Note: Descriptions are shown in the official language in which they were submitted.
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USE OF AN ADHESIVE COMPOSITION OVER A BIOACTIVE
POLYMERIZATION I1~1ITIATOR OR ACCELERATOR
BACKGROUND OF THE INVENTION
Field of Invention
The invention relates to the use of monomer and polymer compositions as
biomedical adhesives and sealants, and particularly to their use in
conjunction with
bioactive materials.
2. Description of Related Art
Products in primary use for wound closure are surgical sutures and staples.
Sutures are recognized to provide adequate wound support. However, sutures
cause
additional trauma to the wound site (by reason of the need for the needle and
suture to
pass through tissue and the need to anesthetize the wound area via needle
puncture) and
are time-consuming to place, and, at skin level, can cause unattractive wound
closure
marks. Surgical staples have been developed to speed wound apposition and
provide
improved cosmetic results. However, surgical staples also impose additional
wound
trauma and require the use of ancillary and often expensive devices for
positioning and
applying the staples. Both sutures and staples are especially problematic in
pediatric
cases where the patient may have a strong fear response and refuse to
cooperate with
their placement, and in geriatric cases where the skin tissue is weaker and
prone to
tearing.
As an alternate to surgical sutures and staples, adhesives have been used in
wound closure. Similarly, adhesives have been proposed for use in wound
covering and
protection in such topical applications as surface lacerations, abrasions,
burns,
stomatitis, and other open surface wounds. One group of such adhesives is the
1,1-
disubstituted ethylene monomers, such as the monomeric forms of a-
cyanoacrylates.
For wound closure and covering using adhesives, mixtures of cyanoacrylate
adhesives and medicaments have been developed. For example, U.S. Patent No.
5,684,042 to Greff et al. discloses a cyanoacrylate composition comprising an
antimicrobially-effective amount of an iodine-containing antimicrobial agent.
The
iodine-containing antimicrobial agent is dispersible in the cyanoacrylate
composition
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2
and does not cause premature polymerization of the cyanoacrylate adhesive
(i.e., does
not initiate polymerization).
U.S. Patent No. 3,483,870 to Coover, et al. discloses the use of methyl a-
cyanoacrylate as a bone cement. The a-cyanoacrylate may be blended with
antibiotics
so long as the antibiotics do not cause early polymerization (i.e., do not act
as
polymerizatiominitiators) or cause adverse effects on the healing process.
Another method for treating or preventing infections associated with wounding
using adhesives involves layering a cyanoacrylate over a medicament on a wound
site.
For example, U.S. Patent No. 5,580,565 to Tighe, et al. discloses the use of a
topical a-
cyanoacrylate tissue adhesive to form a protective barrier over intact or
broken skin to
allow healing of the skin to occur. Polymerization of the a-cyanoacrylate
adhesive is
initiated by contact with skin moisture and tissue protein. Tighe et al. also
disclose the
use of a-cyanoacrylate adhesives as a protective layer over medicaments. The
only
medicament exemplified by Tighe et al. is cortisone, which does not initiate
1 S polymerization of cyanoacrylate monomer compositions.
Others have also disclosed the use of cyanoacrylate adhesives as coverings for
medicaments. For example, Beasley et al. disclose application of antibiotics,
such as
vancomycin powder or tetracycline, to a wound, followed by covering of the
wound
with isobutyl cyanoacrylate. This type of treatment is disclosed as showing
promise for
treatment of bacterially infected tissues. (Beasley, J.D. et al., Effect of
Antibiotics and
Chemical Adhesives on Infected Wounds Mil. Med. 136(6):566-569,1971 ).
However,
neither of these antibiotics act to initiate polymerization of the
cyanoacrylate.
The use of cyanoacrylate adhesives to cover bioactive agents is also disclosed
in:
Miles et al., Oral Surgery, Oral Medicine, Oral Pathology, Vol. 75, No. 3, 397-
402
(using triamcinolone acetonide (Kenalog) or chlorhexidine digluconate
(Peridex) as the
bioactive agent); and Kaufrnan, R.S., The Laryngoscope, 1974, 793-804 (using
dexamethasone sodium phosphate (Decadron) as the bioactive agent).
U.S. Patent No. 4,669,491 to Weisberg et al. discloses the use of biocides
covered by protective acrylic artificial nails. The biocides may be acidic or
phenolic,
but are preferably selected so as not to affect the cure rate or the bond
strength of the
glue layer. They include thymol, chlorothymol, benzoic acid, p-hydroxybenzoate
alkyl
esters, 4- and 6-phenyl-2-chlorophenyl, carvocrol, hexachlorophene,
nitroforans, allicin,
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2-phenylphenol, boric acid, mercurials, and such antibiotics as Bacitracin and
Griseofiilvin, quaternary ammonium halides such as n-
alkyldimethylbenzylammonium
chloride, cetyl pyridinium bromide, 5-methyl-2-isopropyl-cyclohexanol, 2-
bornanone,
cineole, safrole, bornyl chloride, 2-phenoxyethanol, benzylalcohol and
ethanol. The
biocides are applied to human fingernails, then covered by solutions
comprising
cyanoacrylate adhesive. The biocides are applied to the natural fingernails in
a solution,
and the solution is allowed to dry, leaving the active biocides on the nails.
The biocide-
treated fingernails are roughened with an abrasive, then coated with a
monomeric
cyanoacrylate solution to form the artificial fingernails. The cyanoacrylate
monomers
are polymerized by the addition of a polymethacrylate ester composition
containing a
benzoyl peroxide catalyst. There is no suggestion of selecting the monomers
and
biocides such that the biocides affect polymerization.
U.S. Patents Nos. 4,764,377 and 4,892,736 to Goodson disclose the use of a
therapeutic agent and a cyanoacrylate adhesive for treatment of periodontal
diseases.
The therapeutic agent, is placed within the periodontal pocket, then covered
by a
mechanical maintenance system (which may be in the form of a layer of an
adhesive
film, such as n-butylcyanoacrylate), which holds the therapeutic agent in the
periodontal
pocket, allowing the therapeutic agent to be administered to the periodontal
site.
