U.S. patent application number 15/125635 was filed with the patent office on 2017-01-19 for implantable medical device.
The applicant listed for this patent is W.L GORE & ASSOCIATES, INC.. Invention is credited to Per Antoni, Robert L. Cleek, Paul D. DRUMHELLER, Theresa A. HOLLAND, Todd J. JOHNSON, Karin LEONTEIN, Krzysztof R. PIETRZAK, Bruce STEINHAUS, Lars VINCENT.
Application Number | 20170014553 15/125635 |
Document ID | / |
Family ID | 52682735 |
Filed Date | 2017-01-19 |
United States Patent
Application |
20170014553 |
Kind Code |
A1 |
Antoni; Per ; et
al. |
January 19, 2017 |
IMPLANTABLE MEDICAL DEVICE
Abstract
According to the invention there is provided inter alia an
implantable medical device with coatings comprising an immobilized
heparin moiety and elutable paclitaxel and to methods for making
such devices.
Inventors: |
Antoni; Per; (Upplands
Vasby, SE) ; LEONTEIN; Karin; (Upplands Vasby,
SE) ; VINCENT; Lars; (Upplands Vasby, SE) ;
Cleek; Robert L.; (Flagstaff, AZ) ; DRUMHELLER; Paul
D.; (Flagstaff, AZ) ; HOLLAND; Theresa A.;
(Flagstaff, AZ) ; JOHNSON; Todd J.; (Flagstaff,
AZ) ; PIETRZAK; Krzysztof R.; (Flagstaff, AZ)
; STEINHAUS; Bruce; (Flagstaff, AZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
W.L GORE & ASSOCIATES, INC. |
Newark |
DE |
US |
|
|
Family ID: |
52682735 |
Appl. No.: |
15/125635 |
Filed: |
March 13, 2015 |
PCT Filed: |
March 13, 2015 |
PCT NO: |
PCT/US2015/020390 |
371 Date: |
September 13, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14210118 |
Mar 13, 2014 |
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15125635 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 31/16 20130101;
A61F 2/07 20130101; A61L 2300/416 20130101; A61K 45/06 20130101;
A61L 33/064 20130101; A61L 31/08 20130101; A61P 7/02 20180101; A61F
2/915 20130101; A61L 31/048 20130101; A61L 2420/02 20130101; A61K
31/727 20130101; A61L 29/16 20130101; A61L 2300/216 20130101; A61K
31/337 20130101; A61L 31/10 20130101; A61L 2300/61 20130101; A61F
2002/91575 20130101; A61L 2300/606 20130101; A61L 2300/602
20130101; A61L 33/04 20130101; A61L 29/08 20130101; A61K 31/436
20130101; A61L 33/0035 20130101; A61L 27/54 20130101; A61L 29/085
20130101; A61L 2420/06 20130101; A61L 2300/42 20130101; A61P 9/00
20180101; A61L 33/0076 20130101; A61P 35/00 20180101; A61L 27/28
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 31/04 20060101 A61L031/04; A61F 2/07 20060101
A61F002/07; A61L 33/04 20060101 A61L033/04; A61L 31/08 20060101
A61L031/08; A61F 2/915 20060101 A61F002/915; A61L 33/00 20060101
A61L033/00; A61L 33/06 20060101 A61L033/06 |
Claims
1. An implantable medical device with a surface having a coating
comprising: a first coating layer comprising an immobilized heparin
moiety and a second particulate coating layer comprising elutable
paclitaxel and at least one organic additive, wherein at least a
portion of the second particulate coating layer is in contact with
at least a portion of the first coating layer.
2. An implantable medical device according to claim 1, wherein the
medical device is a tubular medical device.
3. An implantable medical device according to claim 1, wherein the
first coating layer comprises a polymer.
4. An implantable medical device according to claim 3, wherein the
heparin moiety is covalently attached to the polymer.
5. An implantable medical device according to or claim 4, wherein
the polymer is a cationic polymer.
6. An implantable medical device according to claim 5, wherein the
first coating layer comprises one or more coating bilayers of
cationic polymer and anionic polymer, the innermost layer being a
layer of cationic polymer and the outermost layer being the layer
of cationic polymer to which the heparin moiety is covalently
attached.
7. An implantable medical device according to claim 3, wherein the
heparin moiety is covalently end-point attached to the polymer and
wherein the end-point attached heparin moiety is connected through
its reducing end.
8. (canceled)
9. (canceled)
10. An implantable medical device according to claim 1, wherein the
or each organic additive is non-polymeric and hydrolytically
stable.
11. (canceled)
12. An implantable medical device according to claim 1, wherein at
least a proportion of the second 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
paclitaxel and the at least one organic additive when in pure
form.
13. An implantable medical device according to claim 1, wherein the
second particulate coating layer is surfactant-free.
14. An implantable medical device according to claim 1, wherein the
second particulate coating layer is polymer-free.
15. An implantable medical device according to claim 1, wherein the
paclitaxel and the or each organic additive are in crystalline
form.
16. An implantable medical device according to claim 1, wherein the
second particulate coating layer comprises crystalline particles of
the therapeutic agent and the at least one organic additive in a
eutectic mixture or comprises crystalline particles of the
therapeutic agent and the at least one organic additive in
co-crystalline form.
17. (canceled)
18. An implantable medical device according to claim 1, wherein the
each organic additive is independently selected from the list
consisting of paminobenzoic acid, saccharin, ascorbic acid, methyl
paraben, caffeine, calcium salicylate, pentetic acid, creatinine,
ethylurea, acetaminophen, aspirin, theobromine, tryptophan,
succinic acid, adipic acid, glutaric acid, theophylline, and
saccharin sodium.
19. An implantable medical device according to claim 18, wherein
the or each organic additive is independently selected from the
list consisting of p-aminobenzoic acid, methyl paraben, caffeine,
calcium salicylate and succinic acid.
20. An implantable medical device according to claim 19, wherein
the or each organic additive is caffeine or succinic acid.
21. (canceled)
22. (canceled)
23. An implantable medical device according to claim 1, wherein the
second particulate coating layer consists of paclitaxel and one
organic additive.
24. An implantable medical device according to claim 1, wherein the
implantable medical device is an implantable endoluminal medical
device.
25. An implantable medical device according to claim 24, wherein
the implantable medical device is a stent.
26. An implantable medical device according to claim 24, wherein
the implantable medical device is a stent-graft, wherein the
stent-graft comprises a stent member and a graft member.
27. An implantable medical device according to claim 26, wherein
the stent member is composed of a metal alloy.
28. (canceled)
29. (canceled)
30. An implantable medical device according to claim 1, wherein the
implantable medical device comprises ePTFE.
31. (canceled)
32. (canceled)
33. An implantable medical device according to claim 2, wherein the
first coating layer is applied to a portion of the luminal side and
to a portion of the abluminal side of the medical device; and
wherein, the second particulate coating layer is applied only to a
portion of the abluminal side of the device.
34. An implantable medical device according to claim 33, wherein
the first coating layer is applied to the entire luminal side and
abluminal side of the medical device.
35. (canceled)
36. (canceled)
37. An implantable medical device according to claim 1, wherein at
least a portion of the second particulate coating layer is applied
on top of at least a portion of the first coating layer.
38. A stent or stent-graft having a coating comprising: a first
coating layer comprising an immobilized heparin moiety; and a
second particulate coating layer comprising elutable paclitaxel and
at least one organic additive; wherein, the first coating layer is
applied to a portion of the luminal side and to a portion of the
abluminal side of the stent or stent-graft; and the second
particulate coating layer is applied only to a portion of the
abluminal side of the stent or stent-graft, wherein at least a
portion of the second particulate coating layer is in contact with
at least a portion of the first coating layer.
39. A stent or stent-graft according to claim 38, wherein the first
coating layer is applied to the entire luminal side and abluminal
side of the medical device.
40. A stent or stent-graft according to claim 38, wherein the
second particulate coating layer is applied only to one end of the
abluminal side of the medical device.
41. A stent or stent-graft according to claim 38, wherein at least
a portion of the second particulate coating layer is applied on top
of at least a portion of the first coating layer.
42. A stent or stent-graft having a coating comprising: a first
coating layer comprising an immobilized heparin moiety; and a
second particulate coating layer comprising elutable paclitaxel and
at least one organic additive; wherein at least a portion of the
second particulate coating layer is in contact with at least a
portion of the first coating layer, and wherein the organic
additive is independently selected from the list consisting of
paminobenzoic acid, saccharin, ascorbic acid, methyl paraben,
caffeine, calcium salicylate, pentetic acid, creatinine, ethylurea,
acetaminophen, aspirin, theobromine, tryptophan, succinic acid,
adipic acid, glutaric acid, theophylline, and saccharin sodium.
43. A stent or stent-graft according to claim 42, wherein the or
each organic additive is independently selected from the list
consisting of p-aminobenzoic acid, methyl paraben, caffeine,
calcium salicylate and succinic acid.
44. A stent or stent-graft according to claim 43, wherein the
organic additive is caffeine or succinic acid.
45. An implantable medical device according to claim 25, wherein
the second particulate coating layer has suitable adherence such
that less than 40% of the paclitaxel (wt % as determined using Test
Method C-I or C-II) is lost during manipulation using Test Method
H-I followed by Test Method H-II, for example less than 30%, less
than 25%, less than 20%, less than 15%, less than 10% or less than
5%.
46. An implantable medical device according to claim 26, wherein
the second particulate coating layer has suitable adherence such
that less than 40% of the paclitaxel (wt % as determined using Test
Method C-I or C-II) is lost during manipulation using Test Method
I-I followed by Test Method I-II, for example less than 30%, less
than 25%, less than 20%, less than 15%, less than 10% or less than
5%.
47. An implantable medical device according to claim 25, wherein
the second particulate coating layer has paclitaxel release and
tissue transfer characteristics such that using Test Method A the
measured drug concentration in the tissue at the 24 hr timepoint is
at least 1 I-Ig drug per g tissue (I-Ig/g), for example at least
2.5 I-Ig/g, at least 5 I-Ig/g or at least 10 I-Ig/g.
48. An implantable medical device according to claim 26, wherein
the second particulate coating layer has paclitaxel release and
tissue transfer characteristics such that using Test Method A the
measured drug concentration in the tissue at the 24 hr timepoint is
at least 1 I-Ig drug per g tissue (I-Ig/g), for example at least 10
I-Ig/g, at least 50 I-Ig/g or at least 100 I-Ig/g.
49. (canceled)
50. (canceled)
51. (canceled)
52. (canceled)
53. An implantable medical device according to claim 1, wherein the
medical device has HCII binding activity of at least 1
pmol/cm.sup.2 of surface according to Test Method J, following
removal of the second particulate coating layer according to Test
Method C-II, e.g. at least 5 pmol/cm.sup.2 or wherein the medical
device has ATII I binding activity of at least 1 pmol/cm.sup.2 of
surface according to Test Method K, following removal of the second
particulate coating layer according to Test Method C-II, e.g. at
least 5 pmol/cm.sup.2.
54. (canceled)
55. (canceled)
56. (canceled)
57. An implantable medical device according to claim 1, wherein at
least 80%, such as at least 85%, 90% or 95% of the paclitaxel
chemical content (determined using Test Method C-II) is retained
following sterilization using Test Method D.
58. An implantable medical device according to claim 1, wherein the
first coating layer is applied to the medical device before the
second particulate coating layer.
59. An implantable medical device according to claim 1, wherein the
second particulate coating layer is applied to the medical device
by dissolving the paclitaxel and the at least one organic additive
in a solvent to form a solution, applying the solution to the
medical device and then evaporating the solvent.
60. (canceled)
61. (canceled)
62. A method for the prevention or treatment of stenosis or
restenosis in a blood vessel which comprises implanting into said
blood vessel in the human body a medical device according to claim
1.
63. A process for preparing a coated implantable medical device
comprising the steps of: i) treating the medical device to provide
a first coating layer comprising an immobilized heparin moiety; and
further ii) treating the medical device to provide a second
particulate coating layer comprising elutable paclitaxel and at
least one organic additive, wherein at least a portion of the
second particulate coating layer is in contact with at least a
portion of the first coating layer.
64. (canceled)
65. (canceled)
66. (canceled)
67. (canceled)
68. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to implantable medical devices
with coatings comprising an immobilized heparin moiety and elutable
paclitaxel and to methods for making such coated devices.
BACKGROUND OF THE INVENTION
[0002] Implantable medical devices are frequently used to treat the
anatomy of patients. Such devices can be permanently or
semi-permanently implanted in the anatomy to provide treatment to
the patient. Examples of such devices include stents, grafts,
stent-grafts, filters, valves, occluders, markers, mapping devices,
therapeutic agent delivery devices, prostheses, pumps, bandages,
combinations thereof, and other endoluminal and implantable
devices.
[0003] Implantable medical devices may be used to deliver a
therapeutic agent in the vicinity of the implant, thereby providing
localized as opposed to systemic delivery. Such devices can be
described as drug-eluting devices. For example, in the case of
localized vascular disease, 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.
[0004] Several devices for localized drug delivery are known,
including stents or stent-grafts which have been coated with an
elutable drug.
[0005] A drug commonly used for the localized treatment of vascular
disease, in particular for the prevention and treatment of
restenosis, is paclitaxel. Paclitaxel can be coated onto the
surface of a device 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 device, either in
the form of a powder or via the application of the solution or
suspension followed by a drying step.
[0006] There are numerous factors that must be considered when
creating a paclitaxel-excipient combination, and when coating the
combination onto a medical device. 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 following compaction (if
coated in its expanded state), as well as maintaining adherence
until it reaches the target site and subsequently delivering the
drug to the target tissues (i.e. deployment then elution) with the
desired release and absorption kinetics. Chemical degradation of
paclitaxel and the excipients upon storage must also be considered,
and a further key requirement is that the paclitaxel, when
formulated in the coating on an implantable medical device, must
survive a sterilization process essentially intact, in particular
an ethylene oxide sterilization process.
[0007] 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 that have good adherence to the device during
manufacturing processes and manipulation, but demonstrate optimum
paclitaxel release characteristics when implanted in the target
vascular tissue.
[0008] When a medical device is implanted in the body a number of
different reactions are set into motion, some of them resulting in
inflammation and some in the coagulation of the blood in contact
with the device surface. In order to counteract these serious
adverse effects, the well-known anti-coagulant compound heparin has
for a long time been administered systemically to patients before
the medical device is placed in their body, or when it is in
contact with their body fluids, in order to provide an
antithrombotic effect. Heparin-coated surfaces also tend to be
biocompatible, thereby preventing/reducing inflammation.
[0009] Thrombin is one of several coagulation factors, all of which
work together to result in the formation of thrombi at a surface in
contact with the blood. Antithrombin (also known as antithrombin
III) ("ATII") is the most prominent coagulation inhibitor. It
neutralizes the action of thrombin and other coagulation factors
and thus restricts or limits blood coagulation. Heparin
dramatically enhances the rate at which antithrombin inhibits
coagulation factors. Heparin cofactor II ("HCII") is another
coagulation factor which rapidly inhibits thrombin in the presence
of heparin.
[0010] Systemic treatment with high doses of heparin is, however,
often associated with serious side-effects of which bleeding is the
predominant. Another rare, but serious complication of heparin
therapy is the development of an allergic response called heparin
induced thrombocytopenia that may lead to thrombosis (both venous
and arterial). High-dose systemic heparin treatment e.g. during
surgery also requires frequent monitoring of the activated clotting
time (used to monitor and guide heparin therapy) and the
corresponding dose adjustments as necessary.
[0011] Therefore, solutions have been sought where the need for a
systemic heparinization of the patient would be unnecessary or can
be limited. It was thought that this could be achieved through a
surface modification of the medical devices using the
anti-coagulative properties of heparin. Thus, a number of more or
less successful technologies have been developed where a layer of
heparin is attached to the surface of the medical device seeking
thereby to render the surface non-thrombogenic. For devices where
long term bioactivity is required, heparin should desirably be
resistant to leaching and degradation.
[0012] Heparin is a polysaccharide carrying negatively charged
sulfate and carboxylic acid groups on the saccharide units. Ionic
binding of heparin to polycationic surfaces was thus attempted, but
the surface modifications suffered from lack of stability resulting
in lack of function, as the heparin leached from the surface.
Thereafter, different surface modifications have been prepared
wherein the heparin has been covalently bound to groups on the
surface.
[0013] One of the most successful processes for rendering a medical
device non-thrombogenic has been the covalent binding of a heparin
fragment to a modified surface of the device. The general method
and improvements thereof are described in various patent documents
(see EP-B-0086186, EP-B-0086187, EP-B-0495820 and U.S. Pat. No.
6,461,665 each of which is incorporated herein by reference in its
entirety).
