U.S. patent application number 10/077852 was filed with the patent office on 2003-08-21 for method for curing cyanoacrylate adhesives.
Invention is credited to Azevedo, Max.
Application Number | 20030158579 10/077852 |
Document ID | / |
Family ID | 27732732 |
Filed Date | 2003-08-21 |
United States Patent
Application |
20030158579 |
Kind Code |
A1 |
Azevedo, Max |
August 21, 2003 |
Method for curing cyanoacrylate adhesives
Abstract
A new adhesive method using an adhesive composition including
cyanoacrylate adhesive and a stabilizing agent to join together
portions of a substrate, particularly useful in suturing and
similar medical procedures, is disclosed. It is based on the
discovery that remarkable improvements are obtained by adding a
step of removing stabilizing agent from such adhesive compositions
in the manufacturing process with the prior known steps of (a)
providing an adhesive composition including cyanoacrylate adhesive
and a stabilizing agent, (b) presenting a substrate to receive at
least a portion of such cyanoacrylate adhesive and (c) applying
such portion to the substrate. Devices for use in performing the
method are described.
Inventors: |
Azevedo, Max; (Lenoir,
NC) |
Correspondence
Address: |
Howard N. Flaxman
WELSH & FLAXMAN LLC
Suite 112
2341 Jefferson Davis Hwy.
Arlington
VA
22202
US
|
Family ID: |
27732732 |
Appl. No.: |
10/077852 |
Filed: |
February 20, 2002 |
Current U.S.
Class: |
606/214 |
Current CPC
Class: |
C09J 4/00 20130101; C09J
4/00 20130101; C08F 222/326 20200201 |
Class at
Publication: |
606/214 |
International
Class: |
A61D 001/00 |
Claims
I claim:
1. A method for the fabrication of a cyanoacrylate adhesive so as
to minimize the presence of contaminants and extraneous additives
in the resulting cured adhesives and enhancing the cure speed of
stabilized cyanoacrylate adhesive by a treatment that removes
excessive stabilizers prior to application onto a substrate, the
method comprising the steps of (a) providing a stable adhesive
composition comprising cyanoacrylate adhesive and a stabilizing
agent to produce a cyanoacrylate adhesive composition, (b)
presenting a substrate to receive at least a portion of the
cyanoacrylate adhesive composition and (c) applying the
cyanoacrylate adhesive composition to the substrate, the
improvement comprising the step of removing stabilizing agent from
the cyanoacrylate adhesive composition prior to the step of
applying.
2. The method according to claim 1, wherein the cyanoacrylate
adhesive comprises one or more monomers having the general
structure.CH2.dbd.C(CN)- --C(O)--R.
3. The method according to claim 2, wherein "R" is selected from
the group consisting of octyl, decyl, dodecyl, and tridecyl.
4. The method according to claim 2, wherein the cyanoacrylate
adhesive comprises a difunctional cyanoacrylate.
5. The method according to claim 1, wherein the step of removing
stabilizing agent from the cyanoacrylate adhesive composition
comprises contacting the cyanoacrylate composition with a
particulate agent.
6. The method according to claim 5, wherein the particulate agent
is selected from the group consisting of vinyl pyrrolidone and
copolymers of pyrrolidone.
7. The method according to claim 5, wherein the particulate agent
is selected from the group consisting of polymeric materials having
carbonyl, hydroxyl, amide, carboxylic, amine, ether, anhydride,
ester, urethane or sulfone structures, silicates anhydride
structures and activated carbon.
8. The method according to claim 1, wherein the substrate is tissue
required to be sutured or sealed, or otherwise protected from its
surroundings.
9. The method according to claim 1, wherein the step of removing
excess stabilizing agent is chosen from the group of mechanisms
consisting of physical adsorption/absorption, chemical reaction,
and hydrogen bonding of acid groups.
10. A method for the fabrication of a cyanoacrylate adhesive so as
to minimize the presence of contaminants and extraneous additives
in the resulting cured adhesives and enhancing the cure speed of
stabilized cyanoacrylate adhesive by a treatment that removes
excessive stabilizers prior to application onto a substrate, the
method comprising the following steps: providing stable adhesive
composition comprising cyanoacrylate adhesive and a stabilizing
agent to produce a cyanoacrylate adhesive composition; removing
stabilizing agent from the cyanoacrylate adhesive composition;
presenting a substrate to receive at least a portion of the
cyanoacrylate adhesive composition; and applying the cyanoacrylate
adhesive composition to the substrate.
11. The method according to claim 10, wherein the cyanoacrylate
adhesive comprises one or more monomers having the general
structure.CH2.dbd.C(CN)- --C(O)--R.
12. The method according to claim 11, wherein "R" is selected from
the group consisting of octyl, decyl, dodecyl, and tridecyl.
13. The method according to claim 11, wherein the cyanoacrylate
adhesive comprises a difunctional cyanoacrylate.
14. The method according to claim 10, wherein the step of removing
stabilizing agent from the cyanoacrylate adhesive composition
comprises contacting the cyanoacrylate composition with a
particulate agent.
15. The method according to claim 14, wherein the particulate agent
is selected from the group consisting of vinyl pyrrolidone and
copolymers of pyrrolidone.
16. The method according to claim 14, wherein the particulate agent
is selected from the group consisting of polymeric materials having
carbonyl, hydroxyl, amide, carboxylic, amine, ether, anhydride,
ester, urethane or sulfone structures, silicates anhydride
structures and activated carbon.
17. The method according to claim 10, wherein the substrate is
tissue required to be sutured or sealed, or otherwise protected
from its surroundings.