Goodson and co-workers also disclose this type of system in, for example, "J.
Periodont.
Res", 1990, Vol. 25, 243-249, and "Recent Advances in Periodontology", Vol.
11, 61-
68. The therapeutic agents include antibacterial agents such as iodine,
sulfonamides,
mercurials, bisbiguanides, or phenolics; antibiotics such as tetracycline,
neomycin,
kanamycin, metranidazole, or canamycin; anti-inflammatory agents such as
indomethacin, eugenol, or hydrocortisone; immunosuppressive or stimulatory
agents
such as methotrexate or levamasole; dentinal desensitizing agents such as
strontium
chloride or sodium fluoride; odor masking agents such as~pepperniint oiI or
chlorophyll;
immune reagents such as immunoglobulin or antigens; local anesthetic agents
such as
lidocaine or benzocaine; nutritional agents such as amino acids, essential
fats, and
vitamin C; antioxidants such as alphatocopherol and butylated hydroxy toluene;
lipopolysaccharide complexing agents such as polymyxin; or peroxides such as
urea
peroxide. There is no suggestion of selecting the monomers and biocides such
that the
biocides affect polymerization.
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U.S. Patents Nos. 5,514,371 and 5,624,669 to Leung, et al. disclose the
addition
of a therapeutic agent in a cyanoacrylate composition. The cyanoacrylate
adhesive
forms a matrix for the therapeutic agent, with the therapeutic agent being
released in
vivo over time from the matrix during biodegradation of the polymer. The
therapeutic
S agent is not used as a polymerization initiator or a polymerization rate
modifier.
U.S. Patent No. 4,940,579 to Randen discloses a composition comprising a
medicament and a cyanoacrylate adhesive. The composition is used to deliver
medicaments to non-mucosal areas of mammal bodies. However, Randen does not
disclose the use of medicaments as polymerization initiators and/or rate
accelerators.
U.S. Patent No. 5,254,132 to Barley et al. discloses the use of cyanoacrylate
adhesives in conjunction with antibiotics. The antibiotics are added to the
cyanoacrylate
compositions and stored in a sterile applicator for use in a single-dose
application. The
composition is maintained in a sealed container to avoid polymerization prior
to
application; therefore, the antibiotic does not initiate or accelerate
polymerization of the
adhesive composition.
Typically, when used in medical applications, cyanoacrylate adhesives are
applied in monomeric form to the surfaces to be joined, sealed, or otherwise
treated.
Typically, in situ anionic polymerization of the monomer occurs, giving rise
to the
desired adhesive bond or covering. Initiation of polymerization in situ
typically utilizes
moisture and/or proteins naturally present in the tissue being treated. Thus,
in
applications where tissue fluids are present, it is not necessary to add
polymerization
initiators or rate accelerators to cyanoacrylate composition. However,
sometimes it is
desirable to apply the cyanoacrylate adhesives to dry tissues (i.e., tissues
that are
essentially free of tissue fluids or the like). In addition, to prolong the
shelf life of these
extremely reactive cyanoacrylate monomers, they are formulated with
stabilizers to
avoid their premature polymerization. In these situations; polymerization of
the
cyanoacrylate adhesive proceeds slowly, causing inconvenience to the user. To
overcome this inconvenience, polymerization initiators and/or rate
accelerators have
been added to the cyanoacrylate adhesive composition.
When an initiator or accelerator is added to the composition, it is not added
until
immediately prior to application of the adhesive. For example, U.S. Patent No.
4,042,442 to Dombroski et al. discloses the addition of a polymerization
initiator (either
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caffeine or theobromine) to a cyanoacrylate adhesive composition. The caffeine
or
theobromine is added to the adhesive composition in one of two ways. In the
first way,
the caffeine or theobromine can be mixed with the cyanoacrylate adhesive
composition
by stirnng just prior to application of the adhesive to the substrates to be
joined. In the
5 second way, the caffeine or theobromine is dissolved in a volatile solvent,
applied to the
surfaces to be joined, the volatile solvent is allowed to evaporate, and then
the
cyanoacrylate adhesive composition is applied to the surfaces of the
substrates to be
joined.
Commonly assigned PCT Application No. WO 96/40797, the disclosure of
which is hereby incorporated in its entirety, discloses the incorporation of a
polymerization initiator or polymerization rate modifier in an applicator tip.
Incorporation of the initiator or the rate modifier into the applicator tip
allows a level of
control over the polymerization rate that cannot be achieved through reliance
on
polymerization initiators naturally present at the wound site. Incorporation
of the
initiator and/or rate modifier into the applicator tip provides convenience to
the user,
since a single applicator is required, and no additional mixing is needed.
However, this
application does not disclose the use of a medicament as an initiator or
accelerator of
polymerization for monomeric cyanoacrylate compositions.
Although the use of medicaments in conjunction with cyanoacrylate adhesive
compositions is known, and the use of polymerization initiators with
cyanoacrylate
adhesive compositions is known, there exists a need to provide a method for
delivering
pharmaceutically-effective levels of medicaments to wound sites along with
cyanoacrylate adhesives that is convenient, reliable, and effective. To
address this need,
the present invention provides methods and compositions that use
pharmaceutically-
effective amounts of medicaments as polymerization initiators or accelerators
for
monomeric adhesive compositions.
SUMMARY OF THE INVENTION
According to the present invention, a medicament acts as both an initiator
and/or
an accelerator of polymerization of a monomeric adhesive composition and as a
pharmaceutically active material. As used herein, a polymerization initiator
is any
material that causes a cyanoacrylate composition applied to a substantially
dry tissue
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6
(i.e., in the substantial absence of plasma or Like tissue fluids) to
polymerize in less than
300 seconds at ambient temperature, for example approximately 21-25°C.
