, hinges, connectors, or materials which fully or partially
line or cover the stent. In one embodiment, the stent structure is
joined with fluoropolymers forming "webs" as described in
US2009/0182413 (Gore Enterprise Holdings, Inc., incorporated herein
by reference).
[0028] In one embodiment, the medical device is a stent such a
bifurcated stent, a balloon expandable stent or a self-expanding
stent. In one embodiment, the medical device is a stent formed from
a metal, a metal alloy, a polymer, a ceramic, a biodegradable
material, or a combination thereof.
[0029] In one embodiment, the medical device is a stent-graft.
Stent-grafts combine at least one stent member with a graft
component. Grafts are typically configured as tubular members, with
closed walls or walls with openings. Graft materials include
biocompatible materials such as fluoropolymers, including
polytetrafluoroethylene (PTFE) and expanded polytetrafluoroethylene
(ePTFE). Other suitable graft materials include polymers such as
polyethylene terephthalate and ultra-high molecular weight
polyethylene (UHMWPE). Graft materials can be made to possess
different strengths, densities, dimensions, porosities and other
functional characteristics and can take the form of films,
extrusions, electrospun materials, coatings, depositions, or molded
articles. Grafts may used alone or graft materials can fully or
partially line or cover a stent structure. In one embodiment, the
stent-graft can take forms as described in U.S. Pat. No. 5,876,432
(Gore Enterprise Holdings, Inc., incorporated herein by
reference).
[0030] In one embodiment, the medical device is a stent graft,
wherein the graft is formed from a polymer, suitably a
biocompatible polymer. Suitably the graft is formed from a
fluoropolymer such as expanded polytetrafluoroethylene (ePTFE).
[0031] Stents, stent-grafts and grafts can be overlain with various
materials such as polymers and primer layers. In an embodiment, the
stent or graft structure is modified to enhance the ability of the
device to hold or release a therapeutic agent applied to the
device. For example, pits or blind holes can be formed in stent
struts into which a therapeutic agent is loaded. When coated onto a
stent, stent-graft, or graft, the composition of the invention will
release a therapeutic agent in a localized manner, therefore a
stent, stent-graft or graft coated with a composition of the
invention is referred to herein as a drug eluting stent (DES).
[0032] In one embodiment, the expandable member is a medical
balloon. Balloons useful in the invention may be formed by using
any conventional manner such as extrusion, blow molding and other
molding techniques. Balloons may be compliant or semi-compliant or
non-compliant and may be of various lengths, diameters, sizes and
shapes. Balloons can be so called "conformable" or "conforming",
"length-adjustable" or "steerable" balloons. In other embodiments,
the expandable members may comprise balloons which are constructed
of wrapped films, are fiber-wound, are of variable length, are
segmented, and/or have controlled or variable inflation profiles.
In other embodiments, balloons may be overlain with a material or
comprise more than one layer or be of composite construction. In an
embodiment, the balloon surface or structure is modified to enhance
the ability of the balloon to hold or release a therapeutic agent
applied to it. For example, the balloon can be folded in such a way
as to hold a therapeutic agent within said folds. When coated onto
a balloon, the composition of the invention will release a
therapeutic agent in a localized manner, therefore a balloon coated
with a composition of the invention is referred to herein as a drug
eluting balloon (DEB).
[0033] According to the present invention, medical balloons may be
formed using any materials known to those of skill in the art.
Commonly employed materials include the thermoplastic elastomeric
and non-elastomeric polymers and the thermosets. Examples of
suitable materials include but are not limited to, polyolefins,
polyesters, polyurethanes, polyamides, polyether block amides,
polyimides, polycarbonates, polyphenylene sulfides, polyphenylene
oxides, polyethers, silicones, polycarbonates, styrenic polymers,
fluoropolymers, copolymers thereof, and mixtures thereof. Some of
these classes are available both as thermosets and as thermoplastic
polymers. Useful polyamides include, but are not limited to, nylon
12, nylon 11, nylon 9, nylon 6/9 and nylon 6/6. Suitable
fluoropolymers include polytetrafluoroethylene (PTFE) or expanded
polytetrafluoroethylene (ePTFE). Examples of some copolymers of
such materials include the polyether-block-amides, available from
Elf Atochem North America in Philadelphia, Pa. under the tradename
of PEBAX.RTM.. Another suitable copolymer is a polyetheresteramide.
Suitable polyester copolymers, include, for example, polyethylene
terephthalate and polybutylene terephthalate, polyester ethers and
polyester elastomer copolymers such as those available from DuPont
in Wilmington, Del. under the tradename of HYTREL.RTM.. Block
copolymer elastomers such as those copolymers having styrene end
blocks, and midblocks formed from butadiene, isoprene,
ethylene/butylene, ethylene/propene, and so forth may be employed
herein. Other styrenic block copolymers include
acrylonitrile-styrene and acrylonitrile-butadiene-styrene block
copolymers. Also, block copolymers wherein the particular block
copolymer thermoplastic elastomers in which the block copolymer is
made up of hard segments of a polyester or polyamide and soft
segments of polyether may also be employed herein. Specific
examples of polyester/polyether block copolymers are poly(butylene
terephthalate)-block-poly(tetramethylene oxide) polymers such as
ARNITEL.RTM. EM 740, available from DSM Engineering Plastics and
HYTREL.RTM. polymers available from DuPont de Nemours & Co,
already mentioned above.
[0034] In one embodiment, the medical device is a balloon formed
from a polyolefin, polyester, polyurethane, polyamide, polyether
block amide, polyimide, polycarbonate, polyphenylene sulfide,
polyphenylene oxide, polyether, silicone, polycarbonate, styrenic
polymer, fluoropolymers, a copolymer thereof, or a mixture thereof.
Suitably the balloon is formed from a polyamide, such as nylon, or
a fluoropolymer such as expanded polytetrafluoroethylene (ePTFE),
polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene
(FEP), perfluorocarbon copolymers, e.g. tetrafluoroethylene
perfluoroalkylvinyl ether (TFE/PAVE) copolymers, copolymers of
tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE),
copolymers of TFE with functional monomers that comprise acetate,
alcohol, amine, amide, sulfonate, functional groups and the like as
described in U.S. Pat. No. 8,658,707 (W.L. Gore and Associates,
incorporated herein by reference), as well as combinations
thereof.
[0035] In one embodiment, the medical devices of the invention
comprise a medical balloon used for Percutaneous Transluminal
Angioplasty (PTA) in patients with obstructive disease of the
peripheral arteries. In another embodiment, said medical device
comprises a medical balloon used for Percutaneous Transluminal
Coronary Angioplasty (PTCA). In another embodiment, medical devices
provided by the present invention can be used to treat coronary
stenosis or obstructions.
[0036] In one embodiment, the expandable member is covered with a
porous material onto which a coating layer of the present invention
is applied. In an embodiment, the expandable member covering
material is a fluoropolymer such as polytetrafluoroethylene (PTFE)
or an expanded PTFE (ePTFE). The structure of expanded PTFE
characterized by nodes interconnected by fibrils, is taught in U.S.
Pat. Nos. 3,953,566 and 4,187,390 (W. L. Gore & Associates;
both incorporated herein by reference). In one embodiment, the
fluoropolymer expandable member covering comprises ePTFE having a
material structure with fibrils or fibrils and nodes. In another
embodiment, the fibrils or fibrils and nodes change in size,
dimension, or orientation as a dimension of the expandable member
covering is changed. In one embodiment, the expandable member is a
balloon, disposed over at least a part of which is a covering, the
covering being made at least in part of ePTFE, and disposed over at
least a portion of the ePTFE balloon covering is a coating of the
present invention.
[0037] In one embodiment, the expandable member comprises a
covering disposed around at least a portion of a coating layer of
the invention. Such a covering may also be described as a sheath.
In one embodiment the covering is removable from over the coating
layer. In one embodiment, the covering is disposed over a coating
layer of the invention applied to an expandable member. The
covering can comprise any biocompatible material, including any
possessing porosity or permeability. In one embodiment, the
porosity or permeability varies as the material is deformed or
otherwise altered in dimension.
[0038] Materials which may exhibit porosities or permeabilities
that change with changes in the dimension of covering include, but
are not limited to, fibrillated structures, such as expanded
fluoropolymers (for example, expanded polytetrafluoroethylene
(ePTFE)) or expanded polyethylene (as described in U.S. Pat. No.
6,743,388 (Sridharan et al.) and incorporated herein by reference);
fibrous structures (such as woven or braided fabrics; non-woven
mats of fibers, microfibers, or nanofibers; materials made from
processes such as electrospinning or flash spinning; polymer
materials consisting of melt or solution processable materials such
as fluoropolymers, polyamides, polyurethanes, polyolefins,
polyesters, polyglycolic acid (PGA), polylactic acid (PLA), and
trimethylene carbonate (TMC), and the like; films with openings
created during processing (such as laser- or mechanically-drilled
holes); open cell foams; microporous membranes made from materials
such as fluoropolymers, polyamides, polyurethanes, polyolefins,
polyesters, PGA, PLA, TMC, and the like; porous
polyglycolide-co-trimethylene carbonate (PGA:TMC) materials (as
described in U.S. Pat. No. 8,048,503 (Gore Enterprise Holdings,
Inc.)) and incorporated herein by reference); or combinations of
the above. Processing of the above materials may be used to
modulate, enhance or control porosity or permeability between a
first, closed state and second, more porous or permeable state.
Such processing may help close the material structure (thus
lowering porosity or permeability) in a first state, help open the
material structure in a second state, or a combination of both.
Such processing which may help close the material structure may
include, but is not limited to: calendaring, coating
(discontinuously or continuously), compaction, densification,
coalescing, thermal cycling, or retraction and the like. Such
processing that may help open the material structure may include,
but is not limited to: expansion, perforation, slitting, patterned
densification and/or coating, and the like. In another embodiment,
said materials comprise pores between fibrils or between nodes
interconnected by fibrils, such as in ePTFE.
[0039] One skilled in the art will appreciate various methods which
characterize the change in porosity or permeability using testing
at a first state comparing to testing done at a second state. These
methods include, but are not limited to, characterizations of air
or liquid flux across the material structure at a given pressure
differential, characterization which determines the pressure
differential at which different fluids strike through the material
structure such as Water Entry Pressure or Bubble Point, and visual
characterization as measured from an image (e.g. from a scanning
electron microscope or light microscope).
[0040] In one embodiment, the covering material is a fluoropolymer
such as expanded polytetrafluoroethylene (ePTFE),
polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene
(FEP), perfluorocarbon copolymers, e.g. tetrafluoroethylene
perfluoroalkylvinyl ether (TFE/PAVE) copolymers, copolymers of
tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE),
copolymers of TFE with functional monomers that comprise acetate,
alcohol, amine, amide, sulfonate, functional groups and the like as
described in U.S. Pat. No. 8,658,707 (W.L. Gore and Associates,
incorporated herein by reference), as well as combinations thereof.
In another embodiment, the fluoropolymer covering possesses a
material structure which changes as a dimension of the covering
changes. In one embodiment, the fluoropolymer covering comprises
ePTFE having a material structure with fibrils or fibrils and
nodes. In another embodiment, the fibrils or fibrils and nodes
change in size, dimension, or orientation as a dimension of the
covering is changed. In one embodiment, the expandable member is a
balloon, disposed over at least a part of which is a covering, the
covering being made at least in part of ePTFE, and the material
structure of the ePTFE changes upon expansion of the balloon.
[0041] In another embodiment, the expandable member is a balloon,
disposed over at least a part of which is a coating layer of the
invention which in turn is covered at least in part with a covering
such as a sheath, the covering being made at least in part of
ePTFE, and the material structure of the ePTFE changes upon
expansion of the balloon. In one embodiment, the porosity or
permeability of the covering is sufficiently low so as to prevent
substantial movement of material in the coating layer from moving
through the covering. In another embodiment, the porosity or
permeability of the covering increases upon expansion of the
balloon and allows at least some of the material in the coating
layer to detach from the surface of the balloon. In one embodiment,
the material detached is a paclitaxel-excipient solid composition
of the invention. Once the paclitaxel-excipient solid composition
passes through the outer covering, it is delivered to a treatment
site.
[0042] In one embodiment the covering is essentially hydrophobic
and is treated to render it hydrophilic using, for example, the
methods described in US2013/0253426 (W. L. Gore & Associates;
incorporated herein by reference). In another embodiment, the
covering comprises a film or film tube of ePTFE.
[0043] In another embodiment of the invention, the surface(s) or
outward configuration of the covering material may be modified with
textures, protrusions, wires, blades, spikes, scorers, depressions,
grooves, coatings, particles, and the like. In another embodiment
of the invention, the surface(s) or outward configuration of the
covering material may be modified with needles, cannulae, and the
like. These modifications may serve various purposes such as to
modify tissues into which therapeutic agents will be (or have been)
delivered, control placement of the system of the invention, and
direct fluid transfer. Such textures may help in increased transfer
of a therapeutic agent onto, more deeply and/or into deeper
tissues. Such textures may be comprised of the covering material,
or may be comprised of an added material.
[0044] In another embodiment of the invention, the location(s) of
the permeable microstructure may be varied. For example, a covering
may be constructed such that only a portion of its microstructure
is variably permeable. Such a configuration may be desirable where
fluid transfer is not desired to occur, for example, at one or both
of the ends of the expandable medical device of the invention. This
may be desirable where multiple drug eluting devices will be used
in a specific anatomy, and it would be undesirable to overlap
treatments sites, i.e., delivering too much drug to a particular
site.
[0045] In another embodiment, the covering may contain or be marked
with radiopaque markers or be constructed to be radiopaque in its
entirety. Such radiopaque indicators are used by clinicians to
properly track and place an expandable medical device of the
invention.
[0046] In one embodiment, the medical device is an expandable
member. In another embodiment, the medical device is a balloon, a
stent, a stent-graft or a graft.
[0047] The solid composition of the invention can be applied to the
entire surface of the device, or only a portion of the surface of
the device. Certain devices may have an external surface and an
internal surface, either or both of which can be coated. For
example, tubular substrates including but not limited to artificial
blood vessels, vascular grafts, stents, and stent grafts, have an
internal surface, or lumen, which can be coated independently from
the external surface. A device comprising an internal and an
external surface may only require the external surface to be
coated. Conversely, only the internal surface may require a coating
of the invention. In one embodiment, the amount or thickness of the
coating may be varied over the surface of the medical device. The
coating layer can be continuous over an entire surface of the
device or be discontinuous and cover only a portion or separate
portions of the device. The coating layer can also be "sculpted" or
modified to create a desired surface topography or modified with
textures, as described supra.
[0048] In one embodiment, up to 99%, for example up to 95%, 90%,
75%, 50% or 25% of the surface of the device is coated with the
coating of the invention. In one embodiment, both the external and
internal surfaces of the device are coated. In another embodiment,
only the external surface of the device is coated.
[0049] The medical device, in particular a surface of the medical
device, can be composed of one or more materials as described
hereinabove. The medical device may comprise, consist, consist
essentially of, or be formed of a metal or a synthetic or naturally
occurring organic or inorganic polymer or a ceramic material, inter
alia.
[0050] Thus, for example, the medical device, in particular a
surface of the medical device, is composed of a synthetic or
naturally occurring organic or inorganic polymer or material,
including but not limited to materials such as polyolefins,
polyesters, polyurethanes, polyamides, polyether block amides,
polyimides, polycarbonates, polyphenylene sulfides, polyphenylene
oxides, polyethers, silicones, polycarbonates,
polyhydroxyethylmethacrylate, polyvinyl pyrrolidone, polyvinyl
alcohol, rubber, silicone rubber, polyhydroxyacids, polyallylamine,
polyallylalcohol, polyacrylamide, and polyacrylic acid, styrenic
polymers, polytetrafluoroethylene and copolymers thereof, expanded
polytetrafluoroethylene and copolymers thereof, derivatives thereof
and mixtures thereof. Some of these classes are available both as
thermosets and as thermoplastic polymers. As used herein, the term
"copolymer" shall be used to refer to any polymer formed from two
or more monomers, e.g. 2, 3, 4, 5 and so on and so forth.
Bioresorbables, such as poly(D,L-lactide) and polyglycolids and
copolymers thereof are also useful. Non-woven, bioabsorbable web
materials comprising a tri-block copolymer such as
poly(glycolide-co-trimethylene carbonate) tri-block copolymer
(PGA:TMC) are also useful (as described in U.S. Pat. No. 7,659,219;
Biran et al.). Useful polyamides include, but are not limited to,
nylon 12, nylon 11, nylon 9, nylon 6/9 and nylon 6/6. Examples of
some copolymers of such materials include the
polyether-block-amides, available from Elf Atochem North America in
Philadelphia, Pa. under the tradename of PEBAX.RTM.. Another
suitable copolymer is a polyetheresteramide. Suitable polyester
copolymers, include, for example, polyethylene terephthalate and
polybutylene terephthalate, polyester ethers and polyester
elastomer copolymers such as those available from DuPont in
Wilmington, Del. under the tradename of HYTREL.RTM. Block copolymer
elastomers such as those copolymers having styrene end blocks, and
midblocks formed from butadiene, isoprene, ethylene/butylene,
ethylene/propene, and so forth may be employed herein. Other
styrenic block copolymers include acrylonitrile-styrene and
acrylonitrile-butadiene-styrene block copolymers. Also, block
copolymers wherein the particular block copolymer thermoplastic
elastomers in which the block copolymer is made up of hard segments
of a polyester or polyamide and soft segments of polyether may also
be employed herein. Other useful materials are polystyrenes,
poly(methyl)methacrylates, polyacrylonitriles, poly(vinylacetates),
poly(vinyl alcohols), chlorine-containing polymers such as
poly(vinyl) chloride, polyoxymethylenes, polycarbonates,
polyamides, polyimides, polyurethanes, phenolics, amino-epoxy
resins, polyesters, silicones, cellulose-based plastics, and
rubber-like plastics. Combinations of these materials can be
employed with and without cross-linking. Polymeric materials may
optionally be blended with fillers and/or colorants, such as a
gold, barium, or tantalum filler to render the polymeric material
radiopaque. Polymeric materials may optionally be modified at their
surface while retaining bulk properties using methods known in the
art, such as acid or base etching, hydrolysis, aminolysis, plasma
modification, plasma grafting, corona discharge modification,
chemical vapour deposition, ion implantation, ion sputtering,
ozonation, photomodification, electron beam modification, gamma
beam modification, and the like. Suitably a surface of the medical
device is composed of nylon.
