U.S. patent application number 11/097467 was filed with the patent office on 2006-10-05 for non-degradable, low swelling, water soluble radiopaque hydrogel polymer.
This patent application is currently assigned to TriVascular, Inc.. Invention is credited to Syed H. Askari, Robert G. Whirley.
Application Number | 20060222596 11/097467 |
Document ID | / |
Family ID | 37070735 |
Filed Date | 2006-10-05 |
United States Patent
Application |
20060222596 |
Kind Code |
A1 |
Askari; Syed H. ; et
al. |
October 5, 2006 |
Non-degradable, low swelling, water soluble radiopaque hydrogel
polymer
Abstract
Hydrogel compositions prepared from amine components and
glycidyl ether components are provided which are biocompatible and
suitable for use in vivo due, in part, to their excellent
stability.
Inventors: |
Askari; Syed H.; (San Jose,
CA) ; Whirley; Robert G.; (Santa Rosa, CA) |
Correspondence
Address: |
Daniel A. Scola, Jr.;Hoffmann & Baron, LLP
6900 Jericho Turnpike
Syosset
NY
11791
US
|
Assignee: |
TriVascular, Inc.
Santa Rosa
CA
|
Family ID: |
37070735 |
Appl. No.: |
11/097467 |
Filed: |
April 1, 2005 |
Current U.S.
Class: |
424/9.41 |
Current CPC
Class: |
A61L 31/06 20130101;
A61K 49/0404 20130101; A61L 2430/36 20130101; A61L 24/0031
20130101; A61L 31/18 20130101; A61K 49/0457 20130101; A61L 31/145
20130101 |
Class at
Publication: |
424/009.41 |
International
Class: |
A61K 49/04 20060101
A61K049/04 |
Claims
1. An in situ formed hydrogel polymer, comprising: (a) a first
amount of a diamine; and (b) a second amount of a polyglycidyl
ether; wherein each of (a) and (b) are present in a mammal or in a
medical device located in a mammal in an amount to produce an in
situ formed hydrogel polymer that is biocompatible; and has a cure
time after mixing of from about 10 seconds to about 30 minutes; and
wherein the volume of said hydrogel polymer swells less than 30
percent after curing and hydration.
2. The composition of claim 1, further comprising a radiopaque
material.
3. The composition of claim 1, wherein said radiopaque material is
selected from the group consisting of sodium iodide, potassium
iodide, barium sulfate, Visipaque 320, Hypaque, Omnipaque 350 and
Hexabrix.
4. The composition of claim 1, wherein said polyglycidyl ether is
selected from the group consisting of trimethylolpropane
triglycidyl ether, sorbitol polyglycidyl ether, polyglycerol
polyglycidyl ether, pentaerythritol polyglycidyl ether, diglycerol
polyglycidyl ether, glycerol polyglycidyl ether, trimethylolpropane
polyglycidyl ether, polyethylene glycol diglycidyl ether,
resorcinol diglycidyl ether, glycidyl ester ether of p-hydroxy
benzoic acid, neopentyl glycol diglycidyl ether, 1,6-hexanediol
diglycidyl ether, bisphenol A (PO).sub.2 diglycidyl ether,
hydroquinone diglycidyl ether, bisphenol S diglycidyl ether,
terephthalic acid diglycidyl ester, and a mixture thereof.
5. The composition of claim 1, wherein said diamine is selected
from the group consisting of (poly)alkylene glycol having amino or
alkylamino termini selected from the group consisting of
polyethylene glycol (400) diamine, di-(3-aminopropyl) diethylene
glycol r, polyoxypropylenediamine, polyetherdiamine,
polyoxyethylenediamine, triethyleneglycol diamine, and a mixture
thereof.
6. The composition of claim 1, wherein said diamine is hydrophilic
and said polyglycidyl ether is hydrophilic prior to curing.
7. The composition of claim 1, wherein said diamine is hydrophilic
and said polyglycidyl ether is hydrophobic prior to curing.
8. The composition of claim 1, wherein said diamine is hydrophobic
and said polyglycidyl ether is hydrophilic prior to curing.
9. The composition of claim 1, wherein said in situ formed polymer
is present in a mammal or in a medical device located in the mammal
in an intraluminal graft, as an embolization device, in an
inflatable occlusion member, as a tissue bulking device.
10. The composition of claim 9, wherein said in situ formed polymer
is present in a mammal or in a medical device located in the mammal
in an intraluminal graft.
11. The composition of claim 10, wherein in said intraluminal
graft, said polymer is comprised of: (a)
di-(3-aminopropyl)diethylene glycol; and (b) a mixture of
polyethylene glycol glycidyl ether and trimethylolpropane
triglycidyl ether.
12. The composition of claim 9, wherein said in situ formed polymer
is present in a mammal or in a medical device located in the mammal
in an embolization device.
13. The composition of claim 12, wherein said embolization device
is comprised of: (a) a mixture of di-(3-aminopropyl)diethylene
glycol and polyoxyethylenediamine; and (b) sorbitol polyglycidyl
ether.
14. The composition of claim 12, wherein said embolization device
is comprised of: (a) Di-(3-aminopropyl)diethylene glycol; and (b) a
mixture of pentaerythritol polyglycidyl ether and
trimethylolpropane polyglycidyl ether.
15. The composition of claim 9, wherein said in situ formed polymer
is present in a mammal or in a medical device located in the mammal
as an inflatable occlusion member or as a tissue bulking
device.
16. The composition of claim 15, wherein in said inflatable
occlusion member or as a tissue bulking device, said polymer is
comprised of: (a) di-(3-aminopropyl)diethylene glycol; and (b)
sorbitol polyglycidyl ether.
17. The composition of claim 2, wherein said diamine is present in
an amount of between about 4 to about 20 weight percent of said
polymer; and said polyglycidyl ether is present in an amount of
between about 15 to about 60 weight percent of said polymer.
18. The composition of claim 2, wherein said diamine is present in
an amount of between about 5 to about 15 weight percent of said
polymer; and said polyglycidyl ether is present in an amount of
between about 25 to about 40 weight percent of said polymer.
19. The composition of claims 2, 17-18, wherein said diamine is
di-(3-aminopropyl)diethylene glycol; said polyglycidyl ether is a
mixture of polyethylene glycol glycidyl ether and
trimethylolpropane triglycidyl ether; and said radiopaque material
is selected from the group consisting of sodium iodide, potassium
iodide, barium sulfate, Visipaque 320, Hypaque, Omnipaque 350 and
Hexabrix.
20. The composition of claims 2, 17-18, wherein said diamine is
di-(3-aminopropyl)diethylene glycol; said polyglycidyl ether is
sorbitol polyglycidyl ether; and said radiopaque material is
selected from the group consisting of sodium iodide, potassium
iodide, barium sulfate, Visipaque 320, Hypaque, Omnipaque 350 and
Hexabrix.
21. The composition of claim 2, wherein said diamine is present in
an amount of between about 7 to about 60 weight percent of said
polymer; said polyglycidyl ether is present in an amount of between
about 7 to about 55 weight percent of said polymer.
22. The composition of claim 2, wherein said diamine is present in
an amount of between about 10 to about 45 weight percent of said
polymer; said polyglycidyl ether is present in an amount of between
about 14 to about 35 weight percent of said polymer.
23. The composition of claim 2, wherein said diamine is present in
an amount of between about 5 to about 30 weight percent of said
polymer; said polyglycidyl ether is present in an amount of between
about 40 to about 90 weight percent of said polymer
24. The composition of claims 2, 21-22, wherein said diamine is
selected from the group consisting of di-(3-aminopropyl)diethylene
glycol and polyoxyethylenediamine; said polyglycidyl ether is
sorbitol polyglycidyl ether; and said radiopaque material is
selected from the group consisting of sodium iodide, potassium
iodide, barium sulfate, Visipaque 320, Hypaque, Omnipaque 350 and
Hexabrix.
25. A kit for preparing an in situ hydrogel polymer composition of
claims 1-24 comprising: (a) a container with a first amount of a
diamine; (b) a container with a second amount of a polyglycidyl
ether; (c) optionally, a radiopaque material; and instructions for
combining the materials present in each of said containers to
produce said hydrogel polymer in situ in a mammal or in a medical
device located in a mammal.
26. A method of forming a hydrogel polymer composition of claims
1-24, said method comprising: (1) forming a mixture comprising a
diamine and a polyglycidyl ether; (2) depositing said mixture in a
mammal or into a medical device located in a mammal; and (3)
allowing said mixture to cure and form said hydrogel polymer
composition.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] Not Applicable
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0002] Not Applicable
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK
[0003] Not Applicable
BACKGROUND OF THE INVENTION
[0004] The present invention relates to the development of hydrogel
polymer compositions that are non-degradable, low-swelling and
initially water soluble. More specifically, the hydrogel polymer
compositions may be formed in situ and are useful as, e.g., embolic
materials, bulking agents, and inflation or support media for
certain types of medical devices. The present invention
additionally includes a kit for preparing the hydrogel polymer
compositions.
[0005] Hydrogel polymers are cross-linked hydrophilic
macromolecules which have use in medical applications. While much
progress has been made in such applications, further developments
are needed to optimize the physical and mechanical properties of
these materials for particular in vivo applications as described
below.
[0006] One exemplary application for the hydrogel polymer materials
discussed herein is as an inflation or support media for inflatable
intraluminal grafts or stent grafts. Examples of such inflatable
stent grafts are described in commonly owned U.S. Pat. No.
6,395,019 to Chobotov, pending U.S. patent application Ser. No.