Preferably,
the initiator causes the cyanoacrylate composition to polymerize in less than
150
seconds, or more preferably less than 135 seconds at ambient temperature, for
example,
at approximately 21-25°C. As used herein, a polymerization accelerator
is any material
that accelerates the rate of polymerization of a cyanoacrylate composition
such that
polymerization that would normally take more than 300 seconds at ambient
temperature,
for example at approximately 21-25°C occurs in less than 300 seconds,
preferably in
less than 150 seconds, and more preferably in less than 135 seconds. The
initiator or
rate accelerator can be, for example, a catalyst, but can also be a material
that is
consumed or chemically modified during the polymerization reaction. The
medicament
can be any material that has both a pharmaceutical effect as applied and a
polymerization initiating or rate accelerating activity, including, but not
limited to,
antibiotics, antimicrobials, antiseptics, bacteriocins, bacteriostats,
disinfectants, steroids,
anesthetics, fungicides, anti-inflammatory agents, antibacterial agents,
antiviral agents,
antitumor agents, and tissue growth promoting substances.
The invention provides, among other things, a method of closing, sealing,
covering, and/or protecting deep and/or surface wounds, such as those
resulting from
surgery or from lacerations, burns, sores, abrasions, and the like. The method
includes
laying down a medicament onto a wound or sore and applying over the medicament
a
polymerizable monomer-containing composition whose polymerization is initiated
or
accelerated by the medicament.
In embodiments, the invention also provides a method of delivering a
medicament locally or systemically to a human or animal by applying the
medicament
to a tissue site and applying over the medicament a polymerizable monomer-
containing
composition whose polymerization is initiated or accelerated by the
medicament. As
used herein, tissue includes any tissue of a human or animal, such as skin,
mucous
membranes, oral/nasal tissues, gastrointestinal tissues, organ tissues,
tumors, non-
keratinous tissue, etc.
The present invention also provides a kit comprising a saleable package
containing (i) a container of a polymerizable monomer composition such as
described
herein, and (ii) a container of a medicament, preferably one that acts as a
polymerization
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initiator or polymerization rate modifier for said monomer composition. The
containers
can preferably be in the form of, or part of, an applicator or applicator
system and are
preferably sterilizable. For example, the package and its contents can
preferably be
sterilized simultaneously.
The present invention also provides a manufacture of a package comprising a
polymerizable monomer composition and an instruction sheet for a method of
delivering
a medicament to a patient, the method comprising:
applying a pharmaceutically effective amount of a medicament to a tissue of
said
patient, and
applying a polymerizable monomer composition onto the medicament,
wherein the medicament is a polymerization initiator or polymerization rate
accelerator and causes polymerization of the monomer composition to form a
polymeric
adhesive covering to said tissue.
The present invention provides several advantages over wound treating methods
now in use, including the ability to:
a) control the molecular weight distribution of the polymerized or cross
linked material (through the use of the polymerization initiator and/or
polymerization
rate accelerator);
b) control the setting time of the polymerized or cross-linked cyanoacrylate
adhesive;
c} control the flow properties of polymerizable cyanoacrylate compositions;
d) provide a medicament to a patient while simultaneously providing
wound closure, protection, and/or coverage;
e) provide a medicament to a patient through topical administration; and/or
f} any combination of the above.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
According to the invention, a medicament is applied to a tissue prior to
application of the monomer-containing composition. The medicament acts to
initiate
and/or accelerate polymerization of the monomer composition. Thus, the
medicament
provides not only a biological activity, but a chemical one as well.
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Examples of such medicaments include, but are not limited to antibiotics,
antimicrobials, antiseptics, bacteriocins, bacteriostats, disinfectants,
steroids,
anesthetics, fungicides, anti-inflammatory agents, antibacterial agents,
antiviral
agents, antitumor agents, growth promoters, and mixtures thereof.
Exemplary medicaments include; but are not limited to, quaternary ammonium
halides such as benzalkonium chloride and benzethonium chloride; chlorhexidine
sulfate; gentamicin sulfate; hydrogen peroxide; quinolone thioureas; silver
salts,
including, but not limited to, silver acetate, silver benzoate, silver
carbonate, silver
chloride, silver citrate, silver iodide, silver nitrate, and silver sulfate;
sodium
hypochlorite; salts of sulfadiazine, including, but not limited to silver,
sodium, and
zinc salts; and mixtures thereof.
Preferable medicaments are those that are anions or help in radical generation
or that are ion pairs or are themselves radicals.
In embodiments, the medicament is preferably a quaternary ammonium halide
such as alkylbenzyldimethylammonium chloride (benzalkonium chloride; BAC) with
an
alkyl containing 6-18 carbon atoms, its pure components, or mixtures thereof,
or
benzethonium chloride; or a salt of sulfadiazine, such as a silver, sodium, or
zinc salt.
The medicaments can be tested for initiation ability by pipetting an
appropriate
volume of a solution of the medicament prepared in a volatile solvent in a
differential
scanning calorimetric aluminum pan. The volatile solvent is allowed to dry
under
ambient conditions. Alternatively, the appropriate quantity of the medicament
is
dispensed directly onto the differential scanning calorimetric pan. In either
of the
abovementioned cases, 25 ~1 of the chosen monomer solution is pipetted into
the pan.
The time taken for the monomer composition to polymerize to the point of a gel
is the
polymerization time.
In embodiments, the composition can comprise other polymerization initiators
and/or rate accelerators in addition to the medicament. Particular additional
initiators
for particular systems may be readily selected by one of skill in the art
without undue
experimentation. Suitable additional polymerization initiators for the
cyanoacrylate
compositions include, but are not limited to, other medicaments; detergent
compositions; surfactants: e.g., nonionic surfactants such as polysorbate 20
(e.g., Tween
20~; ICI Americas), polysorbate 80 (e.g., Tween 80"'x; ICI Americas), and
poloxamers;
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cationic surfactants such as tetrabutylammonium bromide and benzethonium
chloride or
its pure components; anionic surfactants such as, stannous octoate (tin (I17 2-
ethylhexanoate), and sodium tetradecyl sulfate; and amphoteric or zwitterionic
surfactants such as dodecyldimethyl(3-sulfopropyl) ammonium hydroxide, inner
salt;
amines, imines and amides, such as imidazole, tryptamine, urea, arginine and
povidine;
phosphines, phosphites and phosphonium salts, such as triphenylphosphine and
triethyl
phosphite; alcohols such as ethylene glycol; methyl gallate; ascorbic acid;
tannins and
tannic acid; inorganic bases and salts, such as sodium bisulfite, magnesium
hydroxide,
calcium sulfate and sodium silicate; sulfi~r compounds such as thiourea and
polysulfides; polymeric cyclic ethers such as monensin, nonactin, crown
ethers,
calixarenes and polymeric epoxides; cyclic and acyclic carbonates, such as
diethyl
carbonate; phase transfer catalysts such as AliquatTM 336 (General Mills,
Minneapolis,
MIA; organometallics; manganese acetylacetonate; and radical initiators and
radicals,
such as di-t-butyl peroxide and azobisisobutyronitrile.