18. The method according to claim 10, wherein the step of removing
excess stabilizing agent is chosen from the group of mechanisms
consisting of physical adsorption/absorption, chemical reaction,
and hydrogen bonding of acid groups.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application relates to U.S. patent application Ser. No.
09/982,226, filed Oct. 19, 2001, which is currently pending.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates broadly to a method of treating
stabilized cyanoacrylate adhesives prior to their application to a
substrate, particularly with reference to medical procedures using
such adhesives.
[0004] 2. Description of the Prior Art
[0005] Medical interest in cyanoacrylate polymers has been apparent
since at least the mid-nineteen sixties as evidenced by numerous
reports on its use as a tissue bonding agent. Collins et al.
reported on the effectiveness of homologous chain cyanoacrylates
for bonding of biological substrates. J. A. Collins, et al., ARCH.
SURG. Vol. 93, 428 September 1966; F. Leonard et al., J.A.P.S. Vol.
101617, 1966. Both articles report the observation of high rates of
polymerization with longer chain esters than with the methyl or
ethyl monomers. There appeared to be more biocompatability with the
longer chains as noted by the ease of spreading monomer films on
bio-substrates. This contrasted with in vitro polymerizations where
the lower homologues reacted much faster. There was particular
interest in the degradation of these polymers as they related to
possible harmful effects that would preclude their use in
surgery.
[0006] Woodward et al. reported histotoxicity of these monomers in
rat tissue. S. C. Woodward, et al., ANN. SURG. Vol. 162, July 1965.
The study involved in situ polymerization of three cyanoacrylate
monomers: methyl, hexyl, decyl. It was reported that histotoxic
effects were greatest with methyl and decreased with the other two
monomers.
[0007] The same group reported on the use of radioactive methyl
cyanoacrylate for monitoring routes for the loss of the polymer. J.
J. Cameron et al., SURGERY, Vol. 58, August 1965; C. H. McKeever,
U.S. Pat. No. 2,912,454, Nov. 10, 1950. Results indicated that the
polymer was degraded and excreted principally through the urine and
feces. Analysis of the animal's organs revealed no signs of
radioactivity. This implied no degradation products were
incorporated into any of the animal's metabolic pathways. By
analogy to poly-vinylidene cyanide, they noted that the
cyanoacrylate polymer degraded in the presence of water and more so
in the presence of bases. The first observed degradation product
turned out to be one of the starting materials, i.e., formaldehyde.
In vitro studies have shown that the polymers degrade via
hydrolytic scission in homogeneous as well as heterogeneous
conditions. F. Leonard et al., J.A.P.S., Vol. 10: 259, 1966. These
degradation products were confirmed to be formaldehyde and the
corresponding cyanoacetate. The conditions of solution degradation
affected the consequent rates, namely, under neutral conditions
rates decreased as the homologous series was ascended while
alkaline conditions increased all rates.
[0008] The same study reported that the hydroxyl group was evident
in the polymer as the initiating species. This was concluded from
infrared spectral data that displayed hydroxyl group absorption at
3600 cm(-1). Further support for this is the noted suppression of
the OH as water is replaced with methanol and the observed methoxy
absorption at 1100 cm(-1). Preferential initiation was shown to
occur with NH.sub.2 containing substances such as pyridine,
cysteine, alanine, and glycine in aqueous solutions. This suggested
that in vivo adhesion was more than a mechanical interlocking of
the solid polymer with the tissue. This appears to be the case as
it was noted that typical polymer solvents were not effective in
solvating tissue-bound polymer. From this it appears that in vivo
studies of degradation do not necessarily correspond to in vitro
conditions. Part of the degradation mechanism relies on the
conditions of the polymer for hydrolytic scission. The chemical
bonding of the polymer excludes this surface from hydrolytic
activity. A mechanism of degradation was proposed that suggests an
action similar to unzipping in acrylics, however, the difference
being that the monomer is not regenerated. The proposed mechanism
necessitates the presence of the hydroxyl as well as the presence
of water.
[0009] An unusual effect was reported regarding the aqueous
degradation of isobutyl cyanoacrylate. R. H. Lehman et al., ARCH.
SURG. Vol. 93:441,1966. Of the monomers tested (methyl, propyl,
butyl, isobutyl, heptyl, octyl), it was the only one that degraded
more rapidly than any of the unbranched homologues, with the
exception of the methyl monomer.
[0010] A second study reported that in vivo experimentation gives
credence to the chain scission mechanism by hydrolysis. M. Yonezawa
et al., YUKI GOSEI KAGAKU KYOKAISHI, Vol. 25, 1967. When beta-(14)
carbon tagged cyanoacrylate is implanted in rats, radioactive urea
is isolated from urine. This suggests that tagged formaldehyde is
released, converted to carbon dioxide and in turn reacts with
ammonia to produce urea. F. Leonard, ADHES. BIOL. SYS. 1970.
[0011] Rates of degradation on ethyl, butyl, and hexyl
cyanoacrylates were evaluated with regards to molecular weights,
concentrations, and side chain structures. W. R. Vezin et al., J.
PHARM. PHARMACOL., Vol. 30, 1978, Suppl. The method employed
buffered systems of pH ranges from 5.97 to 7.88. As expected, the
rates increased with increasing pH. Scanning electron microscopy of
the degraded polymer indicated that reaction occurs at the surfaces
and not internally through diffusion. It was postulated that the
greater the length of the alkyl side chain, the more protection
provided to the labile hydroxyl end of the polymer chain. This in
turn would provide greater resistance to degradation of the
polymer. Degradation rates do in fact correspond to chain length
protection. The relative rates of degradation for hexyl, butyl, and
ethyl were, respectively, 1.0, 1.36, 9.55.