10/384,103 to Kari et al. entitled "Kink-Resistant Endovascular
Graft", filed Mar. 6, 2003, and U.S. patent application Ser. No.
10/327,711 to Chobotov et al., entitled "Advanced Endovascular
Graft", filed Dec. 20, 2002, the entirety of each of which is
incorporated herein by reference. These documents describe a stent
graft in which additional structural integrity to the device may be
achieved by the introduction of a polymeric fill material to
channels and cuffs located on the graft portion so to act as a
graft inflation and support medium.
[0007] Ideally, the inflation or support medium used in the stent
grafts described above is biocompatible, has a cure time from about
a few minutes to tens of minutes, exhibits minimal volumetric
shrinking and swelling as it cures, exhibits long-term stability
(preferably for at least ten years in vivo), poses as little an
embolic risk as possible in the pre-cure state, and exhibits
adequate mechanical properties, both in its pre-and post-cure
states. For instance, such a material should have a relatively low
viscosity before solidification or curing to facilitate the fill
process into the stent graft.
[0008] Another application for the hydrogel polymers described
herein is as a material for embolizing a body lumen such as a blood
vessel or organ. Embolization, or the artificial blocking of fluid
flow such as blood, may be used to treat a variety of maladies,
including, by way of example only, controlling bleeding caused by
trauma, preventing profuse blood loss during an operation requiring
dissection of blood vessels, obliterating a portion of a whole
organ having a tumor, blocking the blood flow into abnormal blood
vessel structures such as aneurysms, arterio-venous malformations,
arteriovenous fistulae, and blocking the passage of fluids or other
materials through various body lumens. For such treatments, a
variety of embolization technologies have been proposed, including
for example mechanical means (including particulate technology),
and liquid and semi-liquid technologies. The particular
characteristics of such technologies (such as, e.g., the size of
particles, radiopacity, viscosity, mechanism of occlusion,
biological behavior and possible recanalization versus permanent
occlusion, the means by which the material is delivered to the
target body site, etc.), are factors used by the physician in
determining the most suitable therapy for the indication to be
treated.
[0009] Of the mechanical and particulate embolization technologies,
the most prevalent include detachable balloons, macro- and
microcoils, gelfoam and polyvinyl alcohol sponges (such as IVALON,
manufactured and sold by Ivalon, Inc. of San Diego, Calif.), and
microspheres. For example, one embolization technique uses platinum
and stainless steel microcoils. However, significant expertise is
required to choose a proper coil size for the malady prior to
delivery. Moreover, many anatomical sites are not suitable for
microcoils, and removal of microcoils has proved in certain
circumstances difficult.
[0010] Liquid and semi-liquid embolic compositions include viscous
occlusion gels, collagen suspensions, and cyanoacrylate (n-butyl
and iso-butyl cyanoacrylates). Of these, cyanoacrylates have an
advantage over other embolic compositions in their relative ease of
delivery and in the fact that they are some of the only liquid
embolic compositions currently available to physicians. However,
the constituent cyanoacrylate polymers have the disadvantage of
being biodegradable. Moreover, the degradation product,
formaldehyde, is highly toxic to the neighboring tissues. See
Vinters et al. "The histotoxicity of cyanoacrylate: A selective
review", Neuroradiology, 1985; 27:279-291. Another disadvantage of
cyanoacrylate materials is that the polymer will adhere to body
tissues and to the tip of the catheter. Thus, physicians must
retract the catheter immediately after injection of the
cyanoacrylate embolic composition or risk adhesion of the
cyanoacrylate and the catheter to tissue such as blood vessels.
[0011] Another class of liquid embolic compositions is
precipitative materials, which was invented in the late 1980's. See
Sugawara et al., "Experimental investigations concerning a new
liquid embolization method: Combined administration of
ethanol-estrogen and polyvinyl acetate", Neuro. Med. Chir. (Tokyo)
1993; 33:71-76; Taki et al., "A new liquid material for
embolization of arterio-venous malformations", AJNR 1990;
11:163-168; Mandai et al., "Direct thrombosis of aneurysms with
cellulous acetate polymer: Part I: Results of thrombosis in
experimental aneurysms", J. Neurosurgery 1992; 77:497-500. These
materials employ a different mechanism in forming synthetic emboli
than do the cyanoacrylate materials. Cyanoacrylate glues are
monomeric and rapidly polymerize upon contact with blood. On the
other hand, precipitative materials are pre-polymerized chains that
precipitate into an aggregate upon contact with blood.
[0012] Ideally, embolic material formed in situ is biocompatible,
has a relatively short cure time from about a few seconds to a few
minutes, exhibits minimal to moderate controllable swelling upon
curing, exhibits long-term stability (preferably for at least ten
years in vivo), and exhibits adequate mechanical properties, both
in its pre-and post-cure state. For instance, such a material
should have a relatively high viscosity before solidification or
curing to facilitate safe and accurate delivery to the target
site.
[0013] The hydrogel polymer materials described herein are also
suitable for use in tissue bulking applications and more generally
in inflatable devices suitable for implantation in a mammalian
body, which devices are typically occlusive, such as those
described variously in commonly owned copending U.S. patent
application Ser. No. 10/461,853 to Stephens et al. entitled
"Inflatable Implant", filed Jun. 13, 2003, the entirety of which is
herein incorporated by reference. Such devices may be delivered to
a specific site in the body in a low profile form and expanded
after placement to occlude or to support some region, vessel, or
duct in the body. Examples of tissue bulking applications include
the treatment of sphincter deficiencies exhibited by, e.g.,
gastroesophageal reflux disease (GERD), urinary and fecal
incontinence, augmentation of soft tissue, and certain orthopedic
indications. Many of the ideal characteristics of embolic materials
cited above are shared for these applications.
[0014] The majority of the hydrogel polymer materials in the
literature contain ester, polyurethane or silicone groups. Even
though such hydrogel polymers are relatively easy to manufacture
either by free radical, anionic, or cationic polymerizations, they
tend to degrade in the body. For example, most hydrogels containing
ester bonds can be hydrolyzed under physiological pH.
[0015] Despite the advances made in the science of hydrogel polymer
compositions for use in medical applications, there remains a need
in the art for hydrogel polymers having improved physical and
mechanical properties for particular in vivo applications as
described herein.
BRIEF SUMMARY OF THE INVENTION
[0016] The present invention is for an in situ formed hydrogel
polymer, comprising: (a) a first amount of a diamine; and (b) a
second amount of a polyglycidyl ether; in which each of (a) and (b)
are present in a mammal or in a medical device located in a mammal
in an amount to produce an in situ formed hydrogel polymer that is
biocompatible and has a cure time after mixing of from about 10
seconds to about 30 minutes. The volume of the hydrogel polymer of
the invention swells less than 30 percent after curing and
hydration.
[0017] The hydrogel composition may optionally comprise a
radiopaque material. The radiopaque material is preferably selected
from the group consisting of sodium iodide, potassium iodide,
barium sulfate, Visipaque 320, Hypaque, Omnipaque 350 and
Hexabrix.
[0018] In one embodiment, the hydrogel polymer comprises a
polyglycidyl ether selected from the group consisting of
trimethylolpropane triglycidyl ether, sorbitol polyglycidyl ether,
polyglycerol polyglycidyl ether, pentaerythritol polyglycidyl
ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether,
trimethylolpropane polyglycidyl ether, polyethylene glycol
diglycidyl ether, resorcinol diglycidyl ether, glycidyl ester ether
of p-hydroxy benzoic acid, neopentyl glycol diglycidyl ether,
1,6-hexanediol diglycidyl ether, bisphenol A (PO)2 diglycidyl
ether, hydroquinone diglycidyl ether, bisphenol S diglycidyl ether,
terephthalic acid diglycidyl ester, and a mixture thereof.
[0019] In another embodiment, the hydrogel polymer comprises a
diamine selected from the group consisting of (poly)alkylene glycol
having amino or alkylamino termini selected from the group
consisting of polyethylene glycol (400) diamine, di (3 aminopropyl)
diethylene glycol r, polyoxypropylenediamine, polyetherdiamine,
polyoxyethylenediamine, triethyleneglycol diamine, and a mixture
thereof.
[0020] In yet another embodiment of the hydrogel polymer, the
diamine component is hydrophilic and the polyglycidyl ether
component is hydrophilic prior to curing. Alternatively, in the
hydrogel polymer, the diamine component is hydrophilic and the
polyglycidyl ether component is hydrophobic prior to curing. In
another alternative, in the hydrogel polymer, the diamine component
is hydrophobic and the polyglycidyl ether component is hydrophilic
prior to curing.
[0021] The hydrogel polymer composition of the invention can be
formed in situ in a mammal, or in a medical device located in the
mammal, 1) in an intraluminal graft, 2) as an embolization device,
3) in an inflatable occlusion member, and 4) as a tissue bulking
device. In one embodiment, the hydrogel polymer is form in situ in
a mammal in an intraluminal graft. When the hydrogel polymer is
formed in an intraluminal graft, the hydrogel polymer is, in one
embodiment, formed from: (a) di-(3-aminopropyl)diethylene glycol;
and (b) a mixture of polyethylene glycol glycidyl ether and
trimethylolpropane triglycidyl ether.
[0022] The hydrogel polymer may also be formed in situ in a mammal
or in a medical as an embolization device. When the hydrogel
polymer is formed as an embolization device, the polymer is, in one
embodiment, formed from: (a) a mixture of
di-(3-aminopropyl)diethylene glycol and polyoxyethylenediamine; and
(b) sorbitol polyglycidyl ether. In another embodiment, the
hydrogel polymer that is formed in situ in an embolization device
is formed from: (a) di-(3-aminopropyl)diethylene glycol; and (b) a
mixture of pentaerythritol polyglycidyl ether and
trimethylolpropane polyglycidyl ether.