The polymerizable and/or cross-linkable material may also contain an initiator
which is inactive until activated by a catalyst or accelerator (included
within the scope of
the term "initiator" as used herein). These initiators can be activated by
appropriate
stimulation such as heat and/or light (e.g., ultraviolet or visible light).
Compositions employed in the invention are preferably sterilizable.
The amount of medicament applied should be an amount sufficient to cause
initiation or acceleration of the rate of polymerization upon contact and
mixing of the
medicament with the monomeric composition. The medicament should also be
applied
in a pharmaceutically-effective amount and should be selected in conjunction
with the
specific polymerizable monomeric compound such that the medicament will
function as
a polymerization initiator and/or rate accelerator for the chosen monomer.
Such a
selection process can easily be performed by one of skill in the art.
The medicament can have a pharmaceutical effect only at the site of
application
(i.e., limited to the tissue on/in which it is applied), or it can have a
systemic effect (by
systemic, it is not only meant that the medicament has an effect throughout
the patient's
body, but also at a specific site other than the site of application). In
embodiments
where the medicament is applied in an amount sufficient to show a systemic
pharmaceutical activity, it can be absorbed, transported, or otherwise
distributed to the
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site or sites within the patient where the pharmaceutical activity is desired,
e.g., through
the cardiovascular or lymph systems.
Depending on the particular requirements of the user, the medicament and
adhesive compositions of this invention can be applied by any appropriate
device, which
5 can be the same or different for the medicament and adhesive composition.
Examples
include, but are not limited to, a glass stirring rod, sterile brush, or
medicine dropper. In
many situations a pump or pressurized aerosol dispensing package is preferred
in which
the adhesive composition is in solution with a compatible anhydrous
propellant. A
preferred device is an absorbent swab or wipe.
10 The medicament may be in the form of a solid, such as a powder or a solid
film,
or in the form of a liquid, such as a watery, viscous, or paste-like material.
The
medicament may also be compounded with a variety of additives, such as
surfactants or
emulsifiers, and vehicles.
The methods of this invention can be used to join together two surfaces, as a
replacement for or in addition to sutures, by applying the present
compositions to
opposing wound surfaces that are then held together while polymerization
proceeds.
The methods of this invention can also be used to coat, protect, or otherwise
cover
surface, superficial, or otherwise topical wounds or pathologies including,
but not
limited to, superficial lacerations, abrasions, burns, sores, and stomatitis.
The methods
of the invention can also be used on tissues that do not show any signs of
tissue damage.
For example, the methods can be used to deliver medicaments to a patient
through
healthy tissue. They can also be used, for example, to locally deliver
medicaments to
tissues such as tumors or organs.
In one embodiment, the present invention provides a replacement for sutures
and
includes a method of delivering a medicament to a tissue by forming a
biocompadble
film across abutted tissue surfaces, comprising: (a) holding together at least
two tissue
surfaces to form abutted tissue surfaces, (b) applying a medicament which is a
polymerization initiator or polymerization rate accelerator to the abutted
tissue surfaces,
(c) applying on to the medicament and across the abutted tissue surfaces a
polymerizable adhesive monomer composition, and (d) allowing the composition
to
polymerize and form a biocompatible film on the abutted tissue surfaces. A
subsequent
coating may be applied immediately after application of a previous coating or
after a
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previous coating has been completely polymerized. Preferably, the monomer
composition applied to the abutted tissue surface is allowed to at least
partially
polymerize prior to subsequent coatings or applications of additional monomer
composition. A coating of an adhesive composition having a monomer different
from
the monomer of the first or previous coating may be applied as the second or
subsequent
coating.
Addition of a plasticizing agent and acidic stabilizing agent can cause such a
polymer coating to have sufficient bond strength and flexibility even with
significant
film or coating thicknesses. Suitable film thickness range from 0.1 mm to 2.0
mm or
3.0 mm or higher, preferably from 0.2 mm to 1.5 mm, and more preferably from
0.4 mm
to 0.8 mm.
In embodiments, the biocompatible film formed as a replacement for sutures
may have an in vivo film strength of at least 70 mm Hg of vacuum pressure
required to
induce wound failure, generally from 70 mm Hg to 400 mm Hg of vacuum pressure
required to induce wound failure, preferably from 90 mm Hg to 400 mm Hg of
vacuum
pressure required to induce wound failure, and more preferably from I00 mm Hg
to 400
mm Hg of pressure required to induce wound failure.
When repairing injured tissues (for example, to control bleeding), the
invention
comprises first sponging the site to be repaired to remove superficial or body
tissue
fluids. Desired bonding of tissues or hemostasis can also proceed well in the
presence
of blood and other body fluids as well as on dry tissue. The bonds formed are
of
adequate flexibility and strength to withstand normal movement of tissue. In
addition,
bond strength is maintained as natural wound healing proceeds.
In another embodiment, the present invention is directed to a method of
treating
a superficial or topical pathology, including, but not limited to a skin wound
such- as a
superficial laceration, bum, or abrasion, or a sore on a mucous membrane. The
method
comprises (a) applying a medicament that is a polymerization initiator or rate
accelerator
to the affected tissue, (b) applying a polymerizable monomer-containing
composition
over the medicament; (c) allowing the composition to polymerize; and (d)
optionally,
applying the composition at least once more to the same site.
Suitable film thickness for such topical applications is preferably between 1
and
10,000 pm, for example between 1 and 1000 pm. In embodiments, the
biocompatible
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12
filin so formed may have a film strength of at least 5 mm Hg, such as 5-400 mm
Hg,
preferably from 50-400 mm Hg.
