US 200802939 10A1

(19) United States

(12) Patent Application Publication (10) Pub. No.: US 2008/0293910 A1
Kapiamba et al. (43) Pub. Date: Nov. 27, 2008
(54) ADHESIVE FORMULATIONS Publication Classification

(75) Inventors: Mbiya Kapiamba, Cromwell, CT (51) Int. Cl.

(US); Ahmad R. Hadba, CSG 18/7 (2006.01)
Wallingford, CT (US) C08G 63/66 (2006.01)

Correspondence Address: (52) U.S. Cl. .............. 528/70; 528/332: 528/361; 528/76
Tyco Healthcare Group LP
6O MODLETOWN AVENUE
NORTH HAVEN, CT 06473 (US) (57) ABSTRACT
(73) Assignee: Tyco Healthcare Group LP The disclosure relates to biocompatible components useful
for forming compositions for use as medical/surgical Syn
(21) Appl. No.: 12/124,414 thetic adhesives and sealants. Biocompatible components of
the present disclosure may include a multifunctional amine or
(22) Filed: May 21, 2008 multifunctional polyol core, with isocyanate and/or polyalky
Related U.S. Application Data lene oxide arms, which may optionally be capped with elec
trophilic or nucleophilic groups. These biocompatible com
(60) Provisional application No. 60/931,571, filed on May ponents may, in embodiments, be combined with optional
24, 2007. cross linkers to form adhesive and/or sealant compositions.
US 2008/02939 10 A1 Nov. 27, 2008

ADHESIVE FORMULATIONS
-continued
CROSS-REFERENCE TO RELATED (II)
APPLICATIONS O

0001. This application claims the benefit of and priority to

U.S. Provisional Patent Application No. 60/931,571, filed
ls
May 24, 2007, the entire disclosure of which is incorporated
by reference herein. 0009 wherein I may be a core including multifunctional
polyols and multifunctional amines,
TECHNICAL FIELD 0010 X may be carboxylic acids, isocyanates, isothiocy
0002 The present disclosure relates to adhesives and seal anates, and combinations thereof,
ants formed from Synthetic components for medical and Sur 0011 Y may be polyalkylene oxides, polyether polyes
gical use with animal tissues in vivo. ters, polyether polyurethanes, polyether polyester urethanes,
and combinations thereof,
BACKGROUND OF RELATED ART 0012 Z may be N-hydroxysuccinimide, N-hydroxysulfo
Succinimide, pentafluorophenol, p-nitrophenol, and combi
0003. In recent years there has developed an increased nations thereof,
interest in replacing or augmenting Sutures with adhesive 0013 R may be alkyl, aryl, ether, and combinations
bonds. The reasons for this increased interest include: (1) the thereof, and
potential speed with which repair might be accomplished; (2) 0014 w is a number from about 3 to about 250.
the ability of a bonding substance to effect complete closure, 0015. In embodiments, the present disclosure provides a
thus preventing seepage of fluids; and (3) the possibility of biocompatible composition which includes the above bio
forming a bond without excessive deformation of tissue or compatible component in combination with a cross linker. As
additional injury to tissue. noted above, the biocompatible composition may, in embodi
0004 Studies in this area, however, have revealed that in ments, be utilized as an adhesive or sealant.
order for Surgical adhesives to be accepted by Surgeons, they 0016. The present disclosure also provides methods for
should possess various properties. For example, they should producing these compositions. In embodiments, the present
exhibit high initial tack and an ability to bond rapidly to living disclosure provides a method which includes providing a
tissue; the strength of the bond should be sufficiently high to multifunctional amine possessing a functionality of at least 3,
cause tissue failure before bond failure; the adhesive should contacting the multifunctional with a diisocyanate to forman
form a bridge, typically a permeable flexible bridge; and the isocyanate functionalized polyamine, contacting the isocyan
adhesive bridge and/or its metabolic products should not ate functionalized polyamine with a polyalkylene oxide to
cause local histotoxic or carcinogenic effects. form a polyalkylene oxide capped polyamine, contacting the
0005. Several materials useful as tissue adhesives or tissue polyalkylene oxide capped polyamine with an anhydride to
sealants are currently available. One type of adhesive that is form a carboxylic acid group at the terminus of the polyalky
currently available is a cyanoacrylate adhesive. However, lene oxide, and reacting the carboxylic acid group at the
there is the possibility that a cyanoacrylate adhesive can terminus of the polyalkylene oxide with N-hydroxysuccin
degrade to generate undesirable by-products Such as formal imide.
dehyde. Another disadvantage with cyanoacrylate adhesives 0017. In other embodiments, methods of the present dis
is that they can have a high elastic modulus which can limit closure include providing a polyol possessing a functionality
their usefulness.