[0014] These patents describe the preparation of a heparinised
surface by reacting heparin modified to bear a terminal aldehyde
groups with a surface on a medical device which has been modified
to bear primary amino groups. An intermediate Schiff base is formed
which is reduced in situ to form stable secondary amine linker,
thereby covalently immobilizing the heparin.
[0015] Further methods for covalently attaching heparin to a
surface while retaining its bioactivity are described in
WO2010/029189, WO2011/110684 and WO2012/123384 (each of which is
incorporated herein by reference in its entirety).
SUMMARY OF THE INVENTION
[0016] In one aspect, the present invention provides an implantable
medical device with a surface having a coating comprising:
a first coating layer comprising an immobilized heparin moiety and
a second particulate coating layer comprising elutable paclitaxel
and at least one organic additive, wherein at least a portion of
the second particulate coating layer is in contact with at least a
portion of the first coating layer.
[0017] In another aspect, the present invention provides a process
for preparing a coated implantable medical device comprising the
steps of:
i) treating the medical device to provide a first coating layer
comprising an immobilized heparin moiety; and further ii) treating
the medical device to provide a second particulate coating layer
comprising elutable paclitaxel and at least one organic additive,
wherein at least a portion of the second particulate coating layer
is in contact with at least a portion of the first coating
layer.
BRIEF DESCRIPTION OF THE FIGURES
[0018] FIG. 1: shows platelet consumption for stent-grafts of the
invention and comparators following the blood contact evaluation
test (Example 20);
[0019] FIG. 2: shows the absence of clot formation on stent-grafts
of the invention following the blood contact evaluation test
(Example 20);
[0020] FIG. 3: shows a SEM image of the surface of a stent-graft of
the invention before manipulation (Example 21);
[0021] FIG. 4: shows a SEM image of the surface of a stent-graft of
the invention after manipulation (Example 21).
[0022] FIG. 5: shows dye-solvent casting of stent-grafts with and
without a coating of immobilized heparin (first coating layer)
(Example 23).
[0023] FIG. 6: shows a stent with interconnecting fluoropolymer
webs (as described in US2009/0182413).
[0024] FIG. 7: shows a stent-graft consisting of a stent member and
a graft member.
[0025] FIG. 8: shows the paclitaxel content of a stent-graft of the
invention and a comparator pre- and post-compaction and expansion
(Example 5).
[0026] FIG. 9: shows a coating arrangement wherein a tubular device
is coated at both ends with the second particulate coating
layer.
[0027] FIG. 10: shows some possible first coating layer and second
particulate coating layer arrangements in embodiments of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
Implantable Medical Devices and Materials
[0028] Implantable medical devices are devices which are implanted
in the anatomy e.g. into the vasculature or other body lumen, space
or cavity to provide a therapeutic effect. Implantable devices are
left, in part or in whole, in the anatomy after the immediate
surgical procedure to deliver them. Devices which are transiently
inserted into a treatment region (i.e. inserted and then removed in
the same surgical procedure), such as a medical balloon (for
example, one inserted into the vasculature during a Percutaneous
Transluminal Angioplasty (PTA)), are not considered to be
implantable medical devices within the context of the present
invention. Thus, the implantable medical device is not a medical
balloon.
[0029] In one embodiment, the implantable medical device is a
tubular medical device. Suitably the implantable medical device is
an implantable endoluminal medical device, in particular an
implantable endovascular medical device.
[0030] Examples of implantable medical devices include stents,
grafts, stent-grafts, in-dwelling filters, valves, occluders,
markers, mapping devices, therapeutic agent delivery devices,
prostheses, pumps and bandages and other endoluminal and
implantable devices.
[0031] Additional examples of implantable medical devices include
indwelling monitoring 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,
dilation devices to restore patency to an occluded body passage,
occlusion devices to selectively deliver a means to obstruct or
fill a passage or space, and as a centering mechanism device for
transluminal instruments like catheters.
[0032] Further examples of implantable medical devices of the
present invention 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).
[0033] In one embodiment, the implantable medical device is a
stent. In another embodiment, the implantable medical device is a
stent-graft.
[0034] In one embodiment, the implantable 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, or nitinol),
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)
and illustrated in FIG. 6.
[0035] 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, in particular from a metal or a
metal alloy. In one embodiment, the stent is formed from stainless
steel. In another embodiment, the stent is formed from nitinol.
[0036] A stent-graft typically comprises a stent member and a graft
member. Aspects described above with respect to stents apply
equally to the stent members of stent grafts. 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 be 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). A typical stent-graft
construction is illustrated in FIG. 7.
[0037] In another embodiment, the stent-graft is a vascular graft
incorporating a stent into a portion of its length, as described in
US2009/0076587 (Gore Enterprise Holdings, Inc., incorporated herein
by reference).
[0038] In one embodiment, the implantable medical device is a
stent-graft, wherein the stent member comprises nitinol. In another
embodiment, the implantable medical device is a stent-graft wherein
the graft member is formed from a polymer, suitably a biocompatible
polymer. Suitably the graft member is formed from a fluoropolymer
such as expanded polytetrafluoroethylene (ePTFE). In one
embodiment, the graft member is composed of ePTFE.
[0039] In one embodiment, the implantable medical device is a
stent-graft comprising a stent member and a graft member, wherein
the stent member comprises nitinol and the graft member comprises
ePTFE.
[0040] Prior to coating with the first coating layer and second
particulate coating layer, 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, in particular paclitaxel, applied to the device. For
example, pits or blind holes can be formed in stent struts into
which a therapeutic agent is loaded.
[0041] US2010/0152841 (Dave et al., incorporated herein by
reference) describes an expandable, non-removable medical device
which can be implanted within a bodily lumen of a human or animal,
with openings for delivery of a plurality of beneficial agents and
a surface coating of antithrombotic agent. Also described are
primer coatings for use between the antithrombotic agent coating
and other therapeutic agent/polymer matrices.
[0042] In one embodiment, prior to coating the implantable medical
device comprises a surface with, or is covered with, a porous
material. In an embodiment, this porous material is a fluoropolymer
such as polytetrafluoroethylene (PTFE), an expanded PTFE (ePTFE),
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. 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 porous material 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 implantable medical device
covering is changed. In another embodiment, the porous material is
a knitted, woven or braided polyester.
[0043] In one embodiment, the coated implantable medical device has
a covering disposed around at least a portion of a coating. Such a
covering is typically described as a constraint or a sheath and is
used to assist in the tracking and delivery of a medical device
such as a stent or stent-graft. The constraint is considered to be
a separate entity from the implantable medical device of the
invention. In one embodiment, the constraint is disposed over the
coated implantable medical device. The constraint 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.
[0044] The surface(s) or outward configuration of the constraint
material may be modified with textures, protrusions, wires, blades,
spikes, scorers, depressions, grooves, coatings, particles, 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 implantable
medical device 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.
[0045] The constraint 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. As described
in U.S. Pat. No. 8,753,386 (Shaw, incorporated herein by reference)
optimal positioning of the stent-graft may be determined by various
now known or as yet unknown techniques.
[0046] The implantable medical device, in particular a surface of
the implantable medical device, can be composed of one or more
materials as described hereinabove. The implantable 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.
[0047] Thus, in one embodiment the implantable medical device, in
particular a surface of the implantable 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. In one embodiment, a surface of the
medical device is composed of nylon.
[0048] The implantable medical device, in particular a surface of
the implantable 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 useful in the medical
device of the invention. In one embodiment, the implantable medical
device comprises ePTFE. Suitably a surface of the implantable
medical device is composed of ePTFE. The exact porosity of a device
composed of ePTFE will depend on the nature of the ePTFE components
and the manner in which the device is processed. The porosity of a
device composed of ePTFE can be evaluated using various methods and
parameters, as described in US2013/0231733 (W.L. Gore &
Associates, Inc., incorporated herein by reference).
[0049] The implantable medical device, in particular a surface of
the implantable 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 implantable medical device,
in particular a surface of the implantable 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.
Coating Layer
[0050] The coating on the implantable medical device of the present
invention comprises a first coating layer comprising an immobilized
heparin moiety and a second particulate coating layer comprising
elutable paclitaxel and at least one organic additive.
First Coating Layer
[0051] The first coating layer comprises an immobilized heparin
moiety. The term "heparin moiety" refers to a heparin molecule, a
fragment of the heparin molecule, or a derivative or analogue of
heparin. Heparin derivatives can be any functional or structural
variation of heparin. Representative variations include alkali
metal or alkaline earth metal salts of heparin, such as sodium
heparin (e.g. Hepsal or Pularin), potassium heparin (e.g. Clarin),
lithium heparin, calcium heparin (e.g. Calciparine), magnesium
heparin (e.g. Cutheparine), and low molecular weight heparin
(prepared by e.g. oxidative depolymerisationdepolymerisation,
enzymatic degradation or deaminative cleavage, e.g. ardeparin
sodium, tinzaparin or dalteparin). Other examples include heparan
sulfate, heparinoids, heparin-based compounds and heparin having a
hydrophobic counter-ion. Other desirable anti-coagulant entities
include synthetic heparin compositions referred to as
"fondaparinux" compositions (e.g. Arixtra from GlaxoSmithKline)
involving antithrombin-mediated inhibition of factor Xa. Additional
derivatives of heparin include heparins and heparin moieties
modified by means of e.g. mild nitrous acid degradation (U.S. Pat.
No. 4,613,665) or periodate oxidation (U.S. Pat. No. 6,653,457) and
other modification reactions known in the art where the bioactivity
of the heparin moiety is preserved. Heparin moieties also include
such moieties bound to a linker or spacer as described below.
[0052] In one embodiment, the heparin moiety is full length
heparin.
[0053] De-sulphated heparin, and heparin functionalized via e.g.
the carboxylic acid group of the uronic acid moiety, are less
suitable than other forms of heparin because of their generally
reduced anti-coagulant properties relative to other forms of
heparin. Thus, in one embodiment the heparin moiety is not
de-sulphated heparin. Mono-functionalization or low
functionalization degrees of carboxylic acid groups can be
acceptable as long as heparin bioactivity is preserved.
[0054] U.S. Pat. No. 6,461,665 (Scholander; incorporated herein by
reference) discloses improving the antithrombogenic activity of
surface-immobilized heparin by treating the heparin prior to
immobilization. The improvement is achieved by treating the heparin
at elevated temperature or at elevated pH, or by contacting the
heparin with nucleophilic catalysts such as amines, alcohols,
thiols or immobilized amino, hydroxyl or thiol groups.
[0055] The heparin moiety is "immobilized" in the sense that
substantially all of it remains attached to the device (as part of
the first coating layer) for the lifetime of the device. The
heparin moiety does not substantially elute or leach from the first
coating layer. As discussed below, the heparin moiety can be
immobilized by various methods. Preferably the heparin moiety is
covalently immobilized.
[0056] The heparin moiety is immobilized on a surface of the
implantable medical device, preferably via immobilization on a
polymer. Thus, in one embodiment, the first coating layer comprises
a polymer. In another embodiment, the first coating layer comprises
a polymer wherein the heparin moiety is attached to the polymer. In
this embodiment, the polymer can be applied to the medical device,
followed by immobilization of the heparin moiety to the polymer.
Alternatively, the heparin moiety can firstly be immobilized to the
polymer, and then the immobilized polymer-heparin moiety conjugate
can be applied to the surface of the implantable medical
device.
[0057] Thus, in one embodiment, the first coating layer is formed
by a process comprising the steps of:
a) treating the medical device to provide a polymer coating layer;
and then b) reacting said polymer layer with a heparin moiety to
immobilize the heparin moiety to the polymer coating layer.
[0058] In another embodiment, the first coating layer is formed by
a process comprising the steps of:
a) reacting a polymer with a heparin moiety, thereby to form a
polymer-heparin moiety conjugate wherein the heparin moiety is
immobilized to the polymer; b) treating the medical device with the
polymer-heparin moiety conjugate of step a).
[0059] The heparin moiety may be immobilized to the polymer by
various methods. In one embodiment, the heparin moiety is
covalently attached to a polymer. Suitably the heparin moiety is
covalently end-point attached to the polymer, preferably connected
through the reducing end (position C1 of the reducing terminal) of
the heparin moiety.
[0060] A representative end-point attachment process is described
in EP-B-0086186 (Larm; incorporated herein by reference) which
discloses a process for the covalent binding of oligomeric or
polymeric organic substances to substrates of different types
containing primary amino groups. The substance to be coupled, which
may be heparin, is subjected to degradation by diazotation to form
a substance fragment having a free terminal aldehyde group. The
substance fragment is then reacted through its aldehyde group with
the amino group of the substrate to form a Schiff's base, which is
then converted (via reduction) to a secondary amine. The advantage
of end point attachment of heparin, especially reducing end point
attachment (as described above in EP-B-0086186), is that the
biological activity of the heparin moiety is maximized due to
enhanced availability of the antithrombin interaction sites as
compared with attachment elsewhere in heparin moiety.
[0061] The nature of the polymer upon which the heparin moiety is
immobilized can impact the resulting biological activity of the
heparin moiety. EP-B-0086187 (Golander et al.; incorporated herein
by reference) describes the immobilization of anionic compounds,
including heparin, to a substrate carrying a complex of a polymeric
cationic surfactant containing primary amine groups and a
dialdehyde as a cross-linking agent. The addition of the dialdehyde
provides improved surfactant characteristics and can lead to
surprisingly strong electrostatic binding with the anionic
compounds. Examples wherein heparin is firmly bonded to the complex
via covalent or ionic bonding are described. EP-B-0495820 (Larm et
al.; incorporated herein by reference), building on the teaching of
Golander et al., describes that when crotonaldehyde is used as a
cross-linking agent in the complex rather than glutaraldehyde,
heparin which has been covalently attached to the surface (as
described in EP-B-0086186 above) has improved activity.
[0062] Thus, in one embodiment, the first coating layer comprises a
cationic polymer, typically a polyamine. In another embodiment, the
cationic polymer is cross-linked.
[0063] The heparin moiety may be covalently bonded to the polymer
via a linker other than the secondary amine described in
EP-B-0086186 above. WO2010/029189 (Carmeda A B) describes the
covalent attachment of an anticoagulant such as heparin to surface
via a 1,2,3-trizole linkage. The document describes the azide- or
alkyne-functionalization of a polyimine; the preparation of alkyne-
and azide-functionalized heparin (both native and nitrous acid
degraded heparin); and reactions to link the derivatised heparin to
the derivatised polymer via a 1,2,3-triazole linker. WO2011/110684
(Carmeda A B et al.) describes the covalent attachment of an
anticoagulant entity such as heparin to a polymer surface via a
linker comprising a thioether.
[0064] WO2012/123384 (Gore Enterprise Holdings, Inc. et al.,
incorporated herein by reference) discloses a device with a coating
comprising a plurality of hyperbranched polymer molecules bearing
anticoagulant entities, in particular heparin.
[0065] A polymer upon which the heparin moiety is immobilized, in
particular a cationic polymer upon which the heparin moiety is
covalently attached, may itself be disposed upon one or more
coating bilayers of cationic polymer and anionic polymer.
[0066] Thus, in one embodiment the first coating layer comprises
one or more coating bilayers of cationic polymer and anionic
polymer, the innermost layer being a layer of cationic polymer and
the outermost layer being an outer coating layer of cationic
polymer to which the heparin moiety is covalently attached.
[0067] The first coating layer may comprise one or more coating
bilayers, e.g. 2 or more, or 3 or 4 or 5 e.g. up to 20 coating
bilayers such that desirably a portion of the surface (desired to
be non-thrombogenic) or the whole of the surface of the object is
covered (Multilayer Thin Films ISBN: 978-3-527-30440-0). The
optimum number of bilayers will depend on the type of material from
which the object is made, and the contemplated use of the surface.
The surface may, if desired, be made up layer by layer. The number
and nature of the bilayers needed to provide a full coverage of the
surface can be easily determined by those skilled in the art. The
coating bilayer(s) may be formed by adsorbing on the surface of the
solid object high average molecular weight cationic polymer, e.g. a
polyamine (e.g. polyethyleneimine e.g. as used in the examples of
EP0495820B1 (Norsk Hydro A/S; incorporated herein by reference) and
if needed cross-linking the polyamine with, e.g. an aldehyde
crosslinker such as crotonaldehyde and/or glutaraldehyde (see
EP-B-0086187 and EP-B-0495820 above), followed by the application
of a solution of an anionic polymer, e.g. an anionic
polysaccharide, e.g. dextran sulfate, to obtain at least one
adsorbed layer of the polysaccharide. Hence the first coating layer
may comprise a layer of high average molecular weight polyamine and
a layer of anionic polysaccharide. More generally, the first
coating layer may comprise one or more coating bilayers of cationic
polymer (e.g. polyamine) and anionic polymer (e.g. anionic
polysaccharide), the innermost layer being a layer of cationic
polymer and the outer layer being a layer of cationic polymer to
which the heparin moiety is immobilized. This coating procedure is
performed essentially as described in EP-B-0495820 (see above).