[0012] The same group reported on a study whereby degradation rates
were retarded by increasing the chain length of the polymer. W. R.
Vezin et al., J. BIOMED. MAT. RES., Vol. 93, 1980. Very small
quantities of impurities in the monomers had a significant impact
on the final outcome of the degree of polymerization. Further to
this study, within the ethoxyethyl system, longer chain length
enhanced the degradation resistance of the resultant polymer.
[0013] A comparative study of ethyl cyanoacrylate and polyurethane
in-situ generated adhesives and coatings was reported in U.S. Pat.
No. 4,057,535 to Lipatova et al. The study claimed the superiority
of the polyurethane structure due to high flexibility and
compatibility with the treated tissues. The single comparison was
made with incised tissue and consequent application between the
wound edges. Inferiority of this application for the cyanoacrylate
was readily evident, but true topical applications were not
compared. Of eleven examples given, four were of a topical method,
yet no data was presented as no application of the ethyl or any
other homologue was done conjunctively for comparative efficacy. A
further deficiency of this patent is the practicality of use. No
indication is given for a device to properly apply the two part
system and appears to indicate an at-site preparation.
[0014] Another patent, U.S. Pat. No. 5,192,536 to Robinson
overcomes the issue of the apparent difficulties associated with
the invention disclosed in U.S. Pat. No. 4,057,535 by taking
preformed polyurethane and dissolving it in a rapidly evaporating
solvent such as tetrahydrofuran. The composition is designed to
form a "membrane-like cover over the wound" and "assists in
maintaining closure of the wound". Again no comparative studies
were reported.
[0015] U.S. Pat. No. 3,995,641 to Kronauthal et al. discusses the
novelty of modified cyanoacrylates, namely, carbalkoxyalkyl
cyanoacrylates. The patent discloses their usefulness as a tissue
adhesive in surgical applications. The presumed superiority of
these products was attributable to the rapid hydrolytic decay and
concurrent low degree of histotoxicity. Since no data is presented
regarding formaldehyde evolution, it is presumed that the
hydrolysis mechanism does not scission the polymer to generate
it.
[0016] U.S. Pat. No. 5,254,132 to Bartley et al. discloses the use
of a hybrid method of surgical application of cyanoacrylates. It
discloses a combination of sutures and adhesive such as to be
mutually isolated from each other, but to both support the
re-growth of the tissue in the wound area. The '132 patent
addresses the issue of insuring no contact of adhesive in the
suture area so as to assure no inclusions of the cyanoacrylate. The
disclosed method appears to be awkward and cumbersome, and requires
a very effective and controlled dispensing of the adhesive without
contacting the suture. Additional concern is indicated as a
suggestion is made to employ a solvent (acetone) if any surgical
instrument happens to be bonded inadvertently to the treated
area.
[0017] U.S. Pat. No. 5,328,687 to Leving et al. attacks the
formaldehyde issue by incorporating a formaldehyde scavenger, such
as, sodium bisulfite. The various compositions were evaluated via
in-vitro experimentation. The examples presented all had a
presumably excessive level of scavenger. The representative
compositions had loadings of 20% of a scavenging agent that was
designed to offset formaldehyde emissions that were at 0.1%. As
indicated previously, in-vitro and in vivo conditions are not
identical and certainly not in this instance. The in-vitro
conditions presented in the '687 patent do not factor in the
dynamic conditions in living tissue. The surgically treated area
would be under continuous and changing fluids as the organ attempts
to bring in the necessary biocomponents to heal the traumatized
tissue. As such, it would not be expected that the
scavenger/formaldehyde ratio would be maintained as it was in the
in-vitro state. It could be speculated that the use of such high
loadings of any fluid solubilized additives would contribute to
greater formaldehyde emissions. This can be assumed to be a
consequence of dissolution of the additives resulting in cavities
in the polymer, thereby promoting greater surface area for
hydrolytic degradation.
[0018] U.S. Pat. No. 5,403,591 to Tighe et al. relates to the use
of cyanoacrylates for treatment of skin irritations that progress
to ulcerations. It would be assumed that these conditions could be
considered wound formations, e.g., see U.S. Pat. No. 3,995,641.
[0019] U.S. Pat. Nos. 5,928,611 to Leving, 5,981,621 to Clark et
al., 6,099,807 to Leving, 6,217,603 to Clark et al. describe
methods of inducing cure of cyanoacrylates by passing the adhesive
through a porous applicator tip containing substances that initiate
the polymerization. These substances co-elute and dissolve into the
adhesive as it is forced through the porous tip.
[0020] U.S. Pat. No. 6,143,352 to Clark et al. describes methods of
altering the pH environment of cyanoacrylates in order to attenuate
or accelerate the rate of hydrolytic degradation by uses of acid
and alkaline additives. The formulation of acidic modifiers is
problematic as they tend to inhibit the primary characteristic of
these materials, namely, rapid cure on application to tissue. Data
is presented on effects of acidic compositions on previously cured
cyanoacrylates, not on in situ applied compositions.
[0021] All of these methods rely on the addition of various
compositions to affect the accelerated cure onto a desired
substrate. These compositions may induce polymerization by creating
a greater number of initiation sites and or orientation of the
monomer for more facile polymerizations. Other plausible mechanisms
can be evoked, but the fact remains that the added materials become
a part of the composition (undesirable for many medical
applications). As such, these chemical inclusions may elicit
unfavorable reactions in the cured state. In particular, the use of
pH-based accelerators may contribute to the alkaline hydrolysis of
the cyanoacrylate polymer.