[0051] In one embodiment, the medical device, in particular a
surface of the medical device is biocompatible and comprises or
consists of a polyether-block-amides, such as PEBAX.RTM..
[0052] The medical device, in particular a surface of the medical
device, may be composed of fluorinated polymers such as
fluoropolymers, e.g. expanded polytetrafluoroethylene (ePTFE),
polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene
(FEP), perfluorocarbon copolymers, e.g. tetrafluoroethylene
perfluoroalkylvinyl ether (TFE/PAVE) copolymers, copolymers of
tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE),
copolymers of TFE with functional monomers that comprise acetate,
alcohol, amine, amide, sulfonate, functional groups and the like as
described in U.S. Pat. No. 8,658,707 (W.L. Gore and Associates,
incorporated herein by reference, as well as combinations thereof.
Also contemplated are combinations of the above with and without
crosslinking between the polymer chains, expanded polyethylene,
polyvinylchloride, polyurethane, silicone, polyethylene,
polypropylene, polyurethane, polyglycolic acid, polyesters,
polyamides, elastomers and their mixtures, blends and copolymers or
derivatives thereof. ePTFE has a porous microstructure which is
particularly compatible with the coating of the invention. Suitably
a surface of the medical device is composed of ePTFE.
[0053] The medical device, in particular a surface of the medical
device, may also be composed of metals, including, but are not
limited to, biocompatible metals, titanium, stainless steel, high
nitrogen stainless steel, gold, silver, rhodium, zinc, platinum,
rubidium, copper and magnesium, and combinations thereof. Suitable
alloys include cobalt alloys including cobalt-chromium alloys such
as L-605, MP35N, Elgiloy, titanium alloys including nickel-titanium
alloys (such as Nitinol), tantalum, and niobium alloys, such as
Nb-1% Zr, and others. In one embodiment, the medical device is a
stent and is composed of biocompatible metal selected from
stainless steel, tantalum, titanium alloys and cobalt alloys. The
medical device, in particular a surface of the medical device may
also be composed of a ceramic substrate including, but are not
limited to, silicone oxides, aluminum oxides, alumina, silica,
hydroxyapatites, glasses, calcium oxides, polysilanols, and
phosphorous oxide.
[0054] In one embodiment of the invention, the coating layer is
applied to a surface of a device which is composed of nylon. In
another embodiment, the coating layer is applied to a surface of a
device which is composed of ePTFE. In either embodiment, a
proportion or the entire surface of the medical device is composed
of nylon or ePTFE, respectively. In a further embodiment, the
coating layer is applied to a surface of a balloon which is
composed of nylon. In a still further embodiment, the coating layer
is applied to a surface of a balloon which is composed of ePTFE. In
a still further embodiment, the coating layer is applied to a
surface of a balloon which is composed of copolymers of TFE with
functional monomers that comprise acetate, alcohol, amine, amide or
sulfonate functional groups and the like.
Coating Layer
[0055] The paclitaxel-excipient solid compositions of the invention
are of use in coating medical devices. In the context of being used
as a coating in a layer on a medical device, the
paclitaxel-excipient solid compositions are therefore referred to
herein as being "coatings of the invention" or "the coating layers
of the invention".
[0056] The paclitaxel-excipient solid composition comprises a
therapeutic agent which is paclitaxel and at least one excipient
which is a non-polymeric organic additive.
[0057] Paclitaxel is sold commercially in formulations for the
treatment of various cancers and for the prevention and treatment
of restenosis. Paclitaxel is known to exist in several different
physical forms, including amorphous, glassy and crystalline forms,
wherein the crystalline forms can be further differentiated into a
number of different polymorphs. Furthermore, crystalline paclitaxel
can exist as an anhydrate or in hydrated form. The accepted melting
point of crystalline paclitaxel is circa 220.degree. C., depending
on the heating conditions and polymorph form (Liggins et al.
"Solid-state characterization of paclitaxel", J. Pharm. Sci. 1997,
Vol. 86, pages 1458-1463). It is known that the particular form of
paclitaxel can affect the physical properties of the drug when in
solid form. In particular, the adherence of paclitaxel to a surface
may be influenced by its physical form, as can its rate of
dissolution from a surface to the surroundings. Thus, formulating
paclitaxel for solid delivery can be challenging at the first
instance, and the effect of formulating paclitaxel in solid form
with an excipient cannot easily be predicted.
[0058] The coating of the invention also comprises at least one
excipient which is a non-polymeric organic additive. The term
"non-polymeric" will be clear to a person of skill in the art as
meaning a substance which does not contain multiple repeating
monomer units. Typically, a polymer will consist of at least 5
repeating monomer units, for example at least 6, at least 7, at
least 8 or at least 9 repeating monomer units. References to
polymers are intended to include copolymers. Examples of polymeric
substances include proteins which are thus not suitable as organic
additives for use in the invention. Poly(lactic-co-glycolic) acid
(PLGA), polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG)
and poloxamers are examples of polymers which are not suitable as
an organic additive for use in the invention. Thus, coatings and
compositions of the invention do not contain polymers, in
particular poly(lactic-co-glycolic) acid (PLGA),
polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG). A further
example of a material which is polymeric and therefore not suitable
as an organic additive for use in the coating and composition of
the invention is shellac.
[0059] In one embodiment, the coating layer is plasticizer-free
i.e. does not contain a plasticizer. Plasticizers (also known as
dispersants) are defined herein as compounds that increase the
plasticity or fluidity of a material, usually a polymer.
Plasticizers can be in monomeric, oligomeric or polymeric form.
Examples of plasticizers include acetic acid, formic acid,
1-butanol, 2-butanol, ethanol, 2-methyl-1-butanol,
2-methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol, ethyl
acetate, ethyl formate, isopropyl acetate, methyl acetate, propyl
acetate, anisole, tert-butylmethyl ether, ethyl ether, cumene,
heptane, pentane, acetone, methylethyl ketone, methylisobutyl
ketone, dimethyl sulfoxide, glycerin, polyethylene glycols,
polyethylene glycol monomethyl ether, sorbitol, sorbitan, citrate
esters including acetyl tributyl citrate, acetyl triethyl citrate,
tributyl citrate, triethyl citrate and the like, castor oil,
diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate,
triacetin, fractionated coconut oil, and acetylated
monoglycerides.
[0060] The organic additive is hydrolytically stable i.e. resistant
to chemical reaction/decomposition in the presence of water. A
compound which is not hydrolytically stable will undergo an
irreversible chemical transformation in an aqueous solution e.g.
ester or amide or anhydride hydrolysis. Conversely, a compound
which is hydrolytically stable will not undergo an irreversible
transformation in an aqueous solution. A compound may undergo
reversible proton exchange, or reversible hydrate formation and
still be considered as being hydrolytically stable. When a compound
is exposed to an aqueous solution and a chemical transformation
results, and if the resulting compound (degradant) cannot be
converted back to the original compound by simple pH modification,
then the original compound is not hydrolytically stable.
[0061] In one embodiment, a compound is hydrolytically stable if,
when exposed to buffered saline at pH 7.4, for 1 to 24 h (for
example 5 h, 10 h, 15 h or 24 h), it does not show chemical
reaction or degradation when analyzed with ultra-performance liquid
chromatography (UPLC) or high-performance liquid chromatography
(using a method similar to that set out in "Evaluation methods").
In one embodiment, a compound is considered to be hydrolytically
stable if, following the treatment above, at least 80%, for example
at least 90% of 95% of the compound is recovered in un-degraded
form.
[0062] Whether a particular compound is hydrolytically stable or
not can depend on the pH. In one embodiment, the organic additive
is hydrolytically stable at physiological pH. In one embodiment,
physiological pH is pH 7.4.
[0063] Certain chemical functional groups such as esters, in
particular succinimidyl esters, sulfosuccinimidyl esters, acyl
halides, acetals, hemiacetals, and anhydrides are known to be prone
to hydrolysis therefore compounds containing such functionality
might, at the first instance, appear not be suitable as an organic
additive in the coating of the invention. However, the hydrolytic
stability of such functional groups can be enhanced by the
remaining functionality of the compound e.g. by steric or
electronic effects of neighbouring functional groups. Thus,
although the presence of functional groups known to be prone to
hydrolysis may, on a first assessment, indicate that a compound is
unsuitable for the purposes of being the organic additive, the
compound as a whole should be assessed. The following substances at
least are not suitable as organic additives for use in the present
invention because they are not hydrolytically stable:
gluconolactone, maleic anhydride, diglycolic anhydride and acetic
anhydride.
[0064] Early experiments indicated that vanillin was unsuitable for
use as the organic additive as it easily degraded in solution.
Thus, vanillin is not suitable as an organic additive for the
present invention. In one embodiment, the coating layer does not
contain vanillin. In one embodiment, the organic additive does not
contain phenolic aldehyde functionality. In another embodiment, the
coating of the invention does not contain compounds containing
phenolic aldehyde functionality.
[0065] The use of Hansen solubility parameters can assist in the
understanding or rationalization of the behaviour of a composition
comprising two or more components (Mohammed et al. International
Journal of Pharmaceutics 2011, Vol. 407 pp 63-71 and Albers et al.
Journal of Pharmaceutical Sciences 2011, Vol. 100 pp 667-680). In
one embodiment, the organic additive is a substance having a value
for the dispersion component of the Hansen solubility parameter
determined at 25.degree. C. substantially the same as that of
paclitaxel. In one embodiment, "substantially the same" means
within .+-.3.0 MPa.sup.0.5 of the value for the dispersion
component of the Hansen solubility parameter for paclitaxel
(determined at 25.degree. C.). Suitably the dispersion component of
the Hansen solubility parameter determined at 25.degree. C. of the
organic additive is between 16 and 21 MPa.sup.0.5.
[0066] The organic additive will typically have a low molecular
weight. For example, the organic additive will have a molecular
weight of less than 1200 Da, less than 990 Da, less than 750 Da,
less than 500 Da, less than 400 Da or less than 300 Da. In one
embodiment, the organic additive has a molecular weight of between
about 50 Da and about 400 Da, for example between about 80 Da and
about 350 Da. The organic additive is not a protein. In one
embodiment, the coating layer is free of protein. In a further
embodiment, the organic additive is not a therapeutic agent. In an
embodiment the organic additive is not aspirin.
[0067] The organic additive will typically have a melting point of
greater than 80.degree. C. when in pure form, for example greater
than 90.degree. C., greater than 100.degree. C., greater than
110.degree. C. or greater than 120.degree. C. Compounds with a
melting point lower than 80.degree. C. when in pure form generally
have weak intermolecular interactions, potentially leading to the
compound being physically unstable. Compounds that are capable of
forming coordinated solvates, such as a hydrate, with the
paclitaxel and/or the organic additive typically have physical
stability.
[0068] In one embodiment the (at least one) organic additive is
independently selected from the list consisting of p-aminobenzoic
acid, saccharin, ascorbic acid, methyl paraben, caffeine, calcium
salicylate, pentetic acid, creatinine, ethylurea, acetaminophen,
aspirin, theobromine, tryptophan, succinic acid, glutaric acid,
adipic acid, theophylline, and saccharin sodium. The formation of
compositions and coatings of the invention using these organic
additives is described in Examples 1 and 3. Suitably the (at least
one) organic additive is independently selected from the list
consisting of p-aminobenzoic acid, methyl paraben, caffeine,
calcium salicylate and succinic acid. In one embodiment the organic
additive is succinic acid. In another embodiment, the organic
additive is caffeine.
[0069] In an embodiment the organic additive is not sodium
salicylate. In an embodiment the organic additive is not calcium
salicylate. In an embodiment the organic additive is not magnesium
salicylate.
[0070] In an embodiment the organic additive is not a substance
containing magnesium ions i.e. a magnesium salt.
[0071] In an embodiment the organic additive is not ascorbic acid
or a salt thereof e.g. L-ascorbic acid or a salt thereof.
[0072] The therapeutic agent, when formulated in the coating layer,
should be able to withstand a sterilization process essentially
intact. A therapeutic agent within the coating layer is defined as
being essentially intact after sterilization, or is considered to
be stable to sterilization, if it exhibits no more than 20%
degradation after sterilization without aging, for example no more
than 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% degradation.
The therapeutic agent is considered to be degraded if it is
chemically altered following sterilization. Conversely, a
therapeutic agent in the coating layer is defined as being
essentially intact after sterilization, or is considered to be
stable to sterilization, if the coating retains at least 80% of the
therapeutic agent chemical content after sterilization, for example
at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or
substantially all of the therapeutic agent chemical content after
sterilization.
[0073] The amount of intact therapeutic agent in the coating
following sterilization can be determined using high-performance
liquid chromatography (HPLC) techniques such as ultra-performance
liquid chromatography (UPLC), for example using the UPLC method
described in the Evaluation methods section, and/or by mass
spectrometry.
[0074] Suitable sterilization processes include, but are not
limited to sterilization using ethylene oxide, vapour hydrogen
peroxide, plasma phase hydrogen peroxide, dry heat, autoclave steam
sterilization, chlorine dioxide sterilization, gamma ray
sterilization or electron beam sterilization. In one embodiment,
the therapeutic agent is essentially intact after ethylene oxide
sterilization, vapour hydrogen peroxide sterilization, plasma phase
hydrogen peroxide sterilization or electron beam sterilization. In
one embodiment, the therapeutic agent stable to ethylene oxide
sterilization, vapour hydrogen peroxide sterilization, plasma phase
hydrogen peroxide sterilization or electron beam sterilization (or
indeed multiple sterilization methods). Sterilization using
ethylene oxide is the most commonly utilized, proven and readily
available sterilization technique for implantable medical devices
such as stents, stent grafts, balloons and balloon catheters. Thus,
in one embodiment, the therapeutic agent is essentially intact
after sterilization using ethylene oxide. In another embodiment,
the therapeutic agent is stable to ethylene oxide
sterilization.
[0075] Specific evaluation methods "Test Method D", "Test Method
E", "Test Method F", and "Test Method G" are provided in the Test
Methods section for assessing stability to sterilization using
ethylene oxide, electron beam, vapour hydrogen peroxide, and plasma
hydrogen peroxide, respectively.
[0076] In one aspect of the invention is provided a coated medical
device as described herein which has been sterilized, e.g. ethylene
oxide sterilized.
[0077] In Example 12a, balloons coated with a paclitaxel-caffeine
coating and a paclitaxel-succinic acid coating (prepared according
to Example 3b) were testing using Test method D and were found to
retain >80% of their paclitaxel chemical content following
ethylene oxide sterilization.
[0078] In Example 12b, various paclitaxel-organic additive
compositions were tested using Test method D and were found to
retain between 88.5% and 100% of their paclitaxel chemical content
following ethylene oxide sterilization.
[0079] Compounds with certain functional groups such as primary
amides (--C(O)NH.sub.2) and primary alkyl amines (alkyl-NH.sub.2)
have been observed to be incompatible with paclitaxel, when
formulated together as a solid coating and subjected to ethylene
oxide sterilisation. An example of such a compound is niacinamide,
which (as described in Example 12c), when formulated with
paclitaxel and coated onto a balloon, resulted in nearly complete
paclitaxel degradation when the balloon was ethylene oxide
sterilised. Thus, compounds containing such functionality might
cause paclitaxel to degrade under ethylene oxide sterilization,
therefore might not be suitable as an organic additive in the
coating of the invention. However, the interaction of such
compounds with paclitaxel may be altered by the remaining
functionality of the molecule, for example, the reactivity of
primary amide or primary alkyl amine groups adjacent to aromatic
functionality can be tempered to the extent that such compounds
will not cause degradation of paclitaxel under ethylene oxide
sterilization conditions. The following substances at least are not
suitable as organic additives for use in the present invention
because they cause degradation of the paclitaxel under the
conditions of ethylene oxide sterilization: niacinamide and sodium
salicylate.
[0080] Thus, the organic additive is not niacinamide (also known as
nicotinamide) or sodium salicylate. In one embodiment, the coating
layer does not contain niacinamide.
[0081] As discussed in further detail below, coatings of the
invention can be prepared by pipetting a solution containing
therapeutic agent and excipient onto the device to be coated. Using
this method it is difficult to achieve a suitable coating unless
both components are soluble in the solution. The present inventors
found it was not possible to form coatings where the organic
additive has poor solubility in the solvent system. For example,
thiamine-HCl has poor solubility in acetone, ethanol and aqueous
mixtures thereof and attempts to formulate a
paclitaxel-thiamine-HCl coating on a balloon were unsuccessful.
Thus, in one embodiment the organic additive is not thiamine-HCl.