[0023] The hydrogel polymer may also be formed in situ in a mammal
or in a medical device located in the mammal as an inflatable
occlusion member or as a tissue bulking device. In an inflatable
occlusion member or as a tissue bulking device, the hydrogel
polymer is, in one embodiment, formed from: (a)
di-(3-aminopropyl)diethylene glycol; and (b) sorbitol polyglycidyl
ether.
[0024] In yet another embodiment, the hydrogel polymer of the
invention comprises a diamine component and a polyglycidyl
component, in which the diamine component is present in an amount
of between about 4 to about 20 weight percent of said polymer; and
the polyglycidyl ether is present in an amount of between about 15
to about 60 weight percent of said polymer.
[0025] In yet another embodiment, the hydrogel polymer of the
invention comprises a diamine component and a polyglycidyl
component, in which the diamine component is present in an amount
of between about 5 to about 15 weight percent of said polymer; and
the polyglycidyl ether component is present in an amount of between
about 25 to about 40 weight percent of the polymer.
[0026] In yet another embodiment, the hydrogel polymer of the
invention comprises a diamine component and a polyglycidyl
component, in which the diamine is di-(3-aminopropyl)diethylene
glycol; the polyglycidyl ether is a mixture of polyethylene glycol
glycidyl ether and trimethylolpropane triglycidyl ether; and the
radiopaque material is selected from the group consisting of sodium
iodide, potassium iodide, barium sulfate, Visipaque 320, Hypaque,
Omnipaque 350 and Hexabrix.
[0027] In yet another embodiment, the hydrogel polymer of the
invention comprises a diamine component and a polyglycidyl
component, in which the diamine is di-(3-aminopropyl)diethylene
glycol; the polyglycidyl ether is selected from the group
consisting of sorbitol polyglycidyl ether and polyglycerol
polyglycidyl ether; and the radiopaque material is selected from
the group consisting of sodium iodide, potassium iodide, barium
sulfate, Visipaque 320, Hypaque, Omnipaque 350 and Hexabrix.
[0028] In a certain embodiment of the hydrogel polymer, the diamine
component is present in an amount of between about 7 to about 60
weight percent of the polymer; and the polyglycidyl ether is
present in an amount of between about 7 to about 55 weight percent
of the polymer.
[0029] In another embodiment of the hydrogel polymer, the diamine
component is present in an amount of between about 10 to about 45
weight percent of said polymer; and the polyglycidyl ether is
present in an amount of between about 14 to about 35 weight percent
of said polymer.
[0030] In yet another embodiment of the hydrogel polymer, the
diamine component is present in an amount of between about 5 to
about 30 weight percent of said polymer; and the polyglycidyl ether
is present in an amount of between about 40 to about 90 weight
percent of said polymer.
[0031] In yet another embodiment of the hydrogel polymer, the
diamine component is selected from the group consisting of
di-(3-aminopropyl)diethylene glycol and polyoxyethylenediamine; the
polyglycidyl ether is sorbitol polyglycidyl ether; and the
radiopaque material is selected from the group consisting of sodium
iodide, potassium iodide, barium sulfate, Visipaque 320, Hypaque,
Omnipaque 350 and Hexabrix.
[0032] The present invention also provides for a kit for preparing
an in situ hydrogel polymer composition comprising: (a) a container
with a first amount of a diaamine; (b) a container with a second
amount of a polyglycidyl ether; and (c) optionally, a radiopaque
material; and instructions for combining the materials present in
each of said containers to produce the hydrogel polymer in situ in
a mammal or in a medical device located in a mammal.
[0033] The present invention also sets forth a method of forming a
hydrogel polymer composition comprising the steps of: (1) forming a
mixture comprising a diamine and a polyglycidyl ether; (2)
depositing said mixture in a mammal or into a medical device
located in a mammal; and (3) allowing said mixture to cure and form
said hydrogel polymer composition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] Not Applicable.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations and Definitions
[0035] As used herein, the term "biocompatible" describes the
characteristic of a polymer or other material to not have a toxic
or injurious effect (i.e., does not cause infection or trigger an
immune attack, or adversely affect the biological function in the
expected conditions of use) in a mammalian biologic system.
[0036] As used herein, the term "radiopaque" or "contrast agent" is
used to describe a material that is not transparent to X-rays or
other forms of radiation. Radiopaque materials include but are not
limited to sodium iodide, potassium iodide, barium sulfate, gold,
tungsten, platinum, metrizamide, iopamidol, iohexol, iothalamate
sodium, meglumine, Visipaque 320, Hypaque, Onmipaque 350, Hexabrix
and tantalum powder).
[0037] As used herein, the term "embolization device" describes a
substance that is introduced into a space, a cavity, or lumen of a
blood vessel or other like passageway that partially or totally
fills the space or cavity or partially or totally plugs the lumen.
For example, an embolic composition can be used for occlusion of a
vessel leading to a tumor or fibroid, occlusion of a vascular
malformation, such as an arteriovenous malformation, occlusion of a
left atrial appendage, as a filler for an aneurysm sac, as an
endoleak sealant, as an arterial sealant, as a puncture sealant, or
for occlusion of any other lumen such as, for example, a fallopian
tube.
[0038] As used herein, the term "lumen" or "luminal" refers to
various hollow organs or vessels of the body such as veins,
arteries, intestines, fallopian tubes, trachea and the like. Lumen
is also used to refer to the tubes present in a catheter system
(i.e., "multi-lumen" catheter).
[0039] As used herein, the term "alkyl," by itself or as part of
another substituent, means, unless otherwise stated, a straight or
branched chain, or cyclic hydrocarbon radical, or combination
thereof, which can be fully-saturated, mono- or polyunsaturated and
can include di- and multivalent radicals, having the number of
carbon atoms designated (i.e., C.sub.1-C.sub.10 means one to ten
carbons). Examples of saturated hydrocarbon radicals include groups
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,
isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl,
cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,
n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl
group is one having one or more double bonds or triple bonds.
[0040] As used herein, the term "does not degrade" or
"non-degradable" refers to the characteristic of a substance, such
as a polymeric material, to resist being physically, chemically, or
enzymatically decomposed (metabolized) into smaller molecular
weight fragments, in a physiological environment to a degree that
it impacts the function or biocompatibility of the material.
Generally, a composition that does not degrade in an in vivo
environment is one that is stable in aqueous pH 10 solution for at
least 18 days which is equivalent to 10 years in vivo. The amount
of degradation will typically be less than about 5% by weight, more
preferably less than 4%, still more preferably less than 2%, even
more preferably less than 1%, and most preferably less than about
0.5% by weight, relative to the overall weight of the polymer
composition.
[0041] As used herein, the term "weight percent" refers to the mass
of one component used in the formulation of a polymer composition
divided by the total mass of the polymeric product and multiplied
by 100%.
EMBODIMENTS OF THE INVENTION
I. Compositions
[0042] In one aspect, the present invention provides hydrogel
polymer compositions that are biocompatible, pose no embolic risk,
are non-degradable, and are stable in blood contact for >10
years. The gel compositions of the present invention are suitable
for a variety of in vivo applications, including but not limited
to, use in an intraluminal graft, as a luminal embolization device,
in an inflatable occlusion member, and as a tissue bulking device,
among others.
[0043] In its broadest concept, the hydrogel polymer compositions
of the present invention are formed from at least two monomer
components, i.e., a diamine and a polyglycidyl ether. The resulting
gel composition of the invention does not contain a hydrolyzable
group such as an ester group or amide group, among others. As a
result, the present compositions exhibit increased stability in a
physiological environment, and reduce the likelihood of breakdown
in vivo.
[0044] Turning first to the diamine component of the present
compositions, a suitable diamine monomer can be essentially any
diamine compound in which each nitrogen atom is independently
either an amino or an alkylamino group, and is sterically free to
react with an epoxide moiety on a polyglycidyl ether. Typically,
the diamine monomer has a molecular weight of between about 100 to
about 2500; and in certain embodiments the diamine monomer is
biocompatible. In one group of embodiments, the diamine is a
polyoxyalkylene compound having amino or alkylamino termini. In a
preferred embodiment, the polyoxyalkylene compound has amino
termini. Suitable diamine monomers for the hydrogel polymer
composition include, but are not limited to, polyethylene glycol
diamine (also referred to as PEG-diamine or
O,O'-Bis(2-aminoethyl)polyethylene glycol; CAS No. 24991-53-5),
di-(3-aminopropyl) diethylene glycol (also referred to as
O,O'-Bis(3-aminopropyl)diethylene glycol, diethylene glycol
di-(3-aminopropyl)ether or
3-{2-[2-(3-Amino-propoxy)-ethoxy]-ethoxy}-propylamine; CAS No.
4246-51-9), polyoxypropylenediamine (available from Huntsman
Performance Products, Texas, USA; CAS No. 9406-10-0),
polyetherdiamine (available from Huntsman Performance Products,
Texas, USA; CAS No. 194673-87-5), polyoxyethylenediamine (available
from Huntsman Performance Products, Texas, USA; CAS No.