[0022] This is particularly undesirable in medical applications of
the cyanoacrylates as the hydrolysis results in the evolution of
formaldehyde. A certain level of formaldehyde can be tolerated by
tissue as it is able to dispose of reasonable concentrations. A
solution proposed in the prior art has been increasing the chain
length of the cyanoacrylate monomer side group; in particular, that
it be alkyl so as to impart hydrophobic character to the resulting
polymer.
[0023] The prior art methods and compositions have been able to
achieve a synthesis of the octyl cyanoacrylate at economic levels
for applications in the medical field, although improbable for uses
in commercial applications due to reaction yields. A number of
methods have been attempted to improve yields. Yin-Chaos Tseng et
al., BIOMATERIALS, Vol 11, 1990. The variables looked at included:
azeotropes, temperature and formaldehyde/cyanoacetate ratio. Other
methods have also included assessment of different catalysts for
the condensation reaction. Regardless of the methods tried, yields
become increasingly smaller as the cyanoacetate pendant group
becomes larger.
[0024] An attempt to improve yields is reported in U.S. Pat. No.
6,245,933 to Malofsky. This method attempts to avoid yield losses
by producing the high yield cyanoacrylate prepolymers of the lower
homologues (methyl & ethyl) and then proceed through a
transesterification with a longer chain alcohol such as the octyl.
Three reported examples with 2-octanol gave yields ranging from
21.8% to 36.2% of crude monomer.
[0025] From this, it can be seen that high yields are difficult and
no doubt subsequent work-up to medically acceptable products result
in even lower product output. The difficulty with methods such as
discussed above, is the undesirable side products which are
difficult to remove from the main stream. In particular, it is
difficult to achieve complete transesterification reactions on
polymeric moieties because of steric obstruction. As a consequence,
purity is compromised as the initial cyanoacrylate prepolymer is
not completely reacted and the lower homologue co-distills with the
desired product.
[0026] Other additives have been used to attenuate various
properties, such as modulus (elasticity), viscosity, thermal
resistance, etc. Each and every additive becomes a substance that
must be removed by the surrounding tissue, which generally does not
assist in recovery of the damaged area. In that regard, the
addition of these additives must weigh the effect of property
improvements against the effect on tissue compatibility.
[0027] In contrast to additives for the cured adhesives are
additives formulated into the synthesized monomers. The synthetic
route for monomer production relies on two principal groups of
stabilizers. The first group is chosen from substances capable of
preventing free radical polymerization and the second group
inhibits the anionic polymerization.
[0028] The critical step in the production of these monomers relies
on the high temperature thermal degradation of the polymer
generated from the formaldehyde-cyanoacetate reaction. These
temperatures span the range of 150.degree. C. to excesses of
200.degree. C. Under ideal conditions, this polymer will undergo a
clean unzipping reaction that releases the cyanoacrylate monomer.
This begins to take place in the lower temperature regions and must
be gradually elevated to extract the increasingly difficult boiling
off of the monomer. Elevation of the temperature is necessary as
byproducts form and increasingly hamper the volatilization of the
desired monomer.
[0029] In order to prevent the thermal reversal of the monomer back
to polymer as it is generated and exits the body of fluid polymer
in the reaction vessel, retarders or inhibitors are added at the
beginning of this process. These substances react with free
radicals to form a stable unreactive species, thereby halting the
thermal polymerization typical of vinyl monomers. Quinones are the
most often used substances in this group. Typical, but not
exclusive, are hydroquinone and methyl ether hydroquinone. The
presence of these additives is most critical in the monomer-polymer
mix in the reaction vessel. Once the monomer is vaporized, it is
quickly cooled to ambient conditions as it is distilled over to a
suitable receiver.
[0030] The second group of stabilizers are used to prevent the
anionic polymerization of the monomer in the reaction vessel as
well as the vapor and collected liquid monomer in the receiver.
Those knowledgeable in the art are quite familiar with these
substances. Typical, and again, not exclusive, are the sulfonic
acids and sulfur dioxide. In general, acidic substances are chosen
to effect stabilization not only during the production of these
monomers but further for stabilization during storage.
[0031] A fine line exists in the levels of these anionic
stabilizers. If there is insufficient loading of these acids during
the polymer unzipping to monomer, the vaporized and condensing
monomer will begin to repolymerize throughout the system. On the
other hand, if too much anionic stabilizing takes place in the
distilled monomer, the desired repolymerization is not easily
accomplished. This is evidenced by those patents cited above that
deal with the loading of alkaline substances and other anion
polymer promoting initiators in a porous tip. These additives are
necessary to overcome the excessive levels of anionic stabilizers
that co-distill during the distillation of monomer.
[0032] In the manufacture of the lower homologues such as the
methyl, ethyl, and butyl monomers, the degradation of the polymer
to monomer is much more effective and gentle, requiring lower
levels of these anionic stabilizers. The resultant distilled
monomers are thereby stabilized sufficiently and in some cases
additional acid is charged, usually under 100 parts per million, to
effect a useful shelf life for commercial applications.
[0033] These lower homologues are, as are all of the cyanocarylates
(with some exceptions such as the difunctional ones), distilled
under vacuum conditions. The typical vacuum is in the 0.5 mm Hg to
2.0 mm Hg. As the molecular weight of these monomers increases, the
required vacuum conditions become more critical. In order to
effectively distill the higher molecular weights, the vacuum
conditions must continue beyond the range of approximately 0.5 mm
Hg. Higher distillation temperatures with poor vacuum conditions
results in increasing levels of undesirable byproducts, and
consequent poor yields and inferior product.