0006 Another type of tissue sealant that is currently avail of at least 3, contacting the polyol with a diisocyanate to form
able utilizes components derived from bovine and/or human an isocyanate functionalized polyol, contacting the isocyan
sources. For example, fibrin sealants are available. However, ate functionalized polyol with a polyalkylene oxide to form a
as with any natural material, variability in the material is polyalkylene oxide capped polyol, contacting the polyalky
frequently observed and, because the sealant is derived from lene oxide capped polyol with an anhydride to form a car
natural proteins, there may be viral transmission concerns. boxylic acid group at the terminus of the polyalkylene oxide,
0007. It would be desirable to provide a biological adhe and reacting the carboxylic acid group at the terminus of the
sive or sealant that is fully synthetic and therefore highly polyalkylene oxide with N-hydroxysuccinimide.
consistent in its properties without the concern of viral trans 0018. The compositions of the present disclosure can be
mission. Such a composition should be flexible and biocom applied by a variety of methods, including spraying the com
patible and should be suitable for use as an adhesive or seal positions onto a Surgical site. In embodiments, the present
ant. disclosure includes methods for closing wounds by applying
a composition of the present disclosure to a wound and allow
SUMMARY ing the composition to set, thereby closing said wound. Such
wounds may include, in embodiments, incisions. Composi
0008. The present disclosure provides biocompatible tions of the present disclosure may also be utilized to seal
compositions which may be utilized as adhesives, sealants, leaks in animal. In embodiments, compositions of the present
and the like. In embodiments, the present disclosure provides disclosure may also be utilized to adhere a medical device,
a biocompatible component such as: Such as an implant, to a Surface of animal tissue.
DETAILED DESCRIPTION
(I)
I-(X-Y-Z) or 0019. The present disclosure relates to biocompatible
compositions for use as tissue adhesives or sealants, which
US 2008/02939 10 A1 Nov. 27, 2008

are biocompatible, non-immunogenic and biodegradable. 0025. Examples of multifunctional amines which may be
The biocompatible compositions can be employed to utilized to form a multifunctional core in accordance with the
approximate tissue edges, adhere medical devices (e.g. present disclosure include, but are not limited to, poly(allyl
implants) to tissue, seal air/fluid leaks in tissues, and for tissue amine), poly(L-lysine), polyalkylene oxides having three or
augmentation Such as sealing or filling voids or defects in more amine functional groups, polyethylene oxide/polypro
tissue. Thus, as used herein, an “adhesive' is understood to pylene oxide copolymers possessing three or more amine
include a composition which adheres one thing to another, functional groups, trilysine, diethylene triamine, di(heptam
Such as tissue edges to each other or a device. Such as an ethylene)triamine, di(trimethylene)triamine, bis(hexameth
implant, to tissue, and a 'sealant' is understood to include a ylene)triamine, triethylene tetramine, tripropylene tetramine,
composition which is applied to tissue and utilized to seal tetraethylene pentamine, hexamethylene heptamine, penta
air/fluid leaks in tissue or seal or fill small voids or defects in
tissue. However, an adhesive composition herein may be used ethylene hexamine, dimethyl octylamine, dimethyl decy
as a sealant, and a sealant composition may be used as an lamine, rh-collagen, rh-gelatin, chitosan, combinations
adhesive. thereof, and the like.
0020. The biocompatible compositions can be applied to 0026. Where the multifunctional core is a multifunctional
living tissue and/or fleshofanimals, including humans. While amine, the amine can have a molecular weight of from about
certain distinctions may be drawn between the usage of the 130 g/mol to about 100,000 g/mol, in embodiments from
terms “flesh” and “tissue' within the scientific community, about 132 g/mol to about 10,000 g/mol.
the terms are used interchangeably herein as referring to a 0027. The multifunctional core may, in embodiments, be
general substrate upon which those skilled in the art would combined with groups such as polyalkylene oxides (“PAO”),
understand the present composition to be utilized within the isocyanates, combinations thereof, and the like, which groups
medical field for the treatment of patients. As used herein, may form arms extending from the multifunctional core
“tissue' may include, but is not limited to, skin, bone, neuron, thereby forming a biocompatible component of the present
axon, cartilage, blood vessel, cornea, muscle, fascia, brain, disclosure.