65605-36-9), triethyleneglycol diamine (also known as
3,6-dioxa-octamethylenediamine; CAS No. 929-59-9), and mixtures
thereof. In one embodiment, the diamine compound is
di-(3-aminopropyl) diethylene glycol (available from Aldrich
Chemical Company, Wisconsin, USA). In another embodiment, the
diamine is a mixture of polyethylene glycol (400) diamine
(available from Polypure Inc., Oslo, Norway; or from Tomah Inc.,
Wisconsin, USA) and di-(3-aminopropyl)diethylene glycol. In yet
another embodiment, the diamine a mixture of polyoxyethylenediamine
and di-(3-aminopropyl)diethylene glycol. Other suitable diamine
monomers for the present composition will be apparent to those
skilled in the art.
[0045] A second component for the gels of the present invention is
a polyglycidyl ether. As used herein, the polyglycidyl ether
monomer is any compound possessing at least two glycidyl ether
functional groups, and preferably at least three glycidyl ether
functional groups. In some embodiments, the polyglycidyl compound
has at least two glycidyl ether groups and a molecular weight
between 100 and 2000. Polyglycidyl ethers having two glycidyl ether
groups are alternatively referred to in the art as diglycidyl
ethers; while polyglycidyl ethers having three glycidyl groups are
referred to as triglycidyl ethers. In most embodiments of the
present invention, the polyglycidyl ether is biocompatible.
Suitable polyglycidyl ethers for use in the composition include,
but are not limited to, bis[4-(glycidyloxy)phenyl]methane (CAS No.
2095-03-6), 2,2-bis[4-(glycidyloxy)phenyl]propane (CAS No.
1675-54-3), bisphenol A propoxylate diglycidyl ether (CAS No.
106100-55-4), 1,4-butanediol diglycidyl ether (CAS No. 2425-79-8),
1,3-butanediol diglycidyl ether (CAS No. 3332-48-7),
1,4-cyclohexanedimethanol diglycidyl ether (CAS No. 14228-73-0),
diethylene glycol diglycidyl ether (CAS No. 4206-61-5), ethylene
glycol diglycidyl ether (CAS No. 2224-15-9 and CAS No. 72207-80-8),
glycerol diglycidyl ether (CAS No. 27043-36-3), neopentyl glycol
diglycidyl ether (CAS No. 17557-23-2),
poly(dimethylsiloxane)-diglycidyl ether terminated (CAS No.
130167-23-6), polyethylene glycol diglycidyl ether (CAS No.
26403-72-5), poly(propylene glycol) diglycidyl ether (CAS No.
26142-30-3), resorcinol diglycidyl ether (CAS No. 101-90-6),
sorbitol polyglycidyl ether (CAS No. 68412-01-1), polyglycerol
polyglycidyl ether, pentaerythritol polyglycidyl ether (CAS No.
3126-63-4), diglycerol polyglycidyl ether (CAS No. 68134-62-3),
glycerol polyglycidyl ether (CAS No. 25038-04-4), polyproylene
glycol diglycidyl ether (CAS No. 26142-30-3), resorcinol diglycidyl
ether (CAS No. 101-90-6), glycidyl ester ether of p-hydroxy benzoic
acid (CAS No. 7042-93-5), neopentyl glycol diglycidyl ether (CAS
No. 17557-23-2), 1,6-hexanediol diglycidyl ether (CAS No.
16096-31-4), bisphenol A (PO).sub.2 diglycidyl ether (available
from Nagase ChemteX Corp., Osaka, Japan), o-phthalic acid
diglycidyl ester (CAS No. 7195-45-4), hydroquinone diglycidyl ether
(CAS No. 2425-01-6), bisphenol S diglycidyl ether (CAS No.
13410-58-7), terephthalic acid diglycidyl ester (CAS No.
7195-44-0), trimethylolpropane triglycidyl ether (CAS No.
30499-70-8), glycerol propoxylate triglycidyl ether (CAS No.
37237-76-6), trimethylolethane triglycidyl ether,
triphenylolmethane triglycidyl ether (CAS No. 106253-69-4), as well
as mixtures thereof. Other polyglycidyl ethers suitable for use in
the present invention will be apparent to one skilled in the
art.
[0046] In one embodiment, the polyglycidyl ether is a mixture of
trimethylolpropane triglycidyl ether and polyethylene glycol
diglycidyl ether (both available from Aldrich Chemical Company,
Wisconsin, USA). In another embodiment, the polyglycidyl ether is a
mixture of polyethylene glycol (600) diglycidyl ether (available
from Polysciences, Inc., Pennsylvania, USA) and trimethylolpropane
triglycidyl ether. In yet another embodiment, the polyglycidyl
ether is a sorbitol polyglycidyl ether (available from Nagase
ChemteX Corp., Osaka, Japan). In yet another embodiment, the
polyglycidyl ether is a mixture of sorbitol polyglycidyl ether and
polyglycerol glycidyl ether. In yet another embodiment, the
polyglycidyl ether is a mixture of pentaerythritol polyglycidyl
ether and trimethylolpropane polyglycidyl ether. One of skill in
the art will appreciate that the properties of the resultant gel
composition can be carefully controlled by varying the amount of
polyglycidyl ether or combinations of polyglycidyl ethers to
control the amount of cross-linking in the gel, the hydrophilic or
hydrophobic character of the gel, as well as the cure time and
viscosity of the pre-cure combination.
[0047] Optionally, the hydrogel polymer comprises at least one
radiopaque material. Radiopaque materials suitable for the present
invention include but are not limited to sodium iodide, potassium
iodide, barium sulfate, gold, tungsten, platinum, Visipaque 320,
Hypaque, Omnipaque 350, Hexabrix, metrizamide, iopamidol, iohexol,
iothalamate sodium, meglumine, gold and tantalum powder. In some
instances, it is preferable to use a blend of radiopaque material,
as is in the case when it desired that the gel composition loses
radiopacity over time. For instance, a blend of a soluble contrast
agent such as an iodinated aqueous solution and an insoluble
contrast agent such as barium sulfate can serve this purpose. The
soluble contrast agent will leach out of the composition resulting
in a progressive decrease in radiopacity of the composition over
time.
[0048] The utility of the inventive gel compositions for many in
vivo applications is attributed, in part, to the ease in which the
mechanical properties of the pre- and post-cure gel composition can
be modified, as noted above, simply through the judicious selection
of the diamine and polyglycidyl ether components, and the curing
conditions. For example, the cure rate is affected, in part, by the
molecular weight of the monomer components used, and the
concentration of the curing solution. In more detail, using a
polyglycidyl ether having more glycidyl ether groups per monomer
unit will provide a faster cure rate; using a higher concentration
of monomer components in the pre-cure gel composition will provide
a faster cure rate; and having a higher pH composition will provide
a faster cure rate. Other methods of modifying the cure rate of the
inventive composition will be readily apparent to a skilled
artisan.
[0049] In another example, the firmness/hardness property of the
final gel composition will be determined, in part, by the
hydrophilic/hydrophobic balance of the monomer components. A higher
proportion of hydrophobic monomers can provide a firmer gel
composition. The firmness is also affected by the molecular weight
of the monomer (i.e., a lower molecular weight provide a firmer
gel), and the length of the monomer backbone of the polyglycidyl
ether component (i.e., shorter polyglycidyl ether backbone provides
a firmer gel). Other methods of modifying the hardness/firmness
property of the final gel composition will be readily apparent to a
skilled artisan.
[0050] In one embodiment, the composition comprises a hydrophilic
diamine and a hydrophilic polyglycidyl ether. In another
embodiment, the composition comprises a hydrophilic diamine and a
hydrophobic polyglycidyl ether. In yet another embodiment, the
composition comprises a hydrophobic diamine and a hydrophilic
polyglycidyl ether.
[0051] The gel composition can optionally incorporate water or
another aqueous fluid to result in increased volume (or swelling)
of the final gel composition. The swelling of the final gel
composition is inversely related to the firmness of the final gel.
Depending of the proposed application, it is desirable that the
inventive gel swells less than about 30 percent. In certain
applications, such as in a embolization device, minimal swelling
can be preferred.
[0052] The hydrogel polymer composition can optionally comprise
various additives that can alter the mechanical or physical
properties of the pre- or post-cure gel composition, e.g., to
increase cure rate, to reduce viscosity, to introduce radiopacity.
In one illustrative example, hydroxide can be added to the pre-cure
gel mixture to catalyze rate of formation (cure rate) of the
hydrogel polymer. In another illustrative example, fumed silica can
be added to the pre-cure gel mixture to give it a thixiotropic
character desirable for certain embolization applications. Other
comonomers and additives can be incorporated to the gel composition
to alter the thermoresponsiveness, elasticity, adhesiveness and
hydrophilicity of the final gel composition.
[0053] Optionally, the gel compositions of the present invention
can be used to deliver drugs to the target site. The drugs can be
mixed in or attached to the gel composition using a variety of
methods. Some exemplary drugs and methods for attaching the drugs
to the embolic composition are described in J. M. Harris,
"Laboratory Synthesis of Polyethylene Glycol Derivatives," Journal
of Macromolecular Science-Reviews in Macromolecular Chemistry, vol.
C-25, No. 3, pp. 325-373, Jan. 1, 1985; J. M. Harris, Ed.,
"Biomedical and Biotechnical Applications of Poly(Ethylene Glycol)
Chemistry", Plenum, New York, pp. 1-14, 1992; Greenwald et al.,
"Highly Water Soluble Taxol Derivatives: 7-Polyethylene Glycol
Carbamates and Carbonates:", J.Org.Chem., vol. 60, No. 2, pp.