In another embodiment, the coating layer does not contain
thiamine-HCl.
[0082] Suitably the organic additive is not dexpanthenol. Suitably
the organic additive is not ricinoleic acid. Suitably the organic
additive is not resorcin. Suitably the organic additive is not
isomalt.
[0083] The coating layer is surfactant-free i.e. does not contain a
surfactant. Surfactants are defined herein as compounds that are
amphiphilic and contain both hydrophobic and hydrophilic groups and
include ionic, non-ionic, zwitterionic, aliphatic and aromatic
surfactants. Surfactants can be in monomeric, oligomeric or
polymeric form. Examples of surfactants include, but are not
limited to, polysorbate (Tween.RTM. 20, Tween.RTM. 40, Tween.RTM.
60), PEG-fatty esters, PEG mega-3 fatty esters, PEG ethers (such as
Triton X-100/octoxynol-9) and alcohols (such as tyloxapol),
glycerol fatty esters, sorbitan fatty esters, PEG, glyceryl fatty
esters, PEG sorbitan fatty esters, PEG sugar esters, poloxamers
(which may be sold under the trade names of Synperonics.RTM.,
Pluronics.RTM. and Kolliphor.RTM.), ascorbyl palmitate and
p-isononylphenoxypolyglycidol (Olin 10-G.RTM. or Surfactant
10-G.RTM.).
[0084] In one embodiment, the coating of the invention is free of
cyclodextrin.
[0085] In one embodiment, the coating of the invention is free of
inorganic components (e.g. salts having both inorganic cations and
inorganic anions). Suitably the coating of the invention is
bioabsorbable or is biostable.
[0086] In one embodiment, the coating layer consists of the
therapeutic agent and at least one organic additive. In this
embodiment, the coating layer does not comprise components other
than paclitaxel or at least one organic additives as described
herein.
[0087] In one embodiment, the coating layer comprises one organic
additive. In one embodiment, the coating layer consists of the
therapeutic agent which is paclitaxel and one organic additive as
described herein. In this embodiment, the coating of the invention
is a binary composition (See Examples 1 and 3 for examples of
binary compositions and coatings of the invention). In one
embodiment the organic additive is succinic acid. In another
embodiment, the organic additive is caffeine.
[0088] In one embodiment, the coating layer comprises two organic
additives. In one embodiment, the coating layer consists of the
therapeutic agent which is paclitaxel and two organic additives as
described herein. In this embodiment, the coating of the invention
is a ternary composition (see Example 14 for an example of a
ternary composition of the invention). In one embodiment, the two
organic additives are caffeine and succinic acid. In one
embodiment, the coating layer comprises three or more organic
additives.
[0089] In another embodiment, the coating of the invention is not a
ternary composition i.e. the coating consists of more or fewer than
three components. In another embodiment, the coating of the
invention is not a quaternary composition i.e. the coating consists
of more or fewer than four components.
[0090] Coatings of the invention are described as particulate
because when visually examined macroscopically, they appear
opaque/white and not glassy (i.e., transparent). Furthermore, when
the coating surface is analyzed using microscopy techniques such as
scanning electron microscopy (SEM) at a suitable magnification e.g.
5000.times., an abundance of individual particles of roughly 1
.mu.m length can be observed.
[0091] A key characteristic of the coating of the invention
comprising paclitaxel and at least one organic additive is that at
least a proportion of the coating exhibits a depressed melting
endotherm. A melting endotherm is observed in a differential
scanning calorimetry (DSC) measurement. Thus, "melting point" and
"peak melting endotherm" as referred to herein should be considered
as being equivalent. A "depressed melting endotherm" is observed
when a proportion of the coating comprising paclitaxel and at least
one organic additive melts as a single phase at a lower temperature
than the melting point of either paclitaxel or the at least one
organic additive when in pure form. If the coating layer or
composition contains more than one organic additive, the depressed
melting endotherm is lower than the melting points of all of the
organic additives present in the coating layer.
[0092] Reference to "at least a proportion" of the coating
exhibiting a depressed melting point is intended to cover the
scenario when the entire coating comprising paclitaxel and at least
one organic additive exhibits a depressed melting point i.e. the
remaining coating (other than the defined "proportion") can also
exhibit the same depressed melting point.
[0093] The proportion of the coating layer comprising paclitaxel
and the at least one organic additive which exhibits a depressed
melting point melts at the lower temperature as a single phase i.e.
a single depressed melting point is observed at which point both
the paclitaxel and the at least one organic additive melt
simultaneously.
[0094] In at least some embodiments it has been observed that the
coatings of the invention comprising paclitaxel and the at least
one organic additive are predominantly in crystalline form.
[0095] The coating layer may comprise crystalline particles of
paclitaxel and the at least one organic additive in the form of a
eutectic mixture, wherein the eutectic mixture exhibits a depressed
melting point. A eutectic mixture is defined herein as an
intimately blended physical mixture of two or more crystalline
components which melts as a single phase having a melting point
lower than that of either or any of its components. A eutectic
mixture tends to form when the two (or more) different crystalline
components are mismatched in terms of molecular size or molecular
shape such that cohesive interactions are relatively stronger than
adhesive interactions, leading to a conglomerate of the two or more
lattice structures, rather than a new lattice structure. Therefore,
an X-ray powder diffraction ("XRPD") pattern of such a
paclitaxel-organic additive coating would be expected to have an
XRPD pattern identical to, or substantially similar to, a
superimposition of the individual XRPD patterns of paclitaxel and
the organic additive. The XRPD pattern of such a coating would not
have a unique lattice arrangement distinct from the individual
components therefore peaks other than those corresponding to the
paclitaxel and organic additive would not be visible (Cherukuvada
et al., 2014, Chem. Comm, Vol. 50, pages 906-923). Without wishing
to be bound by theory, the inventors believe that the colligative
properties and high thermodynamic functions (e.g. free energy,
enthalpy and entropy) of a eutectic drug coating composition could
allow rapid transfer of the drug from the coating to an adjacent
tissue, while minimizing the nonspecific loss of drug from the
coating prior to transfer to the adjacent tissue.
[0096] Alternatively, the coating layer may comprise particles of
crystalline material comprising paclitaxel and the at least one
organic additive, sometimes referred to as a "co-crystal", wherein
the crystalline material exhibits a depressed melting point. A
co-crystal rather than a eutectic system is more likely to be
formed when the two (or more) individual components have a strong
adhesive interaction leading to an essentially single continuous
crystalline phase. A co-crystalline paclitaxel-organic additive
coating material would therefore be expected to exhibit a unique
XRPD pattern, different from that of the paclitaxel or organic
additive (Cherukuvada et al., 2014, Chem. Comm, Vol. 50, pages
906-923).
[0097] It is widely accepted that there are no ground rules or
structural guidelines as to the point at which the cohesive
interactions dominate over the adhesive interactions (to give a
eutectic) and vice versa (to give a co-crystal). It should be noted
that the exact structural nature of the coating and composition of
the invention (i.e. eutectic, co-crystal or mixture thereof) need
not be determined for the purposes of working the present
invention, as the key feature that all of the embodiments above
share is that of having a depressed melting point.
[0098] As mentioned above, paclitaxel can have an optional amount
of coordinated solvent, e.g. can be present in the composition in
the form of a solvate, such as a hydrate. In one embodiment, the
paclitaxel is present in the coating and composition as anhydrous
paclitaxel. In another embodiment, the paclitaxel is present in the
coating and composition in the form of a paclitaxel hydrate. In an
alternative embodiment, both anhydrous and hydrated forms of
paclitaxel may be present in the coating and composition of the
invention.
[0099] The relative amounts of paclitaxel and at least one organic
additive in the coating of the invention should be such that at
least a proportion of the coating will exhibit a depressed melting
point. This will depend to some extent on the nature of the at
least one organic additives, but can easily be determined by
varying the ratio of the two components and analysing the resulting
coatings by DSC to determine whether the required depressed melting
point is present.
[0100] In one embodiment, substantially all of the particulate
coating layer comprising paclitaxel and the at least one organic
additive melts as a single phase at a lower temperature than the
melting point of either the paclitaxel or the at least one organic
additive when in pure form. In this embodiment, a DSC thermogram of
the coating layer will show a single depressed melting point and no
visible endotherm corresponding to the melting of pure paclitaxel
or at least one pure organic additive. Examples of such thermograms
are shown in FIGS. 1A to 1C, where it is evident that samples of
paclitaxel-PABA (para-aminobenzoic acid), paclitaxel-succinic acid
and paclitaxel-adipic acid compositions of the invention (prepared
according to Example 1) all exhibited a single melting endotherm
which was at a lower temperature than the endotherms for pure
paclitaxel or PABA, succinic acid and adipic acid,
respectively.
[0101] In one embodiment, 20-100% (by weight) of the coating or
composition exhibits a depressed melting point (i.e. a melting
point which is at a lower temperature than the melting point of the
therapeutic agent and the at least one organic additive in pure
form) such as 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100%
90-100% or substantially all of the coating or composition exhibits
a depressed melting point. In embodiments where less than 100% of
the coating or composition is in a form which exhibits a depressed
melting point, the remaining material will be paclitaxel in pure
form, or at least one (if present) of the organic additives in pure
form, or a mixture thereof.
[0102] In one embodiment, a proportion of the particulate coating
layer comprising paclitaxel and at least one organic additive melts
as a single phase at a lower temperature than the melting point of
either the paclitaxel or the at least one organic additive when in
pure form, and the remaining particulate coating layer comprising
paclitaxel and at least one organic additive melts at or close to
the melting point of the at least one organic additive in pure
form. In this embodiment, a DSC thermogram of the coating layer
will show a single depressed melting point and an endotherm at or
close to the known melting point for the at least one pure organic
additive. In one embodiment, "close to" the known melting point
means within .+-.10.degree. C. of the known melting point for the
pure organic additive, for example within .+-.5.degree. C., within
.+-.4.degree. C., within .+-.3.degree. C., within .+-.2.degree. C.
or within .+-.1.degree. C. An example of such a thermogram is shown
in FIG. 8 with a depressed melting endotherm at around 160.degree.
C. (corresponding to paclitaxel-succinic acid) and an endotherm at
around 185.degree. C., corresponding to the melting point of
succinic acid in pure form (around 189.degree. C.). In this
embodiment, the proportion of organic additive which melts at a
temperature at or close to the melting point of the organic
additive in pure form is suitably lower than the proportion of
organic additive in the paclitaxel-organic additive material which
melts with a single depressed melting point. In a coating
comprising two organic additives, a DSC thermogram may show a
single depressed melting point and one or two endotherms
corresponding to the known melting point of one, or both of the
organic additives in pure form.
[0103] In one embodiment, the proportion of organic additive which
melts at a temperature at or close to the melting point of the
organic additive in pure form is 1-80% (wt %) of the organic
additive in the coating or composition e.g. 1-70%, 1-60%, 1-50%,
1-40%, 1-30%, 1-20%, 1-10%, 1-5% or 1-2%.
[0104] In a further embodiment, a proportion of the particulate
coating layer comprising paclitaxel and at least one organic
additive melts as a single phase at a lower temperature than the
melting point of either the paclitaxel or the at least one organic
additive when in pure form, and the remaining particulate coating
layer comprising paclitaxel and at least one organic additive melts
at or close to the melting point of the paclitaxel in pure form. In
this embodiment, a DSC thermogram of the coating layer will show a
single depressed melting point and an endotherm at or close to the
known melting point for paclitaxel. In this embodiment, the
proportion of paclitaxel which melts at a temperature at or close
to the melting point of the paclitaxel in pure form is suitably
lower than the proportion of paclitaxel in the paclitaxel-organic
additive material which melts with a single depressed melting
point.
[0105] In one embodiment, the proportion of paclitaxel which melts
at a temperature at or close to the melting point of the paclitaxel
in pure form is 1-80% (wt %) of the paclitaxel in the coating or
composition e.g. 1-70%, 1-60%, 1-50%, 1-40%, 1-30%, 1-20%, 1-10%,
1-5% or 1-2%.
[0106] In a still further embodiment, a proportion of the
particulate coating layer comprising paclitaxel and at least one
organic additive melts as a single phase at a lower temperature
than the melting point of either the paclitaxel or the at least one
organic additive when in pure form, and the remaining particulate
coating layer comprising paclitaxel and at least one organic
additive exhibits two melting endotherms: one at or close to the
melting point of the paclitaxel in pure form and the other at or
close to the melting point of the at least one organic additive in
pure form. In this embodiment, a DSC thermogram of the coating
layer will show a single depressed melting point and one endotherm
at or close to the known melting point for paclitaxel and another
endotherm at or close to the known melting point for the at least
one organic additive. In this embodiment, the proportion of
paclitaxel which melts at a temperature at or close to the melting
point of the paclitaxel in pure form is suitably less that the
proportion of paclitaxel in the paclitaxel-organic additive
material which melts with a single depressed melting point, and the
proportion of organic additive which melts at a temperature at or
close to the melting point of the at least one organic additive in
pure form is suitably less that the proportion of organic additive
in the paclitaxel-organic additive material which melts with a
single depressed melting point.
[0107] The relative proportions of 1) paclitaxel/organic additive
composition exhibiting a depressed melting point; and 2)
paclitaxel/organic additive composition with a melting point at or
close to the melting point of pure paclitaxel and/or organic
additive can be determined by DSC analysis because the area under
the relevant endotherms can be correlated to the relative amount of
each component 1) or 2) in the coating as a whole (in terms of
weight, which can be converted to a molar ratio if required). A
representative calculation is set out in Example 13.
[0108] As mentioned above, the coating layer or composition of the
invention can be analysed by ultra-performance liquid
chromatography (UPLC) and/or by mass spectrometry to determine the
amount of paclitaxel in the coating layer or composition. When the
weight % of paclitaxel in the solid coating is known, as in the
case of a binary coating layer or composition (i.e. paclitaxel+one
organic additive only) then the weight % of the organic additive
can easily be determined as being 100-paclitaxel wt %.
[0109] In one embodiment, the weight % of therapeutic agent i.e.
paclitaxel in the solid composition or coating is between about 5
wt. % and about 95 wt. %, for example between about 10 wt. % and
about 95 wt. %, between about 20 wt. % and about 95 wt. %, between
about 30 wt. % and about 90 wt. %, between about 45 wt. % and about
85 wt. %, between about 55 wt. % and about 70 wt. %, between about
40 wt. % and about 80 wt. %, between about 25 wt % and about 95 wt.
%, between about 30 wt. % and about 85 wt. %, between about 70 wt.
% and about 95 wt. %, 70 wt. % and about 80 wt. % or between about
75 wt. % and about 80 wt. %.
[0110] In one embodiment, the organic additive is PABA and the
weight % of paclitaxel in the solid composition or coating layer is
between about 30 wt. % and about 90 wt. %, for example between
about 40 wt. % and about 80 wt. %. In one embodiment, the organic
additive is PABA and the ratio (wt. %) of paclitaxel:PABA in the
solid composition or coating layer is between about 3:7 and about
9:1, for example between about 2:3 and about 4:1.
[0111] In one embodiment, the organic additive is methyl paraben
and the weight % of paclitaxel in the solid composition or coating
layer is between about 45 wt. % and about 85 wt. %, for example
between about 55 wt. % and about 70 wt. %. In one embodiment, the
organic additive is methyl paraben and the ratio (wt. %) of
paclitaxel:methyl paraben in the solid composition or coating layer
is between about 4:5 and about 9:1, for example between about 1:1
and about 7:3.
[0112] In one embodiment, the organic additive is caffeine and the
weight % of paclitaxel in the solid composition or coating layer is
between about 70 wt. % and about 95 wt. %, for example between
about 75 wt. % and about 90 wt. %. In one embodiment, the organic
additive is caffeine and the ratio (wt. %) of paclitaxel:caffeine
in the solid composition or coating layer is between about 7:3 and
about 95:5, for example between about 3:1 and about 9:1 wt. %.
[0113] In one embodiment, the organic additive is calcium
salicylate and the weight % of paclitaxel in the solid composition
or coating layer is between about 70 wt. % and about 90 wt. %, for
example between about 75 wt. % and about 80 wt. %. In one
embodiment, the organic additive is calcium salicylate and the
ratio (wt. %) of paclitaxel:calcium salicylate in the solid
composition or coating layer is between about 7:3 and about 9:1,
for example between about 3:1 and about 4:1.
[0114] In one embodiment, the organic additive is succinic acid and
the weight % of paclitaxel in the solid composition or coating is
between about 70 wt. % and about 90 wt. %, for example between
about 75 wt. % and about 85 wt. %. In one embodiment, the organic
additive is succinic acid and the ratio (wt. %) of
paclitaxel:succinic acid in the solid composition or coating layer
is between about 7:3 and about 9:1, for example between about 3:1
wt. % and about 6:1.
[0115] In one embodiment the organic additive is selected from the
group consisting of p-aminobenzoic acid (PABA), saccharin, ascorbic
acid, methyl paraben, caffeine, calcium salicylate, pentetic acid,
creatinine, ethylurea, acetaminophen, aspirin, theobromine,
tryptophan, succinic acid, glutaric acid, adipic acid,
theophylline, and saccharin sodium, and weight % of paclitaxel in
the solid composition or coating layer is between about 30 wt. %
and about 90 wt. %, such as between about 50 wt. % and about 90 wt.
%.