prostate, breast, endometrium, lung, pancreas, Small intes 0028 Suitable polyalkylene oxides which may be com
tine, blood, liver, testes, ovaries, cervix, colon, stomach, bined with a multifunctional core include, but are not limited
esophagus, spleen, lymph node, bone marrow, kidney, to, polyethylene glycols (“PEG'), polypropylene glycols
peripheral blood, embryonic tissue, and/or ascite tissue. (“PPG), polyethylene oxides (“PEO), polypropylene
0021. In accordance with the present disclosure, a bio oxides (“PPO), polyethylene glycols with lactide linkages,
compatible component is provided which includes a multi polypropylene glycol-co-polyethylene oxide block or ran
functional core. Suitable cores which may be utilized include, dom copolymers, polyethylene oxide/polypropylene oxide
but are not limited to, multifunctional polyols, multifunc copolymers, sometimes referred to herein as PEO/PPO
tional amines, polythiols, and the like. As used herein “mul copolymers or poloxamers, including triblock PEO/PPO
tifunctional includes a core possessing at least 3 functional copolymers commercially available as PLURONICSR) from
groups, in embodiments from about 3 to about 250 functional BASF Corporation (Mt. Olive, N.J.), combinations thereof,
groups, in embodiments from about 4 to about 12 functional and the like.
groups, in other embodiments from about 5 to about 8 func 0029. As noted above, in some embodiments the multi
tional groups. functional core can be combined with an isocyanate. Suitable
0022. Examples of multifunctional polyols which may be isocyanates for combination with the multifunctional core
utilized to form a multifunctional core in accordance with the include aromatic, aliphatic and alicyclic isocyanates, includ
present disclosure include, but are not limited to, polyether ing polyisocyanates. Examples include, but are not limited to,
polyols; polyester polyols; block copolymers including aromatic diisocyanates Such as 2,4-toluene diisocyanate, 2.6-
branched chain ethoxylated alcohols; alkoxylated alcohols toluene diisocyanate, 2,2'-diphenylmethane diisocyanate,
such as NEODOL(R) which is sold commercially by Shell 2,4'-diphenylmethane diisocyanate, 4,4'-diphenylmethane
Chemical Company; polyvinyl alcohols; polyhydric alco diisocyanate, diphenyldimethylmethane diisocyanate, diben
hols; carboxylic acid esters of polyhydric alcohols; polygly Zyl diisocyanate, naphthylene diisocyanate, phenylene diiso
cols; polylactone polyols; combinations thereof, and the like. cyanate, Xylylene diisocyanate, 4,4'-oxybis(phenyl isocyan
0023. In some embodiments, suitable polyols for use as ate), and/or 2,4,6-trimethyl-1,3-phenylene diisocyanate;
the multifunctional polyol include polyether-based polyols, aliphatic diisocyanates Such as tetramethylxylylene diisocy
polyester-based polyols such as polycaprolactone-based anate, tetramethylene diisocyanate, hexamethylene diisocy
polyols, and polyhydric alcohols such as glycerol, pen anate, lysine diisocyanate, 2-methylpentane-1,5-diisocyan
taerythritol, sorbitol, mannitol, trimethylol propane, diethyl ate, 3-methylpentane-1,5-diisocyanate, hexane-1,6-
ene glycol, pentaerythritol ethoxylate, pentaerythritol pro diisocyanate, and/or 2,2,4-trimethylhexamethylene
poxylate, dipentaerythritiol, combinations thereof, and the diisocyanate; and alicyclic diisocyanates such as isophorone
like. In some embodiments, the polyol can be glycerol, trim diisocyanate, cyclohexane diisocyanate, hydrogenated
ethylol propane, hexane-1,2,6-triol, polycaprolactone triol, Xylylene diisocyanate, hydrogenated diphenylmethane diiso
or any polyol obtained by partial reaction of any polyol with cyanate, and/or hydrogenated trimethylxylylene diisocyan
polyisocyanates, polycarboxylic acid derivatives, combina ate. In embodiments, combinations of the foregoing isocyan
tions thereof, and the like, to create longer polymeric mol ates may be utilized.