Thus, theoretically it is only the outer coating layer (within the
first coating layer) which comprises the immobilized heparin
moiety. Typically, the outer coating layer (of the first coating
layer) to which the heparin moiety is immobilized is not
cross-linked. The procedure of EP-B-0495820 (see above) may however
be modified so that the outer layer (of the first coating layer) is
the anionic polysaccharide which is then reacted, as described
below, with a polyamine to which is immobilized the heparin moiety
entity.
[0068] Various methods for preparing the first coating layer are
described in Example 1.
[0069] In an alternative embodiment wherein the first coating layer
comprises a polymer, the polymer is an anionic polymer, such as
albumin. U.S. Pat. No. 4,526,714 (Cordis Europa N.V.; incorporated
herein by reference) describes the preparation of heparin-albumin
conjugates.
[0070] In one embodiment, the first coating layer consists of a
polymer and a heparin moiety, suitably wherein the heparin moiety
is covalently attached to the polymer.
[0071] Typically, the first coating layer will have an average
total thickness of about 5 nm to about 1000 nm, such as about 10 nm
to about 500 nm. Coating thickness can be measured using a suitable
coating thickness analyser or gauge, or by using X-ray
photoelectron spectroscopy with depth profiling (see Evaluation
Methods).
Second Particulate Coating Layer
[0072] The second particulate coating layer comprises elutable
paclitaxel and at least one organic additive.
[0073] 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, e.g. as paclitaxel
dihydrate. In one embodiment, the paclitaxel is anhydrous
paclitaxel. In another embodiment, the paclitaxel is paclitaxel
hydrate. In another embodiment, the paclitaxel is paclitaxel
dihydrate. In an alternative embodiment, both anhydrous and
hydrated forms of paclitaxel may be used. It should be noted that
when paclitaxel is dissolved in an aqueous or partially aqueous
solvent, practically speaking it is not of importance whether the
starting paclitaxel is in the form of the hydrate or anhydrate,
since the difference in water content between the two forms will be
minimal, compared with the overall water content of the solution in
which it is dissolved.
[0074] 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;
incorporated herein by reference). 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 (i.e. elution) 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.
[0075] The second particulate coating layer also comprises at least
one organic additive. The organic additive is also sometimes
referred to herein as the "excipient". The organic additive is
preferably non-polymeric. In one embodiment, the second particulate
coating layer is polymer-free. 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. In particular
poly(lactic-co-glycolic) acid (PLGA), polyvinylpyrrolidone (PVP) or
polyethylene glycol (PEG) are not suitable for use as an organic
additive. A further example of a material which is polymeric and
therefore not suitable as an organic additive in the second
particulate coating layer is shellac.
[0076] In one embodiment, the organic additive is not a
plasticizer. In another embodiment, the second particulate 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.
[0077] The organic additive is preferably 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.
[0078] 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; see Evaluation Methods) or high-performance
liquid chromatography. In one embodiment, a compound is considered
to be hydrolytically stable if, following the treatment above, at
least 80%, for example at least 90% or 95% of the compound is
recovered in un-degraded form.
[0079] 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.
[0080] 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. 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.
[0081] 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 second particulate
coating layer does not contain vanillin. In one embodiment, the
organic additive does not contain phenolic aldehyde functionality.
In another embodiment, the second particulate coating layer does
not contain compounds containing phenolic aldehyde
functionality.
[0082] 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; both
incorporated herein by reference). 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.
[0083] 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 second particulate 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.
[0084] 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.
[0085] In one embodiment the or each (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,
adipic acid, glutaric acid, theophylline, and saccharin sodium. The
formation of a second particulate coating layer using caffeine or
succinic acid as organic additive is described in Examples 2, 3,
3a, 3b and 3c. Suitably the or each (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.
[0086] 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. In an embodiment the second particulate coating layer
does not contain sodium salicylate. In an embodiment the second
particulate coating layer does not contain calcium salicylate. In
an embodiment the second particulate coating layer does not contain
magnesium salicylate.
[0087] In an embodiment the organic additive is not a substance
containing magnesium ions i.e. a magnesium salt. In an embodiment
the second particulate coating layer does not contain magnesium
ions i.e. a magnesium salt.
[0088] In an embodiment the organic additive is not ascorbic acid
or a salt thereof e.g. L-ascorbic acid or a salt thereof. In one
embodiment the second particulate coating layer does not contain
L-ascorbic acid or a salt thereof.
[0089] The paclitaxel when formulated in the second particulate
coating layer (and indeed the entire coating layer) should suitably
be able to withstand a sterilization process essentially intact.
Thus, in one embodiment, the paclitaxel, when formulated in the
second particulate coating layer with the or each organic additive,
is stable to sterilization.
[0090] 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 sterilization. An example of such a compound is niacinamide,
which 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 implantable medical device 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.
[0091] Thus, the organic additive is not niacinamide (also known as
nicotinamide) or sodium salicylate. In one embodiment, the second
particulate coating layer does not contain niacinamide or sodium
salicyclate.
[0092] As discussed in further detail below, implantable medical
devices of the invention can be prepared by dipping the medical
device (suitably pre-coated with the first coating layer comprising
an immobilized heparin moiety) into a solution containing
paclitaxel and the at least one organic additive. 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 second
particulate coating layer does not contain thiamine-HCl.
[0093] 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. Suitably the second particulate coating layer does not
contain dexpanthenol, recinoleic acid, resorcin or isomalt.
[0094] In one embodiment, the organic additive is not a surfactant.
In one embodiment, the second particulate 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.).
[0095] In one embodiment, the second particulate coating layer is
free of cyclodextrin.
[0096] In one embodiment, the second particulate coating layer is
free of inorganic components (e.g. salts having both inorganic
cations and inorganic anions). Suitably the second particulate
coating layer is bioabsorbable or is biostable.
[0097] In one embodiment, the second particulate coating layer
consists of paclitaxel and at least one organic additive. In this
embodiment, the second particulate coating layer does not comprise
components other than paclitaxel and the or each organic
additive(s) as described herein.
[0098] In one embodiment, the second particulate coating layer
comprises one organic additive. In one embodiment, the second
particulate coating layer consists of paclitaxel and one organic
additive as described herein. In this embodiment, the second
particulate coating layer is a binary composition (as described in
Examples 2, 3, 3a, 3b and 3c). In one embodiment, the organic
additive is succinic acid. In another embodiment, the organic
additive is caffeine.
[0099] In one embodiment, the second particulate coating layer
comprises two organic additives. In one embodiment, the second
particulate coating layer consists of paclitaxel and two organic
additives as described herein. In this embodiment, the second
particulate coating layer is a ternary composition. In one
embodiment, the two organic additives are caffeine and succinic
acid. In one embodiment, the second particulate coating layer
comprises three or more organic additives.
[0100] In another embodiment, the second particulate coating layer
is not a ternary composition i.e. the second particulate coating
layer consists of more or fewer than three components. In another
embodiment, the second particulate coating layer is not a
quaternary composition i.e. the second particulate coating layer
consists of more or fewer than four components.
[0101] The particulate nature of the second particulate coating
layer may be evident when the coating is visually examined
macroscopically. In one embodiment, 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.
[0102] In general, the release of excess particulates from the
coatings of intracorporeal medical devices is to be avoided, since
the release in vivo of, in particular, polymer particles can pose a
health risk for patients (e.g. inflammation and emboli). However,
these potential problems are usually associated with the release of
e.g. polymer particles of diameter >10 .mu.m, which are
insoluble or sparingly soluble in the blood stream. The second
particulate coating layers described herein are composed of
soluble, typically non-polymer based particles to be delivered to a
treatment site, therefore the release of such particles when the
paclitaxel coating elutes from the surface of the device will have
only a therapeutic effect (associated with the paclitaxel) and none
of the adverse effects mentioned above.
[0103] In one embodiment, the paclitaxel and the or each organic
additive are in crystalline form.
[0104] In one embodiment of the invention, a characteristic of the
second particulate coating layer comprising paclitaxel and at least
one organic additive is that at least a proportion of the second
particulate layer exhibits a depressed melting endotherm. A melting
endotherm can be observed in a differential scanning calorimetry
(DSC) measurement, as described in Example 4. 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 second 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 paclitaxel or the at least one organic additive when in pure
form. If the second particulate coating layer 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
second layer.
[0105] Thus, in one embodiment at least a proportion of the second
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 paclitaxel and the at least one organic
additive in pure form.
[0106] Reference to "at least a proportion" of the second
particulate coating layer exhibiting a depressed melting point is
intended to cover the scenario when the entire second particulate
coating layer comprising paclitaxel and at least one organic
additive exhibits a depressed melting point i.e. the remaining
portion of the second particulate coating layer (other than the
defined "proportion") can also exhibit the same depressed melting
point.
[0107] The proportion of the second particulate 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.
[0108] In some embodiments, the second layer particulate coating
layer comprising paclitaxel and the at least one organic additive
is predominantly in crystalline form.
[0109] The second particulate 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 components (suitably wherein at least one and preferably all
of the components are crystalline) 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; incorporated herein by reference). 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.
[0110] Alternatively, the second particulate 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 second layer could 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).
[0111] 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 second particulate coating
layer (i.e. eutectic, co-crystal or mixture thereof) is not
required to be understood for the working of the present invention,
even in those embodiments wherein the second particulate coating
layer exhibits a depressed melting point.
[0112] In this particular embodiment, the relative amounts of
paclitaxel and the at least one organic additive in the second
particulate coating layer should be such that at least a proportion
of the second particulate coating layer 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
second particulate coating layer coatings by DSC to determine
whether the depressed melting point is present.
[0113] The second particulate coating layer can be analysed
independently of the first coating layer by scraping a sample of
the second particulate coating layer off a coated device of the
invention (see Example 4). Alternatively, where a non-solid
analysis can be performed, the second particulate coating layer can
be extracted by immersing the implantable medical device in a
suitable solvent, e.g. 0.2% acetic acid in methanol, such that the
second particulate coating layer dissolves into the solution,
leaving the first coating layer intact on the surface of the
medical device (see Test Method C-II).
[0114] In one embodiment, substantially all of the second
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 second particulate coating layer would be
expected to show a single depressed melting point and no visible
endotherm corresponding to the melting of pure paclitaxel or at
least one pure organic additive.
[0115] In one embodiment, 20-100% (by weight) of the second
particulate coating layer exhibits a depressed melting point (i.e.
a melting point which is at a lower temperature than the melting
point of the paclitaxel 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 second particulate
coating layer exhibits a depressed melting point. In embodiments
where less than 100% of the second particulate coating layer 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.
[0116] In one embodiment, a proportion of the second 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 second 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 second particulate coating layer would be expected 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. 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 second particulate coating layer 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.
[0117] In an embodiment wherein the second particulate layer
exhibits a depressed melting point, 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 second particulate coating layer e.g.
1-70%, 1-60%, 1-50%, 1-40%, 1-30%, 1-20%, 1-10%, 1-5% or 1-2%.
[0118] In a further embodiment wherein the second particulate layer
exhibits a depressed melting point, a proportion of the second
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 second
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 second particulate 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.
[0119] 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 second
particulate coating layer e.g. 1-70%, 1-60%, 1-50%, 1-40%, 1-30%,
1-20%, 1-10%, 1-5% or 1-2%.
[0120] In a still further embodiment, a proportion of the second
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 second
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
second particulate 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.
[0121] 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 second particulate coating layer as
a whole (in terms of weight, which can be converted to a molar
ratio if required).
[0122] As mentioned above, the second particulate coating layer can
be analysed by ultra-performance liquid chromatography (UPLC--see
Test Method C-II and Evaluation Methods) and/or by mass
spectrometry to determine the amount of paclitaxel in the second
particulate coating layer. When the weight % of paclitaxel in the
second particulate coating layer is known, as in the case of a
binary second particulate coating layer (i.e. paclitaxel+one
organic additive only) then the weight % of the organic additive
can easily be determined as being 100-paclitaxel wt %.
[0123] In one embodiment, the weight % of paclitaxel in the second
particulate coating layer 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. %.
[0124] In one embodiment, the organic additive is caffeine and the
weight % of paclitaxel in the second particulate 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 second particulate coating layer is between about 7:3 and
about 95:5, for example between about 3:1 and about 9:1 wt. %.
[0125] In one embodiment, the organic additive is succinic acid and
the weight % of paclitaxel in the second particulate coating layer
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 second particulate coating layer is
between about 7:3 and about 9:1, for example between about 3:1 wt.
% and about 6:1.
[0126] 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 second particulate coating layer is between about 30 wt. % and
about 90 wt. %, such as between about 50 wt. % and about 90 wt.
%.
[0127] 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 in the second particulate coating layer
is between about 3:7 and about 9:1, such as between about 1:1 and
about 9:1.
[0128] 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 second particulate coating layer is between about
30 wt. % and about 90 wt. %, such as between about 50 wt. % and
about 90 wt. %.
[0129] 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 in the second particulate coating layer
is between about 3:7 and about 9:1, such as between about 1:1 and
about 9:1.
[0130] The second particulate coating layer can be prepared by a
multitude of methods. One method of preparing the second
particulate coating layer is by evaporation of a solution of
paclitaxel and the at least one organic additive, which is applied
to the surface to be coated.
[0131] Thus, in one aspect of the invention is provided an
implantable medical device as described herein wherein the second
particulate coating layer is applied to the medical device by
dissolving the paclitaxel and the at least one organic additive in
a solvent to form a solution, applying the solution to the medical
device (i.e. the surface of the medical device to be coated, which
is suitably pre-coated with the first coating layer) coating the
device with the solution and evaporating the solvent.
[0132] Various methods for forming the second particulate coating
layer by evaporation of a solution of paclitaxel and at least one
organic additive can be 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. Representative procedures are
described in Examples 2, 3, 3a, 3b and 3c. 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.
[0133] Suitably the second particulate coating layer is applied by
dispensing the coating solution comprising paclitaxel, organic
additive and solvent on to the surface of the device to be coated
using a syringe pump, under rotation. Using this method, when a
known volume and concentration of solution is coated on to a device
(via "drop casting") the amount or loading of paclitaxel applied in
the coating can be estimated, as set out in Example 3.
[0134] Suitably the solution of the paclitaxel and 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
about 95/5, between about 60/40 and about 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).
[0135] Following application of the coating solution 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.
[0136] Thus, in one embodiment the second particulate coating layer
is formed by a process comprising the steps of:
A) dissolving the paclitaxel and the at least one organic additive
in a solvent to form a solution; and then B) applying the solution
to the implantable medical device; and then C) evaporating the
solvent.
[0137] Optionally the process includes additional step D) drying
the coating.
[0138] A method of coating a stent with a first coating layer and a
second particulate coating layer of paclitaxel and caffeine is
described in Example 2. Methods of coating a stent-graft
(pre-coated with a first coating layer) with second particulate
coating layers containing paclitaxel and caffeine or succinic acid
are described in Examples 3, 3a, 3b and 3c, each of which utilise
different paclitaxel loadings (500 .mu.g, 25 .mu.g and 150 .mu.g,
respectively). These methods can be adapted for other implantable
devices.
[0139] 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. %.
[0140] 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).
[0141] 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.
[0142] 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).
[0143] 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.
%.
[0144] 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.
[0145] 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).
[0146] 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. %.
[0147] 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.
[0148] 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).
[0149] In one embodiment, the 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 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).
[0150] 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).
[0151] Typically, the second particulate coating layer 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, or
by using X-ray photoelectron spectroscopy with depth profiling (see
Evaluation Methods).
[0152] Alternatively, the second particulate coating layer may be
applied to the implantable 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 (which is
suitably pre-coated with the first coating layer).
[0153] Thus, in one embodiment the second particulate coating layer
is formed by a process comprising the steps of combining the
paclitaxel and the at least one organic additive in powder form,
and then applying the powder to the implantable medical device
(which is suitably pre-coated with the first coating layer) 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.
Additional Coating Layers
[0154] The first coating layer is typically applied to the
implantable medical device before the second particulate coating
layer. However, the first coating layer need not be applied
directly to a surface of the implantable medical device. The
implantable medical device can also include additional coatings
underlying or overlying the first coating layer and second
particulate coating layer. Such additional coatings are separate
and distinct from the first coating layer and the second
particulate coating layer and provide additional benefits while
maintaining the heparin moiety bioactivity of the first coating
layer and the ability of the paclitaxel to elute from the second
particulate coating layer. These additional coatings can include
other therapeutic agents, 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
implantable 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.