[0116] In one embodiment the organic additive is selected from the
group consisting of p-aminobenzoic acid, saccharin, ascorbic acid,
methyl paraben, caffeine, calcium salicylate, pentetic acid,
creatinine, ethylurea, acetaminophen, aspirin, theobromine,
tryptophan, succinic acid, glutaric acid, adipic acid,
theophylline, and saccharin sodium, and the ratio (wt. %) of
paclitaxel:organic additive is between about 3:7 and about 9:1,
such as between about 1:1 and about 9:1.
[0117] In one embodiment the organic additive is selected from the
group consisting of p-aminobenzoic acid, methyl paraben, caffeine,
calcium salicylate and succinic acid, and the weight % of
paclitaxel in the solid composition or coating layer is between
about 30 wt. % and about 90 wt. %, such as between about 50 wt. %
and about 90 wt. %.
[0118] In one embodiment the organic additive is selected from the
list consisting of p-aminobenzoic acid, methyl paraben, caffeine,
calcium salicylate and succinic acid and the ratio (wt. %) of
paclitaxel:organic additive is between about 3:7 and about 9:1,
such as between about 1:1 and about 9:1.
[0119] The coating layer of the invention need not be applied
directly to a surface of the medical device. Embodiments of medical
devices coated with a composition of the invention can also include
additional coatings underlying or overlaying the composition of the
invention. Such additional coatings are separate and distinct from
the coating layer of the invention. Such additional coatings can be
used to increase adherence between the device surfaces and the
composition of the invention or used to limit or meter elution of
therapeutic agents from the composition. These additional coatings
can include other therapeutic agents (such as those listed directly
above), alone or in combination with various excipients or
carriers. In one embodiment, the amount or thickness of the
additional coating may be varied over the surface of the medical
device. The additional coating layer can be continuous over an
entire surface of the device or be discontinuous and cover only a
portion or separate portions of the device. The additional coating
layer can also be "sculpted" or modified to create a desired
surface topography or texture.
[0120] In one embodiment, an adherent layer is interposed between
the solid coating layer and the material of the surface of the
device. The adherent layer, which is a separate and distinct layer
underlying the paclitaxel-excipient coating layer improves the
adherence of the drug coating layer to the surface of the medical
device and further maintains the integrity of the coating,
particularly during transit to the tissue to the be treated. In one
embodiment, the adherent layer comprises a polymer, which is
suitably biocompatible and avoids irritation of body tissue.
Examples of such polymers include, but are not limited to
polyolefins, polyisobutylene, ethylene-.alpha.-olefin copolymers,
acrylic polymers and copolymers, polyvinyl chloride, polyvinyl
methyl ether, polyvinylidene fluoride and polyvinylidene chloride,
fluoropolymers, e.g. expanded polytetrafluoroethylene (ePTFE),
polytetrafluoroethylene (PTFE), fluorinated ethylene-propylene
(FEP), perfluorocarbon copolymers, e.g. tetrafluoroethylene
perfluoroalkylvinyl ether (TFE/PAVE) copolymers, copolymers of
tetrafluoroethylene (TFE) and perfluoromethyl vinyl ether (PMVE),
copolymers of TFE with functional monomers that comprise acetate,
alcohol, amine, amide, sulfonate, functional groups and the like as
described in U.S. Pat. No. 8,658,707 (W.L. Gore and Associates,
incorporated herein by reference, as well as combinations thereof),
polyacrylonitrile, polyvinyl ketones, polystyrene, polyvinyl
acetate, ethylene-methyl methacrylate copolymers,
acrylonitrile-styrene copolymers, ABS resins, Nylon 12 and its
block copolymers, polycaprolactone, polyoxymethylenes, polyethers,
epoxy resins, polyurethanes, rayon-triacetate, cellulose, cellulose
acetate, cellulose butyrate, cellophane, cellulose nitrate,
cellulose propionate, cellulose ethers, carboxymethyl cellulose,
chitins, polylactic acid, polyglycolic acid, polylactic
acid-polyethylene oxide copolymers, polyethylene glycol,
polypropylene glycol, polyvinyl alcohol, elastomeric polymers such
as silicones (e.g., polysiloxanes and substituted polysiloxanes),
polyurethanes, thermoplastic elastomers, ethylene vinyl acetate
copolymers, polyolefin elastomers, EPDM rubbers and mixtures
thereof.
[0121] In another embodiment, an additional coating layer
comprising a therapeutic agent other than paclitaxel is interposed
between the solid coating layer and the material of the surface of
the device. Said coating layer is a separate and distinct layer
underlying the paclitaxel-excipient coating layer and may provide a
therapeutic benefit in addition to the benefit provided by the
paclitaxel i.e. allowing for adjunctive therapies to be combined
with the paclitaxel-organic additive. For example, a coating of the
invention can be applied to a medical device already coated with an
immobilized biologically active heparin coating, while maintaining
the activity of both coatings (i.e. the anti-proliferative effect
of the paclitaxel-organic additive composition and the antithrombin
III (ATIII) binding activity of the heparin, as measured by known
analytical methods. Thus, coated medical devices of the invention
with a heparin bonded under-coating appear to have the added
benefit of producing a reduction in sub-acute thrombosis after
implantation. Example 7 describes such an embodiment, in which a
vascular stent composed of nitinol and ePTFE was coated with a
heparin bonded surface. The heparin-coated stent was then further
coated with a paclitaxel-excipient composition of the invention
(paclitaxel-caffeine). As shown in Example 8, the dual coated stent
was found to demonstrate a high degree of durability. Furthermore,
as described in Example 9, when the paclitaxel-excipient coating
was removed from the surface of the stent, the underlying
heparin-bonded surface had retained its ATIII activity. In one
embodiment, the additional coating layer comprises a therapeutic
agent other than paclitaxel. Alternatively, said additional coating
layer comprising a therapeutic agent other than paclitaxel will
overlay a portion, or all of the coating layer of the invention. As
described above, such coating layer is a separate and distinct
layer overlying the paclitaxel-organic additive(s) coating
layer.
[0122] In one embodiment, the additional coating layer comprises a
therapeutic agent selected from cilostazol, everolimus, dicumarol,
zotarolimus, carvedilol, anti-thrombotic agents such as heparin,
heparin derivatives, urokinase, and dextrophenylalanine proline
arginine chloromethylketone; antiinflammatory agents such as
dexamethasone, prednisolone, corticosterone, budesonide, estrogen,
sulfasalazine and mesalamine, sirolimus and everolimus (and related
analogs), anti-neoplastic/antiproliferative/anti-miotic agents such
as major taxane domain-binding drugs, such as paclitaxel and
analogues thereof, epothilone, discodermolide, docetaxel,
paclitaxel protein-bound particles such as ABRAXANE.RTM. (ABRAXANE
is a registered trademark of ABRAXIS BIOSCIENCE, LLC), paclitaxel
complexed with an appropriate cyclodextrin (or cyclodextrin like
molecule), rapamycin and analogues thereof, rapamycin (or rapamycin
analogs) complexed with an appropriate cyclodextrin (or
cyclodextrin like molecule), 17.beta.-estradiol, 17.beta.-estradiol
complexed with an appropriate cyclodextrin, dicumarol, dicumarol
complexed with an appropriate cyclodextrin, .beta.-lapachone and
analogues thereof, 5-fluorouracil, cisplatin, vinblastine,
cladribine, vincristine, epothilones, endostatin, angiostatin,
angiopeptin, monoclonal antibodies capable of blocking smooth
muscle cell proliferation, and thymidine kinase inhibitors; lytic
agents; anaesthetic agents such as lidocaine, bupivacaine and
ropivacaine; anti-coagulants such as D-Phe-Pro-Arg chloromethyl
ketone, an RGD peptide-containing compound, AZX100 a cell peptide
that mimics HSP20 (Capstone Therapeutics Corp., USA), heparin,
hirudin, antithrombin compounds, platelet receptor antagonists,
anti-thrombin antibodies, anti-platelet receptor antibodies,
aspirin, prostaglandin inhibitors, platelet inhibitors and tick
antiplatelet peptides; vascular cell growth promoters such as
growth factors, transcriptional activators, and translational
promoters; vascular cell growth inhibitors such as growth factor
inhibitors, growth factor receptor antagonists, transcriptional
repressors, translational repressors, replication inhibitors,
inhibitory antibodies, antibodies directed against growth factors,
Afunctional molecules consisting of a growth factor and a
cytotoxin, b (functional molecules consisting of an antibody and a
cytotoxin; protein kinase and tyrosine kinase inhibitors (e.g.,
tyrphostins, genistein, quinoxalines); prostacyclin analogs;
cholesterol-lowering agents; angiopoietins; antimicrobial agents
such as triclosan, cephalosporins, aminoglycosides and
nitrofurantoin; cytotoxic agents, cytostatic agents and cell
proliferation affectors; vasodilating agents; agents that interfere
with endogenous vasoactive mechanisms; inhibitors of leukocyte
recruitment, such as monoclonal antibodies; cytokines; hormones,
radiopaque agents such as iodinated contrast agents, gold, or
barium, or a combination thereof. Suitably an additional coating
layer comprises heparin.
[0123] In one embodiment, the medical device further comprises a
protective top coat overlying the surface of the coating layer. The
top coat may further minimise loss of the paclitaxel-excipient
layer before it is brought into contact with target tissues, for
example during device assembly and packaging, transit to the site
to be treated, or if the device is a balloon or stent, during the
first moments of inflation or expansion before coating layer is
pressed into direct contact with target tissue. The top coat may be
of particular use during crush loading, for example when an
expandable medical device such as a balloon, stent, stent-graft or
graft is coated in its expanded form, before being contracted into
its non-expanded form. The contracted form of the coated device
will usually be stored for a period of time before use. A top
coating may prevent loss of the coating layer of the invention
during storage and during expansion when the device is deployed.
Alternatively, or additionally, the top coat may have lubricious
properties to reduce frictional forces on the device while in
transit. Suitably the top coat is degradable or soluble and will
release slowly in the body lumen while protecting the drug layer.
The top layer will erode more slowly if it is comprised of more
hydrophobic, high molecular weight additives. Surfactants are
examples of more hydrophobic structures with long fatty chains,
such as Tween 20 and polyglyceryl oleate. High molecular weight
additives include polyethylene oxide, polyethylene glycol, and
polyvinyl pyrrolidone. Hydrophobic drug itself can act as a top
layer component. For example, paclitaxel or rapamycin are
hydrophobic. They can be used in the top layer. On the other hand,
the top layer cannot erode too slowly or it might actually slow the
release of drug during deployment at the target site. Other
additives useful in the top coat include additives that strongly
interact with drug or with the coating layer, such as
p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,
Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG
glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,
polyglyceryl oleate, polyglyceryl myristate, polyglyceryl
palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,
polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10
laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,
polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitan
monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG
oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol,
sucrose monopalmitate, sucrose monolaurate,
decanoyl-N-methylglucamide, n-decyl-[beta]-D-glucopyranoside,
n-decyl-[beta]-D-maltopyranoside,
n-dodecyl-[beta]-D-glucopyranoside, n-dodecyl-[beta]-D-maltoside,
heptanoyl-N-methylglucamide, n-heptyl-[beta]-D-glucopyranoside,
n-heptyl-[beta]-D-thioglucoside, n-hexyl-[beta]-D-glucopyranoside,
nonanoyl-N-methylglucamide, n-noyl-[beta]-D-glucopyranoside,
octanoyl-N-methylglucamide, n-octyl-[beta]-D-glucopyranoside,
octyl-[beta]-D-thioglucopyranoside; cysteine, tyrosine, tryptophan,
leucine, isoleucine, phenylalanine, asparagine, aspartic acid,
glutamic acid, and methionine; acetic anhydride, benzoic anhydride,
ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone
carboxylate, ethylenediaminetetraacetic dianhydride, maleic and
anhydride, succinic anhydride, diglycolic anhydride, glutaric
anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;
cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal
5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin
phosphate, thiamine, folic acid, menadiol diphosphate, menadione
sodium bisulfite, menadoxime, vitamin B12, vitamin K5, vitamin K6,
vitamin K6, and vitamin U; albumin, immunoglobulins, caseins,
hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin,
fibronectins, vitronectins, fibrinogens, lipases, benzalkonium
chloride, benzethonium chloride, docecyl trimethyl ammonium
bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium
chloride, and dialkylesters of sodium sulfosuccinic acid,
L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,
tromethamine, triethanolamine, diethanolamine, meglumine,
glucamine, amine alcohols, glucoheptonic acid, glucomic acid,
hydroxyl ketone, hydroxyl lactone, gluconolactone,
glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,
mannoic lactone, ribonic acid lactone, lactobionic acid,
glucosamine, glutamic acid, benzyl alcohol, benzoic acid,
hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate salt,
gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic
acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol,
cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,
ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,
catechin gallate, tiletamine, ketamine, propofol, lactic acids,
acetic acid, salts of any organic acid and organic amine,
polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene
glycol), tri(ethylene glycol), tetra(ethylene glycol),
penta(ethylene glycol), poly(ethylene glycol) oligomers,
di(propylene glycol), tri(propylene glycol), tetra(propylene
glycol, and penta(propylene glycol), poly(propylene glycol)
oligomers, a block copolymer of polyethylene glycol and
polypropylene glycol, PTFE, ePTFE and derivatives and combinations
thereof.
[0124] As discussed above, the coated medical device of the
invention may comprise an additional coating layer such as an
adherent layer, an additional layer comprising a therapeutic agent
or a top coat layer. It should be noted that such additional layers
are considered to be distinct and separate layers to the coating
layer of the invention which comprises paclitaxel and at least one
organic additive and exhibits a depressed melting point. For
example, while the coating layer of the invention (i.e. the coating
layer which comprises the paclitaxel and at least one organic
additive in a form exhibiting a depressed melting point) is
surfactant-free, the medical device can have a distinct and
separate coating layer comprising surfactant, either underlying or
overlying the coating of the invention. Similarly, although in one
embodiment the coating of the invention does not contain protein,
the medical device may have a further coating layer, underlying or
overlying the coating layer of the invention, which comprises
protein. Thus, a component in the additional coating layer will not
form part of the paclitaxel-excipient material which exhibits a
depressed melting point.
[0125] In a situation where a medical device has multiple coating
layers in addition to the coating layer of the invention, the
presence of a depressed melting point may be difficult to confirm.
However, in this situation, the presence of a melting point which
does not correspond to any of the coating components is suggestive
of the formation of paclitaxel-organic excipient material
exhibiting a depressed melting point, particularly if the
characteristic melting endotherms corresponding to paclitaxel and
the organic excipient are also absent.
[0126] As discussed above, a particular challenge when developing a
solid drug coating for a medical device is to achieve a balance
between having sufficient adhesion to the device such that the
coating is not lost/damaged in transit, yet also having suitable
release characteristics such that the drug will transfer from the
coating to the target tissue i.e. if the adhesion of the coating is
too strong, the coating will be durable but an insufficient amount
of the drug will be released and will result in suboptimal
efficacy. Conversely, a coating may have excellent release
characteristics but if the coating does not have sufficient
adhesion to the device then an insufficient amount of drug will
reach the target tissue, and unintentional release of the drug in
areas other than the target tissue may be detrimental to the
patient.
[0127] The coating layer of the present invention provides a good
balance of good adhesion to a medical device, thereby minimising or
even eliminating coating loss during transit of the device, and
suitable release characteristics such that the paclitaxel is
delivered in an effective and efficient manner to the target
tissue. Paclitaxel-excipient compositions of the invention were
coated onto balloons as described in Example 3, and the durability
of the coatings was assessed using an adhesion test, as described
in Example 4. The results of the experiment are summarised in FIG.
2 where it can be seen that the addition of an excipient increased
adhesion of the coating to the balloon, as reflected by the lower %
of drug coating lost during shaking for all coating layers
containing an excipient. As noted in Example 4, the adherence of a
paclitaxel-only coating was found to be prima facie so poor that it
was not included in the test. Examples 5 and 6 describe in vitro
and in vivo tests to examine balloons coated according to Example 2
for their efficacy in transferring paclitaxel from the balloon
surface to a vascular tissue. As summarized in FIGS. 3, 5 and 6,
significant transfer of paclitaxel from the surface of the balloon
to the target tissue was observed.
[0128] In one embodiment, the coating of the invention has suitable
adherence such that less than 40% of the paclitaxel is lost during
shaking, for example less than 30%, less than 25%, less than 20%,
less than 15%, less than 10% or less than 5%, using Test Method C,
as described in Example 4.
[0129] In one embodiment, the coating of the invention has suitable
release characteristics such that using Test Method A a coated
balloon of the invention will release at least 50 .mu.g drug per g
tissue (.mu.g/g), for example at least 60 .mu.g/g, at least 70
.mu.g/g or at least 80 .mu.g/g of paclitaxel to the tested tissue,
as described in Example 5.
[0130] The release characteristics of a composition of the
invention may determine its suitability for a use in coating a
particular type of medical device. Coatings of the invention which
exhibit very fast release of paclitaxel are particularly suitable
for use on DEBs, where once inflated the balloon is in contact with
the target tissue for a relatively short amount of time before
being removed. Conversely, a coating which exhibits relatively
slower release of paclitaxel is better suited for use on a DES (or
stent or stent graft (SSG)) which is retained within the
vessel.
Therapeutic Methods
[0131] Medical devices coated with the novel paclitaxel-excipient
compositions of the invention are of use in medical therapy.
[0132] In one aspect of the invention is provided a medical device
with a coating layer as described hereinabove for use in treating
tissue in the human or animal body. The tissue to be treated
includes any body cavity, space, or hollow organ passage(s) such as
blood vessels, the urinary tract, the intestinal tract, nasal
cavity, neural sheath, intervertebral regions, bone cavities,
esophagus, intrauterine spaces, pancreatic and bile ducts, rectum,
and those previously intervened body spaces that have implanted
vascular grafts, stents, prosthesis, or other type of medical
implants.
