U.S. patent application number 10/321813 was filed with the patent office on 2003-10-16 for compositions useful for remodeling body spaces.
This patent application is currently assigned to PROVASIS THERAPEUTICS, INC.. Invention is credited to Kerber, Charles W., Knox, Kimberly, Krall, Robert E..
Application Number | 20030194390 10/321813 |
Document ID | / |
Family ID | 24307337 |
Filed Date | 2003-10-16 |
United States Patent
Application |
20030194390 |
Kind Code |
A1 |
Krall, Robert E. ; et
al. |
October 16, 2003 |
Compositions useful for remodeling body spaces
Abstract
A composition comprising of a monomer component comprised of at
least one alkyl cyanoacrylate and at least one inhibitor, and a
second component comprised of a resultant aggregate structure
formed from an alkyl cyanoacrylate monomer, an alkyl esterified
fatty acid and an opacificant agent where said composition forms a
resultant aggregate structure when said composition contacts an
anionic environment. The compositions are useful for filling,
occluding, partially filling or partially occluding an unfilled
volume or space in a mass in an anionic environment. The
composition are also useful for ablating diseased or undesired
tissue by cutting off the blood supply to the tissue.
Inventors: |
Krall, Robert E.; (Alpine,
CA) ; Kerber, Charles W.; (La Mesa, CA) ;
Knox, Kimberly; (La Mesa, CA) |
Correspondence
Address: |
GARY CARY WARE & FRIENDENRICH LLP
4365 EXECUTIVE DRIVE
SUITE 1100
SAN DIEGO
CA
92121-2133
US
|
Assignee: |
PROVASIS THERAPEUTICS, INC.
|
Family ID: |
24307337 |
Appl. No.: |
10/321813 |
Filed: |
December 16, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10321813 |
Dec 16, 2002 |
|
|
|
09577115 |
May 23, 2000 |
|
|
|
6538026 |
|
|
|
|
09577115 |
May 23, 2000 |
|
|
|
09497075 |
Feb 2, 2000 |
|
|
|
6476070 |
|
|
|
|
Current U.S.
Class: |
424/78.35 ;
264/238 |
Current CPC
Class: |
A61L 24/06 20130101;
C09J 4/06 20130101; C08F 267/06 20130101; A61K 31/78 20130101; A61P
9/00 20180101; A61K 31/05 20130101; A61K 31/275 20130101; A61K
33/243 20190101; A61K 33/242 20190101; A61K 31/785 20130101; A61P
15/00 20180101; A61L 31/048 20130101; A61P 35/00 20180101; A61K
31/12 20130101; C09J 4/00 20130101; A61P 15/18 20180101; A61K 31/05
20130101; A61K 2300/00 20130101; A61K 31/12 20130101; A61K 2300/00
20130101; A61K 31/275 20130101; A61K 2300/00 20130101; A61K 31/78
20130101; A61K 2300/00 20130101; A61K 31/785 20130101; A61K 2300/00
20130101; A61K 33/24 20130101; A61K 2300/00 20130101; A61L 24/06
20130101; C08L 35/04 20130101; C09J 4/06 20130101; C08F 267/06
20130101; A61L 31/048 20130101; C08L 35/04 20130101; C09J 4/00
20130101; C08F 222/326 20200201; C08F 267/06 20130101; C08F 222/326
20200201 |
Class at
Publication: |
424/78.35 ;
264/238 |
International
Class: |
A61K 031/785; B29C
031/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 28, 2000 |
WO |
US00/02262 |
Claims
We claim:
1. A method of filling, occluding, partially filling or partially
occluding an unfilled volume or space in a mass in an anionic
environment comprising administering a composition comprising of a
monomer component comprised of at least one alkyl cyanoacrylate and
at least one inhibitor, and a second component comprised of a
resultant aggregate structure formed from an alkyl cyanoacrylate
monomer, an alkyl esterified fatty acid and an opacificant agent
where said composition forms a resultant aggregate structure when
said composition contacts an anionic environment with an
administering device comprised, a means for stabilizing fluid flow
distal or proximal to said space being treated, and a means for
delivering said composition to said space.
Description
[0001] This application is a continuation-in-part of U.S. Ser. No.
09/497,075, filed Feb. 2, 2000, which is incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] This invention relates to cyanoacrylate compositions useful
as medical devices.
BACKGROUND OF THE INVENTION
[0003] Cyanoacrylate tissue adhesives have been in clinical
endovascular use since the 1970's. Liquid acrylics are extremely
useful as endovascular embolic agents because of their ability to
create permanent vascular occlusion. They may, however, be
difficult to use technically as they have a variable and sometime
unpredictable polymerization time based on the operator selection
of an acrylic mix with either iodinated oil or glacial acetic acid.
The appropriate choice of polymerization time depends on a number
of variables, including the transit time between arterial and
venous elements in the embolic target, the target volume, the
architecture of the target, for example, a fistula versus nidus,
which affects the relative endovascular turbulence, and the method
of injection (bolus, full column, or wedge-flow arrest). Typical
complications associated with the use of liquid acrylics for
embolization occur when there is occlusion of normal arterial
branches or acrylic penetration into critical venous outflow
channels. Additionally, reflux of acrylic around the delivery
catheter tip can result in permanent endovascular catheter
adhesion, which may require permanent catheter implantation.
Overzealous attempts at withdrawal can produce catheter fracture
(and resultant embolization of flow-directable distal catheter
segment), vascular damage with resultant dissection/occlusion, or
avulsion of the involved vascular pedicle (with resultant
subarachnoid hemorrhage).
[0004] Alkyl alpha cyanoacrylates are a homologous series of
organic molecules which polymerize and can adhere to moist living
tissues. The methyl homolog has been used in homeostasis and
non-suture closure since 1960, but its histoxicity severely limited
its clinical usefulness. The synthesis of longer alkyl chain
homologs and the evaluation of these in various animal species have
shown that the histoxicity of cyanoacrylates could be diminished
without sacrificing their hemostatic and tissue bonding properties.
Extensive animal studies have been completed using n-butyl and
isobutyl homologs, and preliminary human trials have been
undertaken.
[0005] Polymerization speed is another function of chain length. It
has been reported that homologs with six or more carbon atoms on
the alkyl chain polymerize almost immediately upon contact with
moist tissues. The n-butyl and isobutyl monomers require from four
to 15 seconds, while the methyl homolog remains as a monomer for 30
to 55 seconds. The ability to wet and spread easily over the
surface of an anticoagulated blood film is common to homologs with
alkyl chains containing four or more carbon atoms. The ethyl and
propyl derivatives wet and spread poorly, and the methyl not at
all.
[0006] Since the advent of NBCA (n-butyl-2-cyanoacrylate), there
has been very little advancement in the science of "superglue"
embolization of vascular structures, primarily arteriovenous
malformations (AVMs). Certain properties of superglue are
advantageous for embolization, such as adhesion, the ability
transform from a liquid or solid state and rapid polymerization.
However, these properties can be detrimental when present to an
excessive degree, in particular, adhesion which can result in
permanent catheter fixation. Rapid polymerization allows the
material to set in flowing blood without passing through small
channels into venous structures. However, rapid polymerization may
also release amounts of heat that can cause damage to the
surrounding tissue, for example, brain tissue.
[0007] Hydrophilic catheter coatings have been developed in the
hope of reducing the risk of inadvertent endovascular catheter
fixation during embolization due to reduced bond strength between
the hydrophilicly coated catheter and the adhesive. However, micro
catheter cyanoacrylate adhesion remains a problem during
intravascular embolization. Inadvertent gluing of the catheter tip
onto the artery is a well recognized and distressing complication.
Vessel rupture or occlusive embolization of a detached catheter tip
may occur if excessive force is used to attempt to retrieve the
catheter. Fortunately, permanent intra vascular catheter fixation
is usually well tolerated, nonetheless this remains a highly
undesirable event. An in vitro study has shown that recently
available hydrophilic micro catheter coatings decrease catheter
adhesion of both pure normal butyl cyanoacrylate and mixtures of
normal butyl cyanoacrylate and ethiodized oil. Although
hydrophilicly coated catheters have the potential of decreasing the
occurrence of inadvertent endovascular catheter fixation, the level
of operator proficiency and experience, and perhaps most
importantly, the actual adhesive composition that is used stills
play a major role in these events.
[0008] There exists a continuing unmet need for a composition that
has the correct amount of cohesiveness, produces a robust rubbery
casting, is tolerated by the body, can trigger the appropriate
amount of tissue inflammation response and is radiopaque.
[0009] It has now been surprisingly found that such a composition
exists that has the requisite combination of properties in
cohesion, stability, body tolerance, low catheter adhesion and
radiopacity.
SUMMARY OF THE INVENTION
[0010] A composition comprising of a monomer component comprised of
at least one alkyl cyanoacrylate and at least one inhibitor, and a
second component comprised of a resultant aggregate structure
formed from an alkyl cyanoacrylate monomer, an alkyl esterified
fatty acid and an opacificant agent where said composition forms a
resultant aggregate structure when said composition contacts an
anionic environment. The compositions are useful for filling,
occluding, partially filling or partially occluding an unfilled
volume or space in a mass in an anionic environment. The
composition are also useful for ablating diseased or undesired
tissue by cutting off the blood supply to the tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] No drawings are included.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The present invention provides a composition comprising of a
monomer component comprised of at least one alkyl cyanoacrylate, at
least one inhibitor and a second component that functions as a
opacificant agent and polymerization retardant. The composition is
useful for filling, occluding, partially filling or partially
occluding an unfilled volume or space in a mass ("a space"). In
particular, the composition is useful for filling an existing
space, e.g., the lumen of a blood vessel, or the sac of an
aneurysm, a space created by a transiently placed external device,
e.g., a catheter or like device, a space created by a procedure,
e.g., an excision or like procedure or implantation of an object,
e.g., a stent or like device, or a space created by the
composition; the composition is also useful for adhering tissue to
tissue, or adhering tissue to a device. The composition has the
property of polymerizing when it comes in contact with an anionic
environment, or when it is deployed in situ in an existing space,
e.g., the lumen of a blood vessel, or the sac of an aneurysm, a
space created by a transiently placed external device, e.g., a
catheter or like device, a space created by a procedure, e.g., an
excision or like procedure or implantation of an object, e.g., a
stent or like device, or a space created by the composition;
[0013] Another aspect of the present embodiment is where the second
component is comprised of a halogenated oil. Preferred are
iodinated and brominated oils, such as Ethiodol, Lipiodol and
Pantopaque. Most preferred is Ethiodol.
[0014] One embodiment of the present invention is where the second
component is Ethiodol.
[0015] Another aspect of the present embodiment is where the second
component is comprised of a resultant aggregate structure, i.e., an
oligomer or polymer, formed from a composition of alkyl
cyanoacrylate monomer, an alkyl esterified fatty acid and an
opacificant agent.
[0016] Another aspect of the present embodiment is where the
monomer component is comprised of one alkyl cyanoacrylate monomers,
and at least one inhibitor. A preferred aspect is where the monomer
component is comprised of 2-hexyl cyanoacrylate and one inhibitor.
An especially preferred aspect is where the monomer component is
comprised of 2-hexyl cyanoacrylate, and three inhibitors, most
especially preferred is the aspect where the inhibitors are
hydroquinone, p-methoxyphenol and phosphoric acid. An especially
preferred embodiment of the present invention is a composition
comprised of the present monomer component, and a second component
comprising of a resultant aggregate structure, i.e., an oligomer or
polymer, formed from 2-hexyl cyanoacrylate monomer, an alkyl
esterified fatty acid and an opacificant agent, most especially
preferred is where the alkyl esterified fatty acid is ethyl
myristate and the opacificant agent is gold.
[0017] Another aspect of the present embodiment is where the
monomer component is comprised of two or more different alkyl
cyanoacrylate monomers, and at least one inhibitor. A preferred
aspect is where the monomer component is comprised of methyl
cyanoacrylate, n-hexyl cyanoacrylate and at least one inhibitor. An
especially preferred aspect is where the monomer component is
comprised of methyl cyanoacrylate, n-hexyl cyanoacrylate and at
least three inhibitors, a most especially preferred aspect is where
the inhibitors are hydroquinone, p-methoxyphenol and acetic acid. A
particularly preferred embodiment of the present invention is the
composition comprised of the present monomer component, and a
second component comprising of the resultant aggregate structure,
i.e., an oligomer or polymer, formed from n-hexyl cyanoacrylate
monomer, an alkyl esterified fatty acid and an opacificant agent,
most preferred is where the alkyl esterified fatty acid is ethyl
myristate and the opacificant agent is gold.
[0018] Another embodiment of the present invention is a method for
purifying alkyl cyanoacrylate monomer to its crystalline form. In
particular, a method of purifying an alkyl cyanoacrylate to about
95% purity or better, preferred is to about 97% purity or better,
most preferred is to about 98% purity or better, and most
especially preferred is to about 99% purity or better.
[0019] Another embodiment of the present invention is a
substantially pure alkyl cyanoacrylate monomer. In particular,
methyl cyanoacrylate, n-butyl cyanoacrylate, isobutyl
cyanoacrylate, n-hexyl cyanoacrylate, 2-hexyl cyanoacrylate and
2-octyl cyanoacrylate, purified to about 95% purity or better,
preferred is to about 97% purity or better, most preferred is to
about 98% purity or better, and most especially preferred is to
about 99% purity or better. A particularly advantageous aspect of
the present invention is where the alkyl cyanoacrylate monomer is
isolated in its crystalline form.
[0020] It is known to those of ordinary skill in the art that the
predictability of polymerization properties of alkyl cyanoacrylate
monomers is related to the purity of the monomer that are used.
These polymerization properties, include but are not limited to
rate of polymerization, and stability of the monomer during
storage. Another advantage of substantially pure alkyl
cyanoacrylates is that compositions incorporating substantially
pure alkyl cyanoacrylates require smaller amounts of additives,
e.g., inhibitors, stabilizers and the like, to obtain a desired
result that would otherwise have require greater amounts of the
same additive. An immediate benefit of this advantage is in cost
savings from being able to use less material. Another benefit, is
that the composition will quantitatively have lower amounts of
additives. This is a desirable outcome for any composition that is
subject to regulatory approval by the U.S. Food and Drug
Administration, or like agency, prior to marketing. The current
embodiment provides alkyl cyanoacrylate monomers whose rates of
polymerization can be predicted, and where the un-reacted monomer
("pre-polymer") compositions are more stable. The properties
provide beneficial advantages for the use of the compositions of
the present invention because by being able to predict the
polymerization characteristics of a monomer, one of ordinary skill
in the art can select the monomer with the appropriate
polymerization properties for a desired use, or to formulate
monomer compositions having desired polymerization properties.
Prior to the present invention, alkyl cyanoacrylates have not been
available in substantially pure form because they are difficult to
purify using conventional chemical methodology. Moreover, most of
these methodologies involve conditions that cause the alkyl
cyanoacrylate to degrade or to spontaneously polymerize. Therefore
before the present invention, the benefits of substantially pure
alkyl cyanoacrylate monomers were not available.
[0021] Another embodiment of the present invention provides a
method for filling, occluding, partially filling or partially
occluding an unfilled volume or space in a mass by administering a
composition of the present invention with an administering means,
comprising a means for stabilizing fluid flow distal or proximal to
the body space being treated, and a means for delivering said
composition to the desired body space. An embodiment of said
administering means is where said means for stabilizing fluid flow
distal or proximal to the body space being treated is in a first
device, and said means for delivering said composition to the
desired body space is in a second device. An embodiment of said
first device comprises a temporary inflatable balloon, or like
structure, that is inflated to stabilize fluid flow distal or
proximal to the body space to be treated, and deflated for removal
after some period after the composition has been delivered.
Optionally said balloon structure may be juxtaposed adjacent to the
body space where said composition is deposited, and inflated such
that said balloon structure maintains said composition at the body
space while the composition is polymerizing, and deflated for
removal after some period after the composition has been delivered.
An embodiment of the said second device comprises a catheter, or
like device for delivering and depositing the composition of the
present invention at a desired location. Another embodiment of said
administering means is where said means for stabilizing fluid flow
distal or proximal to the body space being treated, and said means
for delivering said composition to the desired body space are
within a single device or apparatus.
[0022] The types of unfilled volumes or spaces within the scope of
the present invention includes, but are not limited to the
following instances.
[0023] For example, one aspect of the present embodiment is a
method of filling, occluding, partially filling or partially
occluding an existing space, such as, a lumen of a passageway in
the body, e.g., a blood vessel, a duct, an aneurysm, or a fistula.