In embodiments, the present invention provides a method of delivering a
medicament to a tissue by (a) applying a medicament that is a polymerization
initiator
S and/or polymerization rate accelerator to a site (e.g., directly to tissue);
(b) applying a
polymerizable monomer-containing composition over the medicament; and (c)
optionally, applying the composition at least once more to the same site.
Suitable filin
thickness and strength are preferably those disclosed above for other uses.
In embodiments, the medicament is released to the tissue to which it is in
contact
at a constant, or near constant, rate over a period of time while in contact
with the
affected tissue.
The present invention also provides a kit for delivering a medicament to a
patient. The kit comprises a container with a polymerizable monomer
composition, such
as a cyanoacrylate adhesive. The kit also comprises another container with a
medicament. The medicament is selected so that it fimctions in conjunction
with the co-
packaged polymerizable monomer composition to initiate polymerization of the
monomer or modify (e.g., accelerate) the rate of polymerization for the
monomer to
form a polymeric adhesive. The proper combination of medicament and
polymerizable
monomer can be determined easily by one of skill in the art. The medicament is
supplied in the kit in an amount that will be pharmaceutically effective when
applied
topically (i.e., directly to tissue).
The monomer composition, in embodiments, is preferably a monomeric
(including prepolymeric) adhesive composition. In embodiments, the monomer is
a 1,1-
disubstituted ethylene monomer, e.g., an a-cyanoacrylate. Preferred monomer
compositions of the present invention and polymers formed therefrom are
usefixl as
tissue adhesives, sealants for preventing bleeding or for covering open
wounds, and in
other biomedical applications. They find uses in, for example, opposing
surgically
incised or traumatically lacerated tissues; retarding blood flow from wounds;
drug
delivery; dressing burns; dressing skin or other superficial or surface wounds
(such as
abrasions, chaffed or raw skin, and/or stomatitis); and aiding repair and
regrowth of
living tissue.
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Monomers that may be used in this invention are readily polymerizable, e.g.
anionically polymerizable or free radical polymerizable, or polymerizable by
zwitterions
or ion pairs to form polymers. Such monomers include those that form polymers,
that
may, but do not need to, biodegrade. Such monomers are disclosed in, for
example,
U.S. Patent No. 5,328,687 to Leung, et al., which is hereby incorporated in
its entirety
by reference herein.
Useful 1,1-disubstituted ethylene monomers include, but are not limited to,
monomers of the formula:
(I) HRC~XY
wherein X and Y are each strong electron withdrawing groups, and R is H, -
CH=CHZ or,
provided that X and Y are both cyano groups, a C,-C4 alkyl group.
Examples of monomers within the scope of formula (I) include alpha-
cyanoacrylates, vinylidene cyanides, C,-C4 alkyl homologues of vinylidene
cyanides,
dialkyl methylene malonates, acylacrylonitriles, vinyl sulfinates and vinyl
sulfonates of
the formula CHZ CX'Y' wherein X' is -SO,R' or -S03R' and Y' is -CN, -COOR', -
COCH" -SOzR' or -SO,R', and R' is H or hydrocarbyl.
Preferred monomers of formula (I) for use in this invention are alpha-
cyanoacrylates. These monomers are known in the art and have the formula
CN
(II) HRZC =
COOR'
wherein RZ is hydrogen and R' is a hydrocarbyl or substituted hydrocarbyl
group; a
group having the formula -R'-O-RS-O-R6, wherein R" is a,1,2-alkylene group
having 2-4
carbon atoms, RS is an allcylene group having 2-4 carbon atoms, and R6 is an
alkyl group
having 1-6 carbon atoms; or a group having the formula
-R'- i-O-Re,
O
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14
wherein R' is
~3
,or-C(CH3)z -,
- (CHZ)n -~ CH -
wherein n is 1-10, preferably 1-5 carbon atoms and RB is an organic moiety.
Examples of suitable hydrocarbyl and substituted hydrocarbyl groups include
straight chain or branched chain alkyl groups having 1-16 carbon atoms;
straight chain
or branched chain C,-C,6 alkyl groups substituted with an acyloxy group, a
haloalkyl
group, an alkoxy group, a halogen atom, a cyano group, or a haloallcyl group;
straight
chain or branched chain alkenyl groups having 2 to 16 carbon atoms; straight
chain or
branched chain aiic~myl groups having 2 to 12 carbon atoms; cycloallcyl
groups; aralkyl
groups; alkylaryl groups; and aryl groups.
The organic moiety Ra may be substituted or unsubstituted and may be straight
chain, branched or cyclic, saturated, unsaturated or aromatic. Examples of
such organic
moieties include C,-C8 alkyl moieties, CZ-C$ alkenyl moieties, CZ C8 alkynyl
moieties,
C,-C,Z cycloaliphatic moieties, aryl moieties such as phenyl and substituted
phenyl and
aralkyl moieties such as benzyl, methylbenzyl and phenylethyl. Other organic
moieties
include substituted hydrocarbon moieties, such as halo (e.g., chloro-, fluoro-
and bromo-
substituted hydrocarbons) and oxy- (e.g., alkoxy substituted hydrocarbons)
substituted
hydrocarbon moieties. Preferred organic radicals are alkyl, alkenyl and
alkynyl moieties
having from 1 to about 8 carbon atoms, and halo-substituted derivatives
thereof.
Particularly preferred are alkyl moieties of 4 to 6 carbon atoms.
In the cyanoacrylate monomer of formula (II), R' is preferably an alkyl group
having 1-10 carbon atoms or a group having the formula -AOR9, wherein A is a
divalent
straight or branched chain alkylene or oxyalkylene moiety having 2-8 carbon
atoms, and
R9 is a straight or branched alkyl moiety having 1-8 carbon atoms.
Examples of groups represented by the formula -AOR9 include 1-methoxy-2-
propyl, 2-butoxy ethyl, isopropoxy ethyl, 2-methoxy ethyl, and 2-ethoxy ethyl.