[0133] The medical device with a coating layer as described herein
can be of use in the removal of obstructions such as emboli and
thrombi from blood vessels, as a dilation device to restore patency
to an occluded body passage, as an occlusion device to selectively
deliver a means to obstruct or fill a passage or space, and as a
centering mechanism for transluminal instruments like
catheters.
[0134] In one aspect of the invention is provided a medical device
with a coating layer as described hereinabove for use in the
prevention or treatment of stenosis or restenosis in a blood vessel
of the human body. In another aspect of the invention is provided a
medical device with a coating layer as described hereinabove for
use in the prevention or treatment of stenosis or restenosis in a
blood vessel of the human body, where previously placed eluting
constructs have failed. In another embodiment, a medical device
with a coating layer as described herein can be used to establish
or maintain arteriovenous access sites, e.g., those used during
kidney dialysis.
[0135] In one embodiment, said medical device with a coating layer
as described herein can be used for Percutaneous Transluminal
Angioplasty (PTA) in patients with obstructive disease of the
peripheral arteries.
[0136] In another aspect of the invention is provided a method for
the prevention or treatment of stenosis or restenosis which
comprises inserting transiently or permanently into said blood
vessel in the human body a medical device with a coating layer as
described hereinabove.
[0137] Paclitaxel-excipient solid compositions exhibiting a
depressed melting endotherm as described hereinabove are of use in
coating an exterior surface of a medical device, but may have
further utility per se as pharmaceutical compositions.
[0138] In one embodiment is provided a solid particulate
composition comprising a therapeutic agent and at least one organic
additive, wherein at least a proportion of the particulate
composition melts as a single phase at a lower temperature than the
melting point of the therapeutic agent and the at least one organic
additive when in pure form; wherein the therapeutic agent is
paclitaxel and wherein the at least one organic additive is
independently selected from the list consisting of p-aminobenzoic
acid, saccharin, ascorbic acid, methyl paraben, caffeine, calcium
salicylate, pentetic acid, creatinine, ethylurea, acetaminophen,
aspirin, theobromine, tryptophan, succinic acid, glutaric acid,
adipic acid, theophylline, and saccharin sodium.
[0139] In another embodiment is provided a solid particulate
composition comprising a mixture of components (a) a therapeutic
agent and at least one organic additive in a particulate form which
melts as a single phase at a lower temperature than the melting
point of the therapeutic agent and the at least one organic
additive when in pure form and (b) a component which is the organic
additive in the form of particles which melt at a temperature at or
close to that of the at least one organic additive in pure form;
wherein the therapeutic agent is paclitaxel and wherein the at
least one organic additive is independently selected from the list
consisting of p-aminobenzoic acid, saccharin, ascorbic acid, methyl
paraben, caffeine, calcium salicylate, pentetic acid, creatinine,
ethylurea, acetaminophen, aspirin, theobromine, tryptophan,
succinic acid, glutaric acid, adipic acid, theophylline, and
saccharin sodium.
[0140] Suitably the solid composition comprises at least one
organic additive independently selected from calcium salicylate,
caffeine, methyl paraben, p-aminobenzoic acid and succinic acid. In
one embodiment, the solid composition comprises succinic acid as
the single organic additive or as one of a number of organic
additives. In one embodiment is provided a solid particulate
composition as described herein above in the form a coating applied
to a surface. Suitably the surface is the exterior surface of a
medical device. It should be noted that all embodiments described
above with respect to the coating of the invention apply equally to
the solid composition of the invention.
[0141] In another embodiment is provided a solid particulate
composition as described hereinabove for use in the prevention or
treatment of stenosis or restenosis. In a further embodiment is
provided a solid particulate composition as described hereinabove
for the treatment of cancer, in particular cancers of the ovary,
breast, lung, oesophagus, head and neck region, bladder, prostate,
brain, liver, colon and lymphomas. The solid particulate
composition can be administered by any convenient method, e.g. by
oral, inhalation, parenteral (including injection or infusion),
buccal, sublingual, nasal, rectal or transdermal administration and
the pharmaceutical compositions adapted accordingly.
[0142] The coated medical device of the invention will typically
comprise a single dose of paclitaxel. The dose of paclitaxel
delivered will depend on many factors including the size of the
coated area, the length of time the coated device is in contact
with the target tissue and the amount of paclitaxel in the coating.
Suitably the medical device has a coating layer containing an
average of 0.1-10 .mu.g/mm.sup.2 of paclitaxel, such as 0.2-8
.mu.g/mm.sup.2, 0.5-5 .mu.g/mm.sup.2, or 1-4 .mu.g/mm.sup.2 e.g. 2
.mu.g/mm.sup.2, 3 .mu.g/mm.sup.2 or 4 .mu.g/mm.sup.2 of paclitaxel.
The apparent coated surface area does not take account of porosity
considerations of a porous substrate material. If the substrate
material is porous, the effect of porosity on surface area is not
considered for these calculations. For example, the apparent
surface area of a cylindrical tubular ePTFE vascular graft (which
is made of a porous material) with a paclitaxel-excipient coating
of the invention comprising the inner surface of the tubular graft
is calculated as it is for any cylindrical geometry as 2.pi.rl:
where r is the graft inner radius; L is the axial length; and .pi.
is the number pi. It is important to note that the porous nature of
ePTFE and its effect on surface area is not accounted for herein.
Accordingly, non-porous substrate materials that are cut into
squares for analysis are taken to have a surface area of the length
multiplied by the width.
[0143] The coated medical device of the invention will typically
contain 0.1-300 mg of paclitaxel in total, for example 0.1-250 mg,
0.1-200 mg, 0.1-150 mg, 0.1-100 mg, 0.1-90 mg, 0.1-80 mg, 0.1-70
mg, 0.1-60 mg, 0.1-50 mg, 0.1-40 mg, 0.1-30 mg, 0.2-20 mg, 0.2-10
mg or 0.2-5 mg. In one embodiment, the coated medical device is a
balloon and the coating layer contains 20 mg of paclitaxel in
total. In one embodiment, the coated medical device is a stent and
the coating layer contains 10 mg of paclitaxel in total. In one
embodiment, the coated medical device is a stent graft and the
coating layer contains 10 mg of paclitaxel in total.
Methods for Preparing Compositions and Coatings of the
Invention
[0144] Solid paclitaxel-excipient particulate compositions can be
prepared by a multitude of methods. One method involves adding
saturated solutions of excipient to a vial containing cast
paclitaxel film. The mixture is stirred until a precipitate is
formed, which is then filtered and dried to yield the particulate
composition. Suitably the at least one organic additive is
dissolved in acetone or a mixture of acetone/water for example
between about 50/50 and 95/5, between about 60/40 and 90/10,
between about 70/30 and about 90/10 or between about 70/30 and
about 75/25 acetone/water (v/v), such as 90/10, 75/25 or 70/30
acetone/water (v/v). A representative procedure is described in
Example 1.
[0145] Another method of preparing a coating of the invention is by
evaporation of a solution of paclitaxel and the at least one
organic additive applied to a device. Suitably, the solution of the
paclitaxel and the at least one organic additive is a solution in a
solvent selected from water, acetone and mixtures thereof, for
example between about 50/50 and 95/5, between about 60/40 and
90/10, between about 70/30 and about 90/10 or between about 70/30
and about 75/25 acetone/water (v/v), such as 90/10, 75/25 or 70/30
acetone/water (v/v). Thus, in one aspect of the invention is
provided a method for preparing a medical device with a coating
layer as described herein which comprises the steps of dissolving
the therapeutic agent and the at least one organic additive in a
solvent to form a solution, coating the device with the solution
and evaporating the solvent.
[0146] A coating of the invention may be applied to a medical
device using a method which involves minimal solvent, or indeed no
solvent. For example, a dry powder method may be used which
involves combining the paclitaxel and at least one organic additive
in powder form before applying to the device to form a solid
particulate composition, optionally followed by thermal treatment.
The powder mixture of paclitaxel and at least one organic additive
is suitably spayed on to the device, which optionally comprises an
adhesive layer (as described hereinabove), which may be followed by
thermal treatment, for example, to affix the layer to the surface
of the device.
[0147] Thus, in one embodiment is provided a method for preparing a
medical device as described herein above which comprises the steps
of combining the therapeutic agent and the at least one organic
additive in powder form, and then applying the powder to the device
to form a solid particulate composition. An additional thermal
treatment step may subsequently be applied, for example to affix
the coating to the surface of the medical device.
[0148] Various methods for forming the coating of the invention by
evaporation of a solution of paclitaxel and at least one organic
additive can used. The solution of paclitaxel and at least one
organic additive can be pipetted over the exterior surface of the
device, which is itself under rotation, e.g. pipetting 90-100 ul of
the coating solution over the device at a time. Alternatively, the
device can simply be dipped into the solution of paclitaxel and at
least one organic additive, removed and then air dried. The dipping
and drying process can be repeated as many times as is necessary to
achieve the desired coating thickness or loading of paclitaxel.
Other techniques such as casting, spinning, spraying, ink jet
printing, electrostatic techniques, painting, dispersion coating,
powder coating, or combinations thereof may be used to form the
coating.
[0149] Following application of the coating a drying step may be
required. The coating drying environment may be controlled as a
function of time, such as by controlling/modulating the air
composition, flow rate and flow patterns, air temperature,
localized heating (e.g., heat lamp), etc, to thereby control
physical properties of the coating.
[0150] In one embodiment, the or an organic additive is PABA and
the weight % of paclitaxel in the pipetting/dipping solution (based
on the total weight of solid components added) is between about 30
wt. % and about 90 wt. %, for example between about 40 wt. % and
about 80 wt. %. In one embodiment, the or an organic additive is
PABA and the ratio (wt. %) of paclitaxel:PABA in the
pipetting/dipping solution (based on the total weight of solid
components added) is between about 3:7 and about 9:1, for example
between about 2:3 and about 4:1.
[0151] In one embodiment, the or an organic additive is PABA and
the ratio (wt. %) of paclitaxel:PABA in the pipetting/dipping
solution (based on the total weight of solid components added) is
between about 3:7 and about 9:1, for example between about 2:3 and
about 4:1, wherein the dipping/pipetting solution is a solution of
between about 70/30 and about 90/10 acetone/water (v/v).
[0152] In one embodiment, the or an organic additive is methyl
paraben and the weight % of paclitaxel in the pipetting/dipping
solution (based on the total weight of solid components added) is
between about 45 wt. % and about 85 wt. %, for example between
about 55 wt. % and about 70 wt. %. In one embodiment, the or an
organic additive is methyl paraben and the ratio (wt. %) of
paclitaxel:methyl paraben in the pipetting/dipping solution (based
on the total weight of solid components added) is between about 4:5
and about 9:1, for example between about 1:1 and about 7:3.
[0153] In one embodiment, the or an organic additive is methyl
paraben and the ratio (wt. %) of paclitaxel:methyl paraben in the
pipetting/dipping solution (based on the total weight of solid
components added) is between about 4:5 and about 9:1, for example
between about 1:1 and about 7:3, wherein the dipping/pipetting
solution is a solution of between about 70/30 and about 90/10
acetone/water (v/v).
[0154] In one embodiment, the or an organic additive is caffeine
and the weight % of paclitaxel in the pipetting/dipping solution
(based on the total weight of solid components added) is between
about 70 wt. % and about 95 wt. %, for example between about 75 wt.
% and about 90 wt. %. In one embodiment, the or an organic additive
is caffeine and the ratio (wt. %) of paclitaxel:caffeine in the
pipetting/dipping solution (based on the total weight of solid
components added) is between about 7:3 and about 95:5, for example
between about 3:1 and about 9:1 wt. %.
[0155] In one embodiment, the or an organic additive is caffeine
and the ratio (wt. %) of paclitaxel:caffeine in the
pipetting/dipping solution (based on the total weight of solid
components added) is between about 7:3 and about 95:5, for example
between about 3:1 and about 9:1, wherein the dipping/pipetting
solution is a solution of between about 70/30 and about 90/10
acetone/water (v/v).
[0156] In one embodiment, the or an organic additive is calcium
salicylate and the weight % of paclitaxel in the pipetting/dipping
solution (based on the total weight of solid components added) is
between about 70 wt. % and about 90 wt. %, for example between
about 75 wt. % and about 80 wt. %. In one embodiment, the or an
organic additive is calcium salicylate and the ratio (wt. %) of
paclitaxel:calcium salicylate in the pipetting/dipping solution
(based on the total weight of solid components added) is between
about 7:3 and about 9:1, for example between about 3:1 and about
4:1.
[0157] In one embodiment, the or an organic additive is calcium
salicylate and the ratio (wt. %) of paclitaxel:calcium salicylate
in the pipetting/dipping solution (based on the total weight of
solid components added) is between about 7:3 and about 9:1, for
example between about 3:1 and about 4:1, wherein the
dipping/pipetting solution is a solution of between about 70/30 and
about 90/10 acetone/water (v/v).
[0158] In one embodiment, the or an organic additive is succinic
acid and the weight % of paclitaxel in the pipetting/dipping
solution (based on the total weight of solid components added) is
between about 70 wt. % and about 90 wt. %, for example between
about 75 wt. % and about 85 wt. %. In one embodiment, the or an
organic additive is succinic acid and the ratio (wt. %) of
paclitaxel:succinic acid in the pipetting/dipping solution (based
on the total weight of solid components added) is between about 7:3
and about 9:1, for example between about 3:1 wt. % and about
6:1.
[0159] In one embodiment, the or an organic additive is succinic
acid and the ratio (wt. %) of paclitaxel:succinic acid in the
pipetting/dipping solution (based on the total weight of solid
components added) is between about 7:3 and about 9:1, for example
between about 3:1 wt. % and about 6:1, wherein the
dipping/pipetting solution is a solution of between about 70/30 and
about 90/10 acetone/water (v/v).
[0160] In one embodiment the at least one organic additive is
independently selected from the group consisting of p-aminobenzoic
acid, saccharin, ascorbic acid, methyl paraben, caffeine, calcium
salicylate, pentetic acid, creatinine, ethylurea, acetaminophen,
aspirin, theobromine, tryptophan, succinic acid, glutaric acid,
adipic acid, theophylline, and saccharin sodium, and the weight %
of paclitaxel in the pipetting/dipping solution (based on the total
weight of solid components added) is between about 30 wt. % and
about 90 wt. %, such as between about 50 wt. % and about 90 wt.
%.
[0161] In one embodiment the at least one organic additive is
independently selected from the group consisting of p-aminobenzoic
acid, saccharin, ascorbic acid, methyl paraben, caffeine, calcium
salicylate, pentetic acid, creatinine, ethylurea, acetaminophen,
aspirin, theobromine, tryptophan, succinic acid, glutaric acid,
adipic acid, theophylline, and saccharin sodium, and the ratio (wt.
%) of paclitaxel:organic additive (total) in the pipetting/dipping
solution (based on the total weight of solid components added) is
between about 3:7 and about 9:1, such as between about 1:1 and
about 9:1.
[0162] In one embodiment the at least one organic additive is
independently selected from the group consisting of p-aminobenzoic
acid, saccharin, ascorbic acid, methyl paraben, caffeine, calcium
salicylate, pentetic acid, creatinine, ethylurea, acetaminophen,
aspirin, theobromine, tryptophan, succinic acid, glutaric acid,
adipic acid, theophylline, and saccharin sodium, and the ratio (wt.
%) of paclitaxel:organic additive (total) in the pipetting/dipping
solution (based on the total weight of solid components added) is
between about 3:7 and about 9:1, such as between about 1:1 and
about 9:1, wherein the dipping/pipetting solution is a solution of
between about 70/30 and about 90/10 acetone/water (v/v).
[0163] In one embodiment, the at least one organic additive is
independently selected from the list consisting of p-aminobenzoic
acid, methyl paraben, caffeine, calcium salicylate and succinic
acid and the weight % of paclitaxel in the pipetting/dipping
solution (based on the total weight of solid components added) is
between about 30 wt. % and about 90 wt. %, such as between about 50
wt. % and about 90 wt. %.
[0164] In one embodiment, the at least one organic additive is
independently selected from the list consisting of p-aminobenzoic
acid, methyl paraben, caffeine, calcium salicylate and succinic
acid and the ratio (wt. %) of paclitaxel:organic additive (total)
in the pipetting/dipping solution (based on the total weight of
solid components added) is between about 3:7 and about 9:1, such as
between about 1:1 and about 9:1.
[0165] In one embodiment, the at least one organic additive is
independently selected from the list consisting of p-aminobenzoic
acid, methyl paraben, caffeine, calcium salicylate and succinic
acid and the ratio (wt. %) of paclitaxel:organic additive (total)
in the pipetting/dipping solution (based on the total weight of
solid components added) is between about 3:7 and about 9:1, such as
between about 1:1 and about 9:1, wherein the dipping/pipetting
solution is a solution of between about 70/30 and about 90/10
acetone/water (v/v).
[0166] In one embodiment, the organic additive is succinic acid and
the ratio (wt. %) of paclitaxel:succinic acid in the
pipetting/dipping solution (based on the total weight of solid
components added) is between about 3:1 and about 6:1, wherein the
dipping/pipetting solution is a solution of between about 70/30 and
about 90/10 acetone/water (v/v).
[0167] Typically, the coating of the invention will have an average
total thickness of about 0.1 .mu.m to about 200 .mu.m, such as
about 0.2 .mu.m to about 100 .mu.m. Coating thickness can be
measured using a suitable coating thickness analyser or gauge.