331-336, 1995, Matsushima et al., "Modification of E. Coli
Asparaginase with 2,4-Bis(O-Methoxypolyethylene
Glycol)-6-Chloro-S-Triazine (Activated PEG.sub.2); Disapperance of
Binding Ability Towards Anti-Serum and Retention of Enzymic
Activity," Chemistry.Letters, pp. 773-776, 1980; and Nathan et al.,
"Copolymers of Lysine and Polyethylene Glycol: A New Family of
Functionalized Drug Carriers," Bioconjugate Chem. 4, 54-62 (1993),
each of which are incorporated herein by reference in its
entirety.
[0054] As previously stated, the selection of monomer components
for the gel composition will depend largely on the desired physical
properties of the pre-cure monomer mixture and the final gel
material, which is in turn is dependent on its intended application
in vivo. Specific uses for the gels of the present invention
(including preferred monomers and amounts of monomers) are provided
below as select embodiments of the invention.
Stent Graft or Intraluminal Graft:
[0055] The present gel compositions are useful in a polymeric
stent-graft or intraluminal graft (e.g., as described in U.S. Pat.
No. 6,395,019) located in a mammal for the purpose of inflating the
channels and cuffs of the graft to conform to the morphology of the
lumen, and to impart sufficient strength to the graft to resist to
kinking. As used herein, the term "stent graft" interchangeably
refers to inflatable intraluminal grafts as well as inflatable
intraluminal stent grafts. For application in a stent graft or
intraluminal device, it is preferable that the pre-cure gel
composition comprise monomer components that are hydrophilic and
biocompatible so as to minimize the embolic risk and toxicity that
can result in the event of accidental release of the monomeric
components in the bloodstream during addition of the pre-cure
composition into the stent graft. Should accidental release occur,
normal blood flow would then rapidly disperse the monomeric
components and their concentration would fall below the level
required to form a solid. Preferably, the pre-cure gel composition
is soluble for at least 3 minutes in the bloodstream; more
preferably for at least 5 minutes; even more preferably for at
least 8 minutes or until just before cure.
[0056] In a stent graft application, it is less desirable for the
gel composition to cure quickly as the pre-cure mixture should
remain fluid in order to travel through a delivery tube into the
stent graft. After the addition of the gel composition to the
stent-graft, it is preferable for the graft to remain initially
less rigid, so that the filled graft material can adjust and
conform to the morphology of the vessel or lumen space. In one
embodiment, the gel composition has a cure time from about 5
minutes to about 20 minutes. In another embodiment, the cure time
is from about 10 to about 17 minutes. As stated above, it is
beneficial for the pre-cure composition be a flowable solution that
can be delivered through a delivery tube (e.g., catheter, syringe).
In one embodiment, the viscosity of the pre-cure mixture is between
about 10 to about 500 cp (centipoise). In another embodiment, the
viscosity of the pre-cure mixture is between about 20 to about 100
cp, more preferably about 30 cp.
[0057] After curing, the gel composition maintains its
biocompatibility and is stable in the event of contact with blood.
The cured gel composition provides desirable mechanical properties
such as, an elastic modulus between about 60 and about 500 psi,
more preferably about 100 to about 400 psi, even more preferably
about 200 to about 300 psi. Still further, the gel compositions
that are used in stent-graft will typically be low swelling
compositions and exhibit a volume change upon curing between about
0 to about 30 percent. As can be appreciated the pre-cure
properties and post-cure properties of the gel composition
described above are merely examples and should not limit the scope
of the present invention.
[0058] The inventive gel composition in a stent graft typically
show little or no volume change after curing. In one embodiment,
the gel composition swells or shrinks less than about 20 percent
after curing and hydration. In another embodiment, the gel
composition swells or shrinks less than about 10 percent after
curing and hydration. In yet another embodiment, the gel
composition swells or shrinks less than 5 percent after curing and
hydration. Low volume change of the gel mixture after curing and
hydration is important in a stent graft material application.
Excessive volume change of the hydrogel polymer after curing and
hydration can adversely affect the strength of the graft material
located inside the body lumen, and possibly jeopardize the safety
of the mammal.
[0059] The hydrogel polymer can be comprised of any diamine or
mixture of thereof; however, in one embodiment, the diamine or
mixture thereof is a hydrophilic diamine. In another embodiment,
the diamine monomer is selected from the group consisting of
polyoxyethylenediamine, triethyleneglycol diamine, polyethylene
glycol diamine, di-(3-aminopropyl)diethylene glycol, or a mixture
thereof. It is desirable that the polyglycidyl ether component is
also hydrophilic. In one embodiment, the polyglycidyl ether
component is a mixture of a diglycidyl ether and a triglycidyl
ether. In another embodiment the polyglycidyl ether component is
mixture of polyethylene glycol diglycidyl ether and
trimethylolpropane triglycidyl ether. In yet another embodiment,
the polyethylene glycol diglycidyl ether is polyethylene glycol
(600) diglycidyl ether. Furthermore, the hydrogel polymer can
comprise a radiopaque material. In one embodiment, the radiopaque
material is sodium iodide.
[0060] In one embodiment, the diamine is present in an amount of
between about 4 to about 20 weight percent of the hydrogel polymer;
and the polyglycidyl ether is present in an amount of between about
15 to about 60 weight percent of the hydrogel polymer. In another
embodiment, diamine is present in an amount of between about 5 to
about 15 weight percent of said polymer; and the polyglycidyl ether
is present in an amount of between about 25 to about 40 weight
percent of the hydrogel polymer.
[0061] In yet another embodiment, the diamine is
di-(3-aminopropyl)diethylene glycol; the polyglycidyl ether is a
mixture of polyethylene glycol diglycidyl ether and
trimethylolpropane triglycidyl ether; and the radiopaque material
is selected from the group consisting of sodium iodide, potassium
iodide, barium sulfate, Visipaque 320, Hypaque, Omnipaque 350 and
Hexabrix.
Embolic Compositions
[0062] In addition to the stent graft embodiments above, the
present gel compositions can be constructed for use as an
embolization device. Embolization devices block or obstruct flow
through a body lumen. Numerous clinical applications exist for
embolization of both vascular and nonvascular body lumens. The most
prevalent uses for an embolization device include, but are not
limited to, the neurological treatment of cerebral aneurysms, AVMs
(arteriovenous malformations) and AVFs (arteriovenous fistula), and
the peripheral treatment of uterine fibroids and hypervascular
tumors. However, embolization devices are also useful in a variety
of vascular or non-vascular body lumens or orifices, such as the
esophagus, genital-urinary lumens, bronchial lumens,
gastrointestinal lumens, hepatic lumens, ducts, aneurysms, varices,
septal defects, fistulae, fallopian tubes, among others. Moreover,
it should be appreciated that the gel composition as an
embolization device can be used in conjunction with other
components, such as endovascular grafts, stents, inflatable
implants, fibers, coils, and the like. Other applications of
embolization devices are described in co-pending U.S. patent
application Ser. No. 11/031,311, titled "Methods, Materials, and
Devices for Embolizing Body Lumens" to Whirley et al., the
disclosure of which is incorporated herein by reference in its
entirety.
[0063] For application in an embolic composition, it is preferable
that the pre-cure gel composition is biocompatible and exhibit
controllable solubility which is independent of the environment in
which the embolic composition is delivered (e.g., in blood or other
body fluid). More specifically, as the pre-cure gel mixture will be
applied directly to the site for occlusion, in one aspect, it is be
desirable for the pre-cure composition to be less soluble in blood
or other body fluid and to remain relatively localized at the site
of administration. In other embodiments, it is be desirable for the
pre-cure gel composition to disperse through the vasculature as to
provide a complete "cast" of a segment of the arterial tree after
the gel composition cures (such as for a hypervascular tumor or an
AVM), thereby reducing the opportunity for development of
collateral perfusion. Typically, the present hydrogel polymer in an
embolic application has a viscosity of 100 cp or higher, a
controllable hydrophobicity and a faster cure rate than the
compositions described above.
[0064] Applicants have found that for embolization applications it
is desirable to increase the viscosity and hydrophobicity of the
uncured material and thereby facilitate controlled placement
without unintended embolization of distal vascular beds. This can
be accomplished by reducing or eliminating saline or water from the
gel composition. Reducing the saline and water prior to curing has
been found to achieve the best viscosity for delivery into the body
lumen, maximizes the degradation resistance of the cured polymer
and maximizes the cohesiveness and hydrophobicity of the gel
material.
[0065] Low viscosity formulations of the gel composition can also
be used to deeply penetrate tumor vascular beds or other target
embolization sites prior to curing of the composition. Occlusion
balloons (such as a Swan-Ganz dual-lumen catheter or the
EQUINOX.TM. Occlusion Balloon Catheter manufactured by Micro
Therapeutics, Inc. of Irvine, Calif.) or other ancillary
flow-blocking devices, such as brushes or other obstructive
devices, some of which can be placed on a catheter or stent, such
as those sometimes placed across a cerebral aneurysm to be
embolized, can be used to prevent flow of the embolic composition
beyond the target embolization site.
[0066] High viscosity and/or thixotropic (shear-thinning)
formulations of these compositions can be used to limit the flow to
the neighborhood of the delivery catheter and to facilitate the
tendency of the gel composition to remain in the vicinity of the
location in which it was delivered, sometimes even in the presence
of substantial blood flow or other forces. Viscosity and/or
thixotropy characteristics can be increased by adding bulking
and/or thixotropic agents, such as fumed silica. The bulking agent
can be added anytime during the formation of the gel composition,
but is typically preloaded with one of the components, and
preferably preloaded with the monomer/polymer or buffer
solution.
[0067] Some examples of additives that are useful include, but are
not limited to, sorbitol or fumed silica that partially or fully
hydrates to form a thixotropic bulking agent, and the like.