Examples of the types treatments covered by this method of use,
include but are not limited to the following. The present invention
is useful as a method of treating arteriovenous malformations (AVM)
where the blood vessel(s) that feed the AVM are occluded thereby
cutting off the blood supply to the AVM. The present invention is
useful as a method to ablate diseased or undesired tissue by
cutting off the tissue's blood supply. In particular, the present
invention is useful as a method of treating a tumor having a
discrete blood supply, where the blood vessel(s) that feed the
tumor are occluded thereby cutting off the blood supply to the
tumor resulting in diminished growth or death of the tumor. The
present invention is useful as a method of preventing or mitigating
the development of an aneurysm by creating a partial occlusion at a
location in the blood vessel selected to modify the fluid dynamics
within the vessel to mitigate the formation or development of an
aneurysm. The present invention is useful as a non-surgical method
of treating symptomatic uterine leiomyomas by embolizing/occluding
the uterine artery. This method has been reported using a non alkyl
cyanoacrylate composition in Journal of Vascular and Intervention
Radiology, 10:891-894, July-August 1999. The present invention is
useful as a method of sterilizing a female mammal by occluding the
fallopian tubes thereby preventing the passage of the eggs from the
ovaries to the uterus. The use of an occluding agent to sterilize a
female mammal is disclosed in U.S. Pat. No. 5,989,580 "Method of
Sterilizing Female Mammals," herein incorporated by reference. The
methods disclosed in this patent can be advantageously applied
using the compositions of the present invention, and are within the
scope of the present invention. The present invention is useful for
obliterating the left atrial appendage. The left atrial appendage
is derived from the left wall of the primary atrium. It has been
observed that patients with atrial fibrillation have a predilection
for thrombus to form in the left atrial appendage. A review of this
condition and the current status of treatment is disclosed in the
article, "Left Atrial Appendage: structure, function, and role in
thromboembolism" N. M. Al-Saady, et. al. The present invention
provides an advantageous method of obliterating the left atrial
appendage.
[0024] Another aspect of the present embodiment is a method of
filling, occluding, partially filling or partially occluding a
space created by a transiently placed external device, such as, a
catheter balloon. a space created by a transiently placed external
device, e.g., a catheter or like device. Examples of the types of
treatments covered by this method of use include, but are not
limited to the following. The present invention is useful as a
method of treating an aneurysm by filling the space within the
aneurysm with a composition of the present invention, where the
composition polymerizes in the space within the aneurysm, thereby
preventing the rupture of the aneurysm. The present method of
treatment can be practiced using an administering means, comprising
a means for stabilizing fluid flow distal or proximal to the body
space being treated, and a means for delivering said composition to
the desired body space. An embodiment of said administering means
is where said means for stabilizing fluid flow distal or proximal
to the body space being treated is in a first device, and said
means for delivering said composition to the desired body space is
in a second device. An embodiment of said first device comprises a
temporary inflatable balloon, or like structure, that is inflated
to stabilize fluid flow distal or proximal to the body space to be
treated, and deflated for removal after some period after the
composition has been delivered. Optionally said balloon structure
may be juxtaposed adjacent to the body space where said composition
is deposited, and inflated such that said balloon structure
maintains said composition at the body space while the composition
is polymerizing, and deflated for removal after some period after
the composition has been delivered. An embodiment of the said
second device comprises a catheter, or like device for delivering
and depositing the composition of the present invention at a
desired location. Another embodiment of said administering means is
where said means for stabilizing fluid flow distal or proximal to
the body space being treated, and said means for delivering said
composition to the desired body space are within a single device or
apparatus. Such apparatuses include, but are not limited to,
catheters, catheter coils, catheter wires, catheter balloons, or
like devices. Many examples of such devices are known to those of
ordinary skill in the art. For example, U.S. Pat. No. 5,795,331
"Balloon Catheter For Occluding Aneurysms of Branched Vessels",
incorporated herein by reference, discloses a device and methods
for delivering compositions, such as those of the present
invention. The device described combines an inflatable balloon with
a catheter as a single apparatus, where the balloon is distal or
proximal to the opening of the catheter. Embodiments of the
described apparatus are commercially available from Micro
Therapeutics, Inc., 2 Goodyear, Irvine, Calif. 92618, as a line of
medical devices, such as, the Rebar.TM. Micro Catheter, Equinox.TM.
Occlusion Balloon System and SilverSpeed.TM. guidewires. Of
additional note is that devices under the Rebar.TM. Micro Catheter
line have been approved by the U.S. Food and Drug Administration
for use in treating conditions such as those within the present
invention. U.S. Pat. No. 5,882,334 "Balloon/Delivery Catheter
Assembly With Adjustable Balloon Positioning," incorporated herein
by reference, assigned to Target Therapeutics, San Jose, Calif.,
and U.S. Pat. No. 6,015,424 "Apparatus and Method For Vascular
Embolization", incorporated herein by reference, assigned to
MicroVention, Inc., Aliso Viejo, Calif., describe like devices that
can be employed in practicing the present invention. Additional
commercial sources for like devices, include but are not limited to
the following corporations, Guidant, Inc., Indianapolis, Ind.; Cook
Incorporated, Bloomington, Ind.; Cordis, a subsidiary of Johnson
and Johnson; and the SciMed, Target Therapeutics, and Medi-tech
Divisions Boston Scientific Corporation. The present invention has
been practiced following the procedure and utilizing like devices
described in Neurosurgery, Vol. 31, No. 3, September 1992, page 591
"Carotid-Cavernous Fistula Caused by a Ruptured Intra-cavernous
Aneurysm: Endovascular Treatment by Electrothrombosis with
Detailable Coils." The reference describes a procedure using a
temporary inflatable balloon catheter, and a catheter for placement
of a detachable-platinum coil. A temporary balloon occlusion is
performed proximally to a fistula, and then followed by the
insertion of a platinum detachable coil into the fistula. The
temporary balloon occlusion stabilizes the immediate environment
near the fistula from the disturbed flow, increased flow,
turbulence, or combination thereof, created by normal unrestricted
blood flow, while a thrombus forms around the platinum wire. In the
present invention, a temporary balloon occlusion performs a similar
function of stabilizing the immediate environment near the body
space to be treated, for example, a fistula or aneurysm, from the
disturbed flow, increased flow, turbulence, or combination thereof
created by normal unrestricted blood flow. The temporary balloon,
optionally, may also be used to temporarily form a seal at the
opening of the body space, while the composition that had been
deposited in the body space is polymerizing to its final form.
After a period of time sufficient for the polymerization to be
completed, the temporary balloon catheter is deflated and
withdrawn.
[0025] Another aspect of the present embodiment is a method of
filling, occluding, partially filling or partially occluding a
space created or resulting from a procedure, such as with the
excision of tissue, or insufflation. Examples of the types of
treatments covered by this method of use include, but are not
limited to the following. The present invention is useful as a
method of treating or mitigating capillary oozing.
[0026] Another aspect of the present embodiment is a method of
filling, occluding, partially filling or partially occluding a
space created by the placement or implantation of an object, such
as, a medical device. Examples of the types of uses covered by this
method of use include, but are not limited to the following. The
present invention is useful as a method of restoring the normal
fluid dynamics at the peripheral edges of a vascular stent by
filling the dead spaces between the stent and the lumen wall
created by the implantation of the stent.
[0027] Another aspect of the present embodiment is a method of
filling, occluding, partially filling or partially occluding a
space created by the composition itself, such as, where the
composition is used as a bulking agent. Examples of the types of
uses covered by this method of use include, but are not limited to
the following. For example, a method of recreating the normal
contours to skin following an adverse event, such as, physical
trauma.
[0028] Another embodiment of the present invention provides a
method of affixing therapeutics, chemotherapeutics, radiation
delivery devices, gene therapy compositions to a desired location
where the active agents can be advantageously maintained in
proximity to the desired location. The active agent is then release
gradually as the resultant aggregate structure from the composition
of the present invention is biodegraded. Alternatively, the
composition of the present invention can be modified to allow for a
specific rate of delivery. This use is particularly beneficial in
the treatment of tumors that are ideally treated by localized
dosages of chemotherapy or radiation. An advantage of this method
is that the patient would not be subjected to as large of a dose of
the therapeutic or radiation as would be necessary, if the
therapeutic or radiation was administered on a systemic basis.
Another advantageous use the present invention is for the delivery
of DNA compositions used in gene therapy. A long standing problem
in the gene therapy arts has been the inability of practitioners to
deliver the DNA therapeutic to the locales in the body most ideally
suited for the treatment. The present invention provides a method
of affixing the DNA composition at a desired site, where the active
agent is then slowly released over a period time as the composition
of the present invention biodegrades. Alternatively, a composition
of the present invention can be modified to release the active
agent in a controlled delivery manner.
[0029] Another embodiment of the present invention provides a
method of utilizing magnetically controlled particles embedded in a
composition of the present invention to deploy the composition to a
desired location, "Magnetic Probe for the Stereotaxic Thrombosis of
Intracranial Aneurysms," Alksne, J. F., et. al, Journal of
Neurology, Neurosurgery and Psychiatry, April 1967, 30(2):159-62;
"Magnetically Controlled Focal Intravascular Thrombosis in Dogs"
Alksne, J. F., et. al, Journal of Neurosurgery, November 1966,
25(5):516-25; "Thrombosis of Intracranial Aneurysms--An
experimental approach utilizing magnetically controlled iron
particles" Alksne, J. F., et. al, Radiology February 1966
86(2):342-3
[0030] Another embodiment of the present invention provides a
method of adhering, joining, connecting or affixing a first section
of tissue to a second section of tissue. Examples of the types of
uses covered by this method of use include, but are not limited to
the following. The present invention is useful as a method of
adhering, joining, or connecting two blood vessels, e.g.,
anastomoses, where blood vessels are quickly and efficiently
adhered, joined or connected, under surgical conditions without the
use of sutures or staples. The present invention is useful as a
method of treating primary wounds or wounds that require immediate
intervention, such as, trauma wounds, where the compositions of the
present invention are used to temporarily close the wound to
minimize the lost of fluids due to evaporation, and to mitigate
infection.
[0031] Another embodiment of the present invention provides a
method of adhering, joining, connecting, or affixing tissue to a
non-tissue surface, such as a medical device. Examples of the types
of uses covered by this method of use include, but are not limited
to the following. The present invention is useful as a method of
implanting or securing venous valves, replacement heart valves, or
stents at their desired location.
[0032] The aforementioned uses are possible because the
compositions of the present invention remain in a controllable
state for a period of time in excess of 1 second after being
deployed from an administration device. This property allows the
practitioner to incremental maneuver the deployment of the
composition to its most ideal location, even though the composition
had been partially deployed distal to the deployment device.
[0033] For instance, the compositions of the present invention have
adequate cohesion to maintain its continuity once it is outside of
the deployment device. Without adequate cohesion the composition
would break into smaller aggregates dispersing into the blood
flow.
[0034] For instance, the compositions of the present invention have
appropriate adhesion properties so that when desired a deployed
composition adheres to the immediate location where it is deployed
so that the resultant aggregate of the monomer is placed where it
is desired.
[0035] The compositions of the present invention have
polymerization rate, such that, the practitioner can effect the
desired amount of penetration of the composition into a particular
type of space. A composition that polymerizes too quickly would
hinder penetration, conversely a composition that polymerizes too
slowly would make it difficult to precisely place the polymerized
composition resultant aggregate of the monomer.
[0036] Another embodiment of the present invention provides a
method for selectively creating an embolic blockage in the lumen of
a blood vessel, duct, fistula or other like body passageways.
[0037] Another embodiment of the present invention provides a
method of treating arteriovenous malformation (AVM)
Definitions
[0038] As used herein the terms "adhesion" or "adhesive" means the
characteristic or tendency of a material to be attracted to the
surface of a second material. Adhesion occurs as the result of
interactions between two materials. Depending on the
characteristics of the second material relative to the first
material, adhesion may or may not occur. For a single material,
e.g., the composition of the present invention, the presence of
adhesion is demonstrated by a material sticking to the wall of a
lumen of blood vessel, i.e., there is adhesion between the material
and the lumen wall. Conversely, the absence of adhesion is
demonstrated for the same material where a micro-catheter tip used
to deposit the material can be removed from the material, i.e.,
there is little adhesion between the material and micro-catheter
tip.
[0039] As used herein the term "alkyl" refers to a carbon chain of
one to sixteen carbon atoms, where the carbon atoms can be linear
or branched.
[0040] As used herein the term "anionic environment" or "an-ionic
environment" refers to an environment that is non-ionic. This an
environment that is devoid of charged ions, or where the charged
ions are complexed with other molecules which effectively
neutralize their charge. For example, a solution of water and a
sugar, such as, dextrose, and blood, is an anionic environment.
[0041] As used herein the term "lower-alkyl" refers to a carbon
chain of one to eight carbon atoms, where the carbon atoms can be
linear or branched. Examples of lower-alkyl moieties include but
are not limited to methyl, ethyl, n-butyl, isobutyl, pentyl,
n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl and 2-octyl.
[0042] As used herein the term "branched alkyl" refers to a carbon
chain of one to sixteen carbon atoms where the carbon chain
contains at least one secondary or tertiary substituted carbon
atom.
[0043] As used herein the term "branched lower-alkyl" refers to a
carbon chain of one to eight carbon atoms where the carbon chain
contains at least one secondary or tertiary substituted carbon
atom, for example, 2-hexyl, isobutyl, 2-heptyl and 2-octyl.
[0044] As used herein the term "cohesion" or "cohesive" means the
characteristic or tendency of a material to stick together to
itself. For example, this characteristic is demonstrated by a
material or composition remaining intact as a single mass when
introduced into a stationary fluid, or a fluid stream in motion,
such as, blood. Lack of cohesive integrity results in the
composition breaking up into multiple smaller subunits.
[0045] As used herein the term "embolic agent" refers to a
non-naturally occurring composition introduced into a body cavity
or the lumen of a blood vessel, duct, fistula or other like body
passageways for the purpose of forming an embolic block.
[0046] As used herein the term "embolic block" or "embolic
blockage" or occlusion refers to the end result from the
administration of a composition useful as an embolic agent. The
resulting embolic block mechanically blocks, totally or partially,
the lumen of a blood vessel, duct, fistula or other like body
passageways; or in a like manner forms an occlusion within a
cavity, such as an aneurysm.
[0047] As used herein the term "alkyl cyanoacrylate monomer" refers
to the chemical entity of the general structure
H.sub.2C.dbd.C(CN)--C(O)O--R, where R is an alkyl moiety of one to
sixteen carbon atoms, linear or branched, saturated or unsaturated,
having the physical characteristic of being able to form the
corresponding alkyl cyanoacrylate.
[0048] As used herein the term "alkyl cyanoacrylate polymer" means
an oligomer or polymer resulting from the polymerization of a alkyl
cyanoacrylate monomer.
[0049] As used herein the term "alkyl esterified fatty acid" means
a fatty acid derivatized to form an ester functional group with a
alkyl moiety, such as ethyl myristate. These compounds are formed
with an alkyl moiety, such as methyl, ethyl, propyl, butyl, pentyl,
hexyl, heptyl, and octyl; and carboxylic acids with alkyl side
chains ranging from 1 carbon, i.e., acetic acid, through to and
including 17 carbons atoms in length, such as, proprionic, butyric,
isobutyric, valeric, isovaleric, pivalic, lauric, myristic,
palmitic and stearic acids.
[0050] As used herein the term "opacificant agent" is compound or
composition which selectively absorbs or deflects radiation making
the material visible under x-ray, or any like imaging technique.
Typically such agents include, iodinated oils, and brominated oils,
as well as commercially available compositions, such as Pantopaque,
Lipiodol and Ethiodol. These commercially available compositions
acts as opacificant agents, and also dilute the amount of liquid
monomer thereby slowing the rate of polymerization. In addition
certain metals, such as, gold, platinum, tantalum, titanium,
tungsten and barium sulfate and the like, have properties enabling
them to act as opacificant agents.
[0051] As used herein the term "polymerization" refers to the
chemical process where identical monomer units react chemically to
form larger aggregates of said monomeric units as oligomers or
polymers.
[0052] As used herein the term "polymerization retardant" means an
agent that can stop or slow down the rate of polymerization.
Examples of such agents are pure phosphoric acid, and 85%
phosphoric acid. Certain opacificant agents, such as Pantopaque,
Lipiodol and Ethiodol can also function as a polymerization
retardant by diluting the amount of liquid monomer and hence
slowing polymerization rate.