[0168] It should be noted that the methods of preparing the coating
layer or composition of the invention described above (e.g. dry
powder methods and solvent evaporation methods) are all equally
suitable for preparing the various coating and composition
embodiments described hereinabove.
FURTHER EMBODIMENTS OF THE INVENTION
[0169] In one aspect of the invention is provided a medical device
for delivering a therapeutic agent to a tissue, the device having a
solid particulate coating layer applied to an exterior surface of
the device, said surface being composed of a material selected from
nylon and ePTFE, the coating layer comprising a therapeutic agent
and at least one organic additive; wherein at least a proportion of
the particulate coating layer comprising the therapeutic agent and
the at least one organic additive melts as a single phase at a
lower temperature than the melting point of the therapeutic agent
and the at least one organic additive when in pure form; wherein
the therapeutic agent is paclitaxel and wherein the at least one
organic additive is independently selected from the list consisting
of calcium salicylate, caffeine, methyl paraben, p-aminobenzoic
acid and succinic acid.
[0170] In another aspect of the invention is provided a medical
device for delivering a therapeutic agent to a tissue, the device
having a solid surfactant-free particulate coating layer applied to
an exterior surface of the device, the coating layer comprising a
therapeutic agent and at least one non-polymeric organic additive
which is hydrolytically stable; wherein the particulate coating
layer comprises a mixture of components (a) the therapeutic agent
and the at least one organic additive in a form which melts as a
single phase at a lower temperature than the melting point of the
therapeutic agent and the at least one organic additive when in
pure form and (b) the at least one organic additive in a form which
melts at a temperature at or close to that of said organic additive
in pure form; wherein the therapeutic agent is paclitaxel; and
wherein the therapeutic agent, when formulated in the coating
layer, is stable to ethylene oxide sterilization.
[0171] In a further aspect of the invention is provided a medical
device for delivering a therapeutic agent to a tissue, the device
having a solid surfactant-free particulate coating layer applied to
an exterior surface of the device, the coating layer comprising a
therapeutic agent and at least one non-polymeric organic additive
which is hydrolytically stable; wherein the particulate coating
layer is formed by evaporation of a solution of the therapeutic
agent and the at least one organic additive applied to the device
to form a solid particulate composition, wherein at least a
proportion of the particulate coating layer melts as a single phase
at a lower temperature than the melting point of the therapeutic
and the at least one organic additive when in pure form; wherein
the therapeutic agent is paclitaxel; and wherein the therapeutic
agent, when formulated in the coating layer, is stable to ethylene
oxide sterilization.
[0172] In a further aspect of the invention is provided a medical
device for delivering a therapeutic agent to a tissue, the device
having a solid particulate coating layer applied to an exterior
surface of the device, said surface being composed of a material
selected from nylon and ePTFE, the coating layer comprising a
therapeutic agent and at least one organic additive; wherein the
coating layer is formed by evaporation of a solution of the
therapeutic agent and the at least one organic additive applied to
the device to form a solid particulate composition, wherein at
least a proportion of the particulate coating layer melts as a
single phase at a lower temperature than the melting point of
either the therapeutic agent or the at least one organic additive
when in pure form; wherein the therapeutic agent is paclitaxel,
wherein the at least one organic additive is independently selected
from the list consisting of calcium salicylate, caffeine, methyl
paraben, p-aminobenzoic acid and succinic acid and wherein the
solution of the therapeutic agent and the at least one organic
additive is a solution in a solvent selected from water, acetone
and mixtures thereof.
[0173] In a further aspect of the invention is provided a medical
device for delivering a therapeutic agent to a tissue, the device
having a solid surfactant-free particulate coating layer applied to
an exterior surface of the device, the coating layer comprising a
therapeutic agent and at least one non-polymeric organic additive
which is hydrolytically stable; wherein the particulate coating
layer is formed by evaporation of a solution of the therapeutic
agent and the at least one organic additive applied to the device
to form a solid particulate composition comprising (a) a component
which melts as a single phase at a lower temperature than the
melting point of either the therapeutic agent or the at least one
organic additive when in pure form and (b) a component which melts
at a temperature at or close to that of the at least one organic
additive in pure form; wherein the therapeutic agent is paclitaxel;
and wherein the therapeutic agent, when formulated in the coating
layer, is stable to ethylene oxide sterilization.
[0174] In a further aspect of the invention is provided a medical
device for delivering a therapeutic agent to a tissue, the device
having a solid surfactant-free particulate coating layer applied to
an exterior surface of the device, the coating layer comprising a
therapeutic agent and at least one organic additive independently
selected from the list consisting of p-aminobenzoic acid,
saccharin, ascorbic acid, methyl paraben, caffeine, calcium
salicylate, pentetic acid, creatinine, ethylurea, acetaminophen,
aspirin, theobromine, tryptophan, succinic acid, glutaric acid,
adipic acid, theophylline, and saccharin sodium; wherein at least a
proportion of the particulate coating layer comprising the
therapeutic agent and the at least one organic additive melts as a
single phase at a lower temperature than the melting point of
either the therapeutic or the at least one organic additive when in
pure form; and wherein the therapeutic agent is paclitaxel.
[0175] In a further aspect of the invention is provided a medical
device for delivering a therapeutic agent to a tissue, the device
having a solid surfactant-free particulate coating layer applied to
a surface of the device, the coating layer comprising a therapeutic
agent and at least one non-polymeric organic additive which is
hydrolytically stable; wherein the particulate coating layer is
formed by combining the therapeutic agent and at least one organic
additive in powder form, and then applying the powder to the device
(with an optional subsequent step of thermal treatment) to form a
solid particulate composition, wherein at least a proportion of the
particulate coating layer comprising the therapeutic agent and the
at least one organic additive melts as a single phase at a lower
temperature than the melting point of the therapeutic agent and the
organic additive when in pure form; wherein the therapeutic agent
is paclitaxel; and wherein the therapeutic agent, when formulated
in the coating layer, is stable to sterilization.
[0176] In a further aspect of the invention is provided a medical
device for delivering a therapeutic agent to a tissue, the device
having a solid particulate coating layer applied to an exterior
surface of the device, said surface being composed of a material
selected from nylon and ePTFE, the coating layer comprising a
therapeutic agent and at least one organic additive; wherein the
coating layer is formed by combining the therapeutic agent and at
least one organic additive in powder form, and then applying the
powder to the device (with an optional subsequent step of thermal
treatment) to form a solid particulate composition, wherein at
least a proportion of the particulate coating layer melts as a
single phase at a lower temperature than the melting point of the
therapeutic agent and the at least one organic additive when in
pure form; wherein the therapeutic agent is paclitaxel, wherein the
at least one organic additive is independently selected from the
list consisting of calcium salicylate, caffeine, methyl paraben,
p-aminobenzoic acid and succinic acid.
[0177] In a further aspect of the invention is provided a medical
device for delivering a therapeutic agent to a tissue, the device
having a solid surfactant-free particulate coating layer applied to
an exterior surface of the device, the coating layer comprising a
therapeutic agent and at least one non-polymeric organic additive
which is hydrolytically stable; wherein the particulate coating
layer is formed by combining the therapeutic agent and the at least
one organic additive in powder form, and then applying the powder
to the device (with an optional subsequent step of thermal
treatment) to form a solid particulate composition comprising (a) a
component comprising the therapeutic agent and the at least one
organic additive which melts as a single phase at a lower
temperature than the melting point of the therapeutic agent and the
organic additive when in pure form and (b) a component which melts
at a temperature at or close to that of the at least one organic
additive in pure form; wherein the therapeutic agent is paclitaxel
and wherein the therapeutic agent, when formulated in the coating
layer, is stable to sterilization.
[0178] Coatings and compositions according to the present invention
are expected to have one or more of the following merits or
advantages:
[0179] good adherence to a medical device during crush loading and
storage e.g. as measured using Test Method C; [0180] good adherence
to a medical device during tracking and insertion, e.g. as measured
using Test Method C; [0181] suitable release characteristics, and
in certain embodiments, rapid release characteristics upon contact
with the target tissue e.g. as measured in Test Method A or Test
Method B. [0182] good stability of the formulated therapeutic agent
to sterilization e.g. as measured using Test Method D (ethylene
oxide sterilization), Test Method E (electron beam sterilization),
Test Method F (vapour hydrogen peroxide sterilization) or Test
Method G (plasma hydrogen peroxide sterilization); [0183]
compatibility with additional therapeutic agents, such as
heparin.
[0184] The invention embraces all combinations of indicated groups
and embodiments of groups recited above.
[0185] All patents and patent applications referred to herein are
incorporated by reference in their entirety.
DEFINITIONS AND ABBREVIATIONS
[0186] DEB drug eluting balloon [0187] DES drug eluting stent
[0188] DSC differential scanning calorimetry [0189] ePTFE expanded
polytetrafluoroethylene [0190] h hour [0191] HPLC high-performance
liquid chromatography [0192] ND not determined [0193] PABA
p-aminobenzoic acid [0194] PEG polyethylene glycol [0195] PBS
phosphate buffered saline [0196] PLGA poly(lactic-co-glycolic) acid
[0197] PVP polyvinylpyrrolidone [0198] SSG stent or stent graft
[0199] UPLC ultra-performance liquid chromatography
EXAMPLES
General Procedures
Chemicals
[0200] Anhydrous crystalline paclitaxel was purchased from Indena.
Hydrated crystalline paclitaxel was purchased from LC labs (P-9600
ASM-114). Deuterated paclitaxel was obtained from Toronto Research
Chemicals, Inc.
Solvent
[0201] Acetone ("dry" with <0.5% water) was purchased from
Sigma.
Materials
[0202] Nylon balloon catheters having dimensions of 5 mm in
diameter and 40 mm in length and 7 mm diameter and 120 mm in length
were obtained (Bavaria Medizin Technologie, We.beta.ling, Germany,
model # BMT-035, article #08GL-504A, 5.times.40 mm, article
#08QL-712B, 7.times.120 mm). Porcine carotid arteries were obtained
from Animal Technologies Inc. (Tyler, Tex.). Luer fittings (#11570)
were purchased from Qosina (Edgewood, N.Y.).
Evaluation Methods
[0203] The parameter being evaluated by each method is given in
parentheses.
Differential Scanning Calorimetry (DSC) Analysis (Peak Melting
Endotherm Determination)
[0204] A solid sample was added to a DSC pan. The mass of the
sample was weighed, and the pan sealed with pinhole lids. The
sample was examined using DSC (model #Q2000, TA Instruments), by
equilibrating at 25.degree. C., ramping 10.degree. C./min to
100.degree. C., dwelling at 100.degree. C. for 20 min (to remove
any trace solvent, in particular acetone or acetone:water), ramping
10.degree. C./min to 225.degree. C.
Ultra-Performance Liquid Chromatography (UPLC) Analysis (Paclitaxel
Concentration)
[0205] UPLC analysis was carried out using a Waters instrument
(model #ACQUITY). The identification of paclitaxel was determined
by the retention time of paclitaxel. The concentration of
paclitaxel was directly proportional to the integrated peak area,
which was determined by external standardization. Samples were
dissolved in a sample diluent or submerged in an extraction solvent
and shaken for one hour. Paclitaxel standards were prepared by
serial dilution of pure paclitaxel in the sample diluent. All
samples and standards were protected from light during preparation.
UPLC chromatography parameters were: phenyl column (1.7 um,
2.1.times.50 mm); mobile phase 2 mM ammonium acetate:0.2% acetic
acid; flow rate 0.6 ml/min; run time 3 min; injection volume 2 ul;
purge solvent methanol:water (60:40 v/v); wash solvent
acetonitrile; column temperature 60.degree. C.; UV detector
wavelength 227.0.+-.1.2 nm; sample rate 20 points/sec.
Tandem Mass Spectrometry (Detection and Quantification of
Paclitaxel)
[0206] Tandem mass spectrometry was carried out using a Waters Xevo
TQ-S instrument. The sodium adduct of paclitaxel was used. Mass
spectrometry parameters were ESI mode positive; 2 kV capillary; 50V
source offset; 7.0 bar nebulizer; 150 L/hr cone gas flow; collision
gas argon 0.15 ml/min.
Test Methods
Test Method A--In Vitro Tissue Transfer and Uptake
Test--Balloon
[0207] Coated balloons are examined for their ability to transfer
paclitaxel from the balloon surface to a vascular tissue in an in
vitro model. Porcine carotid arteries from 6-9 month old pigs,
approximately 6 cm in length, were trimmed of adipose tissue, and
fitted at their distal end with Luer fittings using wax thread. The
vessel diameters at the proximal and distal ends were approximately
5 mm and 2 mm, respectively (vessels tapered as a function of
length). They were flushed with 12 ml of PBS and pinned to a
dissecting pad under a slight axial stretch to straighten the
vessel. The coated balloons, all 5.times.40 mm
(diameter.times.length) were inserted into the proximal ends of the
vessels to the middle of the vessel, held at this position for 30
sec, inflated to 6 atm pressure for 1 min, deflated and removed. A
Luer fitting was fitted to the proximal end with wax thread. Tubing
was connected to the proximal and distal fittings, and the vessel
was flushed with PBS at 60 ml/min for 1 hr at 37.degree. C. The
vessel was analyzed for paclitaxel content using UPLC/Tandem Mass
Spectrometry. The coating of the invention has suitable paclitaxel
release and tissue transfer characteristics from a balloon such
that the measured drug concentration in the tissue at the 1 hr
timepoint is at least 20 .mu.g drug per g tissue (.mu.g/g), for
example at least 50 .mu.g/g, at least 60 .mu.g/g, at least 70
.mu.g/g or at least 80 .mu.g/g.
Test Method B--In Vitro Tissue Transfer and Uptake Test--Stent
[0208] Coated stents are examined for their ability to transfer
paclitaxel from the stent surface to a vascular tissue in an in
vitro model as essentially described by Liao (D. Liao et al.,
Biochem Biophys Res Commun, 372(4): 668-673, 2008. "Vascular smooth
cell proliferation in perfusion culture of porcine carotid
arteries"). The coated stent was compacted diametrically to an
outer diameter of 3.36 mm using means known to those of skill in
the art of self-expanding stents. The stents were constrained in
the compacted state within a constraint tube with an inner diameter
of 3.36 mm. The compacted stent was inserted into the proximal end
of the porcine vessel to the middle of the vessel, and deployed to
its expanded state. A Luer fitting was fitted to the proximal end
with wax thread. Tubing was connected to the proximal and distal
fittings, and the vessel was flushed with PBS at 60 ml/min for 24
hr at 37.degree. C. The stent was removed, and vessel was analyzed
for paclitaxel content using LC/MS-MS according to General
Procedures. The coating of the invention has suitable paclitaxel
release and tissue transfer characteristics from a stent such that
the measured drug concentration in the tissue at the 24 hr
timepoint is at least 1 .mu.g drug per g tissue (.mu.g/g), for
example at least 2.5 .mu.g/g, at least 5 .mu.g/g or at least 10
.mu.g/g.
Test Method C--Coating Adherence Test
[0209] This test measures coating adherence to a medical device
such as a stent or balloon catheter and is intended to gauge
coating adhesion and durability relative to other coatings. The
entire coated device is placed in a 15 ml glass test tube. While at
its minimum diameter (e.g. in the case a balloon catheter, at its
un-inflated diameter), the device is tapped against the test tube
walls for 30 sec. After 30 sec, the device is removed from the test
tube. The test tube is capped and submitted for UPLC analysis of
paclitaxel content. The percent of paclitaxel lost during shaking
is calculated by dividing the amount found in the test tube by the
estimated initial amount coated on the balloon (estimated by
pipetting a known solution volume with a known paclitaxel
concentration).
[0210] The coating of the invention has suitable adherence such
that less than 40% of the paclitaxel is lost during shaking, for
example less than 30%, less than 25%, less than 20%, less than 15%,
less than 10% or less than 5%.
Test Method D--Stability to Ethylene Oxide
[0211] A sample of a composition of the invention or a coated
device of the invention was placed in a breathable polyethylene
pouch (e.g. a Tyvek pouch) and subjected to at least 12 hours
preconditioning at 43.degree. C. and 65% relative humidity followed
by 12 hours exposure to 600 mg/L ethylene oxide at 52.degree. F.
and 25% relative humidity. The chamber was then aerated at
32.degree. F. for at least 12 hours until ethylene oxide
concentration was less than 0.25 ppm.
[0212] After sterilization, the paclitaxel content on the device or
the paclitaxel content of the composition was assessed (through
device extraction for coated medical devices i.e. immersion of the
whole device in an extraction solvent) using UPLC quantification as
described in the evaluation methods section. For each device or
composition, the percentage drug recovery after sterilization was
calculated by normalizing the extracted paclitaxel amount by the
theoretical paclitaxel amount loaded on the device, or present in
the composition pre-sterilization.
Test Method E--Stability to Electron Beam Sterilization
[0213] A further method to sterilize compositions of the invention
includes electron beam sterilization. A sample of the composition
is placed into a breathable polyethylene pouch (e.g. a Tyvek pouch)
and irradiated at a dosage of 15 to 40 kGray under ambient
conditions, using commercial sterilization providers, such as
Sterigenics International, Inc. (Deerfield, Ill.). After e-beam
sterilization, the paclitaxel content on the device is assessed as
described for Test Method D.