Preferred a-cyanoacrylate monomers used in this invention include 2-octyl
cyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butyl
cyanoacrylate,
methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate, 2-butoxyethyl
cyanoacrylate, 2-
isopropoxyethyl cyanoacrylate, or 1-methoxy-2-propyl cyanoacrylate.
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The a-cyanoacrylates of formula (II) can be prepared according to methods
known in the art. U.S. Patents Nos. 2,721,858 and 3,254,111, each of which is
hereby
incorporated in their entirety by reference herein, disclose methods for
preparing
a-cyanoacrylates. For example, the a-cyanoacrylates can be prepared by
reacting an
alkyl cyanoacetate with formaldehyde in a non-aqueous organic solvent and in
the
presence of a basic catalyst, followed by pyrolysis of the anhydrous
intermediate
polymer in the presence of a polymerization inhibitor. The a-cyanoacrylate
monomers
prepared with low moisture content and essentially free of impurities are
preferred for
biomedical use.
10 The a-cyanoacrylates of.formula (II) wherein R' is a group having the
formula
R4-O-RS-O-R6 can be prepared according to the method disclosed in U.S. Patent
No.
4,364,876 to Kimura et aL, which is hereby incorporated in its entirety by
reference. In
the Kimura et ai. method, the a-cyanoacrylates are prepared by producing a
cyanoacetate by esterifying cyanoacetic acid with an alcohol or by
transesterifying an
15 alkyl cyanoacetate and an alcohol; condensing the cyanoacetate and
formaldehyde or
para-formaldehyde in the presence of a catalyst at a molar ratio of 0.5-1.5:1,
preferably
0.8-1.2: l, to obtain a condensate; depolymerizing the condensation reaction
mixture
either directly or after removal of the condensation catalyst to yield crude
cyanoacrylate;
and distilling the crude cyanoacrylate to form a high purity cyanoacrylate.
The a-cyanoacrylates of fomlula (II) wherein R' is a group having the formula
- R' - C - O - R
II
O
can be prepared according to the procedure described in U.S. Patent No.
3,995,641 to
Kronenthal et al., which is hereby incorporated in its entirety by reference.
In the
Kronenthal et al. method, such a-cyanoacrylate monomers are prepared by
reacting an
alkyl ester of an a-cyanoacrylic acid with a cyclic 1,3-dime to form a Diels-
Alder
adduct which is then subjected to alkaline hydrolysis followed by
acidification to form
the corresponding a-cyanoacrylic acid adduct. The a-cyanoacrylic acid adduct
is
preferably esterified by an alkyl bromoacetate to yield the con esponding
carbalkoxymethyl a-cyanoacrylate adduct. Alternatively, the a-cyanoacrylic
acid
adduct may be converted to the a-cyanoacrylyl halide adduct by reaction with
thionyl
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16
chloride. The a-cyanoacrylyl halide adduct is then reacted with an alkyl
hydroxyacetate
or a methyl substituted alkyl hydroxyacetate to yield the corresponding
carbalkoxymethyl a-cyanoacrylate adduct or carbalkoxy alkyl a-cyanoacrylate
adduct,
respectively. The cyclic 1,3-diene blocking group is finally removed and the
carbalkoxy
methyl a-cyanoacrylate adduct or the carballcoxy alkyl a-cyanoacrylate adduct
is
converted into the corresponding carballcoxy alkyl a-cyanoacrylate by heating
the
adduct in the presence of a slight deficit of malefic anhydride.
Examples of monomers of formula (I>) include cyanopentadienoates and a-
cyanoacrylates of the formula:
CN
(III) HZC =
COOK'
wherein Z is -CH=CHz and R' is as defined above. The monomers of formula (III)
wherein R' is an alkyl group of 1-10 carbon atoms, i.e., the 2-cyanopenta-2,4-
dienoic
acid esters, can be prepared by reacting an appropriate 2-cyanoacetate with
acrolein in
the presence of a catalyst such as zinc chloride. This method of preparing 2-
cyanopenta-
2,4-dienoic acid esters is disclosed, for example, in U.S. Patent No.
3,554,990, which is
hereby incorporated in its entirety by reference.
Preferred monomers are alkyl a-cyanoacrylates and more preferably octyi a-
cyanoacrylates, especially 2-octyl a-cyanoacrylate. Monomers utilized in the
present
application should be very pure and contain few impurities (e.g., surgical
grade).
The composition nay optionally also include at least one plasticizing agent
that
imparts flexibility to the polymerized monomer formed on the wound, incision,
or
abrasion. The plasticizing agent preferably contains little or no moisture and
should not
significantly affect the polymerization of the monomer.
Examples of suitable plasticizers include acetyl tributyl citrate, dimethyl
sebacate, triethyl phosphate, tri(2-ethylhexyl)phosphate, trip-cresyl)
phosphate,
glyceryl triacetate, glyceryl tributyrate, diethyl sebacate, dioctyl adipate,
isopropyl
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17
myristate, butyl stearate, lauric acid, trioctyl trimellitate, dioctyl
glutarate and mixtures
thereof. Preferred plasticizers are tributyl citrate and acetyl tributyl
citrate. In
embodiments, suitable plasticizers include polymeric plasticizers, such as
polyethylene
glycol (PEG) esters and capped PEG esters or ethers, polyester glutarates and
polyester
adipates.
The composition may also optionally include at least one stabilizing agent
that
inhibits polymerization. Such stabilizing agents may also include mixtures of
anionic
stabilizing agents and radical stabilizing agents.
Examples of suitable anionic stabilizing agents include, but are not limited
to,
sultones (e.g., a-chloro-a-hydroxy-o-toluenesulfonic acid-y-sultone), sulfur
dioxide,
sulfuric acid, suifonic acid, lactone, boron trifluoride, organic acids, such
as acetic acid
or phosphoric acid, alkyl sulfate, alkyl sulfite, 3-sulfolene, alkylsulfone,
alkyl sulfoxide,
mercaptan, and alkyl sulfide and mixtures thereof. Preferable anionic
stabilizing agents
are acidic stabilizing agents of organic acids such as acetic acid or
phosphoric acid. In
embodiments, the amount of sulfur dioxide stabilizer is less than 100 ppm,
preferably 5-
75 ppm, and more preferably from about 20-SO ppm. The amount of sultone and/or
trifluoracetic acid is about 500-3000 ppm.