[0053] As used herein the terms "a space" and "a body space" refer
to an unfilled volume or cavity in a mass. Examples of such spaces,
include but are not limited by the following, an existing space
within a mass, such as, the lumen of a blood vessel, the sac of an
aneurysm; a space created by a transiently placed external device,
such as, a catheter or like device; a space created by a procedure,
such as, an excision or like procedure; a space created by
implantation of an object, such as, a stent or like device; or a
space created by the composition.
[0054] As used herein the term "stability" refers to the ability of
a monomer component to resist degradation or polymerization after
preparation but prior to use.
[0055] As used herein the term "inhibitor agent" refers to an agent
which stabilizes a monomer composition by inhibiting
polymerization. Within the context of the current invention, this
term refers to agents that stabilize and inhibit polymerization by
various mechanisms. By altering the amounts of one or more
inhibitor agents, the rate of polymerization can be controlled.
Inhibitor agents have different modes of activity, for example,
hydroquinone acts primarily to inhibit high energy free radicals;
p-methoxyphenol acts primarily to inhibit low energy free radicals;
and phosphoric acid influences the rate of anionic
polymerization.
[0056] As use herein the term "Neuracryl M" refers to the
composition comprising of a monomer component ("M1") comprised of
2-hexyl cyanoacrylate, hydroquinone, p-methoxyphenol and phosphoric
acid, and a second component ("M2") comprising of a resultant
aggregate structure formed from 2-hexyl cyanoacrylate monomer,
ethyl myristate and gold. As noted above, the term "M1" refers to
the monomer component of Neuracryl M, and the term "M2" refers to
the second component of Neuracryl M.
[0057] As used herein the term "Neuracryl A" refers to the
composition comprising of a monomer component ("A1") comprised of
n-hexyl cyanoacrylate, methyl cyanoacrylate, hydroquinone,
p-methoxyphenol and acetic acid, and a second component ("A2")
comprising of a resultant aggregate structure formed from n-hexyl
cyanoacrylate monomer, ethyl myristate and gold. The term "A1"
refers to the monomer component of Neuracryl A, and the term "A2"
refers to the second component of Neuracryl A.
[0058] As used herein the term "deployment device" refers a device
used to deploy compositions, such as, those of the present
invention. Examples of such devices, include but are not limited to
the following. Micro Therapeutics, Inc., 2 Goodyear, Irvine, Calif.
92618, markets medical devices, such as, the Rebar.TM. Micro
Catheter, Equinox.TM. Occlusion Balloon System and SilverSpeed.TM.
guidewires, that are used in conjunction for treating conditions
such as those within the present invention. The devices disclosed
in U.S. Pat. No. 5,882,334 "Balloon/delivery Catheter Assembly with
Adjustable Balloon Positioning," incorporated herein by reference,
is directed to a catheter assembly for delivering compositions.
[0059] Nomenclature
[0060] The compound 2-hexyl cyanoacetate is depicted as follows,
and also as Formula 3 in Schemes A and B. 1
[0061] The compound 2-hexyl cyanoacrylate is depicted as follows,
and also as Formula 5 in Scheme B. 2
[0062] The present invention is a composition formed from alkyl
cyanoacrylate monomeric units, such as, methyl, n-butyl, isobutyl,
n-hexyl and 2-hexyl cyanoacrylate with at least one inhibitor
agent, such as hydroquinone, p-methoxyphenol and phosphoric acid.
The composition forms into its resultant aggregate structure, i.e.,
an oligomer or polymer, when it comes in contact with an anionic
environment, such as, blood or tissue. The resultant aggregate
composition has characteristics which makes it particularly well
suited as an embolic agent.
[0063] The composition of the present invention possess the
following properties, which are desirable in an embolization
agent.
[0064] 1) The composition can be prepared and maintained as a
monomeric component and second component until needed.
[0065] 2) The composition has the ability to reliably and
predictably change from a liquid state to a solid state, which is
essential for its introduction and controlled placement into the
lumen of vessel, duct, fistula or other like body passageways.
[0066] 3) The composition has low viscosity, which is essential for
its administration by syringes and micro-catheters or other like
devices.
[0067] 4) The composition has cohesive characteristics such that
when the composition in administered into an anionic fluid
environment, such as blood, the composition forms a single
aggregate structure.
[0068] 5) The composition has adhesive characteristic such that it
attaches to the lumen of vessel, duct, fistula or other like body
passageways, but not to the degree where the device depositing the
composition will become fixed to it before the practitioner can
remove it.
[0069] 6) The composition causes mild tissue inflammation,
sufficient to cause scarring, but not so severe to cause the
formation of pus. Scar formation is necessary to maintain the
functionality of the embolic block after the composition has
biodegraded, or otherwise eliminated from the lumen.
[0070] 7) The composition is sufficiently stable to biodegradation
to allow for scarring to occur.
[0071] 8) The composition is radiopaque. Although not necessary for
its function as an embolic agent, radiopacity allows the embolic
block to be observed with x-ray or other such imaging
techniques.
[0072] 9) The rate of heat released during polymerization of the
composition is low enough such that the heat does not adversely
effect surrounding tissues that may be heat sensitive, such as
brain tissue.
[0073] 10) The composition and its biodegradation products are
sufficiently non-histotoxic and non-cytotoxic so that its presence
is well tolerated in the body.
[0074] The composition of the present invention is used by
combining the monomer component and second component. Upon mixing
of the components, the invention is administered into the lumen of
a blood vessel, duct, fistula or other like body passageways. The
characteristics of the present invention permit its accurate
placement in the lumen. Contact with an anionic environment, such
as blood, or tissue causes the composition to polymerize. The size
of the resultant embolic block formed is determined by the amount
of composition administered.
[0075] The characteristics of the composition of the invention can
be modified for a specific purpose or environment for which the
embolic agent is intended to be utilized. For example, changes in
the length and isomeric configuration of the alkyl side chains can
alter the brittleness of the resultant aggregate of cyanoacrylate
monomers. Alkyl chains that result in the formation of smaller
aggregates tend to be less brittle, while larger aggregates tend to
be less flexible. In addition, by combining monomers with different
alkyl side chains the characteristics of the resultant polymer can
be modified to what is optimal for a desired application.
[0076] Cyanoacrylates generate heat as they change from monomeric
to polymeric form. The amount and rate of heat released, if
excessive, can have a detrimental effect on the living tissue
proximate to the vessel. Control of the amount and rate at which
heat is release during polymerization is critical to the utility of
composition.
[0077] Preparation of the Monomer Component
[0078] The monomer component of the present invention is prepared
by forming the desired precursor ester from the corresponding alkyl
alcohol and cyanoacetic acid resulting in the desired alkyl
cyanoacetate as depicted in Scheme A. The starting materials for
this reaction are commercially available, for example from Aldrich
Chemical Company, Sigma Chemical Company or Fluka Chemical Company,
or can be prepared following procedures known to those of ordinary
skill in the art. 3
[0079] The compound of Formula 2 can be any alkyl alcohol, where R
is from one to sixteen carbons, including but not limited to
alcohols based on alkyl groups, such as, methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, heptyl, octyl, nonyl, deca, undeca,
dodeca, trideca, tetradeca, pentadeca and hexadeca, where the
preceding moieties are linear (e.g., n-propyl, n-butyl, n-pentyl)
or variously branched, such as sec-butyl, iso-butyl, tert-butyl,
iso-propyl, 2-butyl, 2-pentyl, 2-hexyl, 2-heptyl, 2-octyl and the
like. Particularly advantageous alcohols are those disclosed in
U.S. Pat. No. 3,728,375 entitled "Cyanoacrylate Adhesive
Compositions", which is hereby incorporated by reference.
Especially preferred are methyl, n-butyl, iso-butyl, n-hexyl and
2-hexyl alcohols.
[0080] About 1 molar equivalents of the compounds of Formula 1 and
Formula 2 are combined in a solvent like toluene at about 100
ml/molar equivalents. To this mixture is added a catalytic amount
(about 1.0.times.10.sup.-4 molar equivalents) of p-toluene sulfonic
acid. The mixture is stirred and heated to reflux. The preparation
ideally yields the desired alkyl cyanoacetate at a purity level of
about 95%. The experimental conditions can be readily modified by
one of ordinary skill in the art without deviating from the present
invention. Aspects such as, solvent selection, reaction time,
temperature and choice of reagents are well within the skill of one
of ordinary skill in the art. If necessary, the material can be
further purified using multiple distillations and purification
techniques and procedures known to those of ordinary skill in the
art, such as water extraction, vacuum distillation, column
chromatography, and the like.
[0081] Preparation of Alkyl Cyanoacrylate
[0082] The desired alkyl cyanoacrylate monomer component of the
present invention is synthesized from the alkyl cyanoacetate by
reacting the it in a Knoevengel type reaction as depicted in Scheme
B. 4
[0083] About 1 molar equivalents of formaldehyde (Formula 4), which
is prepared from paraformaldehyde, and piperidine (at about 0.33
ml/molar equivalents) are combined in a solvent, such as methanol
(at about 166 ml/molar equivalents). To this mixture is added about
1 molar equivalents of previously prepared alkyl cyanoacetate
(Formula 3) in a dropwise manner. The reaction mixture is refluxed
with stirring yielding the desired alkyl cyanoacrylate polymer
(Formula 5). The reaction mixture is further processed with about
0.2 to 0.7 molar equivalents, preferably about 0.2 to 0.6 molar
equivalents of phosphorous pentoxide yielding the desired alkyl
cyanoacrylate. Care must be taken during purification steps to
prevent the compound of Formula 5 from polymerizing. To this end
the system is treated with trace amounts of sulfur dioxide, and
receiver flasks are treated with hydroquinone and 85% phosphoric
acid. After initial purification, the desired alkyl cyanoacrylate
is further purified using multiple distillations, or other
purification techniques known to those of ordinary skill in the
art, such as, vacuum distillation, spinning band column, and the
like.
[0084] Purification of Composition by Zone Freeze/Melting
[0085] The alkyl cyanoacrylate monomer compositions of the present
invention can be purified using the zone melting technique to a
point where under the correct conditions it is possible to form
pure crystals of the alkyl cyanoacrylate monomers, such as, methyl
cyanoacrylate, -butyl cyanoacrylate, iso-butyl cyanoacrylate,
n-hexyl cyanoacrylate, and 2-hexyl cyanoacrylate.
[0086] The composition is placed in a container fitted with an
exchange apparatus, which will permit the differential removal of
liquid impurities from the composition. The pressure of the
container with the composition is reduced to about 1.5 to 0.5 Torr,
preferably about 1 Torr, at the same time the temperature of the
composition is reduced to about -28 to -8.degree. C., preferably
about -23 to -13.degree. C., most preferably about -17.5 to
-18.5.degree. C. The composition is allowed to equilibrate at this
temperature for a period of about 12 to 36 hours, preferably about
24 hours. After the equilibration period, the alkyl cyanoacrylate
is crystallized out of solution by gently agitating the container,
such as by tapping the side of the container, or gently shaking the
container. If the crystallization does not begin, the process is
repeated every 15 minutes for 1 hour. If after an hour the alkyl
cyanoacrylate still does not crystallize, a small piece of dry ice
is placed against the outside of the container for about 30
seconds. Once the alkyl cyanoacrylate monomer begins to
crystallize, the temperature of the container is increased by about
6.degree. C., preferably about 4.degree. C., most preferably about
2.degree. C. The crystallization process is allowed to sit
undisturbed for about 24 to 72 hours, preferably about 48 hours. At
the end of the crystallization period, the container is inverted so
that the uncrystallized liquid in the container is drained into the
reserve reservoir. The container is allowed to drain for about 30
minute or whatever time is required for the draining of the liquid
to be completed. Once the draining is finished the valve between
the container with the alkyl cyanoacrylate crystals and the reserve
reservoir with the uncrystallized liquid is closed, separating the
crystals from the liquid. The liquid is removed from the reserve
reservoir and analyzed for the type and amount of impurities. Air
is re-introduced into the container with the crystals. The
container is also allowed to equilibrate to ambient room
temperature, at which time the crystals melts. The melted crystals
are analyzed for purity. The purified crystals of the alkyl
cyanoacrylate monomer should be reformed into the stable
composition of the present invention to prevent the monomer from
polymerizing.
[0087] If the desired, the process is repeated in order to obtain
the alkyl cyanoacrylate monomer at a desired purity. Generally, the
process is repeated at least once to gain desired purity. Following
purification, the crystalline alkyl cyanoacrylate should be
re-formulated into the stable composition of the present invention
to prevent the monomer from polymerizing.
[0088] Formulation
[0089] The monomer component of the present invention comprises of
at least one alkyl cyanoacrylate and at least one inhibitor agent.
Typical inhibitors appropriate for cyanoacrylates are, for example,
hydroquinone, p-methoxyphenol, pure phosphoric acid, and alkyl
carboxylic acids, where the alkyl moiety ranges from 1 carbon,
e.g., acetic acid, through to 15 and 17 carbons atoms in length,
i.e., palmitic and stearic acids, respectively; and phosphoric acid
at varying percentage solutions. Preferably hydroquinone,
p-methoxyphenol, acetic acid and phosphoric acid are used,
individually or in combination.
[0090] Different inhibitors have different physical characteristics
and thereby functions to alter the final properties of the
composition. For example, hydroquinone is primarily an inhibitor
for high energy free radicals; p-methoxyphenol is primarily an
inhibitor for low energy free radicals; and phosphoric acid acts to
control or inhibit anionic polymerization and the rate of such
polymerization.
[0091] The quantity of inhibitors used is measured in terms of
parts per million of alkyl cyanoacrylate. For example, for 2-hexyl
cyanoacrylate, hydroquinone is in the range of about 50 to 150
parts per million (PPM), p-methoxyphenol in the range of about 50
to 150 PPM, and phosphoric acid in the range of about 125 to 375
PPM, more preferred is hydroquinone in the range of about 75 to 125
PPM, p-methoxyphenol in the range of about 75 to 125 PPM, and
phosphoric acid in the range of about 187.5 to 312.5 PPM, and most
preferred is hydroquinone in the range of about 95 to 105 PPM,
p-methoxyphenol in the range of about 95 to 105 PPM, and phosphoric
acid in the range of about 200 to 300 PPM. Similarly, for a monomer
component comprising of 90% n-hexyl cyanoacrylate and 10% methyl
cyanoacrylate, hydroquinone is in the range of about 50 to 150
parts per million (PPM), p-methoxyphenol is in the range of about
50 to 150 PPM, and acetic acid is in the range of about 50 to 500
PPM, more preferred is hydroquinone in the range of about 75 to 125
PPM, p-methoxyphenol in the range of about 75 to 125 PPM and acetic
acid in the range of about 100 to 300 PPM, and most preferred is
hydroquinone in the range of about 95 to 105 PPM, p-methoxyphenol
in the range of about 95 to 105 PPM, and acetic acid in the range
of about 150 to 250 PPM.
[0092] The second component functions as an opacificant agent and a
polymerization retardant. To this end, the second component can be
an iodinated oil, such as Ethiodol, or a brominated oil. Typically
the iodinated oil is mixed as some percent of the total volume of
the final composition. The percentage solution of iodinated oil
used will influence the polymerization rate and opacity of the
composition. Generally advantageous ranges are from about 17% to
66%, preferably about 33%.
[0093] Alternatively, the second component can be a composition
comprising, a opacificant material, such as gold, platinum,
tantalum, titanium, tungsten and barium sulfate and the like; an
alkyl cyanoacrylate polymer material, and an esterified fatty acid,
where the fatty acids have 3 carbon atoms, for example, alkyl
butyrate to 17 carbons, for example, alkyl stearate, preferred are,
alkyl laurate, alkyl myristate, alkyl palmatate, and alkyl
stearate, most preferred is alkyl myristate, and most especially
preferred is ethyl myristate. The opacificant material is used in a
fine powder form, typically, with individual particles sized no
larger than about 7 microns in diameter, preferably about 5
microns, most preferred about 2 microns and most especially
preferred is 1 micron or smaller.
[0094] The amount of opacificant material used relative to alkyl
cyanoacrylate polymer will vary according to the specific
materials. Factors that influence the determination of the ratio
include the amount and size of the particles that are being coated
by the alkyl cyanoacrylate polymer. For example, for 2-hexyl
cyanoacrylate and gold, 2 g of 2-hexyl cyanoacrylate is used per
100 g of powdered gold (particle size of about 5.+-.2 microns)
being coated. For example, for n-hexyl cyanoacrylate and gold, 2 mg
of n-hexyl cyanoacrylate is used per 1 gm of gold at a particle
size of about 2 to 10.mu., preferably about 0.1 to 1.0.mu., most
preferably about 1 .ANG.. The amounts vary accordingly with the
opacificant material being coated by the alkyl cyanoacrylate. The
alkyl cyanoacrylate and opacificant material are mechanically mixed
by processing the alkyl cyanoacrylate into small particulate
masses, and mixing with the finely powdered opacificant material.