Desirable viscosities for the pre-cure gels range from about 5
centipoise (cP) for a low-viscosity formulation (such as might be
used to deeply penetrate tissue in a hypervascular tumor) up to
about 1000 cP or higher for a higher viscosity formulation (such as
might be used to treat a sidewall cerebral aneurysm while
minimizing the chance of flow disturbance to the embolic
composition during the curing process). As can be appreciated,
other embodiments of gels can have a higher or lower viscosity, and
the gel composition is not limited to such viscosities as described
above.
[0068] After curing, the embolic composition maintains its high
biocompatibility and is stable in blood. The cured embolic
composition provides desirable mechanical properties such as, a
specific gravity between 1.15 to over 1.4, an elastic modulus
between about 30 and about 500 psi, a strain to failure of about 25
percent to about 100 percent or more, a volume change upon curing
between about 0 percent to about 200 percent or more, and a water
content between less than 5 percent to greater than about 60
percent. In one embodiment, the volume change of the gel
composition upon curing is less than about 20 percent. As can be
appreciated the pre-cure properties and post-cure properties of the
gel composition described above are merely examples and should not
limit the scope of the embolic compositions of the present
invention. The gel composition of the present invention can be
modified to provide other pre-cure and post-cure mechanical
properties, as desired.
[0069] The hydrogel polymer can be comprised of any diamine or
mixture of thereof; however, in one embodiment, the diamine or
mixture thereof is a hydrophilic diamine. In another embodiment,
the diamine is a hydrophobic diamine. The polyglycidyl ether can be
hydrophilic or hydrophobic. In one embodiment, in the gel
composition, a hydrophilic diamine will be paired with a less
water-soluble, hydrophobic polyglyicdyl ether. Alternatively, in
another embodiment, in the gel composition, a more water-soluble
hydrophilic polyglycidyl ether will be paired with a more
hydrophobic diamine. The selection of suitable diamine and
polyglycidyl ether components for the purpose of modify the
mechanical properties of the pre-cure or the post-cure composition
will be readily apparent to a skilled artisan. For example, to
increase the firmness of the final gel composition, a polyglycidyl
ether, such as a triglycidyl ether, which functions as a
crosslinking agent, can be included in the composition. A skilled
artisan will also recognize that the firmness of the formed gel
composition will also be determined in part by the hydrophobic and
hydrophilic balance of the monomer components, e.g., a higher
hydrophobic percent provides a firmer hydrogel. In one embodiment,
the diamine component is selected form the group consisting of
di-(3-aminopropyl)diethylene glycol, polyoxyethylenediamine and,
and a mixture thereof. In another embodiment, the polyglycidyl
ether is selected from the group consisting of sorbitol
polyglycidyl ether, polyglycerol polyglycidyl ether,
trimethylolpropane triglycidyl ether, and mixtures thereof. In
another preferred embodiment, the gel composition includes a
radiopaque agent.
[0070] In one embodiment, the diamine is present in an amount of
between about 7 to about 60 weight percent of the hydrogel polymer;
and the polyglycidyl ether is present in an amount of between about
7 to about 55 weight percent of the hydrogel polymer. In another
embodiment, diamine is present in an amount of between about 10 to
about 45 weight percent of said polymer; and the polyglycidyl ether
is present in an amount of between about 14 to about 35 weight
percent of the hydrogel polymer.
[0071] In one embodiment, the diamine is present in an amount of
between about 5 to about 30 weight percent of the hydrogel polymer;
and the polyglycidyl ether is present in an amount of between about
40 to about 90 weight percent of the hydrogel polymer. In another
embodiment, diamine is present in an amount of between about 50 to
about 75 weight percent of said polymer; and the polyglycidyl ether
is present in an amount of between about 10 to about 20 weight
percent of the hydrogel polymer.
[0072] In yet another embodiment, the diamine is
di-(3-aminopropyl)diethylene glycol; and the polyglycidyl ether is
a mixture of pentaerythritol polyglycidyl ether and
trimethylolpropane polyglycidyl ether; and the radiopaque material
is sodium iodide.
[0073] In yet another embodiment, the diamine is a mixture of
di-(3-aminopropyl)diethylene glycol and polyoxyethylenediamine; the
polyglycidyl ether is sorbitol polyglycidyl ether; and the
radiopaque material is selected from the group consisting of sodium
iodide, potassium iodide, barium sulfate, Visipaque, Hypaque,
Omnipaque, and Hexabrix.
Tissue Bulking Device and Inflatable Occlusion Member:
[0074] The present gel compositions are useful for in vivo
application in an inflatable occlusion member and as a tissue
bulking device. The gel composition are useful in vivo in a number
of tissue bulking applications (e.g., aiding functionality of
various organs or structures, such as assisting in closing a
stricture (including restoring competence to sphincters to treat
fecal or urinary incontinence or to treat gastroesophageal reflux
disease (GERD)), augmentation of soft tissue in plastic or
reconstructive surgery applications (e.g., chin or cheek
reshaping), replacing or augmenting herniated or degenerated
intervertebral disks. The pre-cure composition can be directly
contacted with the tissue material; or can be introduced into an
inflatable bag located in vivo. Alternatively, the pre-cure gel
mixture can be added to an inflatable bag ex vivo, followed by
placement of the bag inside the body.
[0075] It is preferable for the pre-cure gel composition to be
biocompatible and exhibit controllable solubility which is
independent of the environment in which the pre-cure mixture is
delivered (e.g., in blood or other body fluid). More specifically,
it is desirable for the pre-cure composition to be less soluble in
blood or other body fluid and to remain relatively localized at the
site of administration. Alternatively, in some embodiments, it is
desirable for the pre-cure gel composition to diffuse to an in vivo
site distal to the point of administration. Typically, the hydrogel
polymer in a tissue bulking application has a viscosity of 100 cp
or higher and controllable hydrophobicity. The solubility of the
pre- and post-cure composition of the invention can be modified by
any means known to one skilled in the art (e.g., through the choice
of the hydrophobic or hydrophilic monomer components).
[0076] Preferably, the gel composition will have a cure time that
is long enough to allow the gel composition to fill and conform to
the cavity to which it is administered and/or long enough so that a
medical professional can sculpt or otherwise shape the composition
prior to the completion of the gelling process. In one embodiment,
the gel composition has a cure time of from about 10 seconds to
about 30 minutes depending on its intended site of administration.
In another embodiment, the gel composition has a cure time of
between about 30 seconds to about 2 minutes.
[0077] After curing, the gel composition remains biocompatible and
is stable in blood. The cured polymer provides desirable mechanical
properties such as, an elastic modulus between about 30 and about
500 psi, a strain to failure of about 25 percent to about 100
percent or more, a volume change upon curing between about 0 to
about 30 percent or more, and a water content of about less than 60
percent. The volume change of the cured composition is preferably
less than about 15 percent, and more preferably less than about 10
percent. As can be appreciated the pre-cure properties and
post-cure properties of the gel composition in an embolic
application described above are merely examples and should not
limit the scope of the gel compositions of the invention. In one
embodiment, the gel time is between about 30 seconds to about 25
minutes. In another embodiment, the gel time is between about 1 to
about 3 minutes.
[0078] The hydrogel polymer can be prepared from any diamine or
mixture thereof (as described generally above). However, in one
embodiment, the diamine or mixture thereof is a hydrophilic
diamine. In another embodiment, the diamine is a hydrophobic
diamine. Similarly, the polyglycidyl ether can be hydrophilic or
hydrophobic. In one embodiment, in the gel composition, a
hydrophilic diamine will be paired with water-soluble, hydrophilic
polyglyicdyl ether. In another embodiment, the diamine is
di-(3-aminopropyl)diethylene glycol. In another embodiment, the
polyglycidyl ether is sorbitol polyglycidyl ether. In yet another
embodiment, the gel composition comprises a radiopaque agent. In
yet another embodiment, the radiopaque agent is Omnipaque,
Visipaque, or a combination thereof. In yet another embodiment, the
diamine is di-(3-aminopropyl)diethylene glycol; the polyglycidyl
ether is sorbitol polyglycidyl ether; and the radiopaque material
is a mixture of Visipaque and Omnipaque.
[0079] In one embodiment, the diamine is present in an amount of
between about 4 to about 20 weight percent of the hydrogel polymer;
and the polyglycidyl ether is present in an amount of between about
15 to about 60 weight percent of the hydrogel polymer. In another
embodiment, diamine is present in an amount of between about 5 to
about 15 weight percent of said polymer; and the polyglycidyl ether
is present in an amount of between about 25 to about 40 weight
percent of the hydrogel polymer.
Preparation of the Polymeric Hydrogels:
[0080] The gel composition can be made by combining the monomeric
components in any order, as well as any additional monomers
(comonomers) and other additives, under conditions suitable for
formation of the polymer. The reaction is carried out in a suitable
solvent; that being any solvent that dissolves the monomer
components. For example, water, alcohols, such as ethanol or
methanol, also carboxylic amides, such as dimethylformamide,
dimethylsufoxide, and also a mixture thereof, are all solvents
suitable for the reaction to make the hydrogel polymer. In one
embodiment, the reaction is carried out in a substantially aqueous
solution, e.g., in a basic sodium hydroxide solution (pH=7.4).