[0155] In one embodiment, an adherent layer is interposed between
the first coating layer and the material of the surface of the
implantable medical device. The adherent layer, which is a separate
and distinct layer underlying the first coating layer and second
particulate coating layer improves the adherence of the first
coating layer to the surface of the implantable 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.
[0156] An additional adherent layer between the surface of the
device and the first coating layer would be selected by the skilled
person on the basis that it would not impact the heparin moiety
bioactivity of the subsequently-applied first coating layer.
Heparin bioactivity can be assessed following, for example, Test
Method J or K.
[0157] In another embodiment, an additional coating layer
comprising a therapeutic agent other than paclitaxel is interposed
between the first coating layer and the material of the surface of
the implantable medical device, or is applied to at least a portion
of the first coating layer and/or second particulate coating layer.
Said additional coating layer is a layer which is separate and
distinct from the first coating layer and second particulate
coating layer and may provide a therapeutic benefit in addition to
the benefit provided by the paclitaxel and heparin moiety i.e.
allowing for adjunctive therapies to be combined with the
paclitaxel-organic additive and heparin moiety.
[0158] In one embodiment, the implantable medical device further
comprises a protective top coat overlying the surface of the second
particulate coating layer, or the first coating layer and the
second particulate coating layer. The top coat may further minimise
loss of the coating layer, in particular the second particulate
coating layer (paclitaxel-organic additive 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 stent or stent-graft, during the first moments of
expansion before second particulate coating layer is pressed into
direct contact with target tissue.
[0159] In embodiments wherein the implantable medical device of the
invention comprises an additional coating layer, such additional
layers are considered to be distinct and separate layers to the
first coating layer comprising an immobilized heparin moiety and
the second particulate coating layer which comprises paclitaxel and
at least one organic additive. For example, while in certain
embodiments of the invention the second particulate coating layer
is defined as being surfactant free and/or polymer free, the
implantable medical device can still have a distinct and separate
coating layer comprising surfactant and/or polymer, either
underlying or overlying the first coating layer and/or second
particulate coating layer, or residing in between a portion of the
first coating layer and second particulate coating layer.
Similarly, although in one embodiment the second particulate
coating layer does not contain protein, the implantable medical
device may have a further coating layer, underlying or overlying
the first coating layer and/or second particulate coating layer, or
residing in between a portion of the first coating layer and second
particulate coating layer, which comprises protein. Thus, a
component in the additional coating layer will not form part of
first coating layer or second particulate coating layer.
[0160] In a situation where a medical device has multiple coating
layers in addition to the coating layer of the invention, in
embodiments where the second particulate coating layer exhibits a
depressed melting point, this 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.
[0161] Any additional coating layers (in particular an additional
top coating) should still allow the paclitaxel to elute from the
second particulate coating layer, once in contact with the target
tissue. The rate of elution of paclitaxel from a device can be
assessed following Test Method M. The bioactivity of the heparin
moiety of the first coating layer should also not be adversely
affected in a significant way by the application of any additional
coatings.
[0162] In one embodiment, the implantable medical device has a
coating consisting of a first coating layer and a second
particulate coating layer as described herein i.e. the device has
no additional coating layers.
[0163] Prior to applying the first coating layer the surface of the
implantable medical device may be cleaned to improve adhesion and
surface coverage. Suitable cleaning agents include solvents as
ethanol or isopropanol (IPA), solutions with high pH like solutions
comprising a mixture of an alcohol and an aqueous solution of a
hydroxide compound (e.g. sodium hydroxide), sodium hydroxide
solution as such, solutions containing tetramethyl ammonium
hydroxide (TMAH), acidic solutions like Piranha (a mixture of
sulfuric acid and hydrogen peroxide), and other oxidizing agents
including combinations of sulfuric acid and potassium permanganate
or different types of peroxysulfuric acid or peroxydisulfuric acid
solutions (also as ammonium, sodium, and potassium salts).
Composition and Properties of Coating Layers
[0164] The first coating layer and second particulate coating layer
are applied to a surface of an implantable medical device such that
at least a portion of the second particulate coating layer is in
contact with at least a portion of the first coating layer.
[0165] The first coating layer is applied to a surface of the
implantable medical device before application of the second
particulate coating layer, and preferably the second particulate
coating layer is applied to a surface of the implantable medical
device already covered with the first coating layer i.e. preferably
the second particulate coating is applied on top of at least a
portion of the first coating layer (as illustrated in FIG. 10).
[0166] Thus, the present invention provides a process for preparing
a coated implantable medical device comprising the steps of:
i) treating the medical device to provide a first coating layer
comprising an immobilized heparin moiety; and further ii) treating
the medical device to provide a second particulate coating layer
comprising elutable paclitaxel and at least one organic additive,
wherein at least a portion of the second particulate coating layer
is in contact with at least a portion of the first coating
layer.
[0167] In one embodiment, the first coating layer is applied to the
medical device before the second particulate coating layer. In
another embodiment, at least a portion of the second particulate
coating layer is applied on top of at least a portion of the first
coating layer (see for example FIGS. 9 and 10, showing some
possible arrangements of the first coating layer and second
particulate coating layer which would fall under this
embodiment).
[0168] Embodiments described separately above with respect to
preparing the first coating layer (step i)) and the second
particulate coating layer (step ii)) apply equally to the
embodiments describing the overall coating process (i.e. steps i)
and ii)). Embodiments described above with respect to the
composition of the first coating layer and second coating layer
apply equally to all process embodiments.
[0169] The paclitaxel is "elutable" in the sense that it is
released from the coating layer of the implantable medical device
(specifically from the second particulate coating layer) when
implanted at the target area, i.e. the area to be treated with the
paclitaxel. Elution of the paclitaxel results from degradation
and/or dissipation of the second particulate coating layer i.e.
once the paclitaxel has eluted, the second particulate coating
layer no longer exists. It should be noted that degradation in this
context refers to the degradation of the coating structure as a
whole, rather than chemical degradation of the coating
components.
[0170] In one embodiment, the paclitaxel is considered to be
elutable if when immersed 0.2% acetic acid in methanol, the second
particulate coating layer dissolves completely into the solution,
within 15 minutes, as described in Test Method C-II.
[0171] As discussed above, a particular challenge when developing
an elutable 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 (elute) 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.
[0172] The second particulate coating layer of the present
invention provides a good balance of good adhesion to an
implantable medical device, thereby minimising or even eliminating
coating loss during manipulation of the device, and suitable
release characteristics such that the paclitaxel is delivered in an
effective and efficient manner to the target tissue.
[0173] The present inventors have found that the nature of the
first coating layer comprising an immobilized heparin moiety (to
which at least a portion of the second particulate coating layer is
in contact) also impacts the adherence and release characteristics
of the second particulate coating layer.
[0174] As shown in FIGS. 3 and 4 (Example 21) devices of the
invention have a smooth and even outer coating layer which is
maintained even following manipulation. This even coating layer has
been attributed at least in part to the wettability of the
immobilized heparin of the first coating layer (to which at least a
portion of the second particulate coating layer is in contact),
which is illustrated in FIG. 5 (Example 23).
[0175] The paclitaxel release profiles of devices of the invention
were investigated in Example 10. The highest release rate was
observed in the initial period up the first time point (0.25 h)
with even and sustained (lower) release rates being observed over
the remaining period of observation (up to 24 h). Sterilization did
not significantly impact the release profile, as observed in
Example 11.
[0176] The durability of the coated stent prepared in Example 2 was
assessed as described in Example 6 by comparing the mass of the
coating before and after compaction and expansion. The coated stent
was found to have a high degree of durability. The durability of
the coated stent-grafts prepared according to Example 3, 3a, 3b and
3c were assessed via a different method described in Example 7,
wherein the paclitaxel content on the device was measured before
and after compaction and expansion. The coated stent-grafts were
also found to have a high degree of durability.
[0177] In the present Examples the paclitaxel-organic additive
layer (second particulate coating layer) is applied on top of a
first coating layer composed of heparin immobilized onto a
polyamine surface. As discussed above, paclitaxel is known to be
unstable in the presence of amine functionality, therefore the fact
that the paclitaxel content is essentially un-degraded following
coating onto the first coating layer and subsequent storage and
manipulation is surprising (see e.g. Example 7, indicating good
retention of paclitaxel following manipulation).
[0178] In one embodiment, the implantable medical device is a stent
and the second particulate coating layer has suitable adherence
such that less than 40% of the paclitaxel (wt %) is lost during
manipulation using Test Method H-I followed by Test Method H-II,
for example less than 30%, less than 25%, less than 20%, less than
15%, less than 10% or less than 5%, as determined using Test Method
C-I or C-II.
[0179] In one embodiment, the implantable medical device is a
stent-graft and the second particulate coating layer has suitable
adherence such that less than 40% of the paclitaxel (wt %) is lost
during manipulation using Test Method I-I followed by Test Method
I-II, for example less than 30%, less than 25%, less than 20%, less
than 15%, less than 10% or less than 5%, as determined using Test
Method C-I or C-II.
[0180] The durability of the coated surface of a stent-graft of the
invention is further shown in FIGS. 3 and 4, which are SEM images
of the surface of a stent graft prepared according to Example 3c,
before and after manipulation (Example 21).
[0181] Thus, implantable medical devices of the present invention
are durable, while also having desirable paclitaxel release
characteristics.
[0182] The topography of the surface of the medical device onto
which the first coating layer, or first coating layer and second
particulate coating layer are coated can further enhance the
adhesion and release characteristics of the second particulate
coating layer. The present inventors have observed that when the
first coating layer and second particulate coating layers are
coated onto a surface with a porous structure, such as ePFTE, the
adherence and release characteristics are particularly favourable.
Without wishing to be bound by theory, it is thought that when a
surface with pores is coated with the first coating layer and
second particulate coating layer, the paclitaxel-organic additive
layer may be contained within the pores. This could have the effect
of stabilizing the paclitaxel during processing of the device,
thereby enhancing coating durability, and allowing the use of lower
loadings of paclitaxel on the device to be used. As shown in
Example 7, a stent-graft of the invention with a lower initial
loading of paclitaxel was observed to lose a lower amount (wt %) of
paclitaxel following manipulation of the device, compared with a
higher loading. This could also have the effect of slowing the
release of paclitaxel into the target tissue once the medical
device is implanted, thereby providing prolonged release of
paclitaxel from the device to the target tissue.
[0183] Thus, in embodiments wherein the surface of the device being
coated is porous e.g. the surface is composed of ePTFE, or knitted,
woven or braided polyester, the wettable nature of the immobilized
heparin moiety first coating layer and the porous nature of the
surface could provide an implantable medical device with
particularly favourable adhesion and release characteristics.
[0184] The implantable medical device of the invention, in
particular the second particulate coating layer of the device, has
suitable paclitaxel release and tissue transfer characteristics
such that the measured drug concentration in the tissue at the 24
hr timepoint (measured according to Test Method A) 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, at least 10 .mu.g/g, at least 50
.mu.g/g or at least 100 .mu.g/g.
[0185] In one embodiment, the implantable medical device is a
stent, and the second particulate coating layer of the device has
suitable paclitaxel release and tissue transfer characteristics
such that using Test Method A 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.
[0186] In one embodiment, the implantable medical device is a
stent-graft, and the second particulate coating layer of the device
has suitable paclitaxel release and tissue transfer characteristics
such that using Test Method A 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 10 .mu.g/g, at least 50
.mu.g/g or at least 100 .mu.g/g.
[0187] The paclitaxel release characteristics may be further
enhanced by considering the location of the first coating layer and
second particulate coating layer on the implantable medical
device.
[0188] Implantable medical devices suitably have an external
surface and an internal surface, either or both of which can be
coated with the first coating layer and second particulate coating
layer.
[0189] For example, tubular substrates including but not limited to
artificial blood vessels, vascular grafts, stents, and stent-grafts
have an internal surface (luminal surface/side), which can be
coated independently from the external surface (abluminal
surface/side). 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. Alternatively, both the internal and external surfaces
may require coating, but with different coatings, or different
combinations of coatings.
[0190] The amount or thickness of each coating layer may
independently be varied over the surface of the medical device.
Each coating layer can independently be continuous over an entire
surface of the device or be discontinuous and cover only a portion
or separate portions of the device (e.g. as illustrated in FIG.
10).
[0191] In one embodiment, both the external and internal surfaces
of the device are coated with the first coating layer. In another
embodiment, only a portion of the external surface of the device is
coated with the second particulate coating layer.
[0192] In one embodiment, the first coating layer is applied to up
to 100%, for example up to 99%, 95%, 90%, 75%, 50% or 25% of the
surface area of the implantable medical device.
[0193] In one embodiment the implantable medical device is a
tubular implantable medical device with a luminal and an abluminal
side. In this embodiment, suitably the first coating layer is
applied to a portion of the luminal side and to a portion of the
abluminal side of the medical device; and the second particulate
coating layer is applied only to a portion of the abluminal side of
the device. "A portion" as referred to herein should be taken to
mean "at least a portion" such that the entire side may be
coated.
[0194] In one embodiment, the implantable medical device is a
tubular medical device and the first coating layer is applied to up
to 100%, for example up to 99%, 95%, 90%, 75%, 50% or 25% of the
luminal side and up to 100%, for example up to 99%, 95%, 90%, 75%,
50% or 25% of the abluminal side. Suitably the tubular medical
device is a stent or stent-graft.
[0195] In one embodiment, the first coating layer is applied to the
entire luminal side and abluminal side of the medical device. In
one embodiment, the second particulate coating layer is applied to
the entire abluminal side of the medical device.
[0196] In one embodiment, the second particulate coating layer is
applied to up to 100%, for example up to 99%, 95%, 90%, 75%, 50% or
25% of the surface area of the implantable medical device.
[0197] In one embodiment the implantable medical device is a
tubular implantable medical device wherein the second particulate
coating layer is applied to up to 100%, for example up to 99%, 95%,
90%, 75%, 50% or 25% of the abluminal surface side of the
implantable medical device.
[0198] In another embodiment, the implantable medical device is a
stent-graft and the first coating layer is independently applied to
up to 100%, for example up to 99%, 95%, 90%, 75%, 50% or 25% of the
luminal and abluminal sides of a stent-graft, wherein the second
particulate coating layer is applied to up to 95%, 90%, 75%, 50% or
25% of the abluminal side of the graft member, in particular the
graft member directly covering, or in contact with, the stent
member.
[0199] In one embodiment, the first coating layer is applied to the
entire surface area (100%) of the implantable medical device, and
is then entirely over-coated with the second particulate coating
layer (i.e. the second coating layer is also applied to 100% of the
surface are of the medical device, which has been pre-coated with
the first coating layer).
[0200] In another embodiment, the implantable medical device is a
stent or stent-graft and the first coating layer is applied to the
entire luminal and abluminal sides of the device, and the second
particulate coating layer is applied only up to 100%, for example
up to 99%, 95%, 90%, 75%, 50% or 25% of the abluminal side of the
device. In this embodiment, suitably the device is a
stent-graft.
[0201] It should be noted that in the above embodiments and those
that follow, the surface area does not take into account porosity
considerations of a device composed of a porous material. If the
surface of the device is porous, the effect of porosity on surface
area is not considered. For example, the surface area of a
cylindrical tubular ePTFE vascular graft (which is made of a porous
material) 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.
[0202] In one embodiment, the second particulate coating layer is
applied only to a portion of the abluminal side of the implantable
medical device.
[0203] In one embodiment, the second particulate coating layer is
applied only to one end of the abluminal side of the implantable
medical device. If the device has designated proximal and distal
ends, suitably in this embodiment the second particulate coating
layer is applied only to the proximal end of the implantable
medical device. The proximal end of a device can be designated by
considering the flow of blood through the device once it is
implanted. Once implanted, blood flows from the proximal end to the
distal end of the device.
[0204] When the implantable medical device is a tubular medical
device, such as a stent or stent-graft, in one embodiment the
portion of the abluminal surface up to 1 to 20 mm from one end (the
proximal end if designated) is coated with the second particulate
coating layer, e.g. up to 2 to 10 mm, e.g. up to 3 to 7 mm. Where
the end of the device is non-uniform, e.g. scalloped, then this
distance is measured from the outermost point of the end to be
coated.
[0205] Applying the second particulate coating layer only to the
proximal end of the implantable medical device localizes the
delivery of paclitaxel to the vascular tissue at the proximal end,
but also allows migration of the paclitaxel further "downstream"
i.e. along the length of the vessel between the proximal and distal
ends of the device. In such an embodiment, a certain amount of
migration of paclitaxel "upstream" might be observed.
[0206] In one embodiment, the second particulate coating layer is
applied to both ends of the implantable medical device, in
particular to both ends of the abluminal side of the implantable
medical device.