ecules. 0030. In some embodiments, isocyanates which may be
0024. Where the multifunctional core is a multifunctional combined with the multifunctional cores include, but are not
polyol, the polyol can have a molecular weight of from about limited to, toluene diisocyanate (TDI), 4,4'-diphenylmethane
130 g/mol to about 20,000 g/mol, in embodiments from about diisocyanate (MDI), isophorone diisocyanate (IPDI), hexam
134 g/mol to about 1000 g/mol. ethylene diisocyanate (HMDI), m-tetramethylxylylene diiso
US 2008/02939 10 A1 Nov. 27, 2008

cyanate (m-TMXDI), p-tetramethylxylylene diisocyanate ate, ester ethers such as dioxanones including 1,4-dioxane-2-
(p-TMXDI), and combinations thereof. one and 1,3-dioxane-2-one, diacids including Succinnic acid,
0031. In embodiments, the multifunctional core may be adipic acid, sebacic acid, malonic acid, glutaric acid, azelaic
combined with multiple groups forming arms thereon, acid, phosphoesters such as ethyl dichlorophosphate, anhy
including both isocyanates and polyalkylene oxides noted drides including sebacic acid anhydride and azelaic acid
above. Methods for combining Such components are within anhydride, combinations thereof, and the like. Those skilled
the purview of those skilled in the art. In embodiments, each in the art will readily envision reaction schemes for incorpo
free hydroxy group of a multifunctional polyol, or each free rating these degradable linkages into the biocompatible com
amine group of a multifunctional amine, may be combined ponent of the present disclosure.
with an isocyanate, polyalkylene oxide, combinations 0037. The biocompatible component of the present disclo
thereof, and the like. Sure may thus, in embodiments, possess the following for
0032. In embodiments, the multifunctional core may first mula:
be combined with a diisocyanate, thereby forming a multi
functional core possessing isocyanate arms. The free isocy
anate group of the diisocyanate may then, in embodiments, be (I)
I-(X-Y-Z) or
reacted with a polyalkylene oxide as described above, thereby (II)
forming arms having a diisocyanate adjacent the multifunc O
tional core, followed by a polyalkylene oxide.
0033. In other embodiments, the multifunctional core may
first be combined with a polyalkylene oxide, thereby forming
ls
a multifunctional core possessing polyalkylene oxide arms.
The free hydroxyl groups on the polyalkylene oxide arms 0038 wherein I may be a multifunctional core as
may then be reacted, in embodiments, with a diisocyanate as described above, for example a multifunctional polyol or a
described above. The free isocyanate group of the diisocyan multifunctional amine,
ate group may then, in embodiments, be reacted with an 0039 X may be a functional group that allows the attach
additional polyalkylene oxide as described above, thereby ment of a diol or diamine macromer/polymer Such as a car
forming arms having a polyalkylene oxide adjacent the mul boxylic acid, an isocyanate, isothiocyanate, or combinations
tifunctional core, followed by a diisocyanate, followed by thereof,
another polyalkylene oxide. 0040 Y may be a polymeric or macromeric diol or
0034. The free hydroxyl groups of the polyalkylene oxide diamine, including a polyalkylene oxide, a polyether polyes
groups furthest from the multifunctional core may then, in ter, a polyether polyurethane, a polyether polyester urethane,
embodiments, be further functionalized with an end group or combinations thereof, optionally possessing amine groups,
within the purview of those skilled in the art. Examples of 0041 Z may be a group that forms an activated ester and
Such functional groups include nucleophilic groups, electro allows increased reactivity toward amines, such as NHS,
philic groups, combinations thereof, and the like. sulfo-NHS, pentafluorophenol, p-nitrophenol, and combina
0035. In some embodiments it may be desirable to func tions thereof,
tionalize the polyalkylene oxides at the ends of the arms of the 0042 R may be an alkyl, aryl, ether, or combinations
biocompatible component of the present disclosure with elec thereof capable of being derived from a reactive diacid or
trophilic groups. For example, in some embodiments the free anhydride, and
hydroxyl groups may be converted to carboxylic groups by 0043 w may be a number from about 3 to about 250, in
reacting them with anhydrides Such as Succinic anhydride in embodiments from about 4 to about 12, in other embodiments
the presence of tertiary amines such as pyridine or triethy from about 5 to about 8.
lamine or dimethylaminopyridine ("DMAP). Other anhy 0044. In some embodiments it may be desirable to forman
drides which may be utilized include, but are not limited to, adduct of a diisocyanate with a hydrophilic polymer Such as a
glutaric anhydride, phthalic anhydride, maleic anhydride, polyalkylene oxide including ethylene glycolor polyethylene
combinations thereof, and the like. The resultant terminal glycol and use the resulting adduct to functionalize a multi
carboxyl groups may then be converted to an activated ester functional core inaccordance with the present disclosure. The
by reacting with N-hydroxysuccinimide (NHS) and/or N-hy adduct may be formed by reacting a polyalkylene oxide as
droxysulfosuccinimide (Sulfo-NHS), optionally in the pres described above with a diisocyanate described above, fol
ence of dicyclohexylcarbodiimide (DCC) and/or N-(3-dim lowed by reacting the free cyanate group of the diisocyanate
ethylaminopropyl)carbodiimide (EDC), to produce with another polyalkylene oxide.