Alternatively, the reaction can be carried out in under anhydrous
conditions. Additionally, the skilled artisan will recognize that
the mechanical properties of the final hydrogel product can be
modified by changing at least the following variables: the choice
of monomer components, the ratio of the monomer components (e.g.
high or low molecular weight monomers), the concentration of the
monomer(s), the pH of the reaction medium, the reaction time, and
the rate of addition of the individual monomer components. For
example, adding a triglycidyl ether in the composition, which can
function as a crosslinking agent, can result in a gel material
having increased hardness. Details are provided in the examples
below to guide one of skill in the art in the preparation of the
present gel compositions.
II. Method of Use
[0081] The hydrogel composition of the invention can be used in any
medical application, in which the presence of a non-degradable,
biocompatible hydrogel polymer is desired. More specifically, the
present invention is particularly suited for applications that
benefit from the in situ gelling characteristics. The present gel
composition is especially useful in an inflatable occlusion member,
an intraluminal graft, a tissue bulking device, and an embolization
device.
[0082] In one aspect of the invention, the gel composition can be
used in an in vivo environment, for example, as an intraluminal
graft, such as, in a polymeric stent graft, as described in U.S.
Pat. No. 6,395,019, the entirety of which is incorporated herein by
reference, to improve the mechanical integrity of the stent graft.
The '019 patent, describes that monomer components are added into
the cuffs and channels of a stent graft, which upon curing, the
final gel composition imparts additional strength to and conforms
to the stent graft sealing cuffs.
[0083] In another aspect of the invention, the gel composition is
also be useful as a tissue bulking (augmentation) device, such as,
for augmentation of dermal support within intradermal or
subcutaneous regions for the dermis, for breast implants, or for
sphincter augmentation (i.e., for restoration of continence), among
others. In this application, the pre-cure gel composition can be
added to an inflatable bag located inside the body, or the pre-cure
gel composition can be added to an inflatable bag ex vivo, which is
then placed inside the body.
[0084] In yet another aspect of the invention, the gel composition
can be formed directly on the tissue surface in an in vivo
environment. Medical applications in which direct contact of body
tissue with the inventive material is beneficial include, but are
not limited to, as a puncture or wound sealant, and as an
embolization device.
[0085] In one aspect, the gel composition can be used as an
embolization device to form a plug for a variety of biological
lumens. The compositions can be used to occlude blood vessels and
other body lumens, such as, fallopian tubes and vas deferens,
filling aneurysm sacs, and as arterial sealants. The embolization
of blood vessels is useful for a number of reasons; to reduce the
blood flow and encourage atrophy of tumors such as in the liver; to
reduce blood flow and induce atrophy of uterine fibroids; for the
treatment of vascular malformations, such as AVMs and AVFs; to seal
endoleaks in aneurysm sacs; to stop uncontrolled bleeding; and to
slow bleeding prior to surgery.
Method of Delivery:
[0086] The gel composition can be delivered to an in vivo site
using any delivery devices generally known to those skilled in the
art. The selection of the delivery device will depend on a number
of factors, including the location of the in vivo site and whether
a quick or slow curing gel is desired. In most cases, a catheter or
syringe is used. In some cases, a multi-lumen catheter is used to
deliver the hydrogel composition to the intended in vivo location,
wherein the components of the composition are maintained in
separate lumens until the time of administration. For example, a
polyglycidyl ether component can be delivered in the first lumen,
while the diamine compound is delivered through a second lumen. A
third lumen can be used to deliver a contrast agent or other
comonomers and/or additives to the in vivo site.
[0087] Alternatively, the components of the gel composition can be
added to a multi-barrel syringe, wherein the barrels of the syringe
are attached to a multi-pronged connector which is fitted to a
spiral mixer nozzle (e.g., static mixer). As the components of the
composition are pressed out of the syringe, they mix together in
the nozzle and can be directly applied to tissue as needed in a
relatively uniform, controlled manner. Additionally, the mixed
components can be injected directly into tissue if the nozzle is
further connected to a needle.
[0088] Injectable reaction mixture compositions also could be
injected percutaneously by direct palpation, such as, for example,
by placing a needle inside the vas deferens and occluding the same
with the injected embolizing composition, thus rendering the
patient infertile. The composition can be injected with
fluoroscopic, sonographic, computed tomography, magnetic resonance
imaging or other type of radiologic guidance. This would allow for
placement or injection of the in situ formed hydrogel either by
vascular access or percutaneous access to specific organs or other
tissue regions in the body.
[0089] The gel composition can be added to a stent-graft in an in
vivo environment. For example, one method for inflating a stent
graft in such an environment is as follows: after the graft has
been placed in the patient's body, and it is time to inflate the
graft, the monomer components which are contained in a sterile kit
having separate syringes for each monomer or mixtures thereof and
also a timer, will be thoroughly mixed to begin the curing process.
The contents are then transferred to one of the syringes and that
syringe is attached to an autoinjector which is connected to a tube
that is in turn connected to a biopolymer delivery tube located on
the proximal end of the catheter. At the appropriate time, the
autoinjector is turned on and the contents of the syringe is moved
through the tube in the catheter that is connected on the distal
end to a port on the graft where it enters the series of cuffs and
channels to inflate the graft material.
[0090] Additional methods of delivering the composition to an in
vivo site are also decribed in co-pending U.S. application Ser. No.
11/031,311
[0091] The following examples are meant to illustrate certain
embodiments (e.g., stent graft fill, embolic composition, and
tissue bulking compositions) of the invention and should not be
construed in any way as limiting the invention.
EXAMPLES
Abbreviations Used:
PEGGE: Polyethylene glycol glycidyl ether
TPTE: Trimethylolpropane triglycidyl ether
DCA or DCA-221: Di-(3-aminopropyl)diethylene glycol
cc: milliliters
DI: deionized water
1.5 N Gly-Gly: 1.5 N Glycine-glycine buffer
EX-411: pentaerythritol polyglycidyl ether
EX-321: trimethylpropane polyglycidyl ether (CAS No.
30499-70-8)
PBS: Phosphate Buffered Saline
Example 1
[0092] The following table shows formulations (1-7) that are
useful, in one aspect of the invention, as stent graft fill
material. These formulations can also find utility for other in
vivo applications that require a hydrogel polymer having the
properties as shown in Table 1. TABLE-US-00001 TABLE 1 Weight Wt %
of # of % % Wt Notes/ Formulation Material (g) Total Mol Wt mmoles
Gel Time Swelling Gain Observations 1 NaI (50%), pH 9.00 59.0 20
cc, 4.00 min; 10.50% 5.2 Hard material 7.40 1 cc, 12 min PEGGE 2.25
14.8 600 3.75 TPTE 2.50 16.4 302 8.28 DCA221 1.50 9.8 222.00 6.76 2
NaI (50%), pH 9.00 57.1 20 cc, 4 min; 7 0.8 Hard material 7.40 1
cc, 12 min PEGGE 2.25 14.3 600 3.75 TPTE 3.00 19.0 302 9.93 DCA221
1.50 9.5 222.00 6.76 3 NaI (50%), pH 9.00 55.4 20 cc, 3.40 min; 7
1.4 Hard material 7.40 1 cc, PEGGE 2.25 13.8 600 3.75 11.20 min
Epoxy Aldrich 3.50 21.5 302 11.59 DCA221 1.50 9.2 222.00 6.76 4 NaI
(50%), pH 9.00 53.7 20 cc, 3.40 min; 5.6 0.4 Hard material 7.40 1
cc, PEGGE 2.25 13.4 600 3.75 11.20 min TPTE 4.00 23.9 302 13.25
DCA221 1.50 9.0 222.00 6.76 5 NaI (50%), pH 10.00 58.0 20 cc, 4.30
min; 5.6 0 Hard material 7.40 1 cc, PEGGE 2.25 13.0 600 3.75 11.40
min TPTE 3.50 20.3 302 11.59 DCA221 1.50 8.7 222.00 6.76 6 NaI
(50%), pH 10.00 59.7 20 cc, 4.40 min; 7 0 Hard material 7.40 1 cc,
12 min PEGGE 2.25 13.4 600 3.75 TPTE 3.00 17.9 302 9.93 DCA221 1.50
9.0 222.00 6.76 7 NaI (50%), pH 10.00 55.6 20 cc, 4.30 min; 1.20%
-14% Hard material 7.40 1 cc, PEGGE 2.25 12.5 600 3.75 11.40 min
TPTE 3.50 19.4 302 11.59 DCA221 1.50 8.3 222.00 6.76 PBS 0.75
4.2
Example 2
[0093] The following table shows formulations (8-15) that are
useful, in one aspect of the invention, as a stent graft fill
material. These formulations can also find utility for other in
vivo applications that require a hydrogel polymer having the
properties as shown in Table 2. TABLE-US-00002 TABLE 2 Gel
Observations/ # of Weight % Epoxy/amine Gel Times Notes, all with 1
min Formulation Material Weight Mol Wt mmoles Total ratio Time 20
cc 1 cc % Swell mix 8 KI (100%) 9.0 56.3 4.58 8.30 13.45 18 Hard
gel DCA 0.5 221.0 2.26 3.1 polyoxyethylene 3.0 2000.0 1.50 18.8
diamine Sorbitol polyglycidyl 3.5 406.0 8.62 21.9 ether 9 KI (100%)
9.0 62.1 2.62 15.00 15.30 Soft gel DCA 0.5 221.0 2.26 3.4
polyoxyethylene 3.0 2000.0 1.50 20.7 diamine Sorbitol polyglycidyl
2.0 406.0 4.93 13.8 ether 10 KI (100%) 9.0 62.1 5.72 11.00 14.00 5
soft gel DCA 0.5 221.0 2.26 3.4 polyoxyethylene 1.5 2000.0 0.75
10.3 diamine Sorbitol polyglycidyl 3.5 406.0 8.62 24.1 ether 11 KI
(100%) 9.0 69.2 3.27 14.30 14.30 soft gel DCA 0.5 221.0 2.26 3.8
polyoxyethylene 1.5 2000.0 0.75 11.5 diamine Sorbitol polyglycidyl
2.0 406.0 4.93 15.4 ether 12 KI (100%) 7.0 50.0 4.58 9.00 13.00 21
Hard gel DCA 0.5 221.0 2.26 3.6 polyoxyethylene 3.0 2000.0 1.50
21.4 diamine Sorbitol polyglycidyl 3.5 406.0 8.62 25.0 ether 13 KI
(100%) 7.0 56.0 2.62 12.30 14.00 soft gel DCA 0.5 221.0 2.26 4.0
polyoxyethylene 3.0 2000.0 1.50 24.0 diamine Sorbitol polyglycidyl
2.0 406.0 4.93 16.0 ether 14 KI (100%) 7.0 56.0 5.72 7.30 12.30 10
Hard gel DCA 0.5 221.0 2.26 4.0 polyoxyethylene 1.5 2000.0 0.75
12.0 diamine Sorbitol polyglycidyl 3.5 406.0 8.62 28.0 ether 15 KI
(100%) 7.0 63.6 3.27 10.30 12.00 8 Hard gel DCA 0.5 221.0 2.26 4.5
polyoxyethylene 1.5 2000.0 0.75 13.6 diamine Sorbitol polyglycidyl
2.0 406.0 4.93 18.2 ether
Example 3
[0094] The following table shows formulations (16-24) that are
useful, in one aspect of the invention, stent graft fill material.