The alkyl cyanoacrylate polymer coated material is then stored in
an esterified fatty acid, which serves as a medium where the alkyl
cyanoacrylate polymer coated material is maintained prior to use,
and as a medium, which when contacted with the monomer component
will not interfere with the polymerization of the composition. The
unsealed storage containers, preferably appropriately sterilized
bottles and caps or the like, with the cyanoacrylate polymer
suspension is then treated with ethylene oxide, or alternatively
ketene. This treatment should occur no later than about 48 hours
after completion of the coating process, preferably within 24
hours. The treatment process provides sterilization and
stabilization of the alkyl cyanoacrylate polymer coated material
and follows standard procedures for ethylene oxide use, i.e.,
positioning the containers so that they are amply exposed to the
gas for a sufficient period of time.
[0095] Polymer M and Polymer A
[0096] The characteristics of the composition of the invention can
be modified for a specific application or environment in which the
composition is intended to be utilized. For example, changes in the
length and isomeric configuration of the alkyl side chains can
alter the brittleness of a polymer formed from a cyanoacrylate
monomer. Alkyl chains that result in the formation of smaller
aggregates tend to be less brittle, while larger aggregates tend to
be less flexible. Another method of modifying the characteristics
of a polymer is to use a composition comprising of two or more
types of alkyl cyanoacrylate monomers in combination with the
appropriate inhibitors.
[0097] For example, a composition comprised of a monomer component
comprising of 2-hexyl cyanoacrylate, hydroquinone, p-methoxyphenol
and phosphoric acid; and a second component comprising of 2-hexyl
cyanoacrylate polymer, gold, and ethyl myristate results in Polymer
M. Alternatively, a composition comprised of a monomer component
comprising of 90% n-hexyl cyanoacrylate and 10% methyl
cyanoacrylate, hydroquinone, p-methoxyphenol and acetic acid; and a
second component comprising of n-hexyl cyanoacrylate polymer, gold,
and ethyl myristate. results in Polymer A.
[0098] A qualitative survey of Polymer M and A is shown in Table A.
The physical characteristics disclosed are readily recognized by
those of ordinary skill in the art as being relevant to the
applications for which the polymers are used.
1TABLE A (add to definitions section) Characteristics Polymer M
Polymer A cohesion excellent excellent adhesion moderate - low
moderate - high polymerization polymerizes to polymerizes from
profile semi-solid to liquid to soft soft-solid on solid to firm
contact with solid on contact tissue or blood with tissue or blood
tactile rubbery/gummy firm rubbery molecular weight low (1500 to
expected to be 3000) higher inflammatory mild response expected to
be response similar viscosity 14 to 15 expected to be centipoise
similar radio opacity yes yes exothermicity low expected to be
slightly higher
[0099] Polymers M and A have excellent cohesion properties. When
introduced into a stationary fluid, or a fluid stream in motion,
such as, the lumen of a blood vessel or other like passageway, the
composition tend to stick together to itself remaining intact as a
single mass or aggregate. This permits the polymers to be
discretely deposited or placed at the desired location without the
hazard of having potions of the composition breaking away and
depositing at undesired locales. Polymers M and A appear to have
viscosity properties that permit the injection of the liquid
composition into a lumen of a blood vessel, duct, fistula or
passageway in the body without using excessive pressure.
[0100] However, polymers M and A have different adhesion,
polymerization and tactile properties. Polymer M is less adhesive
than Polymer A, its polymerization profile upon contact with an
anionic environment, such as, tissue or blood, is a transition from
a liquid state to a semi-solid state before completing in a soft
solid state, and the resultant polymer is a soft, rubbery, gummy
solid. With these properties Polymer M is ideally suited for
applications where the composition must penetrate further into
anionic environment before arriving at the point of final
placement. A preferred use is the treatment of arteriovenous
malformations, also known as "AVM". Polymer M is also ideally
suited for the treatment of longer type urinary fistulas, this is
because preferred treatment requires greater penetration into
cavity space by the liquid composition. Additional applications
suited for Polymer M are creating a tubal occlusion, and surgical
adhesions. For examples a composition of the present invention is
applied to raw intraperitoneal tissue to prevent the tissue from
adhering to itself or other tissue.
[0101] Polymer A is more adhesive than M, its polymerization
profile upon contact with an anionic environment, such as, tissue
or blood, is a transition from a liquid state to a soft solid and
completing as a firm solid. With these properties Polymer A is
ideally suited for applications where the composition must quickly
adhere and polymerize in the surrounding anionic environment.
Particularly advantageous applications for Polymer A is treatment
of various types of aneurysms.
[0102] Another advantageous application for Polymer A is the
treatment of fistulas, particularly those where it is desirable to
have the resultant aggregate structure form close to the point of
deployment.
[0103] Still another advantageous use for Polymer A is for the
maintenance of homeostasis during surgery, such as, during
hepatectomy, renal surgery, and during gynecologic tumor
surgery.
[0104] Further, Polymer A can be used to treat certain types of
varicose veins, where Polymer A is injected into the portal
vein.
[0105] Utility
[0106] The present invention is useful for filling, occluding,
partially filling or partially occluding an unfilled volume or
space in a mass ("a space"). In particular, the composition is
useful for filling an existing space, e.g., the lumen of a blood
vessel, or the sac of an aneurysm, a space created by a transiently
placed external device, e.g., a catheter or like device, a space
created by a procedure, e.g., an excision or like procedure or
implantation of an object, e.g., a stent or like device, or a space
created by the composition; the composition is also useful for
adhering tissue to tissue, or adhering tissue to a device. The
composition has the property of polymerizing when it comes in
contact with an anionic environment, or when it is deployed in situ
in an existing space, e.g., the lumen of a blood vessel, or the sac
of an aneurysm, a space created by a transiently placed external
device, e.g., a catheter or like device, a space created by a
procedure, e.g., an excision or like procedure or implantation of
an object, e.g., a stent or like device, or a space created by the
composition.
[0107] The present invention is useful as an embolic agent that
selectively creates an embolic blockage in the lumen of a blood
vessel, duct, fistula or other like body passageways.
[0108] The present invention can be prepared and maintained as a
monomeric component and second component until needed. It has the
ability to reliably and predictably change from a liquid state to a
solid state, which is essential for its introduction and controlled
placement into the lumen of vessel, duct, fistula or other like
body passageways. The composition has low viscosity, which is
essential for its administration by syringes and micro-catheters or
other like devices.
[0109] The cohesive characteristics of the invention are such that
when the composition in administered into an anionic fluid
environment, such as blood, the composition forms a single
aggregate structure. Additionally, the adhesive characteristics are
such that the composition attaches to the lumen of vessel, duct,
fistula or other like body passageways, but not to the degree where
the device depositing the composition will become fixed to it
before the practitioner can remove it.
[0110] The present invention causes mild tissue inflammation,
sufficient to cause scarring, but not so severe to cause the
formation of pus. Scar formation is desirable as the scar tissue is
necessary to maintain the functionality of the embolic block after
the composition has biodegraded, or otherwise eliminated from the
lumen. The composition is sufficiently stable to biodegradation to
allow for scarring to occur.
[0111] The present invention is radiopaque. Although this
characteristic is not necessary for its function as an embolic
agent, radiopacity allows the embolic block to be observed with
x-ray or other such imaging techniques.
[0112] The rate of heat released during polymerization of the
present invention is low enough such that the heat does not
adversely effect surrounding tissues that may be heat sensitive,
such as brain tissue.
[0113] The present invention and its biodegradation products are
sufficiently non-histotoxic and non-cytotoxic so that its presence
is well tolerated in the body.
[0114] The composition of the present invention is useful for
filling, occluding, partially filling or partially occluding an
unfilled volume or space in a mass ("a space").
[0115] The present invention provides a method for filling,
occluding, partially filling or partially occluding an unfilled
volume or space in a mass. The types of unfilled volumes or spaces
within the scope of the present invention includes, but are not
limited to the following instances.
[0116] For example, the present invention is used as a method of
filling, occluding, partially filling or partially occluding an
existing space, such as, a lumen of a passageway in the body, e.g.,
a blood vessel, a duct, an aneurysm, or a fistula. Examples of the
types treatments covered by this method of use, include but are not
limited to the following. The present invention is useful as a
method of treating arteriovenous malformations (AVM) where the
blood vessel(s) that feed the AVM are occluded thereby cutting off
the blood supply to the AVM. The present invention is useful as a
method to ablate diseased or undesired tissue by cutting off the
tissue's blood supply. In particular, the present invention is
useful as a method of treating a tumor having a discrete blood
supply, where the blood vessel(s) that feed the tumor are occluded
thereby cutting off the blood supply to the tumor resulting in
diminished growth or death of the tumor. The present invention is
useful as a method of preventing or mitigating the development of
an aneurysm by creating a partial occlusion at a location in the
blood vessel selected to modify the fluid dynamics within the
vessel to mitigate the formation or development of an aneurysm. The
present invention is useful as a non-surgical method of treating
symptomatic uterine leiomyomas by embolizing/occluding the uterine
artery. This method has been reported using a non alkyl
cyanoacrylate composition in the Journal of Vascular and
Interventional Radiology, 10:891-894, July-August 1999. The present
invention is useful as a method of sterilizing a female mammal by
occluding the fallopian tubes thereby preventing the passage of the
eggs from the ovaries to the uterus. The use of an occluding agent
to sterilize a female mammal is disclosed in U.S. Pat. No.
5,989,580 "Method of Sterilizing Female Mammals," herein
incorporated by reference. The methods disclosed in this patent can
be advantageously applied using the compositions of the present
invention, and are within the scope of the present invention.
[0117] The present invention is an embolic agent that provides a
method for selectively creating and placing an embolic blockage
which mechanically blocks, totally or partially, the lumen of a
blood vessel, duct, fistula or other body passageway. In
particular, the current invention is particularly useful in
blocking, totally or partially, or diverting the flow of blood
through the lumen.
[0118] The present invention can be advantageously used to block
blood flow to certain tissues or areas. For example, the present
invention can be used to treat arteriovenous malformation (AVM). An
AVM is a collection of abnormal blood vessels which are neither
arteries or veins. These vessels are packed closely together to
form the nidus of the AVM. Blood flow into the AVM nidus is through
thinned, enlarged, tortuous vessels and is rapidly shunted into
draining veins because the nidus contains no arterioles or
capillaries to provide high resistance. Clinical symptoms
experienced because of AVMs are bleeding, re-direction of blood
from nearby normal structures, or seizures. The primary clinical
problem associated with cerebral AVM is the potential for lethal
hemorrhage. The current standard of care for treating AVMs is
surgical removal, high energy radiation or embolization with
particular devices.
[0119] Further, the present invention can be used for treating
cancer by diverting or blocking blood flow to tumors, the present
invention is particularly useful for treating tumors in areas that
are not easily accessible for surgical intervention, for example,
brain tumors.
[0120] Other advantageous uses of the present invention are for
aortopulmonary closure; treatment of artery pseudoaneursym; hepatic
artery vascular occlusion and for temporary vascular occlusion
during co-administration of cytotoxic drugs; treatment of other
types of vessels, for example, the composition can be used for
creating tubal occlusions, fallopian tube occlusions, vas deferens
occlusions, and urinary occlusions.
[0121] The present invention provides a method of filling,
occluding, partially filling or partially occluding a space created
by a transiently placed external device, such as, a catheter
balloon. Examples of the types of treatments covered by this method
of use include, but are not limited to the following. The present
invention is useful as a method of treating an aneurysm by filling
the space within the aneurysm with a composition of the present
invention, where the composition polymerizes in the space within
the aneurysm, thereby preventing the rupture of the aneurysm. This
treatment can be practiced using an administering means, comprising
a means for stabilizing fluid flow distal or proximal to the body
space being treated, and a means for delivering said composition to
the desired body space. An embodiment of said administering means
is where said means for stabilizing fluid flow distal or proximal
to the body space being treated is in a first device, and said
means for delivering said composition to the desired body space is
in a second device. An embodiment of said first device comprises a
temporary inflatable balloon, or like structure, that is inflated
to stabilize fluid flow distal or proximal to the body space to be
treated, and deflated for removal after some period after the
composition has been delivered. Optionally said balloon structure
may be juxtaposed adjacent to the body space where said composition
is deposited, and inflated such that said balloon structure
maintains said composition at the body space while the composition
is polymerizing, and deflated for removal after some period after
the composition has been delivered. An embodiment of the said
second device comprises a catheter, or like device for delivering
and depositing the composition of the present invention at a
desired location. Another embodiment of said administering means is
where said means for stabilizing fluid flow distal or proximal to
the body space being treated, and said means for delivering said
composition to the desired body space are within a single device or
apparatus. Such apparatuses include, but are not limited to,
catheters, catheter coils, catheter wires, catheter balloons, or
like devices. Many examples of such devices are known to those of
ordinary skill in the art. For example, U.S. Pat. No. 5,795,331
"Balloon Catheter For Occluding Aneurysms of Branched Vessels",
incorporated herein by reference, discloses a device and methods
for delivering compositions, such as those of the present
invention. The device described combines an inflatable balloon with
a catheter as a single apparatus, where the balloon is distal or
proximal to the opening of the catheter. Embodiments of the
described apparatus are commercially available from Micro
Therapeutics, Inc., 2 Goodyear, Irvine, Calif. 92618, as a line of
medical devices, such as, the Rebar.TM. Micro Catheter, Equinox.TM.
Occlusion Balloon System and SilverSpeed.TM. guidewires. Of
additional note is that devices under the Rebar.TM. Micro Catheter
line have been approved by the U.S. Food and Drug Administration
for use in treating conditions such as those within the present
invention. U.S. Pat. No. 5,882,334 "Balloon/Delivery Catheter
Assembly With Adjustable Balloon Positioning," incorporated herein
by reference, assigned to Target Therapeutics, San Jose, Calif.,
and U.S. Pat. No. 6,015,424 "Apparatus and Method For Vascular
Embolization", incorporated herein by reference, assigned to
MicroVention, Inc., Aliso Viejo, Calif., describe like devices that
can be employed in practicing the present invention. Additional
commercial sources for like devices, include but are not limited to
the following corporations, Guidant, Inc., Indianapolis, Ind.; Cook
Incorporated, Bloomington, Ind.; Cordis, a subsidiary of Johnson
and Johnson; and the SciMed, Target Therapeutics, and Medi-tech
Divisions Boston Scientific Corporation. The present invention has
been practiced following the procedure and utilizing like devices
described in Neurosurgery, Vol. 31, No. 3, September 1992, page 591
"Carotid-Cavernous Fistula Caused by a Ruptured Intra-cavernous
Aneurysm: Endovascular Treatment by Electrothrombosis with
Detailable Coils." The reference describes a procedure using a
temporary inflatable balloon catheter, and a catheter for placement
of a detachable platinum coil. A temporary balloon occlusion is
performed proximally to a fistula, and then followed by the
insertion of a platinum detachable coil into the fistula. The
temporary balloon occlusion stabilizes the immediate environment
near the fistula from the disturbed flow, increased flow,
turbulence, or combination thereof created by normal unrestricted
blood flow, while a thrombus forms around the platinum wire. In the
present invention, a temporary balloon occlusion performs a similar
function of stabilizing the immediate environment near the body
space to be treated, for example, a fistula or aneurysm, from the
disturbed flow, increased flow, turbulence, or combination thereof
created by normal unrestricted blood flow. The temporary balloon,
optionally, may also be used to temporarily form a seal at the
opening of the body space, while the composition that had been
deposited in the body space is polymerizing to its final form.
After a period of time sufficient for the polymerization to be
completed, the temporary balloon catheter is deflated and
withdrawn.
[0122] The present invention also provides a method of filling,
occluding, partially filling or partially occluding a space created
or resulting from a procedure, such as with the excision of tissue,
or insufflation. Examples of the types of treatments covered by
this method of use include, but are not limited to the following.
The present invention is useful as a method of treating oozing
capillaries following an excision procedure.
[0123] The present invention further provides a method of filling,
occluding, partially filling or partially occluding a space created
by the placement or implantation of an object, such as, a medical
device. Examples of the types of uses covered by this method of use
include, but are not limited to the following. The present
invention is useful as a method of restoring the normal fluid
dynamics at the peripheral edges of a vascular stent by filling the
dead spaces between the stent and the lumen wall created by the
implantation of the stent.