N-hydroxysuccinimide ester groups, which are electrophilic, 0045. In yet other embodiments, polyalkylene oxides hav
at the ends of the arms of the biocompatible component of the ing functional groups such as Succinimidyl groups may be
present disclosure. obtained from commercial sources. For example, activated
0036. In embodiments, the multifunctional core, the arms, forms of polyethylene glycol described above having electro
or both, may include degradable linkages so as to render the philic groups are commercially available from Shearwater
components of the present disclosure degradable, as well as Polymers, Huntsville, Ala., and Union Carbide, South
any composition including these components. Suitable Charleston, W. Va. Thus, in some embodiments, these func
degradable linkages which can be optionally incorporated in tionalized polyalkylene oxides may be utilized to form arms
the biocompatible component and/or compositions of the on a multifunctional core as described above, with no further
present disclosure include, but are not limited to, hydrolyti functionalization necessary.
cally labile C-hydroxy acids such as lactic acid, glycolic acid, 0046. The resulting adduct may then be added to the mul
and hydroxy-butyric acid, glycolide, lactide, lactones includ tifunctional core so that one of the polyalkylene oxides
ing e-caprolactone, carbonates such as trimethylene carbon becomes attached to the multifunctional core while the free
US 2008/02939 10 A1 Nov. 27, 2008

polyalkylene oxide is available for activation by the forming polyoxyalkylene amines from Texaco Chemical Co. under
of electrophilic groups such as N-hydroxySuccinimide esters the JEFFAMINE(R) brand as D230, D400, D2000, T403, and
as described above. In other embodiments, the adduct may T-3000. Combinations of the foregoing polyether diamines
possess one polyalkylene oxide activated with an electro may be utilized in embodiments.
philic group Such as N-hydroxysuccinimide esters as 0052. In some embodiments, the amine cross linker can be
described above, in some embodiments obtained from a com an amino functional polymer Such as those sold under the
mercial source, which may then be attached to the multifunc JEFFAMINE(R) brand, a poly(allylamine), poly(L-lysine), or
tional core. other amino functional polymers such as a polyalkylene
0047. The electrophilic groups at the ends of the arms of oxide, including PEG. PEO and PPO having two or more
the biocompatible component of the present disclosure may amine functional groups.
then be reacted with a nucleophilic group. Such as an amine 0053 Other suitable amine cross linkers include chitosan,
cross linker or a polyol, polythiol or polyphosphine, to pro recombinant proteins such as rh-collagen, rh-gelatin and rh
duce an adhesive or sealant composition in accordance with albumin, recombinant glycosaminoglycans such as rh-hyalu
the present disclosure. As would be readily apparent to one ronic acid, combinations thereof, and the like.
skilled in the art, the desired properties of the compositions of 0054. In embodiments, combinations of the foregoing
the present disclosure can be adjusted by the selection of the cross linkers may be utilized to forman adhesive composition
specific components utilized to prepare the resulting adhesive and/or sealant composition of the present disclosure.
or sealant compositions. 0055 An adhesive composition and/or sealant composi
0048 Suitable amine crosslinkers which may be reacted tion of the present disclosure may thus possess the biocom
with the biocompatible component of the present disclosure patible component of the present disclosure in an amount of
include those multifunctional amines described above which from about 10 to about 100 percent by weight of the compo
may be used as the multifunctional core. Amine cross linkers sition, in embodiments from about 50 to about 90 percent by
which may be utilized include, for example, primary amines, weight of the composition, with the cross linker component of
secondary amines, diamines, aromatic amines, polyamines, the adhesive composition and/or sealant composition present
polyamidoamines, and combinations thereof. Multifunc in an amount of from about 0 to about 90 percent by weight of
tional amines may also include primary aliphatic amines, the composition, in embodiments from about 10 to about 50
primary aromatic amines, secondary aliphatic or alicyclic percent by weight of the composition.
amines, and/or secondary aromatic amines. The amine group 0056. In some embodiments, the weight ratio of the bio
may be linked to the multifunctional cores by other groups compatible component of the present disclosure to the cross
Such as ester, amide, ether, amine, combinations thereof, and linker in a composition of the present disclosure may be from
the like. Suitable amines which may be utilized as the amine about 5000:1 to about 2.5:1, in embodiments from about
cross linker include poly(allyl amine), poly(L-lysine), poly 1000:1 to about 10:1.