[0207] FIG. 9 illustrates a tubular implantable medical device with
the first coating layer covering the luminal side and abluminal
side of the device, and the second particulate coating layer
covering both ends of the abluminal side of the device.
[0208] When the implantable medical device is a tubular medical
device, such as a stent or stent-graft, in one embodiment the
portion of the abluminal surfaces up to 1 to 20 mm from each end of
the device are independently coated with the second particulate
coating layer, e.g. up to 2 to 10 mm, e.g. up to 3 to 7 mm.
[0209] An immobilized heparin moiety will provide a biocompatible
and antithrombotic effect when in contact with mammalian blood,
e.g. when coated on the luminal side of an implantable medical
device within the vasculature. Surprisingly, the first coating
layer with an immobilized heparin moiety still provides an
antithrombotic effect following processing of the medical device
i.e. heparin moiety bioactivity is preserved during subsequent
coating processes (application of the second particulate coating
layer) as illustrated in Example 14. Given the sensitive nature of
heparin moieties it could not be predicted that the medical device
of the invention, in particular the first coating layer, would
retain therapeutically useful heparin moiety bioactivity following
implantation.
[0210] Heparin moiety bioactivity, in particular heparin
bioactivity, can be quantified using various means, including by
measuring the ability, or capacity, of the heparin moiety to bind a
known quantity of antithrombin III (ATIII) (as described in Test
Method K), or a known quantity of heparin cofactor II (HCII) (as
described in Test Method J).
[0211] In one embodiment, the implantable medical device has ATIII
binding activity of greater than 1 pmol/cm.sup.2 of surface
according to Test Method K, before implantation. In another
embodiment, the implantable medical device has ATIII binding
activity of at least 5 pmol/cm.sup.2, such as at least 10
pmol/cm.sup.2 of surface according to Test Method K. before
implantation.
[0212] In one embodiment, the implantable medical device has HCII
binding activity of greater than 1 pmol/cm.sup.2 of surface
according to Test Method J, before implantation. In another
embodiment, the implantable medical device has HCII binding
activity of at least 5 pmol/cm.sup.2, such as at least 10
pmol/cm.sup.2 of surface according to Test Method J, before
implantation.
[0213] In one embodiment, the implantable medical device has ATIII
binding activity of greater than 1 pmol/cm.sup.2 of surface
according to Test Method K, after elution of the paclitaxel. In
another embodiment, the implantable medical device has ATIII
binding activity of at least 5 pmol/cm.sup.2, such as at least 10
pmol/cm.sup.2 of surface according to Test Method K, after elution
of the paclitaxel.
[0214] In one embodiment, the implantable medical device has HCII
binding activity of greater than 1 pmol/cm.sup.2 of surface
according to Test Method J, after elution of the paclitaxel. In
another embodiment, the implantable medical device has HCII binding
activity of at least 5 pmol/cm.sup.2, such as at least 10
pmol/cm.sup.2 of surface according to Test Method J, after elution
of the paclitaxel.
[0215] In one embodiment, the implantable medical device has ATIII
binding activity of greater than 1 pmol/cm.sup.2 of surface
according to Test Method K, following removal of the second
particulate coating layer according to Test Method C-II. In another
embodiment, the implantable medical device has ATIII binding
activity of at least 5 pmol/cm.sup.2, such as at least 10
pmol/cm.sup.2 of surface according to Test Method K, following
removal of the second particulate coating layer according to Test
Method C-II.
[0216] In one embodiment, the implantable medical device has HCII
binding activity of greater than 1 pmol/cm.sup.2 of surface
according to Test Method J, following removal of the second
particulate coating layer according to Test Method C-II. In another
embodiment, the implantable medical device has HCII binding
activity of at least 5 pmol/cm.sup.2, such as at least 10
pmol/cm.sup.2 of surface according to Test Method J, following
removal of the second particulate coating layer according to Test
Method C-II.
[0217] Heparin moiety bioactivity can also be demonstrated using a
blood contact activation method, as described in Test Method B. As
shown in Example 20, stent-grafts of the invention had similar
preservation compared with a reference stent-graft with a first
coating layer of immobilized heparin but no second particulate
coating layer, indicating that application of the second
particulate coating layer does not adversely affect in a
significant way the thromboresistance of the first coating layer,
which is surprising given the sensitive nature of heparin.
[0218] Furthermore, the application of the second particulate
coating layer does not impact the uniform coverage of the first
coating layer of immobilized heparin, as illustrated in FIG. 5
which shows the staining of a stent-graft of the invention (right)
compared with a reference stent graft with only a first coating
layer (left) (Example 22).
[0219] Thus, when implanted in the target tissue, the medical
device of the present invention is capable of preventing
coagulation or thrombus formation.
[0220] Even when not in contact with the blood, the first coating
layer is expected to provide a biocompatible surface, reducing
unwanted effects associated with the implantation of the implant
(which represents a foreign surface) as demonstrated by Lappegard,
K. T 2008, J. Biomed. Mater. Res. Vol 87, 129-135 (incorporated
herein by reference). Thus, following implantation and elution of
the paclitaxel (and organic additive i.e. dissipation of the second
particulate coating layer) the surface that remains is expected to
be biocompatible e.g. as demonstrated using Test Method O.
[0221] Thus, as illustrated in Examples 14 and 19, an implantable
medical device of the present invention exhibits dual activity--the
elutable paclitaxel in the second particulate coating layer
provides a therapeutic effect, typically an anti-restenosis effect,
while the first coating layer comprising immobilized heparin
exhibits an antithrombotic effect. The first coating layer further
provides the implantable medical device with a biocompatible
surface.
[0222] As shown in Example 8, the implantable medical device of the
present invention is stable to sterilization. In particular, the
paclitaxel, when formulated in the second particulate coating layer
survives a sterilization process essentially intact.
[0223] 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 paclitaxel 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). The method of sterilization
will typically be selected based on the composition of the medical
device material and the coating components e.g. ePFTE will be
degraded by gamma radiation. Sterilization using ethylene oxide is
the most commonly utilized, proven and readily available
sterilization technique for implantable medical devices such as
stents and stent grafts. Thus, in one embodiment, the paclitaxel is
essentially intact after sterilization using ethylene oxide. In
another embodiment, the paclitaxel is stable to ethylene oxide
sterilization.
[0224] Paclitaxel 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 (by weight). Paclitaxel is
considered to be degraded if it is chemically altered following
sterilization. Conversely, paclitaxel in the second particulate
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 paclitaxel chemical content
after sterilization, for example at least 85%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, 99% or substantially all of the paclitaxel
chemical content (i.e. weight) after sterilization.
[0225] The amount of intact paclitaxel 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.
Specific methods of quantifying paclitaxel in a coating are
provided in Test Methods C-I and C-II.
[0226] 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.
[0227] In one embodiment, at least 80%, such as at least 85%, 90%
or 95% of the paclitaxel chemical content (determined using Test
Method C-II) is retained following sterilization using Test Method
D.
[0228] In one aspect of the invention is provided an implantable
medical device as described herein which has been sterilized, e.g.
ethylene oxide sterilized.
[0229] As shown in Example 8, following sterilization using
ethylene oxide according to Test Method D, essentially no
degradation of paclitaxel was observed for a stent-graft of the
invention coated according to Examples 3a, 3b and 3c. When
stent-grafts were subjected to manipulation followed by
sterilization, any loss of paclitaxel activity was attributed to
the manipulation step, as described in Example 9. Examples 10 and
11 comparing paclitaxel release profiles of stent-grafts of the
invention also show that the stent-grafts are unaffected by
sterilization by ethylene oxide.
Therapeutic Methods
[0230] Implantable medical devices as described hereinabove are of
use in medical therapy.
[0231] In one aspect of the invention is provided an implantable
medical device 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.
[0232] The implantable medical device 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.
[0233] In one aspect of the invention is provided an implantable
medical device 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 an
implantable medical device 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, an implantable medical device as
described hereinabove can be used to establish or maintain
arteriovenous access sites, e.g., those used during kidney
dialysis. In a further embodiment, a vascular graft or a
stent-graft may be used to redirect flow around an area of blockage
or vessel narrowing. In another embodiment, a stent-graft may be
deployed to restore patency to an area of diseased vessel or to
exclude an aneurysm. In yet another embodiment, a stent device may
be deployed to reinforce a diseased vessel following
angioplasty.
[0234] In one embodiment, said implantable medical device as
described hereinabove can be used for Percutaneous Transluminal
Angioplasty (PTA) in patients with obstructive disease of the
peripheral arteries.
[0235] In another aspect of the invention is provided a method for
the prevention or treatment of stenosis or restenosis which
comprises implanting into said blood vessel in the human body a
medical device as described hereinabove.
[0236] The second particulate coating layer of the implantable
medical device comprises a single loading of paclitaxel. The dose
of paclitaxel delivered will depend on many factors including the
size of the coated area, the length of time the device is in
contact with the target tissue and the amount of paclitaxel in the
coating. Suitably the medical device has a second particulate
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. 0.5 .mu.g/mm.sup.2, 1 .mu.g/mm.sup.2, 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 second particulate coating layer
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 similar
porous materials such as knitted, woven or braided polyester, and
their effect on surface area is not accounted for herein.
Accordingly, both porous and 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.
[0237] The implantable medical device of the invention will
typically contain 0.025-300 mg of paclitaxel in total, for example
0.025-250 mg, 0.05-200 mg, 0.05-150 mg, 0.05-100 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 e.g. 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.
[0238] 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. In one
embodiment, the coated medical device is a stent-graft and the
coating layer contains 25 mg of paclitaxel in total.
[0239] In one embodiment, at least 80% (by weight) of the
paclitaxel initially loaded on the medical device of the invention
elutes from the device, 28 days after implantation. In another
embodiment, at least 50% (by weight) of the paclitaxel initially
loaded on the medical device of the invention elutes from the
device, 24 hours after implantation.
Further Embodiments of the Invention
[0240] An implantable medical device with a surface having a
coating comprising:
a first coating layer comprising an immobilized heparin moiety and
a second particulate coating layer comprising elutable paclitaxel
and at least one organic additive, wherein the first coating layer
is applied to a portion of the luminal side and to a portion of the
abluminal side of the medical device; and wherein at least a
portion of the second particulate coating layer is in contact with
at least a portion of the first coating layer.
[0241] A stent or stent-graft having a coating comprising:
a first coating layer comprising an immobilized heparin moiety; and
a second particulate coating layer comprising elutable paclitaxel
and at least one organic additive; wherein, the first coating layer
is applied to a portion of the luminal side and to a portion of the
abluminal side of the stent or stent-graft; and the second
particulate coating layer is applied only to a portion of the
abluminal side of the stent or stent-graft, and wherein at least a
portion of the second particulate coating layer is in contact with
at least a portion of the first coating layer.
[0242] A stent or stent-graft having a coating comprising:
a first coating layer comprising an immobilized heparin moiety; and
a second particulate coating layer comprising elutable paclitaxel
and at least one organic additive; wherein at least a portion of
the second particulate coating layer is in contact with at least a
portion of the first coating layer; and wherein the 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,
adipic acid, glutaric acid, theophylline, and saccharin sodium.
[0243] A stent or stent-graft having a coating comprising:
a first coating layer comprising an immobilized heparin moiety; and
a second particulate coating layer comprising elutable paclitaxel
and at least one organic additive selected from caffeine and
succinic acid; wherein at least a portion of the second particulate
coating layer is in contact with at least a portion of the first
coating layer.
[0244] An implantable medical device having a coating
comprising:
a first coating layer comprising an immobilized heparin moiety; and
a second particulate coating layer comprising elutable paclitaxel
and at least one organic additive selected from caffeine and
succinic acid, wherein the second particulate coating layer is
applied on top of at least a portion of the first coating
layer.
[0245] A stent or stent-graft having a coating comprising:
a first coating layer comprising an immobilized heparin moiety; and
a second particulate coating layer comprising elutable paclitaxel
and at least one organic additive selected from caffeine and
succinic acid, wherein the second particulate coating layer is
applied on top of at least a portion of the first coating
layer.
[0246] A stent or stent-graft having a coating comprising:
a first coating layer comprising an immobilized heparin moiety; and
a second particulate coating layer comprising elutable paclitaxel
and at least one organic additive; wherein, the first coating layer
is applied to the entire luminal side and to the entire abluminal
side of the stent or stent-graft; and the second particulate
coating layer is applied only to a portion of the abluminal side of
the stent or stent-graft; and wherein at least a portion of the
second particulate coating layer is in contact with at least a
portion of the first coating layer.
[0247] A process for preparing a coated implantable medical device
comprising the steps of: [0248] i) a) treating the medical device
to provide a polymer coating layer; and then [0249] b) reacting
said polymer layer with a heparin moiety to immobilize the heparin
moiety to the polymer coating layer; and further [0250] ii) A)
dissolving the paclitaxel and the at least one organic additive in
a solvent to form a solution; and then [0251] B) applying the
solution to the implantable medical device; and then [0252] C)
evaporating the solvent. wherein at least a portion of the second
particulate coating layer is in contact with at least a portion of
the first coating layer.
[0253] A process for preparing a coated implantable medical device
comprising the steps of: [0254] i) a) treating the medical device
to provide a polymer coating layer; and then [0255] b) reacting
said polymer layer with a heparin moiety to immobilize the heparin
moiety to the polymer coating layer; and further [0256] ii) A)
dissolving the paclitaxel and the at least one organic additive in
a solvent to form a solution; and then [0257] B) applying the
solution to at least a portion of the implantable medical device
covered in step (i); and then [0258] C) evaporating the
solvent.
Advantages
[0259] Implanted medical devices according to the present invention
at least in some embodiments are expected to have one or more of
the following merits or advantages: [0260] good coating adherence
(in particular the second particulate coating layer) such that loss
of paclitaxel following compaction and constraining e.g. as
measured using Test Method H-I or Test Method I-I is minimal,
thereby allowing a lower paclitaxel dosage to be utilized; [0261]
good coating adherence (in particular the second particulate
coating layer) such that loss of paclitaxel is minimal during
deployment, e.g. as measured using Test Method H-II or Test Method
I-II, thereby allowing a lower paclitaxel dosage to be utilized;
[0262] good coating durability (as indicated by good coating
adherence); [0263] the second particulate coating layer is expected
to exhibit improved adhesion when coating onto a layer of
immobilized heparin moiety (first coating layer) as compared with a
second particulate coating layer coated on a coating layer not
containing immobilized heparin moiety, e.g. a coating layer of just
polymer, such as a coating layer of polyamine, or a device with no
coating layer, or a device which has just been washed; [0264] the
first coating layer comprising an immobilized heparin moiety acts
as a "wetted" or "wetted-out" surface (i.e. provides a surface with
having a lower resistance to fluid transfer), which, when the
second particulate coating layer is applied on top of the first
coating layer comprising an immobilized heparin moiety, provides a
resulting coating layer which is smooth and even; [0265] a smooth
and even coated surface, even following manipulation (e.g. as
determined using SEM visualisation techniques); [0266] suitable
paclitaxel release characteristics, in particular even
paclitaxel-to-tissue transfer and distribution upon contact with
the target tissue e.g. as measured in Test Method A; [0267]
sustained release of the paclitaxel into the target tissue once the
medical device has been implanted; [0268] good coating stability to
sterilization (in particular the second particulate coating layer,
more particularly the paclitaxel therein) 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); [0269] good antithrombotic activity following
implantation, which is maintained following release of the second
particulate coating layer; (e.g. following Test Method J or Test
Method K); [0270] eventual complete degradation and/or dissipation
of the second particulate coating layer following implantation;
[0271] relatively low initial loadings (doses) of paclitaxel on the
implantable medical device; [0272] good biocompatibility, even
following degradation and/or dissipation of the second particulate
coating layer e.g. as evidenced by the ability to reduce
inflammation (e.g. following Test Method O).
[0273] The invention embraces all combinations of indicated groups
and embodiments of groups recited above.
[0274] All patents and patent applications referred to herein are
incorporated by reference in their entirety.
[0275] 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.
DEFINITIONS AND ABBREVIATIONS
[0276] DSC differential scanning calorimetry ePTFE expanded
polytetrafluoroethylene h hour HPLC high-performance liquid
chromatography ND not determined N/T not tested PABA p-aminobenzoic
acid PEG polyethylene glycol PBS phosphate buffered saline PLGA
poly(lactic-co-glycolic) acid PVP polyvinylpyrrolidone SEM scanning
electron microscopy UPLC ultra-performance liquid chromatography
PTX paclitaxel
EXAMPLES
General Procedures
Chemicals
[0277] Anhydrous crystalline paclitaxel was purchased from Indena.
Paclitaxel dihydrate may be purchased from Sigma-Aldrich. Patent
Blue V was purchased from Fluka. Anydrous Caffeine USP 98.5-101.0%
was purchased from Spectrum chemicals MFG. CORP. Succinic acid ACS
Reagent, .gtoreq.99.0% was purchased from Sigma-Aldrich.