[0124] Still another advantageous use is the controlling and
smoothing the blood flow around stents. A major complication from
the balloon angioplasty and the use of stents is disruption of the
smooth flow of blood past and around the stent which can lead to
the formation of blood clots and their associated complications.
The composition of the present invention can be used to modify and
make regular the slip streams of blood through and adjacent to the
stent to mitigate or alleviate the cause of the turbulence, and
such turbulence causing states.
[0125] The present invention further provides a method of filling,
occluding, partially filling or partially occluding a space created
by the composition itself, such as, where the composition is used
as a bulking agent. Examples of the types of uses covered by this
method of use include, but are not limited to the following. For
example, a method of recreating normal external contours, such as
following physical trauma.
[0126] Administration
[0127] The monomer component and second component of the present
invention are combined just prior to use. The composition of the
present invention is administered using any type of deployment
device. The term "deployment device" refers to a device used to
deploy fluids or compositions similar to those of the present
invention, such as, a needle, catheter devices, catheter balloon,
stereotaxic placement devices, or the like. Methods for using these
devices are readily known to one of ordinary skill in the art, and
such devices are commercially available. Such devices and methods
are readily known to those of ordinary skill in art. For example in
U.S. Pat. No. 5,925,683 "Liquid Embolic Agents", herein
incorporated by reference, there is disclosed a method for
introducing liquid embolic agents/solutions into the human body to
form precipitated embolic occlusion masses, and also how this
method is used for treating hepatic tumors using portal vein
embolism. In U.S. Pat. No. 5,702,361 "Method for Embolizing Blood
Vessels", herein incorporated by reference, there is disclosed a
method of embolizing a vascular site in a patient's blood vessel
comprising of introducing, via a catheter, at the vascular site to
be emobolized a non-particulate agent or a plurality of such
agents, and delivering, via a catheter, to said vascular site a
polymer composition comprising a biocompatible polymer, a
biocompatible solvent and contrast agent, wherein the delivery is
conducted under conditions where the polymer precipitate forms in
situ at the vascular site resulting in the embolizing of the blood
vessel and where the non-particulate agent is encapsulated within
the precipitate. An administrating means can be used to deliver the
composition of the present invention to a desired location, said
administering means comprising, a means for stabilizing fluid flow
distal or proximal to the body space being treated, and a means for
delivering said composition to the desired body space. An
embodiment of said administering means is where said means for
stabilizing fluid flow distal or proximal to the body space being
treated is in a first device, and said means for delivering said
composition to the desired body space is in a second device. An
embodiment of said first device comprises a temporary inflatable
balloon, or like structure, that is inflated to stabilize fluid
flow distal or proximal to the body space to be treated, and
deflated for removal after some period after the composition has
been delivered. Optionally said balloon structure may be juxtaposed
adjacent to the body space where said composition is deposited, and
inflated such that said balloon structure maintains said
composition at the body space while the composition is
polymerizing, and deflated for removal after some period after the
composition has been delivered. An embodiment of the said second
device comprises a catheter, or like device for delivering and
depositing the composition of the present invention at a desired
location. Another embodiment of said administering means is where
said means for stabilizing fluid flow distal or proximal to the
body space being treated, and said means for delivering said
composition to the desired body space are within a single device or
apparatus. Such apparatuses include, but are not limited to,
catheters, catheter coils, catheter wires, catheter balloons, or
like devices. Many examples of such devices are known to those of
ordinary skill in the art. For example, U.S. Pat. No. 5,795,331
"Balloon Catheter For Occluding Aneurysms of Branched Vessels",
incorporated herein by reference, discloses a device and methods
for delivering compositions, such as those of the present
invention. The device described combines an inflatable balloon with
a catheter as a single apparatus, where the balloon is distal to
the opening of the catheter. Embodiments of the described apparatus
are commercially available from Micro Therapeutics, Inc., 2
Goodyear, Irvine, Calif. 92618, as a line of medical devices, such
as, the Rebar.TM. Micro Catheter, Equinox.TM. Occlusion Balloon
System and SilverSpeed.TM. guidewires. Of additional note is that
devices under the Rebar.TM. Micro Catheter line have been approved
by the U.S. Food and Drug Administration for use in treating
conditions such as those within the present invention. U.S. Pat.
No. 5,882,334 "Balloon/Delivery Catheter Assembly With Adjustable
Balloon Positioning," incorporated herein by reference, assigned to
Target Therapeutics, San Jose, Calif., and U.S. Pat. No. 6,015,424
"Apparatus and Method For Vascular Embolization", incorporated
herein by reference, assigned to MicroVention, Inc., Aliso Viejo,
Calif., describe like devices that can be employed in practicing
the present invention. Additional commercial sources for like
devices, include but are not limited to the following corporations,
Guidant, Inc., Indianapolis, Ind.; Cook Incorporated, Bloomington,
Ind.; Cordis, a subsidiary of Johnson and Johnson; and the SciMed,
Target Therapeutics, and Medi-tech Divisions Boston Scientific
Corporation. The present invention has been practiced following the
procedure and utilizing like devices described in Neurosurgery,
Vol. 31, No. 3, September 1992, page 591 "Carotid-Cavernous Fistula
Caused by a Ruptured Intra-cavernous Aneurysm: Endovascular
Treatment by Electrothrombosis with Detailable Coils." The
reference describes a procedure using a temporary inflatable
balloon catheter, and a catheter for placement of a detachable
platinum coil. A temporary balloon occlusion is performed
proximally to a fistula, and then followed by the insertion of a
platinum detachable coil into the fistula. The temporary balloon
occlusion stabilizes the immediate environment near the fistula
from the disturbed flow, increased flow, turbulence, or combination
thereof created by normal unrestricted blood flow, while a thrombus
forms around the platinum wire. In the present invention, a
temporary balloon occlusion performs a similar function of
stabilizing the immediate environment near the body space to be
treated, for example, a fistula or aneurysm, from the disturbed
flow, increased flow, turbulence, or combination thereof created by
normal unrestricted blood flow. The temporary balloon, optionally,
may also be used to temporarily form a seal at the opening of the
body space, while the composition that had been deposited in the
body space is polymerizing to its final form. After a period of
time sufficient for the polymerization to be completed, the
temporary balloon catheter is deflated and withdrawn.
[0128] The composition of the present invention are administered
with any type of commercially available needle, catheter devices,
or stereotaxic placement devices, preferably in conjunction with
imaging technology that provides the practitioner with guidance as
to the placement of the composition. The compositions of the
present invention can be used advantageously in conjunction with
any embolization method that employs an embolizing agent, occluding
agent, or such composition that creates an embolic block, or
occlusion, or otherwise in effect is used for filling, occluding,
partially filling or partially occluding an unfilled volume or
space in a mass ("a space"). Delivery can also be made with a micro
catheter made from or coated with an agent that lessens the
likelihood of accidental gluing of the device to the vessel, for
example, hydrophilic coating and silicone derivative coatings.
EXAMPLES
[0129] The following examples are given to enable those of ordinary
skill in the art to more clearly understand and to practice the
present invention. The examples should not be considered as
limiting the scope of the invention, but merely as illustrative and
representative thereof.
Example 1
Preparation of 2-Hexyl Cyanoacetate
[0130] A 5 liter, 24/40 ground glass jointed flask was configured
with a reflux condenser, Dean-Stark trap, and football magnetic
stirring bar. The reaction vessel was charged with the 1,275.0 g of
cyanoacetic acid (Aldrich Chemical Co.), 1,581.5 g of 2-hexanol
(Aldrich Chemical Co.) and 3.0 g of p-toluenesulfonic acid (Aldrich
Chemical Co.), and 1,500 of toluene (Aldrich Chemical Co.). The
reaction mixture was stirred and heated to reflux. Water was formed
as a byproduct of the reaction and was collected during the course
of the reaction. The reaction was continued until there was a
period of over 30 minutes where no water was produced. The amount
of water collected was 230 ml and indicated that the reaction had
completed with a 85.2% theoretical yield. The reaction mixture was
allowed to cool to room temperature.
[0131] The reaction mixture was stirred and 500 ml of a saturated
baking soda (sodium bicarbonate) solution was gradually added to
the mixture. The reaction mixture was stirred vigorously until the
frothing stopped. The reaction mixture was poured into a six liter
separatory funnel, to which an additional 500 ml of water was
added. The funnel was vigorously agitated. The aqueous phase was
separated and saved as Reaction Water. The pH of the aqueous layer
was measured to insure that the pH was over 8. Another 500 ml of
water was added to the organic phase reaction mixture in the
separatory funnel. The contents of the funnel were again agitated,
the aqueous and organic phases were allowed to settle, and the
aqueous phase separated and also saved as Reaction Water. This
washing procedure was repeated two additional times. The organic
phase was moved to a 5-liter flask. The flask was configured with a
distillation condenser. The reaction mixture was heated to reflux,
and the remaining water was separated from the mixture and
discarded. The apparatus was reconfigured for vacuum fractional
distillation. Initially, the toluene and 2-hexanol in the mixture
were removed by reducing the pressure of the apparatus to about 5
Torr, and then by heating the mixture to 60.degree. with stirring.
After the solvents were removed, the pressure was further reduced
to less than 1 Torr and gradually increased heat until the desired
2-hexyl cyanoacetate began to distill off. The heat was adjusted so
that the product was recovered at a rate of 2 drops/sec. The
recovery collected 1921.1 g (70.76% yield) of the 2-hexyl
cyanoacetate, and was halted when no more material came out of the
distillation unit. Gas chromatographic analysis of the purity of
the 2-hexyl cyanoacetate indicated that the product was 98.3% pure,
which was well above 95% purity requirement for proceeding to the
next procedure.
[0132] If the purity of the 2-hexyl cyanoacetate had been below
95%, the material could have be purified by vacuum distillation, or
using any like technique for purification known to those of
ordinary skill in the art.
Example 2
Preparation of 2-Hexyl Cyanoacrylate
[0133] A 5-liter three-necked flask was configured with a reflux
condenser, Dean-Stark trap, an addition funnel and a mechanical
stirrer with a glass paddle in a 5-liter heating mantle.
Paraformaldehyde 272.4 g and methanol 1,500 ml were combined in the
flask. The reaction mixture was heated to reflux and stirred for a
period of 1 hr until the solution began to cleared. 3 ml of
piperidine was washed into the reaction mixture with methanol,
followed by 1521.9 g of 2-hexyl cyanoacetate added in a dropwise
fashion. The resulting reaction was exothermic, and the heat was
adjusted to maintain the reaction mixture at reflux temperature.
The reaction mixture was refluxed for an additional 30 minutes
after the conclusion of the addition. Methanol was distilled from
the reaction mixture and collected through the Dean-Stark trap
until 1420 ml of the original methanol (98%) was recovered
(compensating for spillage). The reaction mixture was halted
overnight at this point.
[0134] The reaction vessel was configured with a vacuum apparatus
to collect residues, and placed under high vacuum to remove
remaining volatile materials. The vacuum was gradually increased
until less than 10 Torr was reached. The apparatus was heated until
all the solvent had been removed. Once the solvent was removed, 75
g of phosphorous pentoxide was added to the mixture taking care to
minimize its exposure to air. The heat was discontinued, and the
mixture was stirred for one hour. The apparatus was then flooded
with sulfur dioxide. The pressure was reduced to less than 10 Torr
and heated slowly, the flow of sulfur dioxide was adjusted for a
constant low-level flow of gas into the apparatus.
[0135] A 1 liter flask was washed with concentrated sulfuric acid,
three times with water, and once with ultra pure water. The flask
was oven dried for one hour at 110.degree. C. and was allowed to
cool to room temperature. 10 drops of 85% phosphoric acid and
approximately 25-50 mg of hydroquinone was added to the 1 liter
flask. The flask was fitted as the receiver flask to the
distillation apparatus. The pressure of the distillation was
reduced to less than 10 Torr. The reaction mixture was heated and
stirred until the distillation began. 418 g of 2-hexyl
cyanoacrylate was collected at a 25% yield. The distillation was
halted when the temperature rose above 110.degree. C.
Example 3
Purification of 2-Hexyl Cyanoacrylate
[0136] The 2-hexyl cyanoacrylate was purified in a two step
process. The compound was first by vacuum distillation, and then
further purified by spinning band column.
[0137] Vacuum Distillation
[0138] A vacuum distillation apparatus was configured with a 2 L
flask, magnetic stirrer, fraction cutter, a 10" Vigreux column a
clasien head, condenser, thermometer and a 100 ml forecut receiving
flask. 10 drops of 85% phosphoric acid and 10 mg of hydroquinone
was added to the forecut flask. The unpurified 2-hexyl
cyanoacrylate was place into the distillation flask and the
pressure of the unit was reduced to just under 1 Torr. The material
was stirred and gradually heated until product was being distilled
and collected at a rate of one drop per minute. After 35 ml of
distillate was collected, a second 2 L receiving flask that had
been prepared by acid washing, followed by the addition of 25 drops
of 85% phosphoric acid and 20 mg hydroquinone was placed to receive
the distillate. The distillation rate was gradually increase till
the product was being collected at a rate of 2-3 drops per second.
When the distillation head temperature rose 2.degree. C. above that
used to collect the main fraction, the distillation was completed.
Heat was discontinued, and the material was allow to cool under dry
air by air filtered through a drying tube.
[0139] Spinning Band Column Purification
[0140] The spinning band column (B/R Instrument Corp., 9119
Centreville Road, Easton, Md. 21601, Model 9600) is a long jacketed
silvered column fitted with a 30/50 socket joint at the bottom. A
magnetic stirring bar was added to the 5 L socket joint flask,
which was then filled with the product to be purified. A heating
mantle is supported on a magnetic stirrer that is raised and
lowered with a laboratory jack to fit to the column. On the upper
right hand side of the column there was another 30/50 male socket
joint for a 100 ml receiving flask. All flasks and joints were
greased with high vacuum grease to assure a good vacuum seal. When
assembled, a glass temperature probe was inserted into the 10/15
joint of the flask, and a metal Tempora probe was inserted inside
the glass probe. The 29/42 joint containing the stopcock was
greased and placed into the flask and connected to a sulfur dioxide
gas line. The pressure of the system was gradually reduced down to
just under 1 Torr of pressure.
[0141] Operation of the spinning band column was controlled by a
microprocessor. The column was programmed to operate under the
following conditions, the water cooling temperature was set to
15.degree. C., the column's motor turns on at 24.degree. C.,
equilibration time was 2 min, open temperature 28.degree. C., close
temperature 90.degree. C., mantle rate 24.degree. C., reflux ratio
20 to 1 and pot temperature to end run 90.degree. C. Just prior to
beginning the distillation a small flow of sulfur dioxide was
leaked into the system. The temperature of the flask was monitored
during the distillation to ensure that the temperature at no time
rose above 100.degree. C. The distillate was collected in the
receiver flask at the end of the distillation.
[0142] The contents in the flask of the spinning band column were
allowed to cool for 30 min. A second high vacuum distillation
apparatus configured identically to the vacuum distillation
apparatus first used in this procedure was setup using a 2 L round
bottom flask. To this flask was added 0.0269 g of hydroquinone,
0.0275 g of p-methoxyphenol, and 0.0794 g of phosphoric acid. The
residue for pot of the spinning band column was added to the 2 L
round bottom flask of the vacuum distillation apparatus. The
contents of the flask was stirred and the pressure of the unit was
reduced to just less than 1 Torr. A small stream of sulfur dioxide
was leaked into the apparatus as the distillation continued. A
receiver flask was prepared by adding 10 mg hydroquinone and 15
drops of 85% phosphoric acid. A forecut fraction of 86.3 g was
collected at the rate of 2-6 drops per minute. The main fraction
was collected in a receiver similarly prepared as the forecut
fraction flask. 1620.1 g of main fraction product was collected at
a rate of 20-25 drops per minute. The material was then
re-distilled by the spinning band column under the previous
conditions.
[0143] The purity of the 2-hexyl cyanoacrylate was determined by
gas chromatography. The gas chromatograph was configured as
follows,
2 HP 5890 Gas Chromatograph with HP Chemstation Software. Column
Description: Supelco Nukol (60 meter, I.D.-0.32 mm, film
thickness-1 micron). Instrument Parameters: Method 1 Injector
Temperature: 220.degree. C. Detector Temperature: 280.degree. C.
Head Pressure: 15 PSI Air Pressure: 35 PSI Hydrogen Pressure: 20
PSI Aux: 60 PSI Initial Oven Temperature: 140.degree. C. for 20
min. Ramp: 5.degree. C./min. Final Oven Temperature: 200.degree. C.
for 50 min. A Splitless System. Injection Volume: 1.0 micro
liter
[0144] 1.0069 g of the 2-hexyl cyanoacrylate was mixed thoroughly
with 2 drops of 1-hexanol (0.0044 g), was analyzed and impurities
were found to be at an acceptable for use. The 2-hexyl
cyanoacrylate was sufficiently pure to use for product.