Examples of suitable radical stabilizing agents include hydroquinone,
hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone, 2-
hydroxybenzoquinone, p-methoxy phenol, t-butyl catechol, butylated hydroxy
arusole
(BHA), butylated hydroxy toluene, and t-butyl hydroquinone. In embodiments,
the
amount of BHA is about 1,000-5,000 ppm.
Suitable acidic stabilizing agents include those having aqueous pKa ionization
constants ranging from -12 to 7, about -5 to about 7, preferably from about -
3.5 to about
6. For example, suitable acidic stabilizing agents include: hydrogen sulfide
(pKa 7.0),
carbonic acid (pK, 6.4), triacetytmethane (pK, 5.9), acetic acid (pK, 4.8),
benzoic acid
(pK,~ 4.2), 2,4-dinitmphenol (pK, 4.0), formic acid (pK, 3.7), nitrous acid
(pKa 3.3),
hydrofluoric acid (pK, 3.2), chloroacetic acid (pK, 2.9), phosphoric acid (pK,
2.2),
dichloroacetic acid (pI~ 1.3), trichloroacetic acid (pKa 0.7), 2,4,6-
trinitrophenol (picric
acid) (pKe 0.3), trifluoroacetic acid (pK, 0.2), sulfuric acid (pK, -3.0),
sulfurous acid,
and mixtures thereof. In embodiments, the amount of trifluoroacetic acid is
about
500-1,500 ppm. Combinations of the above stabilizers, such as sulfur dioxide
and
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18
sulfuric acid, boron trifluoride and sulfiuic acid, sulfiu dioxide and
chloroacetic acid,
boron trifluoride and chloroacetic acid, sulfi~r dioxide and trifluoroacetic
acid, and boron
trifluoride and triflouroacetic acid can be used.
When adding the acidic stabilizing agents mentioned above to the adhesive
composition, the addition of plasticizing agents in amounts ranging from about
0.5 wt.%
to about 16 wt.%, preferably from about 3 wt.% to about 9 wt.%, and more
preferably
from about 5 wt.% to about 7 wt.% provides increased film strength (e.g.,
toughness) of
the polymerized monomer over polymerized monomers having amounts of
plasticizing
agents and acidic stabilizing agents outside of the above ranges.
The concentration of the acidic stabilizing agents utilized may vary depending
on the strength of the acid. For example, when using acetic acid, a
concentration of 80-
200 ppm (wt/wt), preferably 90-180 ppm (wt/wt), and more preferably 100-150
ppm
(wt/wt) may be utilized. When using a stronger acid such as phosphoric acid, a
concentration range of 20-80 ppm (wt/wt), preferably, 30-70 ppm (wt/wt) and
more
preferably 40-60 ppm (wt/wt) may be utilized. In embodiments, the amount of
trifluoroacetic acid is about 100 to 3000 ppm, preferably S00-1500 ppm. In
other
embodiments, the amount of phosphoric acid is about 10-200 ppm, preferably
about 50-
150 ppm, and more preferably about 75-125 ppm.
The compositions of the present invention may also include at least one
biocompatible agent effective to reduce active formaldehyde concentration
levels
produced during in vivo biodegradation of the polymer (also referred to herein
as
"formaldehyde concentration reducing agents"). Preferably, this component is a
formaldehyde scavenger compound. Examples of formaldehyde scavenger compounds
useful in this invention include sulfites; bisulfites; mixtures of sulfites
and bisulfites;
ammonium sulfite salts; amines; amides; imides; nitriles; carbamates;
alcohols;
mercaptans; proteins; mixtures of amines, amides, and proteins; active
methylene
compounds such as cyclic ketones and compounds having a b-dicarbonyl group;
and
heterocyclic ring compounds free of a carbonyl group and containing an NH
group, with
the ring made up of nitrogen or carbon atoms, the ring being unsaturated or,
when fused
to a phenyl group, being unsaturated or saturated, and the NH group being
bonded to a
carbon or a nitrogen atom, which atom is directly bonded by a double bond to
another
carbon or nitrogen atom.
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19
Bisulfites and sulfites useful as the fornzaldehyde scavenger compound in this
invention include alkali metal salts such as lithium, sodium and potassium
salts, and
ammonium salts, for example, sodium bisulfite, potassium bisulfite, lithium
bisulfite,
ammonium bisulfite, sodium sulfite, potassium sulfite, lithium sulfite,
ammonium
sulfite, and the like.
Examples of amines useful in this invention include the aliphatic and aromatic
amines such as, for example, aniline, benzidine, aminopyrimidine, toluene-
diamine,
triethylenediamine, diphenylamine, diaminodiphenylamine, hydrazines and
hydrazide.
Suitable proteins include collagen, gelatin, casein, soybean protein,
vegetable
protein, keratin, and glue. The preferred protein for use in this invention is
casein.
Suitable amides for use in this invention include urea, cyanamide, acrylamide,
benzamide, and acetamide. Urea is a preferred amide.
Suitable alcohols include phenols, 1,4-butanediol, d-sorbitol, and polyvinyl
alcohol.
Examples of suitable compounds having a b-dicarbonyl group include malonic
acid, acetylacetone, ethylacetone, acetate, malonamide, diethyhnalonate or
another
malonic ester.
Preferred cyclic ketones for use in this invention include cyclohexanone or
cyclopentanone.
Examples of suitable heterocyclic compounds for use as the formaldehyde
scavenger in this invention are disclosed, for example, in U.S. Patent No.
4,127,382
(ferry) which is hereby incorporated in its entirety by reference. Such
heterocyclic
compounds include, for example, benzimidazole, 5-methyl benzimidazole, 2-
methylbenzimidazole, indole, pyrrole, 1,2,4-triazole, indoline, benzotriazole,
indoline,
and the like.
A preferred formaldehyde scavenger for use in this invention is sodium
bisulfite.