Solvent
[0278] Acetone ("dry" with <0.5% water) was purchased from
Sigma. Water was deionized before use.
Materials
[0279] Stent-grafts with an immobilized heparin coating with
dimensions of 5 mm in diameter and 25 mm in length, and 6 mm
diameter and 25 mm in length were obtained from W.L. Gore and
Associates Inc. Stent-grafts without an immobilized heparin coating
with dimensions of 5 mm in diameter and 25 mm in length were
obtained from W.L. Gore and Associates Inc. Porcine carotid
arteries were obtained from Lovsta Kott AB (Uppsala, Sweden).
Evaluation Methods
[0280] The parameter being evaluated by each method is given in
parentheses.
Differential Scanning Calorimetry (DSC) Analysis (Peak Melting
Endotherm Determination)
[0281] A solid sample is added to a DSC pan. The mass of the sample
is weighed, and the pan sealed with pinhole lids. The sample is
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)
[0282] UPLC analysis is carried out using a Waters instrument
(model #ACQUITY H-class). The identification of paclitaxel is
determined by the retention time of paclitaxel. The concentration
of paclitaxel is directly proportional to the integrated peak area,
which was determined by external standardization. Samples are
dissolved in a sample diluent or submerged in an extraction solvent
and sonicated for 15 minutes. Paclitaxel standards are prepared by
serial dilution of pure paclitaxel dissolved in the sample diluent.
All samples and standards are protected from light during
preparation. UPLC chromatography parameters are: phenyl column (1.7
um, 2.1.times.50 mm); mobile phase water:acetonitrile; flow rate
0.7 ml/min; run time 12 min; injection volume 3 ul; purge solvent
acetonitrile:water (5:95 v/v); wash solvent isopropanol; column
temperature 35.degree. C.; UV detector wavelength 227.0.+-.1.2 nm;
sample rate 20 points/sec.
Scanning Electron Microscopy with Energy Dispersive X-Ray
Spectroscopy (Coating Coverage and Uniformity)
[0283] SEM images of coated devices of the invention are captured
using a Hitachi TM3000 table top SEM.
X-Ray Photoelectron Spectroscopy with Depth Profiling (XPS)
(Coating Thickness)
[0284] X-ray Photoelectron Spectroscopy (XPS or ESCA) is the most
widely used surface characterization technique providing
non-destructive chemical analysis of solid materials. Samples are
irradiated with mono-energetic X-rays causing photoelectrons to be
emitted from the top 1-10 nm of the sample surface. An electron
energy analyzer determines the binding energy of the
photoelectrons. Qualitative and quantitative analysis of all
elements except hydrogen and helium is possible, at detection
limits of .about.0.1-0.2 atomic percent. Analysis spot sizes range
from 10 .mu.m to 1.4 mm. It is also possible to generate surface
images of features using elemental and chemical state mapping.
Depth profiling is possible using angle-dependent measurements to
obtain non-destructive analyses within the top 10 nm of a surface,
or throughout the coating depth using destructive analysis such as
ion etching.
Test Methods
Test Method A--In Vitro Tissue Transfer and Uptake Test of
Paclitaxel
[0285] Coated implantable medical devices, such as stents or
stent-grafts are examined for their ability to transfer paclitaxel
from the stent-graft 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"). A
procedure which may be used when the implantable medical device is
a stent or stent-graft is as follows. The coated stent or
stent-graft is compacted diametrically according to Test Method H-I
or I-I, respectively. The compacted stents or stent-grafts are
inserted into the proximal end of the porcine vessel to the middle
of the vessel, and deployed to their expanded state according to
Test Method H-II or I-II, respectively. A Luer fitting is attached
to the proximal end and distal ends of the vessel with wax thread.
Tubing was connected to the proximal and distal fittings, and the
vessel is flushed with PBS at 60 ml/min for 24 hr at 37.degree. C.
The stent or stent-graft is removed, and vessel was analyzed for
paclitaxel content using the UPLC technique described in Evaluation
Methods.
Test Method B--Blood Contact Evaluation (Platelet Loss)
[0286] Blood contact evaluation is performed on an implantable
device of the invention, in particular on the implantable device
coated with both the first and the second layer, to evaluate its
thromboresistant properties. A procedure which may be used when the
implantable medical device is a stent-graft is as follows. Firstly
the stent-graft is washed with 0.15M saline solution for 15 min to
ensure complete wetting. The wetted stent-graft is placed in
heparinized PVC tubing containing whole blood and left to rotate in
a circulating loop at 20 rpm (see Ekdahl K. N., Advances in
Experimental Medicine and Biology, 2013, 735, 257-270 for a
representative procedure). The platelets from fresh blood and from
the blood collected from the tubes are counted in a cell counter to
measure the loss of platelets. A great loss of platelets indicates
poor thromboresistant performance of the device, in particular of
the first coating layer. Conversely a minimal loss of platelets
indicates a thromboresistant device, in particular with an
thromboresistant first coating layer.
[0287] The negative control is an empty loop of heparinized PVC
without any device. This represents a thromboresistant control for
which the incubated blood should only demonstrate a minimal loss of
platelets. The positive control is an empty loop of non-heparinized
PVC without any device. This represents a thrombogenic control for
which a great loss of platelets should be observed. The controls
are included for ensuring the quality of the experiment and the
blood.
Test Methods C--Determining Paclitaxel Content of Second
Particulate Coating Layer Following Manipulation
[0288] These tests allow the amount of paclitaxel on the coated
device (in particular in the second particulate coating layer) to
be determined. By comparing the amount of paclitaxel on the device
before and after device manipulation, the durability of the
coating, in particular of the second particulate coating layer, can
be assessed.
Test Method C-I--Weight
[0289] The coated device is weighed before and after manipulation
(e.g. manipulation according to Test Methods H or I). The weight of
the second particulate coating layer lost during manipulation can
therefore be determined. In cases where the coating composition
prior to manipulation is known (e.g. wherein the second particulate
coating layer consists of paclitaxel and a single organic additive,
and the amount (and molecular weight) of each present in the
coating is known), then the weight of paclitaxel lost can
calculated, as can the % of paclitaxel lost, and the % of
paclitaxel remaining on the device.
Test Method C-II--Extraction
[0290] The device is manipulated (e.g. according to Test Methods H
or I) and then the paclitaxel remaining on the device (in the
second particulate coating layer) following manipulation is
extracted by immersing the device in acidified methanol (0.2 v %
acetic acid in 5 mL methanol) for 15 minutes. The
paclitaxel-containing methanol solution is evaluated using UPLC
techniques (as described in Evaluation Methods) to determine the
paclitaxel content. This can be compared with the known loading of
paclitaxel on the device prior to manipulation, and the %
paclitaxel lost, and the % of paclitaxel remaining on the device
may be calculated. This method may also be used (without the
manipulation step) to determine if the paclitaxel in the second
particulate coating layer is considered to be "elutable".
Test Method D--Stability to Ethylene Oxide
[0291] The implanted medical device of the invention is placed in a
breathable polyethylene pouch (e.g. a Tyvek pouch) and subjected to
at least 12 hours preconditioning at 50.degree. C. and 60% relative
humidity followed by 2 hours exposure of ethylene oxide at a
pressure of 366 mBar and 50.degree. C. The chamber is then degassed
at 50.degree. C. for at least 10 hours. Sterilization by ethylene
oxide may be performed at Synergy Health Ireland Ltd.
[0292] After sterilization, the paclitaxel content on the device is
assessed (through device extraction i.e. immersion of the whole
device in an extraction solvent) using UPLC quantification as
described in the evaluation methods section. For each device, the
percentage paclitaxel recovery after sterilization is calculated by
normalizing the extracted paclitaxel amount by the theoretical
paclitaxel amount loaded on the device pre-sterilization.
Test Method E--Stability to Electron Beam Sterilization
[0293] A further method to sterilize an implantable medical device
of the invention is electron beam sterilization. The device 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 C-II.
Test Method F--Stability to Vapour Hydrogen Peroxide
Sterilization
[0294] A further method to sterilize an implantable medical device
of the invention is vapour hydrogen peroxide sterilization. The
device 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 C-II.
Test Method G--Stability to Plasma Hydrogen Peroxide
Sterilization
[0295] A further method to sterilize an implantable medical device
of the invention is plasma phase hydrogen peroxide sterilization.
The implantable medical device 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 C-II.
Test Methods H-I, H-II, I-I and I-II Manipulation of Stents and
Stent-Grafts
[0296] The impact of manipulation on a stent or stent-graft (e.g.
during typical manufacturing processing and then implantation) can
be assessed by comparing, for example, the weight of the entire
stent or stent-graft before and after manipulation, or the amount
of paclitaxel on the stent or stent-graft before and after
manipulation (using Test Method C-I or C-II). Stents are
manipulated according to Test Method H-I, or Test Method H-I
followed by Test Method H-II, and stent-grafts are manipulated
according to Test Method I-I, or Test Method I-I followed by Test
Method I-II.
Test Method H-I--Compaction and Constraining of Stents
[0297] Stents are compacted diametrically to an outer diameter of
3.36 mm using means known to those of skill in the art of
self-expanding stents and stent-grafts. Once compacted according to
Test Method H-II, the stents are constrained in the compacted state
within a constraint tube with an inner diameter of 3.6 mm.
Test Method H-II--Deployment of Stents
[0298] Stents are deployed from the containment tube with the use
of a push rod. When the stent is pushed out from the containment
tube, the stent shears against the containment tube inner
surface
Test Method I-I--Compaction and Constraining of Stent-Grafts
[0299] Stent-grafts are compacted diametrically to an outer
diameter of 3.0 mm using means known to those of skill in the art
of self-expanding stent-grafts. Once compacted according to Test
Method I-I, stent-grafts are constrained in the compacted state
within a constraint tube with an inner diameter of 3.0 mm.
Test Method I-II--Deployment of Stent-Grafts
[0300] Stent-grafts are deployed by pulling them out using attached
wax threads. When the stent is pulled out of the constraint tube,
the stent shears against the sharp edges at the outlet.
Test Method J--Evaluation of Heparin Moiety Bioactivity Via HCII
Binding Activity (Quantitative Heparin Function)
[0301] The heparin bioactivity of a device, in particular the first
coating layer comprising an immobilized heparin moiety can be
measured according to WO2009/064372 (Gore Enterprise Holdings,
Inc.; incorporated herein by reference) by measuring the ability,
or capacity, of the heparin moiety to bind a known quantity of
heparin cofactor II (HCII), using an assay as described by Larsen
M. L., et al., in "Assay of plasma heparin using thrombin and the
chromogenic substrate H-D-Phe-Pip-Arg-pNA (S-2238)." Thromb Res
13:285-288 (1978) and Pasche B., et al., in "A binding of
antithrombin to immobilized heparin under varying flow conditions."
Artif. Organs 1991; 15:281-491). The results are expressed as
picomoles heparin cofactor II (HCII) bound per apparent square
centimetre of device surface (pmol HCII/cm.sup.2 device surface).
The apparent device surface area does not take into account
multiple covered surfaces nor porosity considerations of a device
composed of a porous material. If the surface of the device 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 heparin immobilized on substrate material 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.
Test Method K--Evaluation of Heparin Moiety Bioactivity Via ATIII
Binding Activity (Quantitative Heparin Function)
[0302] The heparin bioactivity of a device, in particular the first
coating layer comprising an immobilized heparin moiety is measured
as the capacity of the surface bound heparin to bind antithrombin
III (ATIII) as described by Pasche, et al. in "A binding of
antithrombin to immobilized heparin under varying flow conditions"
(Artif. Organs 1991; 15:281-491) and Larsen M. L., et al. in "Assay
of plasma heparin using thrombin and the chromogenic substrate
H-D-Phe-Pip-Arg-pNA" (S-2238) (Thromb. Res. 1978; 13:285-288).
Washed samples are incubated with an excess antithrombin in
solution to saturate all available antithrombin-binding sites of
the heparin surface. Non-specifically adsorbed antithrombin is
rinsed away using a salt solution. Subsequently, antithrombin
specifically bound to the surface bound heparin is released by
incubating with a solution of heparin at high concentration.
Finally, the antithrombin released from the heparin-surface is
measured in a thrombin inhibition assay, based on a chromogenic
thrombin substrate. The results are expressed as picomoles
antithrombin III (ATIII) bound per apparent square centimetre of
device (pmol ATIII/cm.sup.2 device surface). The apparent device
surface area does not take into account multiple covered surfaces
nor porosity considerations of a device composed of a porous
material. If the surface of the device 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
heparin immobilized on substrate material 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.
Test Method L--Evaluation of Heparin Moiety Density (Quantitative
Heparin Attachment)
[0303] Quantification of surface immobilized heparin can be
performed by complete degradation of heparin followed by
colorimetric determination of the reaction products released into
solution. Degradation is achieved by reacting the heparin surface
with an excess of sodium nitrite under acidic conditions. The
degradation products, mainly disaccharides, are quantified
colorimetrically in a reaction with MBTH (3-methyl-2-bezotiazolinon
hydrazone hydrochloride), essentially as described in Smith R. L.
and Gilkerson E (1979), Anal Biochem 98, 478-480, which is
incorporated herein by reference in its entirety.
Test Method M--In Vitro Evaluation of Paclitaxel Elution
Profile
[0304] In order to study the release rate of paclitaxel from the
device (in particular from the second particulate coating layer) in
vitro, the profile of accelerated elution can be studied. For this
purpose, the coated device is put in a solution of a suitable
buffer at a fixed temperature. The eluted paclitaxel is dissolved
in the aqueous buffer solution containing cyclodextrine which
increases the solubility of paclitaxel in water up to the necessary
concentration. Withdrawal of samples at chosen time points,
analysis of the paclitaxel content by UPLC techniques (as described
in Evaluation Methods and Test Method C-II) for paclitaxel content
and plotting of paclitaxel content against time, an elution profile
is created.
Test Method N--Staining Techniques
[0305] Devices of the invention can be subjected to toluidine blue
stain solution (200 mg/L in water) by immersing in the solution for
2 minutes followed by extensive water rinse. A blue or violet
colour is observed on surfaces that contain a net negative charge
e.g. immobilized heparin moiety.
Test Method O--Surface Biocompatibility
[0306] The biocompatibility of a surface of an implantable medical
device of the invention with a first coating layer and second
particulate coating layer can be assessed as described in
Lappegard, K. T 2008, J. Biomed. Mater. Res. Vol 87, 129-135
(incorporated herein by reference). A procedure which may be used
to evaluate the inflammatory response of a stent-graft of the
invention following removal of the second particulate coating layer
(according to Test Method C-II) is as follows. Firstly the
stent-graft is washed with 0.15 M saline solution for 15 min. The
wetted stent-graft is placed in heparinized PVC tubing containing
whole blood and left to rotate in a circulating loop at 20 rpm (see
Ekdahl K. N., Advances in Experimental Medicine and Biology, 2013,
735, 257-270 (incorporated herein by reference) for a
representative procedure). After incubation, the blood is
centrifuged for 15 min, 3220 g at 4.degree. C. The plasma is frozen
in aliquots at -70.degree. C. for later analysis of cytokines.
Plasma samples are analyzed using multiplex cytokine assay
(Bio-Plex Human Cytokine 27-Plex Panel, Bio-Rad Laboratories,
Hercules, Calif.) according to the method described by Lappegard et
al. (above).
[0307] The negative control is an empty loop of heparinized PVC
without any device. This represents a non-inflammatory control for
which the incubated blood should demonstrate no or minimal amount
of inflammatory markers. The positive control is an empty loop of
non-heparinized PVC without any device. This represents an
inflammatory control for which a greater amount of inflammatory
markers should be observed. The controls are included for ensuring
the quality of the experiment and the blood.
Example 1
Methods for Preparing Immobilized Heparin Coating (First Coating
Layer) on an Implantable Medical Device
[0308] The surface of the medical device to be coated is cleaned
with isopropanol and an oxidizing agent. The surface is then
treated using the method described in Larm et al. in EP-B-0086186
and EP-B-495820 to form coating bilayers ending with a layer of
sulfated polysaccharide.
[0309] The bilayers are built-up by alternating adsorption of a
positively charged polyamine (polyethyleneimine (e.g. as used in
the examples of EP0495820B1) and negatively charged sulfated
polysaccharide (dextran sulfate). Polyethyleneimine is diluted with
water to prepare a stock solution (5 g polyethyleneimine was added
to 20 mL purified water). The polyamine is cross-linked with a
di-functional aldehyde (crotonaldehyde). Every pair of polyamine
and sulfated polysaccharide is called one bilayer. The surface of
the device is primed with four bilayers, the final layer being
dependent on the subsequent method of immobilizing the heparin
moiety.