[0034] As a typical example, it is necessary to achieve a vacuum in
the range of approximately 0.01 mm Hg to 0.05 mm Hg for the octyl
monomer and higher homologues in order to effectively distill the
monomers in a nondestructive process. This, however, is the crux of
the problem in the isolation of these monomers as confronted in the
prior art methods and systems.
[0035] The lower homologues and typical anionic stabilizers have a
sufficiently large difference in their respective boiling points,
such that very little stabilizer is co-distilled with the monomer.
This, however, becomes an increasingly important issue as the
vacuum levels proceed to better distill over the higher boiling
monomers like the octyl, decyl and so on. The consequence then is
that increasing levels of the stabilizer co-distill along with the
desired monomer. The resultant isolated monomer is excessively
loaded with anionic stabilizer(s) thus requiring the devices
referred to above.
[0036] In addition, and as generally discussed above, prior art
methods for the synthesis of cyanoacrylate monomers generally
require the addition of acids and free radical inhibitors during
the monomer synthesis. The free radical inhibitors prevent
premature polymerization during the thermal unzipping reaction as
well as the follow-up distillation step(s). The acid additives are
necessary to prevent premature polymerization during workup and
storage of these compositions. However, and as discussed above, as
the chain lengths become increasingly longer, higher temperatures
are necessary to effect the unzipping reaction. A direct unintended
result is that excessive levels of acid are necessary with the
consequent overstabilization of the distilled product.
[0037] It, therefore, becomes necessary to negate this
overstabilization in order to facilitate the anionic
polymerization. To date, all means of effecting this have been by
pretreatment of the substrate with, for example, alkaline and/or
organic soluble amines that are intended to initiate the anionic
polymerization by dissolution into the adhesive. Though not
specifically stated, this approach is apparently based on the view
that as the mass of the side chain group increases, the
polymerizability drops off. This is apparent, as all current
techniques rely on overriding the excess stabilizer levels.
Alternative methods employ a solution of these initiators being
sprayed over the adhesive after it has been applied to the
substrate. The other variant of this soluble initiator method are
those referenced above incorporating the initiator in the porous
applicator tip. As those skilled in the art certainly appreciate,
neither of these approaches is desirable for medical
procedures.
[0038] With the foregoing in mind, a need currently exists for a
method by which cyanoacrylate adhesives may be rapidly cured
without contaminants or extraneous additive. The present invention
provides such a method.
SUMMARY OF THE INVENTION
[0039] It is, therefore, a principal object of the present
invention to provide a new and unobvious method for curing
cyanoacrylate adhesives, permitting utilization of the resulting
adhesives in the treatment of human, or animal, tissue and/or
flesh, required to be otherwise sealed or sutured, or otherwise
protected from its surroundings. The method has been developed so
as to minimize the presence of contaminants and extraneous
additives in the resulting cured medical adhesives.
[0040] It is further an object of the present invention to enhance
the cure speed of stabilized cyanoacrylate adhesives by a treatment
that removes excessive stabilizers prior to application onto the
substrate. The present cyanoacrylate adhesives curing method allows
for reduced levels of stabilizers therein to be formulated to
provide commercially sufficient shelf life and improved speed of
cure upon application. The present method also enhances the cure
speed of cyanoacrylate adhesives by a destabilization treatment
that purifies the cyanoacrylate prior to the application onto the
substrate and results in the production of improved cyanoacrylate
adhesives that exhibit greater biocompatibility as a consequence of
modified polydispersity and longer monomeric chain groups,
especially such adhesives that exhibit attenuated degradation of
the polymer thereby exposing tissue contacting the adhesive to
lower levels of formaldehyde. The present cyanoacrylate adhesives
curing method further allows for formulating unadulterated
adhesives containing no plasticizers while achieving the
elastomeric properties necessary for bonded substrates undergoing
multidimensional stresses.
[0041] The objects are achieved by an adhesive method comprising
the steps of providing a long shelf life stable adhesive
composition comprising cyanoacrylate adhesive and a stabilizing
agent(s), presenting a substrate to receive at least a portion of
the cyanoacrylate adhesive composition and applying the
cyanoacrylate adhesive composition to the substrate. The method is
further achieved by removing a predetermined quantity excess
stabilizing agent(s) from the cyanoacrylate adhesive composition
prior to application to the substrate.
[0042] Other objects and further scope of applicability of the
present invention will become apparent from the detailed
descriptions given herein; it should be understood, however, that
the detailed descriptions, while indicating preferred embodiments
of the invention, are given by way of illustration only, since
various changes and modifications within the spirit and scope of
the invention will become apparent to those skilled in the art from
such descriptions.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0043] The detailed embodiments of the present invention are
disclosed herein. It should be understood, however, that the
disclosed embodiments are merely exemplary of the invention, which
may be embodied in various forms. Therefore, the details disclosed
herein are not to be interpreted as limited, but merely as the
basis for the claims and as a basis for teaching one skilled in the
art how to make and/or use the invention.
[0044] As discussed above, the present invention generally relates
to a method for curing reactive monomeric cyanoacrylates to undergo
macromolecular formations via appropriate modification of anionic
stabilizer levels in a manner permitting utilization of the
resulting adhesives in the treatment of human, or animal, tissue
and/or flesh, required to be otherwise sealed or sutured, or
otherwise protected from its surroundings. While certain
distinctions may be drawn between the usage of the terms "flesh"
and "tissue" within the scientific community, the terms are used
herein interchangeably as referring to a general substrate upon
which those skilled in the art would understand the present
adhesive to be utilized within the medical field for the treatment
of patients. Without being bound to a specific mechanism, such
modification of the anionic stabilizer levels chemically and/or
physically removes stabilizing agents so the present method allows
for reformulation of compositions capable of reasonable cure speeds
without external anionic initiators.