Example 4
Formulation of the Monomer Component
[0145] The monomer component was formulated with the following
materials 2-hexyl cyanoacrylate 1249.9 g, hydroquinone 0.0764 g,
p-methoxyphenol 0.0874 g and phosphoric acid 0.1693 g. The
hydroquinone and p-methoxyphenol were kept under reduced pressure
in a desiccator over a drying agent. The pure phosphoric acid was
particularly deliquescent and care was taken not permit water
contamination. The calculated molar quantities and PPM of each
material were as follows,
3 Material Moles PPM 2-hexyl cyanoacrylate 6.8964 999,547
hydroquinone 0.000694 100 p-methoxyphenol 0.000704 102 phosphoric
acid 0.001726 250
[0146] Overall purity of the formulation was determined by gas
chromatograph to be less than 1%, using 1-hexanol as an internal
standard.
4 Instrument Description: HP5890 Gas Chromatograph with HP
chemstation software. Column Description: Supelco Nukol (60 meters-
length, I.D., 0.32 mm, Film Thickness 1 micron) Instrument
Parameters: Method 1 Injector Temperature: 220.degree. C. Detector
Temperature: 280.degree. C. Head Pressure: 15 PSI Air Pressure: 35
PSI Hydrogen Pressure: 40 PSI Aux.: 60 PSI Initial Oven
Temperature: 140.degree. C. for 20 min. Ramp: 5.degree. C./min.
Final Oven Temperature: 200.degree. C. for 50 min. A Splitless
System: 1.0 microliter Injection Volume:
Example 5
Preparation of the 2-Hexyl Cyanoacrylate Polymer Component ("the
Second Component")
[0147] Ethyl myristate was obtained commercially from Aldrich
Chemical Company at 97% purity. Prior to use, the ethyl myristate
was further purified by vacuum distillation to 99.8% purity
following standard routine chemical procedures.
[0148] Six 3 ml syringes were fill with purified 2-hexyl
cyanoacrylate. 500 mg of sodium bicarbonate and 250 ml of ultra
pure water were placed into a Waring blender. The lid of the
blender was adjusted so that the contents of the syringes could be
emptied dropwise into the center of blender while the blender was
stirring. With the speed of the blender set to high, each of the
syringes were emptied in a dropwise fashion into the stirring
blender. When the addition was completed, the lid of the blender
was closed and the mixture was stirred for another minute. The
solution was decanted from the blender leaving just solid material
in the blender. Residual solid material that was inadvertently
removed with the decanted solution was recovered by filtration,
washed with ultra pure water and placed back into the blender.
Solid material adhering to the inside portion of the blender was
rinsed with ultra pure water back with the rest of the solids in
the blender. An additional 250 ml of ultra pure water was added
into the blender, and the water and solid mixture was blended for 1
minute. Following the last procedure, water solution was decanted
through a large coarse fritted glass funnel filter that recovered
solid material in the solution. The solid material was washed with
methanol prior to be added back to the rest of the solid material.
The walls of the blender were rinsed with methanol to collect all
the solid material back into the blender. 250 ml of Methanol was
added to the blender. The solids were blended for one minute. The
solid material is filtered from the methanol. Any residual solid
material in the blender is washed with methanol and combined with
the solid material filtered from the methanol. The solid material
on the filter was placed under a low vacuum to remove the rest of
the methanol. The solid material was moved quantitatively to a 100
ml round bottom standard tapered flask. The flask was placed under
reduced pressure to remove the remaining methanol. 2 g of the solid
material was combined with 100 g of powdered gold. The mixture was
placed into a standard laboratory blender and blended for one
minute. The blender was agitated constantly during the blending to
ensure that the gold did not settle during the blending. 1.020 g
portions of the blended material were placed into previously
cleaned and prepared bottles. To each bottle was added 500 mg of
ethyl myristate at 99.8% purity. The filled bottles were kept under
a Laminar flow hood. The unsealed bottles were arranged in trays
for immediate ethylene oxide sterilization by Sharp Coronado
Hospital, Sterile Processing Department under standard
conditions.
Example 6
Comparison of Catheter Adhesion Force for 2-Hexyl Cyanoacrylate
(Neuracryl M) and n-Butyl Cyanoacrylate (Histoacryl)
Compositions
[0149] The present invention is also known by the name of Neuracryl
M, where Neuracryl M1 corresponds to the monomer component, and
Neuracryl M2 corresponds to the second component comprising of the
gold coated 2-hexyl acrylate. This example demonstrates differences
in adhesion between the two cyanoacrylates by measuring the amount
of force required to remove a catheter from various compositions of
Neuracryl and Histoacryl. Histoacryl is commercially available from
Braun GmbH. It is similar to Neuracryl M in that it is a polymer
composition also based on a cyanoacrylate structure, i.e., n-butyl
cyanoacrylate. However, the force required to withdraw a catheter
from Histoacryl is greater than that required for Neuracryl M, and
in this key aspect, Neuracryl M possesses a surprising and
unexpected advantage over Histoacryl.
[0150] The force resulting from catheter adhesion was determined
for Neuracryl M1 and M2 (mixed), pure Neuracryl M1, Neuracryl M1
mixed with 33% Ethiodol, Neuracryl M1 mixed with 50% Ethiodol, pure
Histoacryl, Histoacryl mixed with 33% Ethiodol, and Histoacryl
mixed with 50% Ethiodol were measured and compared.
[0151] All the mixtures were injected through a TurboTracker micro
catheter device (Medi-tech/Boston Scientific, Watertown, Ma.). All
mixtures were prepared immediately prior to use to prevent
separation of the components or contamination. The catheter tips
were placed at the bottom of 10 mm deep by 5 mm diameter wells
filled with 0.2 mL of heparinized human whole blood. Through the
micro catheter, 0.15 mL of each embolic mixture was injected into
each well, surrounding the tip of the micro catheter. Mixtures
containing Histoacryl were allowed to polymerize for 1 minute, and
those containing Neuracryl for 3 minutes. The microcatheters were
then extracted from the polymerized cyanoacrylates at a constant
speed of 8.3 mm/sec (Model 1000 Materials Testing System; Instron,
Canton, Ma.) and the forces required for extraction were measured
and recorded (Minibeam Force Transducer, 25-lb capacity; Interface
Advanced Force Measurement, Scottsdale, Ariz.). Five samples of
each mixture were tested. Comparison of the results was performed
using the Student t test.
[0152] Successful mesurements of the peak forces required for the
extraction of the catheters from the polymerized cyanoacrylates
were obtained for six of the seven mixtures tested. A wide range of
peak forces were required to extract the microcatheters from the
various mixtures. The force of extraction for the Neuracryl M1 and
50% Ethiodol mixture was less than 0.05 Newtons and beyond the
ability of the apparatus to obtain precise measurements. The peak
forces required to extract the microcatheters from either
Histoacryl mixed with 33% Ethiodol (1.44 N.+-.0.33) were
significantly higher (P<0.01; P<0.05) than those for pure
Neuracryl M1 (1.00N.+-.0.23). Histoacryl had to be mixed with 50%
Ethiodol to decrease the force of extraction (0.34N.+-.0.14) to
less than that associated with pure Neuracryl M1 (P<0.01).
[0153] When Neuracryl M1 and M2 were mixed together the force
required for micro catheter extraction (0.41N.+-.0.14) was
significantly lower than that for either pure Histoacryl (1.83
N.+-.0.21), Histoacryl mixed with 33% Ethiodol (1.44 N.+-.0.33), or
Neuracryl M1 alone (1.00 N.+-.0.23) (P<0.01; P<0.01;
P<0.01, respectively). The force required to extract
microcatheters from the Neuracryl M1 and M2 mixture was not,
however, significantly different from that of Histoacryl-mixed with
50% Ethiodol (0.41 N.+-.0.14 vs. 0.34 N.+-.0.14)
[0154] Although Neuracryl Ml was not designed to be mixed with
Ethiodol, like Histoacryl, Neuracryl M1 demonstrated markedly
decreased micro catheter adhesion when mixed with 33% and 50%
Ethiodol. The extraction force was reduced significantly from 1.00
N.+-.0.23 to 0.28 N.+-.0.12 when Neuracryl M1 was mixed with 33%
Ethiodol (P<0.01). There was no significant difference between
the peak extraction forces for Neuracryl M1 mixed with 33% Ethiodol
and Neuracryl M1 and M2 mixed was intended for clinical use. (0.28
N.+-.0.12 vs 0.41 N.+-.0.14). When Neuracryl M1 was mixed with 50%
Ethiodol, the force of extraction was less than 0.05 N and below
our limit for accurate measurement. The force was so low that,
unlike with the other mixtures, no effacement of the slight natural
curve of the catheter was observed prior to the tip of the catheter
pulling out of the cyanoacrylate.
Example 7
Comparison of 2-Hexyl Cyanoacrylate and n-Butyl Cyanoacrylate
Interaction with Blood and in an Arteriovenous Malformation
Model
[0155] The following example compares the interaction of 2-hexyl
cyanoacrylate composition of the present invention (2HCA) and a
composition of 33% n-butyl cyanoacrylate and 66% ethiodol (NBCA),
which is the clinical standard, with blood.
[0156] 2HCA was compared to NBCA in heparinized pig blood under
four conditions:
[0157] (1) a drop of each composition was placed on the surface of
blood, observed, and the polymerization process was timed.
[0158] (2) a 22 gauge needle was placed below the surface of static
blood, and 0.4 milliliter of each composition was injected and
observed over a 1 minute period;
[0159] (3) blood was circulated through a 4 millimeter I D
polyvinyl chloride tubing at 40 centimeters per second. A 22 gauge
needle inserted into the central slipstream introduced the
compositions at rates varying from 0.1 ml to 8 ml per second
powered by a Medrad mk 4 pressure injector. Behaviors were recorded
via fluoroscopy on S VHS T V;
[0160] (4) standardized arteriovenous malformation models were
placed in a circuit of pulsatile flowing blood, and the
compositions were introduced via microcatheters under direct
fluoroscopic control, using the same techniques used in humans. The
models were later opened, the polymerized compositions were removed
and their characteristics were compared. Polymer which escaped from
the models were also collected downstream and examined.
[0161] Findings:
[0162] (1) Dropping the compositions onto the surface of blood
yielded generally equal polymerization times, about 2 seconds.
[0163] (2) When injected below the surface of static blood, the
2HCA formed a rubbery elastic mass which remained at the needle's
tip. The NBCA compound fell away from the needle, to the bottom of
the beaker and polymerized to a friable mass.
[0164] (3) When injected into blood flowing at physiologic
velocities, the NBCA compound formed small, individual, nearly
spherical droplets that did not remain as a cohesive mass, but
rather broke away and embolized down stream. There was no injection
rate at which we could keep the device from embolizing away, or to
make it block the tube. Conversely, there was no rate of injection
which could prevent the 2HCA from remaining as a cohesive
polymerized mass and the tube was blocked solidly for the length of
the injection.
[0165] (4) When injected into the AVM model, the 2HCA yielded
significantly better penetration than the NBCA compound. The
character of the polymerized compositions was significantly
different: the NBCA compound made a firm yet friable mass much like
dry cottage cheese; the 2HCA mass was elastic much like chewing
gum.
[0166] In summary, the standard test of the cyanoacrylate drop on
blood yielded no predictive information. However, when the
cyanoacrylates were respectively injected below blood, strikingly
different outcomes were observed. The NBCA immediately fell away
from the needle to the bottom of the beaker, whereas the 2HCA
remained as a cohesive whole at the needle tip. There was no
introduction rate which could disrupt the cohesiveness of 2HCA;
there was no introduction rate which allowed the NBCA composition
to remain a cohesive whole. Particles of the NBCA composition
formed and continually pushed downstream. Injection of 2HCA into
standard AVM models yielded consistently better control penetration
of the nidus of the AVM.
Example 8
Preparation of n-Hexyl Cyanoacetate
[0167] The following is a scaled up procedure that can be used for
preparing manufacturing quantities of n-hexyl cyanoacrylate. This
prospective procedure is based on a smaller scale laboratory bench
top synthesis used for preparing n-hexyl cyanoacrylate, and
procedures developed employed for preparing 2-hexyl cyanoacrylate,
as were taught in the preceding examples.
[0168] Equip a 50 liter resin flask with 29/42 ground glass jointed
bulbed reflux condenser, a 100 ml Dean-Stark trap and mechanical
stirring. To the flask is added 150 moles (12,754.8.+-.10 g) of
Cyanoacetic acid, 150.5 moles (15,810.+-.10 g) of n-hexanol, ten
liter (10,000.+-.20 ml) of toluene, and 10 grams (10.+-.0.1 g) of
p-toluenesulfonic acid. The mixture is heated until homogeneous.
The heat is removed, and the mixture is allowed to stand for 4
days.
[0169] After 4 days, the mixture is heated over a period of five
hours to boiling. Water is collected and measured in the Dean-Stark
trap as it is formed. The distillation is stopped after 8 to 10
hours and allowed to sit overnight. The next day the same exact
process is repeated to get the mixture to boiling. To the mixture
is added 10.+-.0.01 g of p-toluenesulfonic acid with stirring. As
with the previous day, water is collected and measured in the
Dean-Stark trap as it is formed. The heat is removed after 8 to 10
hours and the mixture is allowed to cool overnight. The following
morning, while the mixture is stirred, 5 liters of a saturated
baking soda solution is gradually added. Tap water can be used for
preparing the saturated baking soda wash solution. The mixture is
stirred while continually added the saturated baking soda solution
until the frothing stops. The pH of the aqueous solution should be
above 9.
[0170] A filter flask configured with a vacuum attachment is used
to transfer the mixture quantitatively from the 50 liter flask into
a series of eight 6-liter separatory funnels with approximately 4
liters in each funnel. Add 1 liter of tap water to each funnel,
seal and shake vigorously several times. Allow the funnel to set in
the stand until the aqueous and organic layers separate. The water
is removed from the mixture and saved. The pH of the organic layer
is measured, if the pH is less than 8, add 500 ml of saturated
baking soda to the organic solution in the funnel, seal and shake
vigorously several times.
[0171] Another 1 liter of water was added to each funnel. The
funnel were sealed and shaken vigorously. The mixture was allowed
to settle until the aqueous and organic layers separated. The
aqueous layer was removed as before and its pH measures, and then
added to the aqueous layer saved from the previous wash. The pH
should be above 7. This procedure was repeated two more times for a
total of four times. This procedure was repeated for each
separatory funnel.
[0172] After the washes, the organic layers of each funnel is
combined in a 50 liter reaction flask equipped as Apparatus A. The
save aqueous layers from the washes are then added back to the
separatory funnels and allowed to separate again. The organic layer
from the funnels is added to the combined organic layer in
Apparatus A. The pH of the aqueous wash solution is measure, if the
pH is above 7 the solution can be disposed.
[0173] The organic solution in Apparatus A is heated to reflux.
Water from the reaction is collected and discarded. The apparatus
is reconfigured for a distillation procedure. Under vacuum and
heat, the toluene removed from the reaction solution. The toluene
that is removed will contain some amount of n-hexanol. The reaction
apparatus is re-configured for high vacuum distillation procedure.
With stirring and with pressure reduced to just under 5 Torr,
additional amounts of solvent are removed from the solution. The
pressure is further reduced to just less than 2 Torr. Using a 500
ml flask, about 300 to 400 ml of the forecut is collected. The
temperature will climb and level to about 60.degree. C. The
temperature will vary according to the actual pressure. When the
distillation temperature is constant for 10 minute, the forecut
flask is replaced with a 22.4 collection flask. The distillation is
continued under reduced pressure of about 2 Torr. When the
distillation is completed, the recovered n-hexyl cyanoacetate is
purified.
[0174] The n-hexyl cyanoacetate is placed in a 22.4 liter resin
flask with a mechanical stirrer, glass paddle, reflux column,
condenser and fraction cutter on two interlocking movable
platforms. The pressure in the apparatus is reduced, and the
material is slowly stirred with a slow gradual increase in
temperature. The gradual increase in temperature is continued until
the product has moved up the distillation column up to the point of
distillation. As distillation material is collected, about 200 ml
of the forecut is collected at a slow rate. The collection flask is
replaced with a 22.4 liter round bottom receiver into which the
distilled n-hexyl cyanoacetate is collected. The purity of the
n-hexyl cyanoacetate is determined using gas chromatography.