[0310] Immobilization of heparin as described in EP-B-0086186--via
reductive amination. Heparin is subjected to degradation by
diazotation to form terminal (end point) free aldehyde group, which
subsequently reacts via the aldehyde with an amino group on the
surface of the implantable medical device to form a Schiff base
which is converted to a secondary amine linker by reduction.
[0311] A solution of heparin (1 g) in 300 ml water is cooled to
0.degree. C. on an ice bath. Sodium nitrite (10 mg) is added with
stirring. Then acetic acid is added drop-wise (2 ml). The solution
is allowed to stand under stirring for two more hours at 0.degree.
C. The reaction mixture is worked up by dialysis against distilled
water and lyophilization to produce end-point
aldehyde-functionalized heparin.
[0312] The surface of the device to be heparinized is primed with
four bilayers as described above, ending with a final layer of
polyethyleneimine (e.g. as used in the examples of EP0495820B1).
Following rinsing, the surface to be coated is incubated with a
solution of the end-point aldehyde-functionalized heparin (2-20
mg/mL) and sodium cyanoborohydride (0.5 mg/ml) in a phosphate
buffer at pH 7.0 for 24 hours at room temperature. The heparinized
surface is carefully rinsed with water.
[0313] Immobilization as described in WO2011/110684--via a
thioether linker. Thiol-functionalized heparin is reacted with a
maleimide-functionalized polyamine surface
[0314] Thiol-functionalized heparin is prepared as follows.
Nitrite-degraded heparin with end-point aldehyde groups (prepared
as described above) (5.00 g, 1.0 mmol), cysteamine hydrochloride
(0.57 g, 5.0 mmol) and sodium chloride (0.6 g) are dissolved in
purified water. The pH is adjusted to 6.0 with 1 M NaOH (aq) and 1
M HCl (aq). To the solution is added 3.1 ml of 5 (aq.) NaCNBH.sub.3
(0.16 g, 2.5 mmol) and the reaction is stirred overnight at room
temperature. The pH is adjusted to 11.0 with 1 M NaOH (aq) and the
resulting product is dialyzed against purified water with a
SpectraPor dialysis membrane mwco 1 kD (flat width 45 mm) for three
days. The reaction mixture is then concentrated and freeze dried to
obtain 2.6 g of the thiol-functionalized heparin (at the C1 of the
reducing terminal) as a white fluffy powder.
[0315] Maleimide-functionalized polyethyleneimine
(polyethyleneimine as used in the examples of EP0495820B1 (above))
is prepared as follows. 4-maleimidobutyric acid (0.50 g, 2.7 mmol)
and N-hydroxysuccinimide (NHS) (0.32 g, 2.7 mmol) are dissolved in
3 mL of dichloromethane and stirred at 0.degree. C. A solution of
N,N'-dicyclohexylcarbodiimide (0.56 g, 2.7 mmol) in 3 mL of
dichloromethane is added slowly to the reaction mixture at
0.degree. C. The reaction mixture is stirred overnight and the
byproducts are filtered off and the NHS activated
4-maleimidobutyric acid is concentrated and dried under vacuum. The
dried NHS activated 4-maleimidobutyric acid is dissolved in 30 mL
of purified water and mixed with 7.6 mL of the polyethyleneimine
stock solution at 0.degree. C. and left to react overnight at room
temperature to obtain a 1% solution of the maleimide functionalized
polyethyleneimine.
[0316] The surface of the device to be heparinized is primed with
four bilayers as described above, ending with a final layer of
negatively charged sulfated polysaccharide (dextran sulfate). Then
next coating step uses a solution of 10 mL of a 1% solution of the
maleimide-functionalized polyethyleneimine in 1000 mL of a 0.04
M/0.04 M borate/phosphate buffer at pH 8.0. The adsorption of the
maleimide-functionalized polyethyleneimine to the sulfate surface
is carried out for 20 minutes at room temperature. A two minute
water rinse is performed after the adsorption to rinse off excess
polymer. 500 mg of thiol functionalized heparin is dissolved in
1000 mL of de-ionized water and 50 mg tris(2-carboxyethyl)phosphine
hydrochloride, 500 mg 4,4'-azobis(4-cyanovaleric acid), and 2.9 g
NaCl were added. The pH is adjusted to 3.7 with 1 M HCl (aq).
[0317] The reaction between the solution of the
thiol-functionalized heparin and the maleimide functionalized
polyethyleneimine surface is carried out at 70.degree. C. for 3 h.
Purification is performed by rinsing off non-covalently linked
heparin for 10 minutes using a 0.04 M/0.04 M borate/phosphate
buffer at pH 8.0. A final rinse with de-ionized water for two
minutes is performed to wash away buffer salt residues. The flow
used during the entire process is 100 mL/min.
Example 2
Method for Preparing Paclitaxel-Organic Additive Layer (Second
Particulate Coating Layer) on a Stent where the Organic Additive is
Caffeine
[0318] 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 (via reductive amination to
form the first coating layer) according to U.S. Pat. No. 6,461,665,
incorporated herein by reference in its entirety.
[0319] The aforementioned heparin coated vascular stents were
over-coated in expanded form with a paclitaxel-excipient coating
comprising paclitaxel and caffeine (second particulate coating
layer) as follows. Paclitaxel (anhydrate) 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.
[0320] 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-caffeine 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.
Example 3
Method for Preparing Paclitaxel-Organic Additive Layer (Second
Particulate Coating Layer) on a Stent-Graft
[0321] GORE.RTM. VIABAHN.RTM. endoprostheses with Heparin Bioactive
Surface ("Stent-grafts"--as described in "Materials") are
stent-grafts which have been pre-coated with a coating layer of
immobilized heparin i.e. are purchased pre-coated with the first
coating layer of immobilized heparin.
[0322] The afore-mentioned pre-coated devices were over-coated in
expanded form with paclitaxel-organic additive coatings comprising
paclitaxel and succinic acid, or paclitaxel and caffeine, as the
second particulate coating layer. Paclitaxel (anhydrate) and the
organic additive were co-dissolved in 95/5 (v/v) acetone/water to
form a coating solution which was applied to the pre-coated devices
as shown in Table 1 (wherein "excipient" refers to the organic
additive). Specific coating compositions are described in Examples
3a, 3b and 3c below.
TABLE-US-00001 TABLE 1 Coating solution composition % Total
Excipient Paclitaxel Paclitaxel* solids Example Excipient (wt %)
(wt %) (wt %) (mg/ml) 3a Caffeine 0.04 0.12 75 1.3 3b Caffeine 0.42
1.25 75 13.3 3c Succinic acid 0.12 0.37 75 4.0 *% of paclitaxel (wt
%) in solid components of coating solution
[0323] The stent-grafts were coated at the proximal end (covering
the portion up to 5 mm from the proximal end) by dispensing the
coating solution (25-50 .mu.l of solution, using a syringe pump)
under rotation. The final drug loading on the coated area for all
devices was approximately 0.32-6.37 .mu.g/mm.sup.2 (estimated by
dispensing a known solution volume with a known paclitaxel
concentration). Coated stent-grafts can be sterilized according to
Test Methods D, F or G.
Example 3a
Method for Preparing Paclitaxel-Caffeine Layer (Second Particulate
Coating Layer) on a Stent-Graft with 500 .mu.g Paclitaxel
Loading
[0324] 100 mg of paclitaxel and 33 mg of caffeine were added to a
glass vial. A mixture of acetone (9.5 mL) and water (0.5 mL) was
added to form a solution which was allowed to dissolve while
stirring at room temperature. The resulting coating solution (10 mg
paclitaxel/mL) was applied to the stent-graft using a syringe pump
by dispensing 50 .mu.L onto the end of the stent-graft as described
in Example 3. The coated stent-graft was thereafter allowed to dry
at room temperature overnight.
Example 3b
Method for Preparing Paclitaxel-Caffeine Layer (Second Particulate
Coating Layer) on a Stent-Graft with 25 .mu.g Paclitaxel
Loading
[0325] 100 mg of paclitaxel and 33 mg of caffeine were added to a
glass vial. A mixture of acetone (9.5 mL) and water (0.5 mL) were
added to form a solution which was allowed to dissolve while
stirring at room temperature. The resulting solution was diluted
.times.10 to yield a final coating solution with concentration of 1
mg paclitaxel/mL which was applied to the stent-graft using a
syringe pump by dispensing 25 .mu.L onto the end of the stent-graft
as described in Example 3. The coated stent-graft was thereafter
allowed to dry at room temperature overnight.
Example 3c
Method for Preparing Paclitaxel-Succinic Acid Layer (Second
Particulate Coating Layer) on a Stent-Graft with 150 .mu.g
Paclitaxel Loading
[0326] 30 mg of paclitaxel and 10 mg of succinic acid were added to
a glass vial. A mixture of acetone (9.5 mL) and water (0.5 mL) were
added to form a solution which was allowed to dissolve while
stirring the solution under room temperature. The resulting
solution (3 mg paclitaxel/mL) was applied to the stent-graft using
a syringe pump by dispensing 50 .mu.L onto the end of the
stent-graft as described in Example 3. The stent-graft was
thereafter allowed to dry at room temperature overnight.
Example 4
Thermal Analysis of Second Particulate Coating Layer of Implantable
Medical Device
[0327] The coated implantable medical devices of the invention can
be examined by DSC using the method described in General
Procedures. In particular, the thermal behavior of the second
particulate coating layer can be analyzed. A sample of the second
particulate coating layer can be obtained by scraping the coating
with a stainless steel spatula. The particulate sample can then be
added to a pre-weighed DSC pan and DSC analysis performed.
[0328] In certain embodiments, samples of second particulate
coating layer obtained from implantable medical devices of the
present invention are expected to exhibit depressed melting
endotherms i.e. a depressed melting point which is lower that the
melting points of both the paclitaxel and the or each organic
additive will be observed.
Example 5
Adhesion Test Analysis of Second Particulate Coating Layer of
Stent-Graft Prepared According to Example 3c
[0329] The adhesion of the paclitaxel-succinic acid layer (second
particulate coating layer) of the stent-graft prepared according to
Example 3c was investigated. Adhesion was assessed by comparing the
weight and content of paclitaxel on the stent-graft (according to
Test Methods C-I and C-II) before and after compaction and
constraining (according to Test Methods I-I and I-II). A lower % of
paclitaxel lost (as determined by both Test Methods C-I and C-II)
indicates better adhesion and a more durable device, and in
particular better adhesion and a more durable second particulate
coating layer. To provide comparative references, stent-grafts with
no immobilized heparin coating layer (i.e. no first coating layer)
or any other coating layer, were also prepared according to Example
3c. The results are summarized in Table 2 and FIG. 8.
TABLE-US-00002 TABLE 2 Paclitaxel (PTX) content pre- and post-
compaction and deployment (test) PTX-excipient PTX* PTX-excipient
Prepared in pre test** pre-test post test** PTX* post % PTX % PTX
Example: [.mu.g] [.mu.g] [.mu.g] test [.mu.g] loss* loss** Example
3c 215 .+-. 1 155 .+-. 3 197 .+-. 5 131 .+-. 5 14 8 Reference 182
.+-. 36 150*** 74 .+-. 64 102 .+-. 19 32 59 *Paclitaxel content
determined according to Test Method C-II **Paclitaxel content
determined according to Test Method C-I ***Paclitaxel as loaded on
the device based on known concentration and known volume.
[0330] It is evident from Table 2 and FIG. 8 that the stent-graft
wherein the paclitaxel-succinic acid layer (second particulate
coating layer) was applied to a surface of immobilized heparin
(first coating layer) has a higher paclitaxel content post
compaction, (using both Test Methods C-I and C-II) compared with
the stent-graft wherein the paclitaxel-succinic acid layer (second
particulate coating layer) was applied to a surface not comprising
immobilized heparin.
[0331] It is therefore evident that the first coating layer
comprising an immobilized heparin moiety enhances the adhesion
properties of second particulate coating layer. Without wishing to
be bound by theory, the present inventors believe that the first
coating layer containing immobilized heparin aids the wetting of
the surface which allows for a better contact of the second
particulate coating layer to the surface of the medical device.
[0332] One skilled in the art would be able to design a coated
implantable device with a larger surface area covered by the second
coating layer. Similar results in term of adhesion would be
expected.
Example 6
Durability Analysis of Second Particulate Coating Layer--Coated
Stent
[0333] The coated stents of Example 2 underwent compaction and
deployment to examine durability and robustness of the coating
layer, in particular the second particulate coating layer. The
durability was determined by comparing the coating weight before,
and after, compaction and deployment.
[0334] The coated stents of Example 2 were compacted and
constrained according to Test Method H-I and then deployed
according to Test Method H-II. After deployment, the stent was
weighed and compared to its weight before compaction. The results
are shown in Table 3.
TABLE-US-00003 TABLE 3 Summary of Coating Durability Coating Stent
Device Weight (mg) Coating Lost (mg) % of coating lost 1 0.588
0.085 14.5 2 0.642 0.038 5.9 3 1.2 0.107 8.9
[0335] The average coating mass loss was 9.8% 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 7
Durability Analysis of Second Particulate Coating Layer--Coated
Stent-Graft
[0336] The coated stent-grafts of Examples 3a, 3b and 3c underwent
compaction, and were then constrained and deployed, to examine
durability and robustness of the coating layer, in particular the
second particulate coating layer. The durability was determined by
comparing the weight of paclitaxel in the coating before, and
after, compaction and deployment (manipulation).
[0337] The coated stent-grafts of Examples 3a, 3ba and 3c were
compacted and constrained according to Test Method I-I and then
deployed according to Test Method I-II. After deployment, the
amount of paclitaxel in the coating was determined using Test
Method C-II. Results are shown in Table 4.
TABLE-US-00004 TABLE 4 Paclitaxel (PTX) content pre- and
post-compaction, constraining and deployment (test) Prepared in PTX
mean content* PTX mean content* example: pre-test** [.mu.g] post
test** [.mu.g] % PTX loss Example 3a 471 .+-. 4.6 347 .+-. 17 26
.+-. 4 Example 3b 23.8 .+-. 0.7 19.1 .+-. 3.2 20 .+-. 13 Example 3c
155 .+-. 2.7 129 .+-. 1 17 .+-. 0.5 *Paclitaxel content according
to Test Method C-II **Test Method I-I followed by Test Method
I-II
[0338] The stent-grafts show good resistance to internal stress
indicated by the low amount of paclitaxel that is lost during
manipulation. On average, the stent-grafts lost 21% of the
paclitaxel in the coating following manipulation, representing a
high degree of durability.
Example 8
Sterilization Stability Analysis of Second Particulate Coating
Layer--Coated Stent-Graft
[0339] The coated stents of Examples 3a, 3b and 3c were sterilized
using ethylene oxide as set out in Test Method D. Following
sterilization, the amount of paclitaxel in the coating was
determined using UPLC (as described in Test Method CA) to determine
the stability of the implantable medical device, in particular the
stability of the second particulate coating layer. The results are
shown in Table 5.
TABLE-US-00005 TABLE 5 Paclitaxel (PTX) content pre- and
post-sterilization PTX PTX mean content* Prepared mean content*
pre- post sterilization** in example: sterilization** [.mu.g]
[.mu.g] % PTX loss Example 3a 471 .+-. 4.6 473 .+-. 0.4 0 Example
3b 23.8 .+-. 0.7 24.8 .+-. 0.2 0 Example 3c 155 .+-. 2.7 150 .+-.
0.3 3 *Paclitaxel content according to Test Method C-II
**Sterilized according to Test Method D
[0340] Essentially no degradation of paclitaxel was observed
post-sterilization, indicating that the devices of Examples 3a, 3b
and 3c devices have excellent paclitaxel stability following
ethylene oxide sterilization.
Example 9
Durability of Second Particulate Coating Layer
Post-Sterilization--Coated Stent Graft
[0341] The coated stents of Examples 3a, 3b and 3c were sterilized
using ethylene oxide as set out in Test Method D. Following
sterilization, the stent-grafts were compacted and constrained
according to Test Method I-I and then deployed according to Test
Method I-II. After deployment, the amount of paclitaxel in the
coating was determined using Test Method C-II. The results are
shown in Table 6.
TABLE-US-00006 TABLE 6 Paclitaxel (PTX) content pre- and
post-sterilization and subsequent compaction, constraining and
deployment (test) PTX PTX mean content* Prepared mean content* as
post-sterilization** in example: coated [.mu.g] and post-test***
[.mu.g] % PTX loss Example 3a 471 .+-. 4.6 359 .+-. 32.3 24 .+-. 7
Example 3b 23.8 .+-. 0.7 22.0 .+-. 1.6 8 .+-. 7 Example 3c 155 .+-.