alkylene oxides having two or more primary or secondary 0057 The resulting composition of the present disclosure
amine functional groups, spermidine, spermine, 1,4-bis(3- can be used in a medical/surgical capacity in place of, or in
aminopropyl)piperazine, diaminobicyclooctane, and the like. combination with, Sutures, staples, clamps, combinations
0049 Other examples of suitable amines which may be thereof, and the like.
used as the at least one amine cross linker include, but are not 0.058 Optional components may be added to the compo
limited to, triethylamine, diisopropylethylamine, ethylene sition of the present disclosure to adjust its viscosity accord
diamine, 1,4-butane diamine, hexamethylene diamine, iso ing to a specific application of use, e.g., as an adhesive or a
mers of hexamethylene diamine, diethylene triamine, trieth sealant. Such optional components can include, for example,
ylene tetramine, lysine and lysine containing polypeptides, diethylene glycol dimethyl ether (“DIGLYME), dimethyl
arginine and arginine containing polypeptides, tetraethylene formamide (“DMF), dimethyl succinate, dimethylglutarate,
pentamine, bishexamethylene triamine, N,N'-Bis(3-amino dimethyl adipate, combinations thereof, and the like. Thick
propyl)-1,2-ethane diamine, N-(3-Aminopropyl)-1,3-pro ening agents which can be used to adjust the viscosity of the
pane diamine, N-(2-aminoethyl)-1.3 propane diamine, cyclo compositions of the present disclosure include polycy
hexane diamine, isomers of cyclohexane diamine, 4,4'- anoacrylates, polylactic acid, polyglycolic acid, lactic-gly
methylene biscyclohexane amine, 4'4'-methylene bis(2- colic acid copolymers, poly-3-hydroxybutyric acid, poly
methylcyclohexane amine), isophorone diamine, orthoesters, polyanhydrides, pectin, combinations thereof,
phenalkylene polyamines, combinations thereof, and the like. and the like.
0050 Aromatic amines may also be used as the amine 0059. Where utilized, such additives can be included so
cross linker. Suitable aromatic amines include, for example, that they are present in an amount of from about 1 to about 30
di-(4-aminophenyl)sulfone, di-(4-aminophenyl)ether, 2.2- percent by weight of the composition, in embodiments from
bis(4-aminophenyl)propane, 4,4'-diamino diphenylmethane, about 2 to about 15 percent by weight of the composition.
3,3'-dimethyl-4,4'-diaminodiphenyl methane, m-phenylene 0060 Optionally, stabilizers can also be added to increase
diamine, p-phenylene diamine, m-xylylene diamine, toluene the storage stability of the compositions of the present dis
diamine, 4,4'-methylene dianiline, benzidine, 4,4'-thiodi closure. Suitable stabilizers can include those which prevent
aniline, 4-methoxy-1,3-phenyldiamine, 2,6-diaminopyri premature polymerization Such as quinones, hydroquinone,
dine, dianisidine, combinations thereof, and the like. hindered phenols, hydroquinone monomethyl ether, catechol,
0051 Polyether diamines may also be utilized as the pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-meth
amine cross linker. Suitable polyether diamines include, but oxyphenol, t-butyl catechol, butylated hydroxyanisole, buty
are not limited to, 4,9-dioxadodecane-1,12-diamine, 4,7,10 lated hydroxy toluene, t-butyl hydroquinone, combinations
trioxamidecane-1,12-diamine, bis(3-amino propyl)polytet thereof, and the like. Suitable stabilizers can also include
rahydrofurans, Bis(3-aminopropyl)amine, 1.2-Bis(3-amino anhydrides, silyl esters, Sultones (e.g., C.-chloro-O-hydroxy
propylamino)ethane, and commercially available o-toluenesulfonic acid-y-Sultone), Sulfur dioxide, Sulfuric
US 2008/02939 10 A1 Nov. 27, 2008

acid, Sulfonic acid, Sulfurous acid, lactone, borontrifluoride, nates, hyaluronic acid, pectins, dextrans, cellulosics such as
organic acids, alkyl sulfate, alkyl Sulfite, 3-sulfolene, alkyl carboxymethyl cellulose, methyl cellulose, combinations
Sulfone, alkyl Sulfoxide, mercaptan, alkyl Sulfide, combina thereof, and the like.