5 Column Description: Supelco Nukol (60 meters, 0.32 mm-column
thickness, 1.00 micron film thickness. Integrator Program: Ar Rej
1000, Peak Wd 0.20 Gas Chromatograph Program: Initial Temperature
140.degree. C. Initial Time: 20 minutes Ramp Speed: 5.degree.
C./minute Final Temperature 200.degree. C. Final Time: 52 minutes
Detector Temperature: 230.degree. C. Injector Temperature:
220.degree. C. Detector: Flame Ionization Injector Volume: 1.0
microliter with simulaneous start up.
Example 9
Preparation of n-Hexyl Cyanoacrylate
[0175] The following is a scaled up procedure that can be used for
preparing manufacturing quantities of n-hexyl cyanoacrylate. This
prospective procedure is based on a smaller scale laboratory bench
top synthesis used for preparing n-hexyl cyanoacrylate, and
procedures developed employed for preparing 2-hexyl cyanoacrylate,
as were taught in the preceding examples.
[0176] A 22.4 liter, 29/42 ground glass jointed three neck Resin
flask is equipped with a reflux condenser, Dean-stark trap, an
additional funnel and a mechanical stirrer with a glass paddle. The
following materials are added to the flask, 1,357.1.+-.1.0 g (45.2
moles) of paraformaldehyde, 12,500.+-.10 ml of methanol and 10 ml
of piperidine. A small amount methanol is used to washed into the
reaction mixture. The reaction mixture is heated with stirring to
reflux. After refluxing for one hour, the heat is removed and
7615.4.+-.1.0 g (45 moles) of n-hexyl cyanoacetate is added. The
reaction is exothermic and the rate of addition is adjusted to
maintain the reflux without flooding the condenser. The reflux is
continued for an additional 30 minutes after the completion of the
addition of n-hexyl cyanoacetate. The methanol from the reaction
flask is collected by distillation through the Dean-stark trap. The
amount of methanol collected is measured and compared with the
amount initially added to the reaction mixture, when 11,875 ml
(95%) of the methanol was collected the heat was turned off.
[0177] A 1 liter round bottom receiver is fitted to the bottom of
the distillation apparatus. The system is placed under high vacuum
with a gradual increase in heat. Additional volatile materials are
collected. Heat is removed and the apparatus is re-pressurized with
air.
[0178] While the reaction mixture is stirred, 400 g of phosphorous
pentoxide is added to it through a powder funnel. Exposure of the
phosphorous pentoxide to air should be kept to a minimum. Upon
completion of the addition, the apparatus was immediately closed to
exposure to air. The reaction mixture is stirred for 30 minute and
the pressure in the apparatus reduced to less than 10 Torr. The
reaction mixture is gradually heated until the reaction began. A
very slow flow of sulfur dioxide is introduced into the vacuum
system. As the distillation began, no forecut is collected, rather
all the materials are collected into a 2 liter receiver. This
receiver is prepared by washing it with concentrated sulfuric acid
and then three times with tap water followed with a final wash with
Ultra pure water. The flask is dried in an oven at 100.degree. C.
for one hour. Allow the flask to cool to room temperature. Add 40
drops of 85% phosphoric acid and approximately 100 mg of
hydroquinone. Place the prepared receiving flask in the
distillation apparatus while maintain the vacuum in the system.
Collect the product until the pressure cannot be maintained and the
temperature of the distillate increases by 10.degree. C. above that
for the main collection of the fraction. The distillate is analyzed
for purity by gas chromatography according to the following
conditions.
6 Instrument Description: HP5890 Gas Chromatograph with HP
Chemstation software Column Description: Supelco Nukol (60 meter,
I.D.- 0.32 mm, film thickness 1.0 micron Instrument parameters:
Method 1 Injector Temperature: 220.degree. C. Detector Temperature:
280.degree. C. Head Pressure: 15 PSI Air Pressure: 35 PSI Hydrogen
Pressure: 20 PSI Aux: 60 PSI Initial Oven Temperature: 140.degree.
C. for 20 minutes Ramp: 5.degree. C./minute Final Oven Temperature:
200.degree. C. for 50 minutes Split less system Injection Volume:
1.0 micro liters
Example 10
Purification of n-Hexyl Cyanoacrylate by Distillation
[0179] The following is a scaled up procedure that can be used for
preparing manufacturing quantities of n-hexyl cyanoacrylate. This
prospective procedure is based on a smaller scale laboratory bench
top synthesis used for preparing n-hexyl cyanoacrylate, and
procedures developed employed for preparing 2-hexyl cyanoacrylate,
as were taught in the preceding examples.
[0180] Prepare an apparatus for high vacuum distillation using
magnetic stirring, a fraction cutter, a two liter flask, a 10"
Vigreux column, a Claisen head, condenser, thermometer and a 500 ml
forecut receiving flask. About 30 mg of hydroquinone and add ti to
the forecut receiving flask. Add 25 drops of 85% phosphoric acid to
the receiving flask. Add the n-cyanoacrylate from the previous
example to the distillation flask. The pressure of system is
reduced to less than 2 Torr.
[0181] Begin heating the stirring pot and adjust the heating so
that the rate of the distillation is controlled to about 2 to 3
drops per minute. Collect about 250 ml of the material in the
forecut flask. Add approximately 25 drops of 85% phosphoric acid
and approximately 25 mg of hydroquinone to an acid washed 3 liter
receiving flask. A small amount of the hydroquinone and 85%
phosphoric acid is left in the receiving flask to avoid
polymerization of the distillate. The receiver is attached to the
distillation apparatus without losing vacuum. The distillation is
continued. The main fraction is collected at a rate of about 1
drop/second. When the distillation head temperature has risen
2.degree. C. above that used to collect the main fraction, the
distillation is discontinued by shutting off the heat and allowing
dry air to be filtered through a drying tube into the high vacuum
of the system. This phase of the distillation should require 4 to 6
hours to complete.
[0182] The product placed into a 5 liter socket jointed flask with
a magnetic stirring bar. The flask is fitted onto spinning band
column. A heating mantle is supported on a magnetic stirrer that is
raised and lowered with a laboratory jack to fit to the column. A
250 ml receiving flask is prepared for the spinning band column by
adding about 15 mg of hydroquinone and 20 drops of 85% phosphoric
acid. All joints of the spinning band column are greased with high
vacuum grease to assure a good vacuum seal. When assembled, insert
the glass temperature probe into the 10/15 joint of the flask and
insert the metal Tempora probe into the glass probe. Grease the
29/42 joint, containing the stopcock, into the flask and connect
the sulfur dioxide gas line. The system is carefully placed under
high vacuum to less than 0.5 Torr. The distillation on the spinning
band is carried out according to the following conditions.
[0183] a. To begin the distillation, start the water cooler and
adjust the cooling temperature to 15.degree. C. Set the micro
processor as follows to set up the memory for data input.
7 1) System On "Select a Command Key" 2) Press modify "Enter access
code" 3) 0000 "Enter" 4) Modify Run "Select 10-19 (2)" 5) Modify
Run "then to 14" Program 1) Enter name or number of run: 2) Enter
mantle rate: 25 volts 3) Enter motor on temperature: 24.degree. C.
4) Enter equilibration time: 2 minutes 5) Open temperature:
28.degree. C. 6) Close temperature: 90.degree. C. 7) Enter mantle
rate: 24.degree. C. 8) Enter reflux rate: 20 to 1 9) Enter pot
temperature to end run: 90.degree. C.
[0184] A small flow of sulfur dioxide is leaked into the system.
The leak is detected and controlled with the gas flow gauge, but it
must be so small that the pressure of the system is not effected.
The microprocessor is set to run the procedure. About 1 hour is
required for the system to warm enough to heat the top of the
distillation head. At the point of equilibration, when the head
temperature is reading about 15 to 20.degree. C. more than the pot,
the cutting procedure begins after the equilibration is reached in
about 10 minutes more. About 250.+-.10 ml of the distillate is
collected. The pot temperature should not be allowed to exceed
100.degree. C. When the pressure reading is 1 Torr, the temperature
of the distillation will be 57 to 58.degree. C. The spinning band
apparatus is allowed to cooled down (about 30 minutes). A 2 liter
round-bottom flask, 24-40 ground glass jointed flask is acid
washed, and is configured for high vacuum distillation. The flask
is set up for magnetic stirring and equipped with a fraction
cutter, a 10" Vigreux column, condenser, Claisen head and
thermometer, all which have been acid washed. The residue remaining
in the pot of the spinning band apparatus is poured into the 2
liter flask of the vacuum distillation apparatus. About 25 mg of
hydroquinone and 25 drops of 85% phosphoric acid is added into the
flask containing the residue. The pressure of the vacuum
distillation apparatus is reduced to less than 1 Torr, and the
residue is stirred. A small leak of sulfur dioxide is injected into
the main pot as the distillation continues. The forecut receiver is
prepared by adding approximately 10 mg of hydroquinone and 20 drops
of 85% phosphoric acid. The forecut receiver is attached to the
vacuum distillation and 75 ml of forecut is collected at a rate of
2 to 3 drops/minute. The main cut receiver is prepared by adding 5
to 15 mg of hydroquinone, 5 to 15 mg of p-methoxyphenol and 30 to
80 mg of pure crystalline phosphoric acid into a 2-liter round
bottom receiving flask. The main receiver is attached to the vacuum
distillation system without breaking the vacuum of the overall
system. The total distillation will require 4 to 5 hours to
complete. The distillation product, n-hexyl cyanoacrylate is
analyzed for purity by gas chromatography. Ten grams of the n-hexyl
cyanoacrylate is placed into a small weighing bottle. To this
sample is added 1 drop of 1-hexanol. The net weight gained after
each addition to the weighing bottle is noted so that the PPM of
1-hexanol in the chromatographic sample can be determined. The gas
chromatograph instrument conditions are as follows:
8 Instrument Description: HP 5890 Gas Chromatograph with HP
Chemstation Software Column Description: Supelco Nukol (60 meter,
I.D.- 0.32 mm, film thickness 1 micron Instrument Parameters:
Method 1 Injector Temperature: 220.degree. C. Detector Temperature:
280.degree. C. Head Pressure: 15 PSI Air Pressure: 35 PSI Hydrogen
Pressure: 40 PSI Aux: 60 PSI Initial Oven Temperature: 140.degree.
C. for 20 minutes Ramp: 5.degree. C./minute Final Oven Temperature:
200.degree. C. for 50 minutes A Splitless System Injection Volume:
1.0 micro liter
[0185] If the distillate is insufficiently pure, the spinning band
and vacuum distillation procedures are repeated.
Example 11
Purification of n-Hexyl Cyanoacrylate by Zone Melting
[0186] The following is a scaled up procedure that can be used for
purifying manufacturing quantities of n-hexyl cyanoacrylate.
[0187] In a controlled temperature area, an exchange apparatus is
attached to a flask containing the n-hexyl cyanoacrylate to be
purified with the reserve flask attached to the other end of the
exchange apparatus. The pressure in the assembly is lowered to less
than 1 Torr. The temperature is maintained at -18.+-.0.5.degree. C.
The assembly is allowed to equilibrate to the temperature for 24
hours. After 24 hours, touch or shake the n-hexyl cyanoacrylate
gently, if it does not crystallize, repeat the procedure every 15
minutes for 1 hour. If the solution does not crystallize after 1
hour, take a small piece of dry ice and touch it to the side of the
flask for 30 seconds. Once the crystallization begins, raise the
temperature of the environment to -16.5.+-.0.5.degree. C. Allow the
solution to sit undisturbed for 48 hours, while the crystallization
goes to completion.
[0188] Reverse the position of the apparatus so that the liquid
from the crystallization runs into the reserve flask. This should
take 30 minutes to complete the draining. Keep the assembly in the
controlled environment while the draining is being completed. The
stopcock between the main flask and the reserve flask is closed to
isolate the crystals. Allow air into the assembly on the side of
the liquid through a drying tube and remove the liquid from the
assembly. Allow air into the assembly through a drying tube. The
assembly with the crystals are placed on the bench top and allowed
to warm to room temperature and melt. The melted crystals are
analyzed for purity. The purification procedure removed all of the
inhibitors. The melted crystals are weighed to determine the amount
of inhibitors to add. From the weight of the n-hexyl cyanoacrylate,
the amount of the inhibitors that is added is determined according
to these proportions relative to the amount of n-hexyl
cyanoacrylate present, 100 PPM of hydroquinone, 100 PPM of
p-methoxyphenol and 200 PPM of acetic acid.
[0189] The zone melting process is repeated a second time as
follows. In a controlled temperature area, an exchange apparatus is
attached on a flask containing the n-hexyl cyanoacrylate to be
purified with the reserve flask attached to the other end of the
exchange apparatus. The pressure in the assembly is lowered to less
than 1 Torr. The temperature is maintained at -17.+-.0.5.degree. C.
The assembly is allowed to equilibrate to the temperature for 24
hours. After 24 hours, touch or shake the n-hexyl cyanoacrylate
gently, if it does not crystallize, repeat the procedure every 15
minutes for 1 hour. If the solution does not crystallize after 1
hour, take a small piece of dry ice and touch it to the side of the
flask for 30 seconds. Once the crystallization begins, raise the
temperature of the environment to -16.5.+-.0.5.degree. C. Allow the
solution to sit undisturbed for 48 hours, while the crystallization
goes to completion.
[0190] Reverse the position of the assembly so that the liquid from
the crystallization runs into the reserve flask. This should take
30 minutes to complete the draining. Keep the assembly in the
controlled environment while the draining is being completed. The
stopcock between the main flask and the reserve flask is closed to
isolate the crystals. Allow air into the assembly on the side of
the liquid through a drying tube and remove the liquid from the
assembly. Allow air into the assembly through a drying tube. The
assembly with the crystals are placed on the bench top and allowed
to warm to room temperature and melt. The melted crystals are
analyzed for purity. The purification procedure removed all of the
inhibitors. The melted crystals are weighed to determine the amount
of inhibitors to add to the crystals. From the weight of the
n-hexyl cyanoacrylate, the amount of the inhibitors that is added
is determined according to these proportions relative to the amount
of n-hexyl cyanoacrylate present, 100 PPM of hydroquinone, 100 PPM
of p-methoxyphenol and 200 PPM of acetic acid.
Example 12
Preparation of Methyl Cyanoacrylate
[0191] The following is a scaled up procedure that can be used for
preparing manufacturing quantities of n-hexyl cyanoacrylate. This
prospective procedure is based on a smaller scale laboratory bench
top synthesis used for preparing n-hexyl cyanoacrylate, and
procedures developed employed for preparing 2-hexyl cyanoacrylate,
as were taught in the preceding examples.
[0192] Equip a 5 liter three-necked flask with a reflux condenser,
Dean-Stark trap, an addition funnel and a mechanical stirrer with a
glass paddle in a 5 liter heating mantle. To the flask is added the
following ingredients, 136.0.+-.1.0 g (4.56 moles) of powdered
paraformaldehyde, 136.0.+-.1.0 g (4.56 moles) of prills of
paraformaldehyde and 2,500.+-.5 ml of methanol. The reaction
mixture is stirred and heated to reflux. The reflux is continued
until the solution becomes clear. Add 3 ml of piperidine to the
refluxing mixture and wash into the reaction mixture with methanol
from the reaction. Begin adding drop wise 9.1 g of methyl
cyanoacetate. Turn down the heat to the reaction flask. The
reaction is exothermic and the rate of addition should be adjusted
to keep the reaction mixture at reflux temperature. The addition
will take 45 minutes to one hour and will be more rapid near
completion to the reaction. After completion of the addition,
continue to reflux for 30 minutes. Collect the methanol distilled
from the reaction flask through the Dean-Stark trap. Measure the
amount recovered. Continue the reaction until 95% or more of the
original volume of methanol is recovered.
[0193] The residues are collected in a 500 ml round bottom 24/40
ground glass jointed flask on the vacuum apparatus to collect the
residues. The apparatus is placed under reduced pressure to
continue to remove volatile materials. The procedure is continued
until all water and organic condensate is removed from the mixture.
The pressure is gradually reduced further until the pressure is
less than 10 Torr. Heat is applied until hot to the touch, or all
the solvent is removed. The heat is removed and the solution is
allowed to cool. Add 25 to 30 g of phosphorous pentoxide through a
powder funnel into the distillation flask. After completion of the
addition of phosphorous pentoxide, close the apparatus at once in
order to minimize the exposure of the phosphorous pentoxide to air.
The heat is turned off and the mixture is allowed to stir for one
hour. After one hour, the apparatus is flooded with sulfur
dioxide.