These formulations can also find utility for other in vivo
applications that require a hydrogel polymer having the properties
as shown in Table 3. TABLE-US-00003 TABLE 3 # of Weight %
Epoxy/amine % Formulation Material Weight Mol Wt mmoles Total ratio
Gel Time 20 cc Gel Time 1 cc Swell 16 Omnipaque 9.0 51.4 2.90 8.30
14:30 7.0% Buffer 1.5N pH 7.6 3.0 17.1 DCA221 1.5 221 6.79 8.6
Sorbitol 4.0 406 9.85 22.9 polyglycidyl ether 17 Omnipaque 10.0
50.0 3.99 11.00 14:20 5.6-7.0% Buffer 1.5N pH 7.6 3.0 15.0 DCA221
1.5 221 6.79 7.5 Sorbitol 5.5 406 13.55 27.5 polyglycidyl ether 18
Visipaque 12.0 60.0 3.63 11.13 12.56 2.80% DCA 1.5 221.0 6.79 7.5
1.5N Gly--Gly 1.5 7.5 Sorbitol 5.0 406.0 12.32 25.0 polyglycidyl
ether 19 Visipaque 11.0 59.5 2.90 13 14.3 DCA 1.5 221.0 6.79 8.1
1.5N Gly--Gly 2 10.8 Sorbitol 4.0 406.0 9.85 21.6 polyglycidyl
ether 20 Omnipaque 10.0 47.6 3.99 11.00 14:20 5.6-7.0% Buffer 1.5N
pH 7.6 3.0 14.3 DI 1.0 4.8 DCA221 1.5 221 6.79 7.1 Sorbitol 5.5 406
13.55 26.2 polyglycidyl ether 21 Omnipaque 10.5 48.3 3.81 11.00
20.00 5.6-7.0% Buffer 1.5N pH 7.6 4.5 20.7 DCA221 1.5 221 6.79 6.9
Sorbitol 5.3 406 12.93 24.1 polyglycidyl ether 22 Visipaque 12.0
55.8 3.63 16 15.4 5.6-7.0% Di 1.0 4.7 DCA 1.5 221.0 6.79 7.0 1.5N
Gly--Gly 2 9.3 Sorbitol 5.0 406.0 12.32 23.3 polyglycidyl ether 23
Visipaque 12.0 58.5 3.63 12.08 13.2 4% in DI 0.5 2.4 graft DCA 1.5
221.0 6.79 7.3 1.5N Gly--Gly 1.5 7.3 Sorbitol 5.0 406.0 12.32 24.4
polyglycidyl ether 24 Visipaque 11.4 55.6 3.63 11 14.3 6.00%
Omnipaque 0.6 2.9 DCA 1.5 221.0 6.79 7.3 1.5N Gly--Gly 2 9.8
Sorbitol 5.0 406.0 12.32 24.4 Polyglycidyl ether
Example 4
[0095] The following table shows formulations (EM1-EM12) that are
useful, in one aspect of the invention, as embolic materials. These
formulations can also find utility for other in vivo applications
that require a hydrogel polymer having the properties as shown in
Table 4. TABLE-US-00004 TABLE 4 # of Reactive Components Weight (g)
FW mmoles Sites Weight % Gel Time Comments EM-1 1 EX-411 3.00 411
7.30 4 60.0 7:10 syringe Some floating material. EX-321 0.50 321
1.56 3 10.0 Soft, non-elastic, 2 NaI (100%) 1.00 20.0 fractionating
slug. 3 DCA221 0.50 221 2.26 2 10.0 Total 5.00 100.0 EM-2 1 EX-411
3.00 411 7.30 4 57.1 7:15 syringe Floating material. EX-321 0.25
321 0.78 3 4.8 Slightly firm slug 2 NaI (100%) 1.00 19.0 3 DCA221
1.00 221 4.52 2 19.0 Total 5.25 100.0 EM-3 1 EX-411 3.00 411 7.30 4
54.5 10:27 syringe Floating material. Soft, EX-321 1.00 321 3.12 3
18.2 wet, non-elastic slug. 2 NaI (100%) 1.00 18.2 3 DCA221 0.50
221 2.26 2 9.1 Total 5.50 100.0 EM-4 1 EX-411 3.00 411 7.30 4 50.0
6:12 syringe Floating material. Very EX-321 1.00 321 3.12 3 16.7
hard slug. 2 NaI (100%) 1.00 16.7 3 DCA221 1.00 221 4.52 2 16.7
Total 6.00 100.0 EM-5 1 EX-411 2.00 411 4.87 4 53.3 6:20 syringe
Floating material. Soft, EX-321 0.25 321 0.78 3 6.7 elastic slug. 2
NaI (100%) 1.00 26.7 3 DCA221 0.50 221 2.26 2 13.3 Total 3.75 100.0
EM-6 1 EX-411 2.00 411 4.87 4 47.1 No cure time Floating material.
EX-321 0.25 321 0.78 3 5.9 collected. Material in PBS does not 2
NaI (100%) 1.00 23.5 Extended, cure- demonstrate 3 DCA221 1.00 221
4.52 2 23.5 should have re- hydrophobicity. Slightly Total 4.25
100.0 mixed "grainy" texture. EM-7 1 EX-411 2.00 411 4.87 4 44.4
6:20 syringe Floating material. Soft, EX-321 1.00 321 3.12 3 22.2
non-elastic, fractionating 2 NaI (100%) 1.00 22.2 slug. 3 DCA221
0.50 221 2.26 2 11.1 Total 4.50 100.0 EM-8 1 EX-411 2.00 411 4.87 4
40.0 4:25 syringe At Very small amount EX-321 1.00 321 3.12 3 20.0
4:00 drops floating material. Hot 2 NaI (100%) 1.00 20.0 became
strings. exotherm, .about.75 C. Very 3 DCA221 1.00 221 4.52 2 20.0
hard slug. Total 5.00 100.0 EM-9 1 EX-411 2.50 411 6.08 4 62.5 10:5
syringe Material in PBS cured at EX-321 0.20 321 0.62 3 5.0 8:00 2
NaI (100%) 1.00 25.0 3 DCA221 0.30 221 1.36 2 7.5 Total 4.00 100.0
EM-10 1 EX-411 2.50 411 6.08 4 56.8 7:05 syringe Drops became
strings at EX-321 0.40 321 1.25 3 9.1 2:45. Soft, fractionating 2
NaI (100%) 1.10 25.0 slug. 3 DCA221 0.40 221 1.81 2 9.1 Total 4.40
100.0 EM-11 1 EX-411 3.00 411 7.30 4 47.6 5:36 syringe At 1:37,
drops became EX-321 1.00 321 3.12 3 15.9 1 cc @37 C strings. 5:50
material 2 NaI (100%) 1.70 27.0 cured at 7:36 cure in PBS. Soft,
elastic 3 DCA221 0.60 221 2.71 2 9.5 slug. Total 6.30 100.0 EM-12 1
EX-411 3.00 411 7.30 4 44.1 4:45 Syringe Material cure in PBS @
EX-321 1.50 321 4.67 3 22.1 1 cc @8:15 5:47 2 NaI (100%) 1.70 25.0
Injected 1 cc in blood 3 DCA221 0.60 221 2.71 2 8.8 6.80 100.0
Example 5
[0096] Formulation 7 was prepared according to the following
experimental procedure.
[0097] The mixture of polyethylene glycol diglycidyl ether and
trimethylolpropane triglycidyl ether is added to a single syringe.
Di-(3-aminopropyl)ether diethylene glycol is added to a second
syringe. The two syringes are connected using a delivery tube and
ping-ponged mixed between syringes for approximately 20 seconds,
with the syringed emptied fully every time with each stroke
(approximately 1 stroke/second). A two milliliter sample stored in
a 20 milliliter syringe cures in approximately 13 minutes at room
temperature. This corresponds to an in vivo cure time of 13 minutes
in an inflatable endovascular graft.
* * * * *