Test Method F--Stability to Vapour Hydrogen Peroxide
Sterilization
[0214] A further method to sterilize compositions of the invention
includes vapour hydrogen peroxide sterilization. A sample of the
composition is placed into a breathable polyethylene pouch (e.g. a
Tyvek pouch) and exposed to vapour hydrogen peroxide using a
commercially available sterilization chamber, such as the VHP-MD880
system (Steris Corp., Mentor, Ohio) following the manufacturer's
recommended protocol. After vapour hydrogen peroxide sterilization,
the paclitaxel content on the device is assessed as described for
Test Method D.
Test Method G--Stability to Plasma Hydrogen Peroxide
Sterilization
[0215] A further method to sterilize compositions of the invention
includes plasma phase hydrogen peroxide sterilization. A sample of
the composition is placed into a breathable polyethylene pouch
(e.g. a Tyvek pouch) and exposed to plasma phase hydrogen peroxide
using a commercially available sterilization chamber, such as the
Sterrad 100NX system (Advanced Sterilization Products, Irvine,
Calif.) following the manufacturer's recommended protocol. After
plasma phase hydrogen peroxide sterilization, the paclitaxel
content on the device is assessed as described for Test Method
D.
Example 1
Method for Preparation of Paclitaxel-Excipient Solid Composition
Particulates
[0216] A paclitaxel stock solution was prepared. Paclitaxel (110
mg/ml) was dissolved in dichloromethane. 300 .mu.l of solution was
aliquoted into 4 ml clear glass vials and the dichloromethane
allowed to evaporate overnight, to produce a cast paclitaxel
film.
[0217] 1 g of excipient was placed into a 7 ml clear glass vial. 1
ml of either acetone (dry) or acetone:water (75:25 v/v) was added
to the vial, as indicated in Table 1. The vial placed on a desktop
shaker. Either additional excipient or additional solvent was added
as needed to produce a solution saturated with the excipient. The
saturated solution was filtered through a 0.2 um PTFE filter into a
4 ml glass vial.
[0218] 400 .mu.l of the filtered solution was added to the vial
containing the cast paclitaxel film. The solution was stirred with
a magnetic stir bar. The contents became cloudy or opaque, due to
the formation of precipitate. The mixtures were filtered through a
PTFE filter. The wet precipitate was collected from the filter
membrane, and dried to produce the paclitaxel-excipient solid
compositions.
Example 2
Thermal and Compositional Analysis of Paclitaxel-Excipient Solid
Compositions of Example 1
[0219] The paclitaxel-excipient compositions of Example 1 were
examined by DSC using the method described in General Procedures.
Samples of each composition were added to a DSC pan and dried
overnight. Samples of pure paclitaxel and pure excipient were also
examined as controls.
[0220] Peak melting temperatures of each starting component and of
the paclitaxel-excipient solid compositions are shown in Table 1.
Thermograms of paclitaxel-PABA, paclitaxel-succinic acid and
paclitaxel-adipic acid compositions are shown in FIGS. 1A to
1C.
[0221] The concentration of paclitaxel (wt %) in each
paclitaxel-excipient composition was determined using UPLC as
described in General Procedures. A sample of each composition was
dissolved in the same solvent system from which precipitation
occurred (Table 1) prior to analysis.
TABLE-US-00001 TABLE 1 Melting points and compositions
paclitaxel-excipient solid compositions of Example 1 T.sub.m Ex
T.sub.m Px T.sub.m NF Ptx:ex Excipient Solvent (.degree. C.)
(.degree. C.) (.degree. C.) (wt/wt) Device.sup.d # Compositions of
Example 1 2-1 PABA 75/25 acetone/water 189 217 140 62:38 DEB 2-2
PABA Acetone 189 >220 159 77:23 SSG 2-3 saccharin 75/25
acetone/water >220 217 150 78:22 DEB 2-4 saccharin Acetone
>220 >220 167 68:32 ND 2-5 ascorbic acid 75/25 acetone/water
193 217 187 35:65 DEB 2-6 methyl paraben 75/25 acetone/water 127
217 90 61:39 DEB 2-7 caffeine 75/25 acetone/water .sup. 158.sup.a
217 134 87:13 DEB 2-8 calcium 75/25 acetone/water >220.sup.b 217
165 77:23 DEB salicylate 2-9 pentetic acid 75/25 acetone/water
>220 217 210 90:10 ND 2-10 creatinine 75/25 acetone/water 220
217 171 86:14 ND 2-11 ethylurea 75/25 acetone/water 95 217 92 45:55
ND 2-12 acetaminophen 7525 acetone/water 170 217 160 41:59 ND 2-13
aspirin 75/25 acetone/water 144 217 133 35:65 ND 2-14 theobromine
75/25 acetone/water >220 217 206 84:16 ND 2-15 tryptophan 75/25
acetone/water >220 217 206 74:26 ND 2-16 succinic acid Acetone
189 >220 169 84:16 SSG 2-17 saccharin 75/25 acetone/water
>220.sup.c 217 121 60:40 ND sodium 2-18 succinic acid 75/25
acetone/water 189 217 164 82:18 DEB 2-19 glutaric acid 75/25
acetone/water 98 217 94 36:64 DEB 2-20 adipic acid 75/25
acetone/water 152 217 149 51:49 DEB 2-21 theophylline 75/25
acetone/water >220 217 207 80:20 DEB T.sub.m Ex--peak max
(determined by DSC) of pure excipient; T.sub.m Px--peak max
(determined by DSC) of pure paclitaxel; T.sub.m NF--peak max
(determined by DSC) of novel form; Ptx:ex (wt/wt)--ratio of
paclitaxel:excipient (determined by measuring wt % of paclitaxel in
coating using UPLC); .sup.asublimation observed; .sup.bdehydrated
at 176.degree. C.; .sup.cdehydrated at 129.degree. C.;
.sup.dpreferred device substrate utility ND = not determined
[0222] It can be seen that all of the compositions formed in
Example 1 melted as a single phase with a depressed melting point.
The preferred device substrate utility for each composition was
assigned based on the adhesion test described in Example 4 and the
in vitro tissue transfer test described in Example 5.
Example 3a
Construction of an ePTFE Covered Balloon for Use with the Coating
of the Invention
[0223] Expanded polytetrafluoroethylene (ePTFE) material was
obtained with the following typical properties: thickness of 38.1
microns, width of 2.7 cm, mass/Area of 8.73 g/m.sup.2, longitudinal
(i.e., "machine direction") matrix tensile strength (MTS) of 283.5
MPa, transverse MTS of 11.0 MPa, longitudinal force to break of
0.112 kgf/mm, and IPA bubble point of 9.93 kPa.
[0224] A 1.7 mm.times.170 mm stainless steel mandrel was obtained
and a length of the ePTFE material described above was cut to 160
mm. The ePTFE piece was wrapped longitudinally around the mandrel
(i.e., "cigarette-wrapped") approximately five times, with the
machine direction parallel to the length of the mandrel.
[0225] Another type of ePTFE material was obtained to serve as a
manufacturing aid. This ePTFE had the following typical properties:
thickness of 8.9 microns, width of 24 mm, mass/Area of 2.43
g/m.sup.2, longitudinal MTS of 661.9 MPa, transverse MTS of 9.9
MPa, and IPA bubble point of 4.83 kPa.
[0226] This second ePTFE material was helically wrapped over the
first ePTFE wrapped tube on a first bias at a 45 degree pitch with
a 50% overlap from one end of the previously wrapped tube to the
other and then on a reversed bias at a 45 degree pitch from end to
end of the underlying wrapped ePTFE tube. This produced
approximately 4 layers of overwrap.
[0227] The mandrel and ePTFE wraps were thermally treated for 3
minutes at 380.degree. C. and allowed to cool to room temperature.
The helical ePTFE overwrap was removed and discarded.
[0228] A nylon tube was obtained having an inside diameter of 2.16
mm and a 0.038 mm wall thickness. The first ePTFE material wrapped
tube was trimmed to a length of 44 mm on the mandrel and removed
from the mandrel. The inside diameter of the ePTFE tube was
increased to fit over the nylon tube by using a tapered stainless
steel mandrel. The ePTFE tube was then positioned co-radially over
the nylon tube.
[0229] A 5 mm.times.40 mm long nylon balloon catheter with a 0.89
mm guidewire lumen was obtained (Bavaria Medizin Technologie, model
# BMT-035, article #08GL-504A). A 0.89 mm stainless steel mandrel
was inserted into the distal guidewire lumen of the balloon
catheter to stiffen the area of the catheter proximate the balloon.
The balloon was inflated to 2 atmospheres. The partially inflated
balloon was manually dipped into a solution comprising Fluorinert
FC-72 (3M, Saint Paul, Minn.) and a thermoplastic fluoroelastomer
copolymer of tetrafluoroethylene/perfluoromethylvinylether
(TFE/PMVE) as taught in U.S. Pat. No. 7,049,380 and U.S. Pat. No.
8,048,440 (Gore Enterprise Holdings, Inc., incorporated herein by
reference).
[0230] The balloon was held in the solution for approximately 1
second, removed and gently tapped to remove excess of the solution.
The coated balloon was allowed to dry for 15 seconds. This manual
dip coating process was repeated 3 times to produce 3 coats over
the balloon. The balloon was then deflated to approximately its
original compacted diameter by pulling a vacuum on its catheter
inflation port.
[0231] The nylon tube and ePTFE wrapped tube assembly as described
above was fitted co-radially over the re-compacted and coated
balloon and centered on the balloon catheter radiopaque marker
bands. The ePTFE wrapped tube was held in place while the nylon
tube was manually removed. The balloon was inflated to
approximately 2-3 atmospheres for 30 seconds. This created an
adhesive bond between the inner wall of the ePTFE wrapped tube and
the TFE/PMVE coating on the nylon balloon. The balloon was then
deflated to approximately its original compacted dimensions.
Example 3b
Method of Preparing a DEB with a Paclitaxel-Excipient Coating
[0232] Paclitaxel and excipient were co-dissolved in acetone:water
(65-75 v % acetone) to form a coating solution, at concentrations
listed in Table 2. Percutaneous transluminal angioplasty balloon
catheters ("nylon balloons"--as described in "Materials") were
coated with certain paclitaxel-excipient combinations as shown in
Table 2. Additional balloons ("ePTFE covered balloons") were first
modified by attachment of an ePTFE covering layer (as described in
Example 3a) and then coated with certain paclitaxel-excipient
combinations as shown in Table 2.
TABLE-US-00002 TABLE 2 Coating solution composition Solution/
Excip- Pacli- % Pacli- Total Coating ient taxel taxel* solids No.
Excipient (wt %) (wt %) (wt %) (g/ml) 3-1 PABA 0.26-0.64 2.30-2.51
80-90 0.022-0.027 3-2 PABA 2.53 2.51 50 0.045 3-3 Methyl 0.98-0.99
2.29 70 0.029 paraben 3-4 Ca 0.71-0.80 2.30-2.39 75-76 0.026-0.027
salicylate 3-5 Caffeine 0.70-0.77 2.30 75-77 0.026-0.027 3-6
Succinic 0.32-0.60 1.98-2.30 79-86 0.020-0.025 acid 3-7 Ascorbic
2.75 2.25 45 0.046 acid *% of paclitaxel (wt %) in solid components
of coating solution
[0233] The working regions of the nylon balloon and the ePTFE
covered balloons were inflated to full diameter and coated by
pipetting the coating solution (90-100 ul of solution for
5.times.40 mm balloons and 420 ul for 7.times.120 mm balloons)
under rotation. As the solvent from the coating solution
evaporated, the balloon was deflated and refolded to its
un-inflated diameter. Coated balloons were dried overnight at room
temperature in their folded state. The final drug loading on all
devices was approximately 3 .mu.g/mm.sup.2 balloon surface area
(estimated by pipetting a known solution volume with a known
paclitaxel concentration). Coated balloons were packaged and
sterilized by ethylene oxide exposure.
Example 4
Adhesion Test
[0234] Coated balloons prepared according to a method of Example 3b
were examined for the adhesion of the paclitaxel-excipient solid
compositions to the balloon pre-dilation, using Test Method C, as
described in General Procedures.
[0235] The results of the test are summarized in FIG. 2. The
asterisk in FIG. 2 indicates that there was no testing of the
coating on a nylon substrate. It should be noted a paclitaxel-only
coated balloon was prepared (for use as a control) but was not
included in the adhesion testing due to a high degree of drug being
lost with little balloon manipulation (quantified visually). The
excipient had an effect on the strength of adhesion, as exemplified
by the extent of paclitaxel particulation and transfer to the test
tube. Coatings on ePTFE generally showed greater adhesion than the
same coating on nylon.
Example 5
In Vitro Tissue Transfer and Uptake Test
[0236] Coated balloons prepared according to a method of Example 3b
were examined for their ability to transfer paclitaxel from the
balloon surface to a vascular tissue using Test Method A, as
described in General Procedures. The vessel was analyzed for
paclitaxel content using LC/MS-MS according to General Procedures
and the results are summarized in FIG. 3. The asterisk in FIG. 3
indicates that there was no testing of the coating on a nylon
substrate. Approximately 120-240 .mu.g paclitaxel per gram tissue
was transferred from the balloon surface to the porcine vascular
tissue.
Example 6
In Vivo Uptake Test
[0237] Samples of coated balloons prepared according to a method of
Example 3b were deployed in a porcine model in an in vivo test
employing the peripheral arteries in an adult swine. Angiography of
the peripheral artery determined balloon inflation pressure
required for appropriate vessel over-sizing. The balloon was
tracked to the target site, inflated to the required inflation
pressure for 60 seconds, deflated and removed. Post-deployment, the
spent device was submitted for UPLC analysis of remaining
paclitaxel content as described in General Procedures.
[0238] Animals were euthanized after 7 days or after 28 days. The
treated arteries were harvested. An untreated carotid artery was
also harvested to assess potential systemic drug delivery to a
remote site. Adipose tissue was removed from each artery, radial
cross-sections (100.+-.50 mg) were cut from each artery, and the
arteries analyzed for paclitaxel content using UPLC/tandem mass
spectrometry. For the treated artery, mean paclitaxel levels were
calculated by averaging paclitaxel levels in all radial
cross-sections in the indicated segment.
[0239] The tissue samples were homogenized and extracted with 0.2%
acetic acid in methanol, containing 2 mg/ml deuterated paclitaxel
as an internal standard. The samples were centrifuged to remove all
particulates and the supernatant was used for the analysis. The
retention and separation of paclitaxel was achieved essentially as
per Example 3b (and General Procedures), using a phenyl column with
a sodium acetate/acetic acid mobile phase in acetonitrile:water.
The detection and quantification of paclitaxel was achieved by
tandem mass spectrometry using the sodium adduct of paclitaxel, as
described in General Procedures. FIG. 4 shows the percent
paclitaxel (mean.+-.s.d.) remaining on the balloon after in vivo
deployment and inflation. The asterisk in FIG. 4 indicates that
there was no testing of the coating on a nylon substrate. All
samples had less than 50% of their initial paclitaxel remaining on
the balloon, indicating significant transfer of paclitaxel from the
balloon surface to the porcine tissue.
[0240] FIGS. 5 and 6 show respectively the 7 and 28 day paclitaxel
levels in porcine arterial tissue in treated arterial tissue
segments (see also Table 3 below for 28 day results). The asterisk
in FIG. 6 indicates that there was no testing of the coating on a
nylon substrate. Paclitaxel levels in untreated vascular tissues
were several orders of magnitude lower, on the order of 3 to 6 ng
paclitaxel per gram of tissue, demonstrating that the delivery of
paclitaxel from the balloon was localized to the target tissue, and
was retained at the target tissue for up to 28 days.
TABLE-US-00003 TABLE 3 Paclitaxel tissue levels at 28 days in vivo
porcine model. 28 day tissue 28 day Mass concentration localized
Sub- released .mu.g PTX/g drug delivery # Excipient strate (mg)
.sup.1 tissue) efficiency (%).sup.2 3-6 Succinic ePTFE 1.51 .+-.
0.02 5.6 .+-. 0.4 0.09 .+-. 0.02 acid 3-5 Caffeine Nylon 1.79 .+-.
0.13 2.6 .+-. 3.4 0.03 .+-. 0.03 ePTFE 1.34 .+-. 0.10 0.4 .+-. 0.3
0.005 .+-. 0.004 3-4 Calcium Nylon 1.84 .+-. 0.04 3.0 .+-. 2.6 0.03
.+-. 0.02 salicylate ePTFE 1.36 .+-. 0.20 3.0 .+-. 3.2 0.03 .+-.
0.03 3-3 Methyl- Nylon 1.78 .+-. 0.04 1.8 .+-. 2.1 0.02 .+-. 0.03
paraben ePTFE 1.06 .+-. 0.30 1.3 .+-. 0.8 0.03 .+-. 0.03 3-1 PABA
Nylon 1.84 .+-. 0.06 1.6 .+-. 1.8 0.02 .+-. 0.01 ePTFE 1.30 .+-.
0.17 1.2 .+-. 1.0 0.01 .+-. 0.01 .sup.1 mg originally on balloon -
mg left on balloon following procedure .sup.2calculated as (total
mg in tissue/mass released)*100
Example 7
Vascular Stent Coated with Pre-Coated with a Heparin-Bonded
Surface
[0241] Vascular stents were pre-coated to form a heparin-bonded
surface before being over-coated with a paclitaxel-excipient solid
composition of the invention. Vascular stents (5 mm by 30 mm),
featuring a dual component design, constructed from a single wire
nitinol stent interconnected by a durable, biocompatible, expanded
polytetrafluoroethylene (ePTFE) structure, were made according to
US2009/0182413A1 (Gore Enterprise Holdings, Inc., incorporated
herein by reference in its entirety). The durable, biocompatible,
expanded ePTFE structure was coated with a heparin-bonded surface
according to U.S. Pat. No. 6,461,665 (Carmeda AB, which is
incorporated herein by reference in its entirety).