[0194] The pressure in the apparatus is reduced to less than 10
Torr, and heat is slowly applied. The system is flooded with sulfur
dioxide and the stirring is maintained.
[0195] A 1 liter flask is prepared as a receiver by acid washing.
Add 10 drops of 85% phosphoric acid and approximately 25 to 50 mg
of hydroquinone. This receiver flask is attached to the
distillation apparatus without breaking vacuum. Heat and stir the
hot cracking reaction until distillation begins. Collect 800 to
1200 g of product. The crack reaction will require about 3 to 4
hours. Discontinue the distillation of the product when the
temperature begins to rise past 110.degree. C.
[0196] The purity of the methyl cyanoacrylate is determined by gas
chromatography under the following conditions.
9 Instrument Description: HP 5890 Gas Chromatograph with HP
Chemstation Software Column Description: Supelco Nukol (60 meter,
I.D.- 0.32 mm, film thickness 1 micron Instrument Parameters:
Method 1 Injector Temperature: 220.degree. C. Detector Temperature:
280.degree. C. Head Pressure: 15 PSI Air Pressure: 35 PSI Hydrogen
Pressure: 40 PSI Aux: 60 PSI Initial Oven Temperature: 140.degree.
C. for 20 minutes Ramp: 5.degree. C./minute Final Oven Temperature:
200.degree. C. for 50 minutes A Splitless System Injection Volume:
1.0 micro liter
Example 13
Purification of Methyl Cyanoacrylate by Zone Melting
[0197] The following is a scaled up procedure that can be used for
purifying manufacturing quantities of methyl cyanoacrylate.
[0198] In a controlled temperature area, an exchange apparatus is
placed on a flask containing the methyl cyanoacrylate to be
purified with the reserve flask attached to the other end of the
exchange apparatus. The pressure in the assembly is lowered to less
than 1 Torr. The temperature is maintained at 3 to 5.degree. C. The
assembly is allowed to equilibrate to the temperature for 24 hours.
After 24 hours, touch or shake the methyl cyanoacrylate gently, if
it does not crystallize, repeat the procedure every 15 minutes for
1 hour. If the solution does not crystallize after 1 hour, take a
small piece of dry ice and touch it to the side of the flask for a
few seconds. Once the crystallization begin, allow the solution to
sit undisturbed for 24 hours, while the crystallization goes to
completion.
[0199] Reverse the position of the assembly so that the liquid from
the crystallization runs into the reserve flask. This should take
about 15 minutes to complete the draining. Keep the assembly in the
controlled environment while the draining is being completed. The
stopcock between the main flask and the reserve flask is closed to
isolate the crystals. Allow air into the assembly on the side of
the liquid through a drying tube and remove the liquid from the
assembly. Allow air into the remainder of the assembly through a
drying tube. The assembly with the crystals are placed on the bench
top and allowed to warm to room temperature and melt. The melted
crystals are analyzed for purity. The weight of the melted crystals
is taken to determine the amount of inhibitors to add to the
crystals. The purification procedure removes all of the inhibitors
and the inhibitors are needed to maintain the stability of the
methyl cyanoacrylate. From the weigh of the methyl cyanoacrylate,
the amount of the inhibitors to added is determined according to
the following portions relative to the amount of methyl
cyanoacrylate, 100 PPM of hydroquinone, 100 PPM of p-methoxyphenol
and 200 PPM of acetic acid.
[0200] The zone melting process is repeated a second time as
follows. In a controlled temperature area, an exchange apparatus is
placed on a flask containing the methyl cyanoacrylate to be
purified. The pressure in the overall assembly is lowered to less
than 1 Torr. The temperature is maintained at 3 to 5.degree. C. The
apparatus is allowed to equilibrate to the temperature for 24
hours. After 24 hours, touch or shake the methyl cyanoacrylate
gently, if it does not crystallize, repeat the procedure every 15
minutes for 1 hour. If the solution does not crystallize after 1
hour, take a small piece of dry ice and touch it to the side of the
flask for 30 seconds. Once the crystallization begins allow the
solution to sit undisturbed for 24 hours, while the crystallization
goes to completion.
[0201] Reverse the position of the apparatus so that the liquid
from the crystallization runs into the reserve flask. This should
take 5 to 10 minutes to complete the draining. Keep the assembly in
the controlled environment while the draining is being completed.
The stopcock between the main flask and the reserve flask is closed
to isolate the crystals. Allow air into the assembly on the side of
the liquid through a drying tube and remove the liquid from the
apparatus. Allow air into the assembly through a drying tube. The
assembly with the crystals are placed on the bench top and allowed
to warm to room temperature and melt. The melted crystals are
analyzed for purity. The purification procedure removed all of the
inhibitors. The weight of the melted crystals is taken to determine
the amount of inhibitors to add to the crystal. From the weigh of
the n-hexyl cyanoacrylate, the amount of the inhibitors is
calculated as such, 100 PPM of hydroquinone, 100 PPM of
p-methoxyphenol and 200 PPM of acetic acid.
Example 14
Formulation of a Monomer Component with n-Hexyl Cyanoacrylate
[0202] The following is a scaled up procedure that can be used for
preparing manufacturing quantities of Polymer A, also known as,
Neuracryl A. This prospective procedure is based on a smaller scale
laboratory bench top synthesis used for preparing the monomer
component, and procedures developed employed for preparing Polymer
M, also known as Neuracryl M, as were taught in the preceding
examples.
[0203] A. A monomer component with n-hexyl cyanoacrylate is
formulated with the following materials, n-hexyl cyanoacrylate,
hydroquinone, p-methoxyphenol and glacial acetic acid. The
hydroquinone and p-methoxyphenol are kept under reduced pressure in
a desiccator over a drying agent. The glacial acetic acid is taken
up in a syringe and the syringe and the inhibitor is weighed, an
amount of glacial acetic acid is added, and the syringe with the
glacial acetic acid is re-weigh to determine the amount of glacial
acetic acid that had been added. This process is repeated until the
desired amount of glacial acetic acid is added.
[0204] The monomer component is analyzed by gas chromatography for
purity under the following conditions.
10 Instrument Description: HP5890 Gas Chromatograph with HP
chemstation software. Column Description: Supelco Nukol (60 meters
length, I.D., 0.32 mm, Film Thickness 1 micron) Instrument
Parameters: Method 1 Injector Temperature.: 220.degree. C. Detector
Temperature: 280.degree. C. Head Pressure: 15 PSI Air Pressure: 35
PSI Hydrogen Pressure: 40 PSI Aux.: 60 PSI Initial Oven
Temperature: 140.degree. C. for 20 min. Ramp: 5.degree. C./min.
Final Oven Temperature: 200.degree. C. for 50 min. A Splitless
System: 1.0 microliter Injection Volume:
[0205] The component is sufficient pure if the combined impurities
present totals to less than 1%.
[0206] B. Following the procedures taught in Part A of the present
Example, a monomer component with a combination of methyl
cyanoacrylate and n-hexyl cyanoacrylate can be made.
[0207] In place of the amount of n-hexyl cyanoacrylate called for
in the above procedure, a combination of methyl cyanoacrylate and
n-hexyl cyanoacrylate is use. The amounts of each material used is
determined according to the following ratio:
moles of methyl cyanoacrylate=0.111.times.moles n-hexyl
cyanoacrylate
Example 15
The Behavior of Neuracryl M in the Pig Rete
[0208] This example compares the intravascular behavior of
Neuracryl M to the current clinical standard, n-butyl cyanoacrylate
40% in the rete of the pig.
[0209] Methods and Materials
[0210] Neuracryl M is available from Prohold Technologies, El
Cajon, Calif. Neuracryl M is a two-part embolization agent
consisting of a glass ampule of 1.25 ml Neuracryl M1 and a
rubber-stoppered glass vial of Neuracryl M2 (a mixture of 2-hexyl
cyanoacrylate, an esterified fatty acid, and gold particles
measuring approximately 5 .mu.m in diameter. Prior to use, the
contents of the Neuracryl M1 vial are injected into the vial
containing Neuracryl M2, and the two are shaken together thoroughly
until mixed. The gold particles and esterified fatty acid are used
to retard polymerization and provide radiopacity. To avoid
separation of the components or contamination, the two moieties
were not mixed until immediately before use. NBCA (Histacryl Blue)
was obtained from B. Braun, Melsungen, Germany, and mixed with
Ethiodol to form a 40% solution.
[0211] Nine barnyard pigs were placed under general anesthesia.
Using sterile technique a catheter was placed in the right femoral
artery and a guiding catheter in the left common artery. A
microcatheter was introduced into the region of the rete, through
which the entire cerebral blood passes.
[0212] With the pigs under general endotracheal anesthesia, using
sterile technique, the right femoral artery was catheteried and a
guiding catheter was placed into the left common carotid artery of
nine pigs. A microcatheter was introduced into the region of the
rete, and 0.1 to 0.3 of NBCA (n-butyl cyanoacrylate) or Neuracryl M
was infused without flow arrest. After follow-up angiography, the
opposite carotid and pharyngeal arteries were catheterized, and the
alternative agent was infused. One pig was sacrificed immediately,
six were sacrificed at 3 weeks, and two were sacrificed at 3
months.
[0213] Results
[0214] One pig was sacrificed immediately due to clinical
infarction. Distal embolization of NBCA was found to be the
cause.
[0215] In one pig (sacrificed immediately because of clinical
infarction), distal embolization of the NBCA was found. In the
other pigs, penetration of the embolic agent into the rete was
graded as follows, 0, no penetration; 1, penetration of 25% or
less; 2, 25-50% penetration; 3, 50-75% penetration; and 4, 75-100%
penetration.
[0216] Summary of the Results
11 Penetration Catheter Embolization Material mean Trapped Distal
to Rete Neuracryl M 3.7 0/9 0/9 NBCA 1.8 4/9 2/9 (one death)
[0217] Neuracryl M had a mean penetration grade of 3.7, compared to
1.8 for NBCA. Trapping of the catheter by the glue mass occurred in
four of nine pigs with NBCA, whereas there were no occurrences in
the pigs treated with Neuracryl M. Embolization occurring distal to
the rete occur-red in two pigs infused with NBCA, with one
resultant death. There were no occurrences of embolization
occurring distal to the rete in pigs infused with Neuracryl M.
12 Giant Material Intraluminal Mural Perivascular Interstitial
Cells Inflammation at 3 weeks (6 pigs) Neuracryl M 1.9 2.2 2.0 1.0
5/7 NBCA 0.6 0.8 0.8 0.2 2/7 Inflammation at 3 months (2 pigs)
Neuracryl M 3.0 3.0 3.0 0.3 2/2 NBCA 1.5 1.5 1.5 0.3 2/2
[0218] An initial inflammatory response is the essential initiator
of the healing process, and leads to fibroblastic ingrowth. If the
inflammatory response is excessive, pus is produced. Too little
response, and no scar, or only temporary occlusion occurs. The
Neuracryl M yielded a consistently greater inflammatory response
than the present clinical standard, NBCA.
[0219] Conclusion
[0220] Neuracryl M compares favorably with NBCA, showing greater
penetration into the rete of the pig while being less likely to
cause catheter trapping or distal embolization.
Example 16
Comparison of Cyanoacrylate Compositions for Conformal Endovascular
Obliteration Utility
[0221] The endovascular treatment of cerebral berry aneurysms has
improved over the last decade, but aneurysms with wide necks or
having shapes other than spherical remain technically challenging.
An ideal device would, when delivered, conform exactly to the
aneurysm lumen, stay together as a cohesive whole, reestablish the
contours of the parent vessel, and be permanent. We report initial
experiments modifying cyanoacrylate monomers to develop such a
device.
[0222] Methods and Materials
[0223] Transparent silicone models of aneurysms representing both
narrow and wide neck configurations were constructed. Model A
consisted of a straight 4 mm tube with three 7 mm aneurysms
attached. The neck diameter was 3 mm. Model B consisted of a
helical 4 mm tubing containing four aneurysms positioned along the
greater curvature. Two were 5 mm in diameter (1 having a 2 mm neck,
and the other having a 4 mm neck), and two were 9 mm in diameter (1
having a 3 mm neck, and the other a three by 5 mm neck). The
helical model ended in a bifurcation, a 4 mm wide neck aneurysm was
positioned at the bifurcation to simulate a basiler tip
aneurysm.
[0224] Twelve compounded cyanoacrylates were tested, six based upon
the 2-hexyl cyanoacrylate monomer, six based upon the 1-hexyl
cyanoacrylate monomer. Additives consisted of various oils, gold
for opacification, and polymerization retardants. The silicone
aneurysms were filled with heparinized pig blood, and were injected
with microcatheters under direct visualization during static
conditions, and under fluoroscopic guidance during pulsatile flow
conditions.
[0225] Model A was filled with heparinized pig blood, and each of
the twelve compounds was injected into three aneurysms, directly
visualizing the degree of filing. The models were then
radiographed, opened, and the contents examined by microscopy.
[0226] Model B was perfused with heparinized pig blood, pulsatile
flow, 40 centimeters per second. The mixtures were introduced via
micro-catheters; injection was controlled with fluoroscopic
visualization.
[0227] Results
[0228] All twelve mixtures remained cohesive and conformed nicely
to the outline of the aneurysm. Many of the mixtures based upon the
2-hexyl monomer exhibited delayed polymerization,and could not be
kept witin the aneurysm lumen, even with adjacent balloon control
of the infusion process. Four of the mixtures based upon the
1-hexyl monomer gave good cohesion, good conformation, remained
within the aneurysm, and allowed some degree of angioplasty and
remodeling of the arterial lumen by silicone balloon.
[0229] Conclusion
[0230] Several of the cyanoacrylate mixtures show promise as a
liquid embolic agent to treat berry aneurysms by direct injection
through microcatheters.
Example 17
Clinical Trial Comparing Neuracryl M to PVA Foam
[0231] This example reports the results of a randomized clinical
trial with 12 patients comparing Neuracryl M and PVA Foam.
[0232] Materials and Methods
[0233] The procedure for the clinical study was conducted under the
purview of the FDA and within approved institutional guidelines.
Twelve pre-surgical patients satisfied the criteria to enter the
study. After angiographic evaluation and randomization (75 percent
to Neuracryl M/25 percent to PVA form according to the FDA
recognized standard). Ten patients were treated using standard
micro-catheter technique with Neuracryl M; and two were treated
with PVA. Patients were subsequently operated upon, and any
residual nidus was removed. The angiograms were analyzed by three
independent observers who compared the area of the nidus both
before and after treatment in both AP and lateral planes.
[0234] Results
[0235] No patient's condition worsened clinically. Of the two who
randomized to PVA, one showed an 81 percent reduction in nidus
size; the second had no significant change in nidus size. Of the
ten who randomized to Neuracryl M, 5 were angiographically
obliterated (using measurement criteria submitted to the FDA), 2
had nidus size reduction between 50 and 99 percent, 2 were
obliterated less than 50 percent, and one nidus was judged to have
actually enlarged by 25 percent. No catheter was glued in
place.
[0236] Conclusion
[0237] Neuracryl M provides a better angiographic obliteration rate
than the historical standard, PVA form particles, and a better
obliteration rate than the literature reports of patients treated
with Histoaryl. In the patient whose AVM appeared to enlarge, the
Neuracryl M slowed flow through the lesion sufficiently to make it
more conspicuous and thus easier to measure.
Example 18
Initial Neuropathologic Observation after Treatment of a Human
Arteriovenous Malformation with Neuracryl M
[0238] This example reports the treatment of a 34 year old male
presented after acute hemorrhage of a right parieto-occipital
arteriovenous malformation (AVM). The pathologic features of the
AVM after embolization with Neuracryl M.
[0239] Materials and Methods
[0240] Transcatheter embolization was performed on post-bleed day
21 using a novel, proprietary cyanoacrylate-based compound,
Neuracryl M. Four days after embolization, the patient underwent
surgical resection.
[0241] Results
[0242] Scattered foci of Neuracryl M completely contained within
vessels were observed. Embolic material formed a lamellar,
spongiform configuration, was non-polarizable, and stained
moderately eosinophilic with hematoxylin and eosin. A profound
acute inflammatory response was seen surround many of the AVM
vessels, including frank necrosis and giant cell foreign body
reaction.
[0243] Conclusion
[0244] Neuracryl M was an effective embolic agent which was
retained within vessel lumina and initiated a marked localized
inflammatory reaction by 4 days. This report represents the initial
pathologic observations of Neuracryl M in the first human subject
treated. As further specimens are obtained, a more complete
description of the behavior of Neuracryl M in the human brain will
emerge.
* * * * *