2.7 124 .+-. 10.6 20 .+-. 7 *Paclitaxel content according to Test
Method C-II **Sterilized according to Test Method D ***Compaction,
constraining and deployment according to Test Methods I-I and
I-II
[0342] On average, the coated stents lose 17% of the paclitaxel in
the coating following sterilization and compaction, constraining
and deployment. Based on the results shown in Table 5 of Example 8,
the loss of paclitaxel in the present Example is attributed to the
manipulation process rather than the sterilization. The 17% loss of
paclitaxel is considered to represent a high degree of
durability.
Example 10
Paclitaxel-Organic Additive Release Profile--Coated Stent Graft
[0343] The coated stent-grafts of Examples 3b and 3c were immersed
in an aqueous acetate buffer containing 30% cyclodextrin. The
release profile of paclitaxel from the device was measured over 24
hours at 37.degree. C. according to Test Method M and the results
are shown in Table 7.
TABLE-US-00007 TABLE 7 Paclitaxel content in media Paclitaxel
content in media* [ug] Prepared in Timepoint [h] example: 0.25 0.5
1 1.5 2 4 6 8 24 Example 3b 13 15 14 15 18 19 19 19 20 Example 3c
51 66 73 75 85 94 103 105 122 Mean of N = 2 *Content in media
according to Test Methods M and C-II
[0344] The highest rate of paclitaxel release was observed in the
initial period up the first time point (0.25 h) with even and
sustained (lower) release rates being observed over the remaining
period of observation (up to 24 h). An average of 80% of the PTX
load of the coated stent-grafts was retrieved after 24 h (Example
3b and 3c devices were initially loaded with 25 and 150 .mu.g
respectively, see Examples 3b and 3c).
Example 11
Paclitaxel-Organic Additive Release Profile
Post-Sterilization--Coated Stent Graft
[0345] The coated stents of Examples 3a, 3b and 3c were sterilized
using ethylene oxide as set out in Test Method D. Following
sterilization, the stent-grafts were immersed in an aqueous acetate
buffer containing 30% cyclodextrin. The release profile of
paclitaxel from the device was measured over 24 hours at 37.degree.
C. according to Test Method M and the results are shown in Table
8.
TABLE-US-00008 TABLE 8 Paclitaxel content in media -
post-sterilization Paclitaxel content in media* [ug] Prepared in
Timepoint [h] example: 0.25 0.5 1 1.5 2 4 6 8 24 Example 3b 8 10 13
15 16 20 22 22 23 Example 3c 23 27 39 51 63 84 100 109 119 Mean of
N = 2 *Content in media according to Test Methods M and C-II
[0346] Surprisingly, an average of 86% of the PTX load of the
coated stent-grafts was retrieved, showing that sterilization has
no significant impact on the paclitaxel release profile (as
compared with the release profile of the non-sterilized devices of
Example 10).
Example 12
Heparin Activity of First Coating Layer--Coated Stent
[0347] Heparin activity of the underlying heparin bonded surface
(first coating layer) of the compacted and deployed stents of
Example 6 was measured according to WO2009/064372 (Test method J),
which is incorporated herein by reference by its entirety. The
paclitaxel-caffeine coating (second particulate coating layer) 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.
[0348] These results attest to the surprising activity of the
heparin-bonded surface (first coating layer) under the conditions
of coating with a paclitaxel-organic additive layer (second
particulate coating layer), mechanical stress including compaction
and expansion, and mechanical shear including deployment.
Example 13
Heparin Activity of First Coating Layer Post Sterilization--Coated
Stent
[0349] Stents coated as in Example 2 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 14
Dual Activity Test: Acute Tissue Transfer of the Second Particulate
Coating Layer; and Heparin Activity of First Coating Layer--Coated
Stent
[0350] Stent Device number 3 of Example 6 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 A. 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.
[0351] 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")
[0352] Heparin activity of the stent after it was removed from the
vessel was measured according to Example 12, and was determined to
be a therapeutically useful heparin activity of greater than 1
pmole/cm.sup.2.
[0353] Thus, when a vascular stent with a coating of immobilized
heparin (first coating layer) over-coated with a paclitaxel-organic
additive coating (second particulate coating layer) 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, an implantable medical device of the
invention has the potential to exhibit dual therapeutic activity,
when a first coating comprising heparin is applied to the stent,
followed by an over coat of the paclitaxel-organic additive coating
layer.
Example 15
Effect of the Second Particulate Coating Layer on the Heparin
Bioactivity of the First Coating Layer; Pre- and
Post-Sterilization--Coated Stent-Graft
[0354] The heparin bioactivity of stent-grafts prepared as
described in Example 3a, 3b and 3c was determined according to Test
Method K and compared with the heparin bioactivity of a stent-graft
with an immobilized heparin coating (first coating layer) but no
paclitaxel-organic additive layer (no second particulate coating
layer), referred to as the Heparin reference. The results are shown
in Table 9.
TABLE-US-00009 TABLE 9 Relative heparin bioactivity of stent-grafts
of the invention compared with heparin reference Prepared in
example: Relative heparin bioactivity* (%) Heparin reference 100
Example 3a 78 Example 3b 86 Example 3c 92 Mean of N = 2 *Heparin
Bioactivity according to Test Method K
[0355] It is evident from the results in Table 9 that a small
decrease in heparin bioactivity (average 14.7%) was observed for
stent-grafts coated with the second particulate coating layer (as
compared to the heparin reference with only the first coating layer
of immobilized heparin).
[0356] The heparin activity of the stent-grants was also determined
post-sterilization using ethylene oxide according to Test Method D.
The results are shown in Table 10.
TABLE-US-00010 TABLE 10 Heparin bioactivity before and after
sterilization Relative heparin Prepared in Relative heparin
bioactivity* bioactivity* post example: pre sterilization (%)
sterilization** (%) Example 3a 100 94 Example 3b 100 92 Example 3c
100 83 EO reference*** 100 30 Mean of N = 2 *Heparin Bioactivity
according to Test Method K **Sterilization according to Test Method
D ***Mean of N = 4
[0357] Surprisingly, essentially no loss in heparin bioactivity was
observed for stent-grafts that were subsequently subjected to
sterilization according using ethylene oxide. The EO reference
sample consisting of PVC tubing coated with immobilized heparin
moiety lost 70% of its heparin bioactivity when subjected to Test
Method D.
Example 16
Heparin Density of the First Coating Layer Pre- and
Post-Sterilization--Coated Stent Graft
[0358] Stent-grafts prepared as described in Examples 3a, 3b and 3c
were compared pre- and post-sterilization with ethylene oxide
(according to Test Method D) with respect to their heparin density,
using the procedure set out in Test Method L. The results are shown
in Table 11.
TABLE-US-00011 TABLE 11 Heparin density pre-and post-sterilization
Mean heparin Mean heparin density* pre density* post % Loss of
heparin Prepared in sterilization** sterilization** density post
example: [.mu.g/cm.sup.2] [.mu.g/cm.sup.2] sterilization Example 3a
8.9 .+-. 0.6 9.3 .+-. 0.8 0 Example 3b 10.1 .+-. 0.4 9.6 .+-. 0.5 5
Example 3c 9.4 .+-. 0.3 9.5 .+-. 0.4 0 Values are mean of N = 2
*Heparin Density according to Test Method L **Sterilization
according to Test Method D
[0359] Surprisingly, a comparatively small loss in heparin density
was observed for stent-grafts that were subjected to
sterilization.
Example 17
Acute Tissue Transfer of Second Particulate Coating Layer--Coated
Stent-Graft
[0360] Stent-grafts prepared according to Examples 3a, 3b and 3c
were examined for their ability to transfer paclitaxel from the
stent-graft surface (specifically the second particular coating
layer) to a vascular tissue in an in vitro model as described in
Test Method A. Following removal of the stent-grafts from the
vessel after 24 h, the vessels were analyzed for paclitaxel content
using UPLC techniques (Test Method C-II).
TABLE-US-00012 TABLE 12 Paclitaxel (PTX) transfer from device to
vascular tissue PTX PTX content* content* on PTX on device as
device PTX content* content* Prepared in coated [.mu.g] pre test**
on device post in tissue example: (Reference) [.mu.g] test**
[.mu.g] [.mu.g/g] Example 3a 471 .+-. 4.4 347 .+-. 16.8 176 .+-.
0.7 25 (N = 1) Example 3b 23.8 .+-. 0.7 19.1 .+-. 3.2 10.6 .+-. 0.1
8.2 .+-. 2.9 Example 3c 155 .+-. 2.7 128 .+-. 0.8 89.3 .+-. 7.9 24
(N = 1) Values are mean of N = 2 *PTX content according to Test
Method C-II **PTX transfer from device to tissue according to Test
Method A
[0361] As can be seen from Table 12, approximately 8.2-25 .mu.g
paclitaxel per gram tissue was transferred from the stent-graft
surface to the porcine vascular tissue. The test shows that
paclitaxel can migrate from the implantable device into the vessel
wall in therapeutically relevant levels.
Example 18
Acute Tissue Transfer of Second Particulate Coating Layer--Coated
Stent Graft Post-Sterilization
[0362] Stent-grafts prepared according to Examples 3a, 3b and 3c
were sterilized using Test Method D and then examined for their
ability to transfer paclitaxel from the stent-graft surface
according to Test Method A. As can be seen from Table 13,
approximately 18-41 .mu.g paclitaxel per gram tissue was
transferred from the stent-graft surface to the porcine vascular
tissue.
TABLE-US-00013 TABLE 13 Paclitaxel (PTX) transfer from device to
vascular tissue, post-sterilization PTX PTX content* content* PTX
on device as PTX content* on on device content* Prepared in coated
[.mu.g] device pre test** post in tissue example: (Reference)
[.mu.g] test** [.mu.g] [.mu.g/g] Example 3a 473 .+-. 0.3 359 .+-.
32 172 .+-. 35 41 (N = 1) Example 3b 24.8 .+-. 0.2 22.0 .+-. 1.6
10.0 .+-. 1.3 18 .+-. 0.1 Example 3c 150 .+-. 0.3 124 .+-. 10.6
64.0 .+-. 2.9 35 .+-. 14 Values are mean of N = 2 *PTX content
according to Test Method C-II **PTX transfer from device to tissue
according to Test Method A
[0363] The test shows that paclitaxel can migrate from the
implantable device into the vessel wall in therapeutically relevant
levels. Also, the migration of paclitaxel is not affected by the
sterilization process according to Test Method D.
Example 19
Heparin Bioactivity of Stent-Grafts Subjected to Manipulation and
In Vitro Tissue Transfer and Uptake, Pre and Post Sterilization
[0364] The heparin bioactivity of stent-grafts prepared as
described in Examples 3a, 3b and 3c was analysed according to Test
Method K. Stent-grafts prepared as described in Examples 3a, 3b and
3c were manipulated according to Test Methods I-I and I-II and then
subjected to Test Method A. Again, the heparin bioactivity was
analysed according to Test Method K. The heparin bioactivity
results of both experiments are shown in Table 14.
TABLE-US-00014 TABLE 14 Heparin bioactivity of stent-graft before
and after: manipulation according to Test Methods I-I and I-II
followed by Test Method A Relative Heparin Relative heparin
bioactivity* pre- bioactivity* post Test Prepared in Test Methods
I-I, I-II and Test Methods I-I, I-II and Test example: Method A (%)
Method A (%) Example 3a 100 60 Example 3b 100 66 Example 3c 100 63
Values are mean of N = 2 *Heparin bioactivity according to Test
Method K
[0365] The experiment was repeated but the stent-grafts prepared as
described in Examples 3a, 3b and 3c were sterilized using ethylene
oxide according to Test Method D prior to being subjected to Test
Methods I-I, I-II and Test Method A. The results are shown in Table
15.
TABLE-US-00015 TABLE 15 Heparin bioactivity of stent-graft before
and after: sterilization according to Test Method D, then
manipulation according to Test Methods I-I and I-II followed by
Test Method A Relative heparin bioactivity* post Relative Heparin
bioactivity* pre- Test Methods Prepared in Test Methods D, I-I,
I-II and Test D, I-I, I-II and Test example: Method A (%) Method A
(%) Example 3a 100 73 Example 3b 100 64 Example 3c 100 55 Values
are mean of N = 2 *Heparin bioactivity according to Test Method
K
[0366] It is evident from the results of Tables 14 and 15 that the
tested stent-grafts retained a high proportion of their initial
heparin bioactivity following compaction, constraining and
deployment (Test Methods I-I and I-II) and subsequent in vitro
tissue transfer and uptake testing (Test Method A). Essentially no
difference was observed between stent-grafts which were
pre-sterilized (using Test Method D) and those that were not,
indicating that the main loss of heparin bioactivity occurs as the
device is subjected to Test Methods I-I and I-II, followed by Test
Method A.
[0367] Thus, a coated stent-graft of the invention has the
potential to exhibit dual therapeutic activity: transfer of a
therapeutic amount of paclitaxel (from the second particulate
coating layer) to the vascular tissue (as illustrated by Test
Method A, and evidenced by Example 17) while a therapeutically
useful amount of heparin bioactivity is retained on the immobilized
heparin surface (first coating layer). Sterilization does not
significantly affect the retained heparin bioactivity.
Example 20
Blood Contact Activation
[0368] Stent-grafts prepared as described in Examples 3a, 3b and 3c
were evaluated according to Test Method B. The platelet consumption
of these stent-grafts of the invention was compared to platelet
levels of a reference stent-graft (a stent-graft with only first
coating layer and no paclitaxel-organic additive (second
particulate coating layer)), and with a pre-sample (a heparinized
PVC tubing) and the results are shown in FIG. 1.
[0369] It was found that there were no clot formations in any the
stent-grafts. All stent-grafts had similar platelet preservation,
and there was no difference between the reference stent-graft and
those coated according to Examples 3a, 3b and 3c. Also, visual
examination of the luminal side of the stent-graft showed no clot
formation, as shown in FIG. 2. The numbering shown in FIG. 2
correlates to the different coatings of the invention. Numbers 9
and 10 are coated according to Example 3a, numbers 5 and 6 are
coated according to Example 3b, numbers 7 and 8 are coated
according to Example 3c, and numbers 3 and 4 are reference devices
coated with just the first coating layer of immobilized heparin
moiety. Thus, there was no difference in thromboresistance between
the reference stent-graft compared with those coated with according
to Examples 3a, 3b and 3c, indicating that the application of the
second particulate coating layer does not significantly impact the
thromboresistance of the first coating layer.
Example 21
SEM Analysis of Stent-Graft Pre- and Post-Manipulation
[0370] Scanning electron microscopy was performed according to
techniques described under Evaluation Methods. Stent-graft prepared
according to Example 3c was analyzed before and after manipulation
according to Test Methods I-II and I-II. The abluminal side of the
implantable device carrying the first and second coating layer)
pre-manipulation is shown in FIG. 3 and the abluminal side of the
implantable device (carrying the first and second coating layer)
post-manipulation is shown in FIG. 4. The fact that no visual
damage is evident post-manipulation indicates that the adhesion of
the coating is surprisingly good, considering the amount of
internal stress applied to the coating during the manipulation
process.
Example 22
Toluidine Blue Staining of Stent-Grafts of the Invention
[0371] Stent-grafts prepared as described in Example 3c were
evaluated according to Test Method N, and compared with a reference
stent-graft (stent-graft with a coating of immobilized heparin
(first coating layer) but no second particulate coating layer). It
was observed that the uniform coverage of the immobilized heparin
layer (first coating layer) on the luminal side is not damaged by
the addition of the second particulate coating layer on the
abluminal side since the two stent-grafts stains equally darkly on
the luminal side (dark areas being indicative of the immobilized
heparin). The dark staining was seen throughout the whole luminal
side of the device.
Example 23
Application of Dye-Solvent Formulation to a Stent-Graft with and
without a First Coating Layer of Immobilized Heparin
[0372] Stent-grafts with a layer of immobilized heparin (first
coating layer) were evaluated in terms of wettability and
distribution by application of a dye-solvent formulation.
Application of the formulation was performed essentially as
described in Example 3c, but interchanging the second particulate
coating layer with Patent Blue V dye. The results are shown in FIG.
5 wherein the poor wettability of the solvent used for dissolving
PTX-excipient and casting of the formulation onto the implantable
device with no first layer (left stent-graft) is illustrated by
areas of high concentration of dye formed on the device. The dye is
more evenly distributed on the device that contains the first
coating layer of immobilized heparin (right stent-graft). This
example clearly shows that the first coating layer comprising
immobilized heparin is capable of improving the even distribution
of a subsequent coating to the device, which it is envisaged may be
extrapolated to the distribution of the second particulate coating
layer containing of paclitaxel. This should allow improved, even
distribution of paclitaxel to surrounding tissue.
* * * * *