tions thereof, and the like. In some embodiments, an anhy 0067. The biocompatible component may be present in the
dride Such as maleic anhydride, sebacic acid anhydride, and/ first solution in an amount from about 10% to about 100% by
oraZelaic acid anhydride, can be used as a stabilizer. In other weight of the first solution, in embodiments from about 50%
embodiments antioxidants such as Vitamin E, Vitamin K1, to about 90% by weight of the first solution. The amount of
cinnamic acid, and/or flavanone can be used as stabilizers. cross linker in the aqueous media, sometimes referred to
0061. Where utilized, such stabilizers can be included so herein as a second solution, may be from about 0.01% to
that they are present in an amount from about 0.01 to about 10 about 10% by weight of the second solution, in embodiments
percent by weight of the composition, in embodiments from from about 0.05% to about 5% by weight of the second
about 0.1 to about 2 percent by weight of the composition. solution. Where present, a biodegradable thickener may be
0062. In some embodiments, solid supported catalysts present in an amount from about 0% to about 10% by weight
of the second solution.
may be used during synthesis to improve stability of the
resulting composition of the present disclosure. The presence 0068. The first component solution and the second cross
of such catalysts may increase reactivity during use. Suitable linker Solution may then be combined upon application to
catalysts are within the purview of those skilled in the art and form a sealant or adhesive composition of the present disclo
can include Stannous octoate, triethylamine, diethylaminoet Sure. For example, the composition of the present disclosure
hanol, dimethylaminopyridine (DMAP), combinations can be dispensed from a conventional adhesive dispenser,
thereof, and the like. The amount of catalyst employed can be which may provide mixing of the first and second compo
from about 0.5 grams to about 50 grams per kilogram of the nents prior to the dispenser. Such dispensers are disclosed, for
other components of the composition. example, in U.S. Pat. Nos. 4,978.336, 4.361,055, 4,979.942,
4,359,049, 4,874,368, 5,368,563, and 6,527,749, the disclo
0063. The compositions of the present disclosure can be sures of each of which are incorporated by reference herein.
used for a number of different human and animal medical 0069. In some embodiments, a dual-compartment appli
applications including, but not limited to, wound closure cator may be utilized and mixing of the first component
(including Surgical incisions and other wounds), adhesives Solution and second component solution may occur to form
for medical devices (including implants), Void fillers, and an adhesive upon dispensing by an aerosol or by means of a
embolic agents. Adhesive compositions and/or sealant com mixing head attached to the applicator or Syringe. Other addi
positions may be used to bind tissue together either as a tives can be introduced into the first component Solution, the
replacement of, or as a Supplement to, Sutures, staples, second component Solution, or both.
clamps, tapes, bandages, and the like. Use of the disclosed 0070 For example, the adhesive composition may be
compositions can eliminate or Substantially reduce the num sprayed onto mammalian tissue, which lowers the risk of
ber of sutures normally required during current practices, and additional mechanical stress on the tissue. The spray applica
eliminate the Subsequent need for removal of Staples and tion can be by any means within the purview of those skilled
certain types of Sutures. The compositions of the present in the art such that the composition can be applied as a fine
disclosure thus can be particularly useful for use with delicate mist or aerosol. For example, the composition can be placed
tissues where sutures, clamps or other conventional tissue in a spray bottle and delivered with a hand pump. Alterna
closure mechanisms may cause further tissue damage. tively, the composition can be placed in a container with a
0064. Application of the compositions of the present dis non-chlorofluorohydrocarbon propellant (e.g., air, nitrogen,
closure, with or without other additives, can be done by any carbon dioxide, and/or hydrocarbons) and delivered using a
conventional means. These include dripping, brushing, or pressurized spray can. In either case, the composition is
other direct manipulation of the composition on the tissue passed through a fine orifice to form a mist and delivered to
Surface, by Syringe. Such as with a mixer nozzle, or spraying the Surgical location.
of the composition onto the Surface. In open Surgery, appli 0071. In other embodiments, especially where the compo
cation by hand, forceps, or the like is contemplated. In endo sition of the present disclosure is to be utilized as a void filler
scopic Surgery, the composition can be delivered through the or to fill a defect in an animal's body, it may be advantageous
cannula of atrocar, and spread at the site by any device within to more precisely control the conditions and extent of cross
the purview of those skilled in the art. linking; in Such a case, it may be desirable to partially cross
0065. In embodiments, the biocompatible component of link the composition prior to its use to fill a void in animal
the present disclosure, optionally in combination with the tissue. The composition of the present disclosure may then be
cross linker, may be dissolved in a solvent to form a solution applied to the void or defect and allowed to set, thereby filling
for application. Suitable solvents include those that are water the void or defect.