[0045] The present method generally includes the steps of providing
a long shelf life stable adhesive composition comprising
cyanoacrylate adhesive and a stabilizing agent(s), removing excess
stabilizing agent(s) from the adhesive composition, presenting a
substrate to receive at least a portion of the cyanoacrylate
adhesive composition and applying the cyanoacrylate adhesive
portion to the substrate.
[0046] Cyanoacrylate adhesives that may be used in accordance with
the present invention, comprise one or more monomers having the
following general structure:
CH2.dbd.C(CN)--C(O)--R
[0047] Without encumbering the body of this patent with specific
examples of moieties, reference is made to the numerous patents
delineating the myriad of groups that can be represented by the
moiety designated as R, many representative examples being given in
the cited references. With this in mind, these, as well as other
moieties, may be employed without departing from the spirit of the
present invention. In the case of difunctional cyanoacrylates, R
would be bound to two reactive groups. These are, therefore,
intended to define and be included by general reference to such
prior art and by those knowledgeable thereof.
[0048] As discussed above in the Background of the Invention, the
various methods for the synthesis of these monomers generally
require the addition of acids and free radical inhibitors during
the monomer synthesis. The free radical inhibitors prevent
premature polymerization during the thermal unzipping reaction as
well as the follow-up distillation step(s). The acid additives are
necessary to prevent premature polymerization during work-up and
storage of these compositions.
[0049] However, as the chain lengths become increasingly longer,
higher temperatures are necessary to effect the unzipping reaction.
A direct unintended result is that excessive levels of acid are
necessary with the consequent overstabilization of the distilled
product. It, therefore, becomes necessary to negate this
overstabilization in order to facilitate anionic polymerization of
the adhesive composition.
[0050] Prior art techniques rely upon pretreatment of the substrate
with, for example, alkaline and/or organic soluble amines that are
intended to initiate the anionic polymerization by dissolution into
the adhesive. This approach is apparently based on the view that as
the mass of the side chain group increases, the polymerizability
drops off. This is apparent, as all current techniques rely on
overriding the excess stabilizer levels. Alternative prior art
methods employ a solution of these initiators being sprayed over
the adhesive after it has been applied to the substrate. The other
variant of this soluble initiator method are those referenced above
incorporating the initiator in the porous applicator tip.
[0051] Since the difficulty in polymerization of these longer chain
moieties is due to excessive acid levels, in accordance with the
present invention the acids are removed rather than neutralized. As
noted above, polymerization is achieved by the addition of
initiators to overcome the stabilizing effects of these acids and
so remain in the resultant polymer matrix. The concept of acid
removal is also the focus of a co-pending U.S. patent application
Ser. No. 09/982,226, filed Dec. 19, 2001, which is incorporated
herein by reference. The '226 application describes the use of acid
removing particulates during the coincidental application of these
adhesives. The utility of this method is limited by a period of
time in which the adhesive can be applied. It would be most
desirable to have a greater degree of freedom in time to apply
these adhesives.
[0052] This present method achieves this goal by removing
stabilizers in cyanoacrylate adhesives prior to their application
to substrates. This renders the resultant purified compositions
highly susceptible to polymerizations when applied to the
substrates. Again, without being bound to any single specific
mechanism, this process relies on a combination of physical
adsorption/absorption, chemical reaction, and hydrogen bonding of
the acid group(s) onto particulate surfaces. It is necessary to
have the acid removing particulate substances, in fluid contact
with the excessively stabilized monomer(s), be insoluble or
otherwise isolatable from the monomers, such as by filtration,
centrifugation, phasing out, membrane separation, or other
appropriate isolating mechanism. The requisite is the isolation of
the acids or other stabilizers from the monomers.
[0053] Substances exhibiting these mechanisms encompass polymers
capable of forming hydrogen bonds with the stabilizing acids. These
polymeric materials can have carbonyl, hydroxyl, amide, carboxylic,
amine, ether, anhydride, ester, urethane, sulfone or other
structures or combination structures capable of coupling or
otherwise fixing the acid stabilizer to the isolatable substances.
These polymeric materials can also be inorganic such as silicates.
Other contemplated particulates are those in which the stabilizers
are selectively trapped in zeolytic substances or otherwise caged
in molecular sieves.
[0054] Chemical isolation can be achieved by, for example, reactive
contact with anhydride structures such as on copolymers containing
maleic anhydride. It is postulated that the anhydride structure
reacts to form an anhydride link with the mobile (stabilizing) acid
and a carboxylic group, both being bound to the polymer chain; an
example for this being maleic anhydride copolymers of styrene and
ethylene.
[0055] Physical removal of the excess stabilizers may be
accomplished by such substances as activated carbon, which appears
to rely on adsorption of the stabilizer(s) as a result of the high
surface area and polar surface structures.
[0056] These mechanisms of treatment are not meant to be mutually
exclusive, but can, in fact, be acting by any and all combinations
to remove the excessive stabilizers. A typical example is the use
of activated carbon, which has oxidation structures that are likely
to participate in hydrogen bonding as well as physical adsorption.
A further example is the use of more than one substance, such as
polymer(s) and inorganic(s) in a single treatment.
[0057] To most effectively use stabilized cyanoacrylate adhesives
for medical applications in accordance with the invention, they are
stored in a device that houses a crushable ampoule containing such
adhesives. Such ampoule containing devices may be constructed of
any number of materials that can be shaped or molded or otherwise
fabricated to contain the adhesive and ampoule. The application
devices are preferably manufactured from such materials as to
effect a resilient wall capable of transmitting pressure to the
crushable ampoule without loss of its containment properties. These
application devices advantageously further comprise a filtering
component and nozzle for application of the filtered adhesive to
the substrate, for example, tissue of the patient being treated.