In practicing the present invention, the formaldehyde concentration reducing
agent, e.g., formaldehyde scavenger compound, is added in an effective amount
to the
cyanoacrylate. The "effective amount" is that amount sufficient to reduce the
amount of
formaldehyde generated during subsequent in vivo biodegradation of the
polymerized
cyanoacrylate. This amount will depend on the type of active formaldehyde
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concentration reducing agent, and can be readily determined without undue
experimentation by those skilled in the art.
The formaldehyde concentration reducing agent may be used in this invention in
either free form or in microencapsulated form. Other compositions are
exemplified by
5 U.S. Patent Application Serial No. 08/714,288, incorporated by reference
herein in its
entirety.
When microencapsulated, the formaldehyde concentration reducing agent is
released from the microcapsule continuously over a period of time during the
in vivo
biodegradation of the cyanoacrylate polymer.
10 For purposes of this invention, the microencapsulated form of the
formaldehyde
concentration reducing agent is preferred because this embodiment prevents or
substantially reduces polymerization of the cyanoacrylate monomer by the
formaldehyde concentration reducing agent, which increases shelf life and
facilitates
handling of the monomer composition during use.
15 Microencapsulation of the formaldehyde scavenger can be achieved by many
known microencapsulation techniques. For example, microencapsulation can be
carried
out by dissolving a coating polymer in a volatile solvent, e.g., methylene
chloride, to a
polymer concentration of about 6% by weight; adding a formaldehyde scavenger
compound in particulate form to the coating polymer/solvent solution under
agitation to
20 yield a scavenger concentration of 18% by weight; slowly adding a
surfactant-
containing mineral oil solution to the polymer solution under rapid agitation;
allowing
the volatile solvent to evaporate under agitation; removing the agitator;
separating the
solids from the mineral oil; and washing and drying the microparticles. The
size of the
microparticles will range from about 0.001 to about 1000 microns.
The coating polymer for microencapsulating the formaldehyde concentration
reducing agent should be polymers which undergo in vivo bioerosion, preferably
at rates
similar to or greater than the cyanoacrylate polymer formed by the monomer,
and
should have low inherent moisture content. Such bioerosion can occur as a
result of the
physical or chemical breakdown of the encapsulating material, for example, by
the
encapsulating material passing from solid to solute in the presence of body
fluids, or by
biodegradation of the encapsulating material by agents present in the body.
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Examples of coating materials which cambe used to microencapsulate the
formaldehyde concentration reducing agent include polyesters, such as
polyglycolic
acid, polylactic acid, poly-1,4-dioxa-2-one, polyoxaltes, polycarbonates,
copolymers of
polyglycolic acid and polylactic acid, polycaprolactone, poly-b-
hydroxybutyrate,
copolymers of epsilon-caprolactone and delta-valerolactone, copolymers of
epsilon-
caprolactone and DL-dilactide, and polyester hydrogels; polyvinylpyrrolidone;
polyamides; gelatin; albumin; proteins; collagen; poly(orthoesters);
poly(anhydrides);
poly(alkyl-2-cyanoacrylates); poly(dihydropyrans); poly(acetals);
poly(phosphazenes);
poly(urethanes); poly(dioxinones); cellulose; and starches.
Examples of surfactants which can be added to the mineral oil include those
commercially available under the designations Triton X-100TM (Rohm and Haas),
Tween 20TM (ICI Americas), and Tween 80TM (ICI Americas).
The composition may also optionally include at least one thickening agent.
Suitable thickeners include, for example, polycyanoacrylates, polylactic acid,
poly-1,4-
1 S dioxa-2-one, polyoxalates, polyglycolic acid, lactic-glycolic acid
copolymers,
polycaprolactone, lactic acid-caprolactone copolymers, poly-3-hydroxybutyric
acid,
polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl
acetate,
polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene.
Examples of alkyl methacrylates and acrylates are poly(2-ethylhexyl
methacrylate) and
poly(2-ethylhexyl acrylate), also poly(butylinethacrylate) and
poly(butylacrylate), also
copolymers of various acrylate and methacrylate monomers, such as
poly(butylmethacrylate-co-methylacrylate).
To improve the cohesive strength of adhesives formed from the compositions of
this invention, difunctional monomeric cross-linking agents may be added to
the
monomer compositions of this invention. Such crosslinking agents are known.
U.S.
Patent No. 3,940,362 to Overhults, which is hereby incorporated in its
entirety by
reference, discloses such cross-linking agents. Examples of suitable
crosslinking agents
include alkyl bis(2-cyanoacrylates), triallyl isocyanurates, alkylene
diacrylates, alkylene
dimethacrylates, trimethylol propane triacrylate, and alkyl bis(2-
cyanoacrylates). A
catalytic amount of an amine activated free radical initiator or rate modifier
may be
added to initiate polymerization or to modify the rate of polymerization of
the
cyanoacrylate monomer/crosslinking agent blend.
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22
The compositions of this invention may further contain fibrous reinforcement
and colorants, i.e., dyes and pigments. Examples of suitable fibrous
reinforcement
include PGA microfibrils, collagen microfibrils, cellulosic microfibrils, and
olefinic
microfibrils. Examples of suitable colorants include 1-hydroxy-4-[4-
methylphenyl-
amino]-9,10 anthracenedione (D+C violet No. 2); disodium salt of 6-hydroxy-5-
[(4-
sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD+C Yellow No. 6); 9-{0-
carboxyphen0yl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one, disodium salt,
monohydrate (FD+C Red No. 3); 2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-
2,3-dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt (FD+C Blue No. 2);
and
[phtha-locyaninato (2-)] copper.
Other compositions that are contemplated by the present invention are
exemplified by U.S. Patents Nos. 5,624,669; 5,582,834; 5,575,997; 5,514,371;
5,514,372; and 5,259,835; the disclosures of all of which are hereby
incorporated in
their entirety by reference.
Example
A sample of 120 microliters.of 1000 ppm BAC solution in methanol was
tested for its initiation property with 2-octyl cyanoacrylate in accordance
with the
method described above. The following polymerization times were obtained:
Sample Number Set Time lseconds)
1 109
2 106
111
4 121
102
6 101
7 109
8 57
126