[0242] The aforementioned heparin coated vascular stents were
over-coated with an embodiment of the paclitaxel-excipient solid
composition comprising paclitaxel and caffeine. Paclitaxel and
caffeine at a weight ratio of 75:25 were dissolved in 90/10 (v/v)
acetone/water to obtain a 20 mg/ml paclitaxel solution.
[0243] The aforementioned heparin coated vascular stents were tied
to a thread at one end for handling during the coating process.
They were dipped into the paclitaxel solution, removed, and air
dried; the coating procedure was repeated 10 to 30 additional times
to produce three coated stents. At the end of the coating procedure
each coated stent was weighed (stent device 1 had a coating weight
of 0.588 mg, stent 2 had a coating weight of 0.642 mg and stent 3
had a coating weight of 1.2 mg) before being examined using DSC. A
stent was compacted into a high mass DSC pan and sealed with an
o-ring and lid (TA Instruments, part #900825.902) and analyzed
using the DSC method described in General Procedures (except that
the sample was not dwelled at 100.degree. C.); an uncoated vascular
stent was analyzed as a reference. A single depressed melting
endotherm at 132.degree. C. was observed for the
paclitaxel-caffeine solid composition. This melting temperature is
consistent with the paclitaxel-caffeine solid compositions as
prepared by Example 1.
Example 8
Compaction and Deployment of Vascular Stent Coated with
Paclitaxel-Excipient Solid Composition
[0244] The coated stents of Example 7 underwent compaction and
deployment to examine durability and robustness of the coating.
[0245] The coated stents of Example 7 were compacted diametrically
to an outer diameter of 3.36 mm using means known to those of skill
in the art of self-expanding stents. The stents were constrained in
the compacted state within a constraint tube with an inner diameter
of 3.36 mm. Stents were deployed from the containment tube with the
use of a push rod. After deployment, the stent was weighed and
compared to its weight before compaction.
TABLE-US-00004 TABLE 4 Summary of Coating Durability Stent Coating
Weight Coating Lost % of Device (mg) (mg) coating lost 1 0.588
0.085 14.5 2 0.642 0.038 5.9 3 1.2 0.107 8.9
[0246] The average drug coating mass loss was 9.7% and this was
determined to represent a high degree of durability. This
durability not only considers the compaction and expansion of the
coated stent, but also considers the stent being pushed out from
the containment tube, wherein the stent sheared against the
containment tube inner surface.
Example 9
Heparin Activity of Vascular Stent Coated with Paclitaxel-Excipient
Solid Composition
[0247] Heparin activity of the underlying heparin bonded surface of
the compacted and deployed stents of Example 8 was measured
according to WO2009/064372, which is incorporated herein by
reference by its entirety. The paclitaxel-caffeine solid
composition coating was first extracted from the vascular stent
surface by immersion in a glass vial containing 0.2% acetic acid in
methanol, with shaking at 300 rpm for 1 hr at 40.degree. C. The
washed stents demonstrated therapeutically useful heparin
activities of greater than 1 pmol/cm.sup.2.
[0248] These results attest to the surprising activity of the
heparin-bonded surface under the conditions of coating with a
paclitaxel-excipient solid composition, mechanical stress including
compaction and expansion, and mechanical shear including
deployment.
Example 10
Heparin Activity of Vascular Stent Coated with Paclitaxel-Excipient
Solid Composition Post Sterilization
[0249] Stents coated as in Example 7 are sterilized by ethylene
oxide. The stents can subsequently undergo compaction and
deployment to examine durability and robustness of the coating
along with retention of heparin activity.
Example 11
Acute Tissue Transfer of Vascular Stent Coated with
Paclitaxel-Excipient Solid Compositions and Heparin Activity
[0250] Stent Device number 3 of Example 8 was examined for its
ability to transfer paclitaxel from the stent surface to a vascular
tissue in an in vitro model as described in Test Method B. The
stent was removed, and vessel was analyzed for paclitaxel content
using LC/MS-MS according to General Procedures. Approximately 16
.mu.g paclitaxel per gram tissue was transferred from the stent
surface to the porcine vascular tissue.
[0251] These paclitaxel tissue levels were within the reported
therapeutic range of paclitaxel-coated vascular stents of 20 ug
paclitaxel per gram tissue at 24 hrs, as described in the
literature (M.D. Dake et al., J Vasc Interven Rad, 22(5): 603-610,
2011, "Polymer-free Paclitaxel-coated Zilver PTX Stents--Evaluation
of Pharmacokinetics and Comparative Safety in Porcine
Arteries")
[0252] Heparin activity of the stent after it was removed from the
vessel was measured according to Example 9, and was determined to
be a therapeutically useful heparin activity of greater than 1
pmole/cm.sup.2.
[0253] Thus, when a heparin coated vascular stent over-coated with
a paclitaxel-excipient coating of the invention was contacted with
vascular tissue a therapeutic amount of paclitaxel was transferred
from the coating to the vascular tissue and a therapeutically
useful heparin activity was retained for the heparin-bonded
surface. Thus, a coated stent of the invention has the potential to
exhibit dual therapeutic activity, when a first coating comprising
a therapeutic agent is applied to the stent, followed by an over
coat of the paclitaxel-excipient composition of the invention.
Example 12a
Ethylene Oxide Stability of Coated DEB Prepared Substantially
According to the Method of Example 3b
[0254] Two ePTFE balloons coated according to Example 3b were
sterilized and their paclitaxel content analyzed
post-sterilization, in accordance with Test Method D. The
paclitaxel percentage recovery is shown in Table 5 below.
TABLE-US-00005 TABLE 5 Paclitaxel % recovery post-ethylene oxide
sterilization % Recovery (normalized to theoretical) N# Excipient
avg .+-. st dev 3-5 Caffeine 97.2 .+-. 1.4 3-6 Succinic acid 82.9
.+-. 1.5
[0255] Post-sterilization both samples showed greater than 80%
paclitaxel recovery, indicating that these devices have adequate
paclitaxel stability following ethylene oxide sterilization.
Example 12b
Ethylene Oxide Stability of Paclitaxel-Excipient Films Prepared
According to Example 1
[0256] Approximately 30 mg of excipient was weighed into a 7 mL
glass vial and 6 mL of 75/25 v/v acetone/water was added. A small
stirrer bar was added to each vial and all samples were stirred
overnight at room temperature to ensure full dissolution. Next, a
stock solution of paclitaxel in the casting solvent was made at 5
mg/mL. A specific volume of paclitaxel stock and excipient stock
was added to a new vial to achieve the target paclitaxel/excipient
weight fraction listed in Table 6. The vials were then mixed and
aliquoted to N=6 of the 20 mL vials (0.5 mL each). A
paclitaxel-only control was also added to N=6 vials (0.25 mL each).
All vials were left in a fume hood overnight to evaporate the
solvents. After drying, the samples were capped with cellulose
membranes cut to septa size to allow ethylene oxide and moisture
permeability. All samples were packaged in breathable polyethylene
pouches. N=3 of each paclitaxel/excipient mixture were kept as
non-sterilized controls, and the remainder (N=3) were sent for
ethylene oxide sterilization (see Test Method D). Non-sterilized
controls were stored at room temperature prior to analysis.
Paclitaxel content analysis was performed as described in the
Evaluation Methods section. Percent paclitaxel recovery was
calculated by normalizing to either theoretical initial loading or
pre-sterilized samples.
TABLE-US-00006 TABLE 6 Paclitaxel % Recovery on cast formulations
pre- and post- sterilization (Mean value of N = 3 shown) Ptx:ex %
PTX recovery, % PTX recovery, Excipient (wt/wt) theoretical vs. pre
pre vs. post Ca salicylate 75/25 99.0 99.3 caffeine 75/25 98.5 99.1
p-aminobenzoic acid 80/20 97.6 100.2 methylparaben 70/30 100.5 98.7
succinic acid 80/20 97.2 100.5 ascorbic acid 45/55 98.4 99.8
saccharin 80/20 99.4 99.2 acetaminophen 40/60 97.9 99.5
theophylline 80/20 99.0 99.7 aspirin 35/65 99.0 88.5 glutaric acid
40/60 92.2 98.5 adipic acid 50/50 93.4 98.0 PTX only 100/0 98.2
101.7
[0257] Pre-sterilization, all samples showed greater than 90%
paclitaxel recovery. Post-sterilization, all samples showed greater
than 80% paclitaxel recovery. Altogether, these results indicate
that the formulations have adequate paclitaxel stability to
ethylene oxide sterilization.
Example 12c
Ethylene Oxide Sterilization Instability of Paclitaxel-Niacinamide
Formulations
[0258] Paclitaxel/niacinamide coated balloons are reported in
Example 22 of patent application US2012/0310210 A1 (Campbell et
al., herein incorporated by referenced in its entirety). When these
same balloon samples were subjected to ethylene oxide
sterilization, paclitaxel quantification via UPLC showed nearly
complete paclitaxel degradation (paclitaxel recovery after
sterilization was 4%, normalized to unsterilized samples).
Example 13
DSC Analysis of DEB Coated with a Paclitaxel-Excipient Coating
[0259] 30 mL of 75/25 (v/v) acetone/water was added to a
scintillation vial. 600 mg of paclitaxel was weighed and added to
the vial to achieve approximately 20 mg/mL paclitaxel
concentration. In a separate vial, 10 mL of 99/1 (v/v)
acetone/water was added along with 200 mg of paclitaxel (to also
arrive at 20 mg/mL). The vials were stirred using a stir bar to
dissolve the paclitaxel.
[0260] Next, using a microbalance, excipients were weighed into 4
or 7 mL glass scintillation vials (see Table 7 below). One of the
two paclitaxel stock solutions was added to each vial as noted in
Table 7. The volume of stock paclitaxel solution to be added was
adjusted based on excipient mass so that the target
paclitaxel/excipient ratio was achieved. Each formulation was
stirred using a stir bar until the excipient dissolved, which took
several minutes for all formulations except 13-2, which failed to
dissolve even after approximately 30 minutes of stirring. As a
result formulation 13-2 was not evaluated further.
[0261] Nylon balloons of 7 mm.times.120 mm dimension were coated in
the same manner as described in Example 3B. 420 .mu.l of coating
was added to each balloon surface (volume scaled by surface area so
that same coating density as Example 3B). Also coated were ePTFE
films supported by embroidery hoops. The ePTFE film was of the type
described first in Example 3A and used in that example to cover a
nylon balloon. 100 .mu.l of formulation 13-1 and 13-7 was added to
separate locations on the ePTFE film (100 .mu.l to each location)
and spread around to cover a surface area of approximately 22 mm
diameter.
[0262] After drying, the balloons were mechanically agitated to
remove the coatings from the nylon surface (using a stainless steel
spatula to scrape the coating and/or rubbing the balloon surface
against wax weighing paper). The generated particulate was then
added to a pre-weighed DSC pan. The pan was then weighed again and
DSC analysis was performed as described in General Procedures.
[0263] Similarly, the coated region of the ePTFE film was cut out
using a scissors and compacted into a pre-weighed DSC pan which was
then weighed again. An uncoated region of the ePTFE (similar size)
was also cut out and added to a pre-weighed DSC pan which was then
weighed again. The uncoated PTFE sample mass was subtracted from
the coated ePTFE sample masses to provide an approximation for mass
of coating in the DSC pans. DSC analysis was performed on all
samples as in General Procedures. The peak max endotherm was
calculated in the same fashion as Table 1.
[0264] Coatings 13-1, 13-4, 13-5, 13-6, 13-7 and 13-8 were
formulated with the same or very similar paclitaxel/excipient
weight ratios as for compositions prepared according to Example 1
(weight ratios are shown in Table 1). All six coatings showed a
single depressed endotherm at around the same temperature as the
corresponding composition, as can be seen by comparing the final
two columns of Table 7. It can therefore be concluded the
precipitation method described in Example 1 and the solvent
evaporation method of Example 3b and the present Example produce
substantially similar materials.
[0265] FIG. 7 shows an overlay of three DSC thermograms. The lower
plot is a thermogram of pure succinic acid as a control, the middle
plot is a thermogram of a paclitaxel-succinic acid composition
prepared according to Example 1 (composition 2-18), and the upper
plot is a thermogram of the corresponding paclitaxel-succinic acid
coating formed in the present example (coating 13-7). For the
middle and upper plots (composition 2-18 and coating, 13-7,
respectively) a depressed melting point is observed (at around the
same temperature in each case) with no endotherm corresponding to
pure succinic acid.
[0266] Coatings corresponding to coatings 13-1 and 13-7 were
prepared for nylon balloons and were found to exhibit similar
depressed melting endotherms (137-139.degree. C. for caffeine and
161.degree. C. for succinic acid).
TABLE-US-00007 TABLE 7 Formulations coated on balloons and ePTFE
substrates and DSC analysis Excipient Mass Ptx:ex Solution 1
Solution 2 T.sub.m coating T.sub.m NF (.degree. C.) N# (ex) ex (g)
(wt/wt) (mL) (mL) (.degree. C.) (Table 1) 13-1 caffeine 0.0149
87:13 4.979 0 135 134 (3-6) 13-2 caffeine 0.1344 13:87 1.004 0 ND
-- 13-3 caffeine 0.0171 87:13 5.722 None -- 13-4 PABA 0.0254 62:38
2.075 0 139 140 (3-1) 13-5 calcium 0.0151 77:23 2.528 0 165 165
(3-8) salicylate 13-6 Methyl 0.0263 61:39 2.054 0 110 90 (3-6)
paraben 13-7 succinic acid 0.0170 82:18 3.875 0 160 164 (3-18) 13-8
succinic acid 0.0172 82:18 0 3.911 159 169 (3-16) 13-9 succinic
acid 0.0934 18:82 1.025 0 160, 185 -- N# = coating number Ptx:ex =
ratio of paclitaxel to excipient T.sub.m--peak max (determined by
DSC) of the coating of Example 13 T.sub.m NF--peak max (determined
by DSC) of corresponding compositions formed in Examples 1 and 2
(composition no. in parenthesis); Solution 1 = 20 mg/mL paclitaxel
in 75/25 (v/v) acetone/water Solution 2 = 20 mg/mL paclitaxel in
99/1 (v/v) acetone/water
[0267] Coating 13-9 has the reciprocal paclitaxel/excipient weight
ratio of composition 2-18 in Table 1, i.e. 18:82 instead of 82:18
paclitaxel/succinic acid. A DSC analysis of coating 13-9 is shown
in FIG. 8, which shows two melting endotherms (unlike compositions
13-7 and 13-8 in which a single depressed melting point was
observed). A melting endotherm at 160.degree. C. corresponded to a
depressed melting endotherm while a melting endotherm at
185.degree. C. was very close to the melting point of pure succinic
acid (189.degree. C.). Note that when increasing organic solvent
content in the coating solution, the endotherm signal intensity was
greatly diminished (formulation 13-7>13-8, and formulation 13-3
had no discernible endotherm).
[0268] The proportion of succinic acid which melted at 185.degree.
C. (i.e. the temperature close to the melting point of succinic
acid in pure form) was determined using the enthalpy of fusion
value. It was found that of the succinic acid present in the
composition as a whole (82% of the total coating mass), 70%
corresponded to pure crystalline succinic acid (i.e. the remaining
30% of succinic acid in the coating would be assumed to be present
in the crystalline depressed endotherm form or in amorphous form).
This was calculated as follows:
[0269] % succinic acid in original crystalline form=(balloon
coating enthalpy of fusion circa 185.degree. C./control succinic
acid enthalpy of fusion circa 185.degree. C.)*100, where the
balloon coating sample mass entered into the DSC software=weighed
sample mass added to DSC pan*mass fraction succinic acid in coating
(i.e. 0.82).
Example 14
A Ternary Formulation Exhibiting a Singular Depressed Melting
Point
[0270] A ternary formulation was created by combining succinic
acid, caffeine, and paclitaxel. Each component was added to 3 mL of
75/25 v/v acetone/water and stirred until dissolved. The entire
solution was then cast into a disposable aluminum pan and allowed
to dry. The subsequent dried formulation was added to a DSC pan
with a pinhole lid. DSC analysis was performed in the same manner
as described in General Procedures, with the exception that the
samples were not dwelled at 100.degree. C.
TABLE-US-00008 TABLE 8 Composition and peak max of a ternary
formulation Excipient Pac- % Total Excipient (wt % litaxel
Paclitaxel* solids T.sub.m NF No. 1 & 2 each) (wt %) (wt %)
(g/ml) (.degree. C.) 14-1 Succinic 0.3 2.3 79 0.023 111 acid,
caffeine *% of paclitaxel (wt %) in solid components of coating
solution T.sub.m NF--peak max (determined by DSC) of novel
form;
[0271] As shown in FIG. 9, ternary composition 14-1 exhibited a
single endotherm (circa 100-150.degree. C.) which was depressed
compared to the individual starting components (see Table 1 for
individual Tm's).
[0272] All references referred to in this application, including
patent and patent applications, are incorporated herein by
reference to the fullest extent possible.
[0273] Throughout the specification and the claims which follow,
unless the context requires otherwise, the word `comprise`, and
variations such as `comprises` and `comprising`, will be understood
to imply the inclusion of a stated integer, step, group of integers
or group of steps but not to the exclusion of any other integer,
step, group of integers or group of steps.
* * * * *