Examples of application devices which may be used in accordance
with the present method are disclosed in detail in the '226
application which, as discussed above, is incorporated herein by
reference.
[0058] The application devices can also be designed to apply the
product in a continuous manner. An example of such a device is one
that incorporates a reservoir of the appropriate adhesive feeding
through a valving mechanism, thereby providing a source of adhesive
without an ampoule.
[0059] In multi-application uses the properly treated cyanoacrylate
is contained in appropriate vessels such as glass or high density
polyethylene. These containers may be pretreated so as to effect
useful shelf life. Reference again is made to those familiar with
the art and patents delineating the various methods to achieve this
treatment. Typically a container would hold 2-5 grams of product to
provide many topical applications with appropriate disposable
applicators such as pipettes.
[0060] In a preferred embodiment, one of the above described
devices houses iso-octyl cyanoacrylate which has been previously
treated with poly(vinyl pyrrolidone/vinyl acetate) copolymer. The
ampoule is crushed and the contents are then expressed through the
appropriate filter and dispenser tip onto the substrate,
specifically human, or animal tissue, or skin. The application is
accomplished in such fashion as to prevent encapsulation of
adhesive by any surrounding tissue. Though ultimately these
inclusions are degraded and excreted, it is most desirable to
minimize this occurrence to maximize reconstitution of the
surrounding tissue. The need to assure this minimization was noted
in U.S. Pat. No. 3,667,472 which pointed out the requisite to
bridge the wound without diffusing into it. This was accomplished
by bringing the wound edges together followed by application so as
to effect a bridging over the wound to circumvent necrosis and
irritation by this technique.
[0061] A second preferred embodiment utilizes the above described
devices containing iso-decyl cyanoacrylate
[0062] A third preferred embodiment utilizes the above described
devices containing dodecyl cyanoacrylate.
[0063] A fourth preferred embodiment includes the above with
combinations of cyanoacrylate monomers to achieve control over the
rate of hydrolytic degradation so as to improve compatibility with
tissue by control of formaldehyde emissions.
[0064] In accordance with a preferred embodiment, the invention
employs vinyl pyrrolidone polymers and copolymers to remove
stabilizers from the cyanoacrylate adhesives formulation. These
particulate agents are combined with the monomer adhesive in mutual
contact until the adhesive is destabilized, whereupon the adhesive
becomes isolated from the destabilizing agent by various means such
as to effect isolation of the adhesive from the destabilizing
component. Once isolated, the adhesive is restabilized at reduced
levels so as to effect timely cure rates in the 5 seconds to
approximately one minute range.
[0065] Advantageously, the device of the invention is one that (a)
delivers the cyanoacrylate adhesive of convenient viscosity, (b)
contains a porous segment for the containment of the ampoule and
other components so as to permit the release of the adhesive with
no particulate components being released onto the substrate to
which it is applied, (c) delivers the adhesive through a nozzle
applicator tip configured for appropriate application onto the
substrate, and (d) can be used with other monomer formulations
prior to application to effect the desired result such as
polymerizations to produce various thermoplastic and thermoset
resins of both organic and inorganic nature.
[0066] All of preferred embodiments disclosed in accordance with
the present invention should be understood to further include all
of the various additives useful in the alteration and improvement
to cyanoacrylate adhesives as would make them suitable for
placement into the above devices and modifications to these and
similar devices. These can include plasticizers, stabilizers,
surface insensitive additives, tougheners, thickeners, adhesion
promoters, other monomers, comonomers, and other such compositions
as would be evident to those familiar with the cyanoacrylate
adhesives art.
[0067] The following preferred examples further disclose the new
method and display its effectiveness.
EXAMPLE 1
[0068] A quantity of particulate destabilizing agent (5 grams) in
the form of vinyl pyrrolidone vinyl acetate copolymer is blended
with (25 grams) iso-octyl cyanoacrylate for a period of 24 hours.
The resultant slurry is filtered to effectively remove the
destabilizing agent and is restabilized at a level to achieve the
desired cure speed for the following test. In particular, 6 grams
of the treated monomer is blended with 0.012 grams of pretreated
monomer. A glass ampoule is charged with 0.5 grams of treated
monomer and sealed with a gas flame. The ampoule is inserted into a
tubular device referred to as a Tandem Dropper supplied by James
Alexander Company of Blairstown, N.J., that also provided unsealed
ampoules. In order to filter matter dispensed from the dispenser
tip of the Tandem Dropper, it is plugged internally with a small
wad of polyester fiber also supplied by James Alexander Company.
The dispenser tip press fits onto the end of the Tandem Dropper
after insertion of the sealed ampoule. The assembled device is
squeezed to effect rupture of the ampoule. Pressure is applied so
as to exude a drop of adhesive through the filtering tip. The drop
is applied to skin and timed to determine when the film has
undergone cure to a non-tacky surface. The iso-octyl cyanoacrylate
undergoes cure in 10-20 seconds upon application to skin on the
back of the hand. This contrasts with untreated iso-octyl
cyanaocrylate which shows no sign of cure up to 3 minutes whereupon
the test is terminated.
EXAMPLE 2
[0069] A 10 milliliter glass vial is charged with 0.5 grams of
activated charcoal Calgon WPX, sourced from Calgon Carbon Corp. of
Pittsburgh Pa. Followed by this is a 6.0 gram charge of iso-octyl
cyanoacrylate which is mixed for a period of 30 minutes. The
resulting dispersion is filtered to isolate the cyanoacrylate into
a small ampoule. A test of cure speed on skin of the isolated
monomer results in the formation of a protective film in 10 to 20
seconds in a manner similar to example 1 above.
EXAMPLE 3
[0070] A 3 milliliter test tube is charged with 0.016 grams of
anhydrous potassium carbonate and 2.030 grams of iso-octyl
cyanoacrylate which is then sealed and shaken for approximately 2
hours. It is stored for 17 days. A sample is removed and applied to
the skin with a consequent film cure in a range of 110 to 120
seconds.
EXAMPLE 4
[0071] Example 3 is repeated with a higher loading of the anhydrous
carbonate: 0.27 grams and 2.46 grams of iso-octyl cyanoacrylate.
The test tube is stored for 15 days whereupon a test of cure
exhibits film formation in 120 seconds.
EXAMPLE 5
[0072] A 50 milliliter flask is charged and sealed with 1.5 grams
of polyvinyl alcohol granules (BP-05) and 18.5 grams of iso-octyl
cyanoacrylate. The dispersion is intermittently shaken for a period
of 48 hours due to the more coarse nature of the polymer. A sample
is taken and tested on skin to show a cure of film in 90 to 100
seconds.
EXAMPLE 6
[0073] A flask is charged and sealed with 1.0 grams of
ethylene-vinyl acetate copolymer RP251 (Wacker Polysystems) and
18.5 grams of iso-octyl cyanaocrylate. The dispersion is
intermittently shaken for 48 hours prior to the skin test. Upon
testing the treated monomer cured in approximately 100 seconds
EXAMPLE 7
[0074] Example 6 is repeated with RP140, a vinyl acetate
homopolymer. The resultant treated monomer gave a cure after 130
seconds.
EXAMPLE 8
[0075] A 10 milliliter flask is charged and sealed with 1.0 grams
of poly(methyl methacrylate) (Rhohadon M449, Rohmtech Inc.) and 6
grams of iso-octyl cyanaocrylate After intermittent shaking for 24
hours, the dispersion is filtered and the isolated monomer is
tested to reveal a film formation in 30 to 35 seconds.
EXAMPLE 9
[0076] A 10 milliliter flask is charged and sealed with 1.0 grams
of styrene-maleic anhydride copolymer (SMA-3000, Atochem Inc.) and
6 grams of iso-octyl cyanoacrylate. Subsequent isolation of the
monomer after 24 hours of treatment gave a cured film on skin in
approximately 65 seconds.
EXAMPLE 10
[0077] A 10 milliliter flask is charged and sealed with 0.5 grams
of zinc oxide (AZO66, US Zinc Products Inc.) and 6 grams of
iso-octyl cyanoacrylate After shaking the dispersion for 30
minutes, subsequent filtration and testing on skin gave a cure in
50 to 60 seconds.
EXAMPLE 11
[0078] A 10 milliliter flask is charged and sealed with 0.5 grams
of "Hydrosource" (12 mm average diameter particles) polyacrylamide
(Castle International) and 6.0 grams of iso-octyl cyanoacrylate.
Subsequent testing after 4 hours of mixing gave a 30 second cure on
skin.
EXAMPLE 12
[0079] A 10 milliliter flask is charged and sealed with 1.6 grams
of glass spheres (Class 4A size 203 from Cataphote Corp.) and 4.4
grams of iso-octyl cyanoacrylate. The mix was shaken for 2 hours
prior to testing. The sampled droplet was spread on skin giving a
60 second cure.
EXAMPLE 13
[0080] A 10 milliliter flask is charged and sealed with 1.6 grams
of pulverized polyimide resin (Dupont Kapton 700HPP-ST film) and
4.4 grams of iso-octyl cyanoacrylate. The mix was shaken overnight
prior to testing. An isolated sample gave a skin surface cure of
120 seconds.
EXAMPLE 14
[0081] A two ounce opaque polyethylene bottle is charged with 0.57
grams of vinyl pyrrolidone vinyl acetate copolymer and 30 grams of
iso-octyl cyanoacrylate. The container is shaken for five minutes
and stored for 3 months. A sample was taken and passed through a
0.2 micron filter with a 1 milliliter syringe. Application onto
skin gave a very rapid cure of 10-15 seconds with a noticeable
warmth due to the more rapid polymerization.
[0082] As evidenced by the last example, these additives can be
left in contact with the cyanoacrylate with no apparent detriment
to the shelf life and cure of the final product. It is further
evident that these products can be kept without the need to isolate
and store in glass ampoules. This further leads to the capability
of large reservoirs of product to be dispensable through a
disposable fibrous or porous tip. This is particularly advantageous
in procedures where quantities necessary exceed the capacity of the
crushable ampoules. The only limitations to the various treatments
is the ability to isolate a practical level of cyanoacrylate
monomer, i.e., that concentrations even at levels creating slurries
can be filtered off to achieve economic quantities. These examples
serve to show the extensive applicability of the primary requisite:
to remove excessive stabilizer(s). No other references have
addressed this issue, as those knowledgeable in the science and art
of this technology have always understood the need to add, not
remove, these stabilizing substances. It has not previously been
recognized that the synthesis and isolation of these long chain
side group cyanoacrylates results in excessive levels of these
stabilizers. The preceding examples are intended to show the
various types of cyanoacrylate insoluble materials that can perform
the extraction of stabilizers. They are therefore intended to
exemplify, not define the limits, of applicable substances.
[0083] While the preferred embodiments have been shown and
described, it will be understood that there is no intent to limit
the invention by such disclosure, but rather, is intended to cover
all modifications and alternate constructions falling within the
spirit and scope of the invention as defined in the appended
claims.
* * * * *