miscible and biologically acceptable for medical/surgical 0072 To effectuate the joining of two tissue edges, the two
use. In some embodiments, the solvents can include DIG edges may be approximated, and the biocompatible compo
LYME (diethylene glycol dimethyl ether), N,N-dimethylfor nent may be applied in combination with the cross linker. In
mamide (“DMF'), dimethylsulfoxide, combinations thereof, other embodiments, the biocompatible component may be
and the like. applied to one tissue edge, the cross linker may be applied to
0066. In embodiments, the biocompatible component may a second tissue edge, and the two edges then brought into
be in a first solution, with the at least one cross linker dis contact with each other. The components crosslink rapidly,
Solved in an aqueous media which optionally contains at least generally taking less than one minute. The composition of the
one biodegradable thickener. Suitable biologically accept present disclosure can thus be used as an adhesive to close a
able thickeners include disaccharides, polysaccharides, algi wound, including a Surgical incision. In such a case, the
US 2008/02939 10 A1 Nov. 27, 2008

composition of the present disclosure can be applied to the gesic agents, anti-inflammatory agents, vasodilators, antihy
wound and allowed to set, thereby closing the wound. pertensive and antiarrhythmic agents, hypotensive agents,
0073. In another embodiment, the present disclosure is antitussive agents, antineoplastics, local anesthetics, hor
directed to a method for using the adhesive composition of the mone preparations, antiasthmatic and antiallergic agents,
present disclosure to adhere a medical device to tissue, rather antihistaminics, anticoagulants, antispasmodics, cerebral cir
than secure two edges of tissue. In some aspects, the medical culation and metabolism improvers, antidepressant and anti
device includes an implant. Other medical devices include, anxiety agents, vitamin D preparations, hypoglycemic
but are not limited to, pacemakers, stents, shunts and the like. agents, antiulcer agents, hypnotics, antibiotics, antifungal
In some embodiments, depending on the composition of the agents, sedative agents, bronchodilator agents, antiviral
medical device, a coating may be required on the medical agents, dysuric agents, combinations thereof, and the like.
device. In some aspects Such a coating can include the bio 0079 Imaging agents such as iodine, barium sulfate, or
compatible component of the present disclosure in combina fluorine, can also be combined with the compositions of the
tion with the cross linker. Generally, for adhering a device to present disclosure to allow visualization of the Surgical area
the Surface of animal tissue, the composition of the present through the use of imaging equipment, including X-ray, MRI,
disclosure can be applied to the device, the tissue surface, or and/or CAT scan.
both. In other embodiments, the biocompatible component of 0080 Additionally, an enzyme may be added to the com
the present disclosure can be applied to either the device or the positions of the present disclosure to increase their rate of
tissue surface, with the crosslinker applied to the other (i.e., degradation. Suitable enzymes include, for example, peptide
where the biocompatible component has not been applied). hydrolases such as elastase, cathepsin G, cathepsin E, cathe
The device and tissue surface are then brought into contact psin B, cathepsin H. cathepsin L, trypsin, pepsin, chymot
with each other and the composition is allowed to set, thereby rypsin, Y-glutamyltransferase (Y-GTP), and the like; Sugar
adhering the device and tissue Surface to each other. chain hydrolases such as phosphorylase, neuraminidase, dex
0074 The composition of the present disclosure can also tranase, amylase, lysozyme, oligosaccharase, and the like;
be used to prevent post Surgical adhesions. In such an appli oligonucleotide hydrolases such as alkaline phosphatase,
cation, the composition may be applied and cured as a layer endoribonuclease, endodeoxyribonuclease, and the like. In
on Surfaces of internal tissues in order to prevent the forma Some embodiments, where an enzyme is added, the enzyme
tion of adhesions at a Surgical site during the healing process. may be included in a liposome or microsphere to control the
In addition to the formation of adhesion barriers, in embodi rate of its release, thereby controlling the rate of degradation
ments the adhesive may be utilized to form implants such as of the composition of the present disclosure. Methods for
gaskets, buttresses or pledgets for implantation. incorporating enzymes into liposomes and/or microspheres
0075. In another embodiment, the composition can be are within the purview of those skilled in the art.
used to attach skin grafts and position tissue flaps during I0081. The present compositions have a number of advan
reconstructive Surgery. In still another embodiment, the com tageous properties. The resulting compositions of the present
position can be used to close tissue flaps in periodontal Sur disclosure are safe and biocompatible, possess enhanced
gery. adherence to tissue, are biodegradable, have hemostatic
0076 Applications for the compositions of the present potential, have low cost, and are easy to prepare and use. The
disclosure also include sealing tissues to prevent or control composition has a rapid curing time. Application of the com
blood or other fluid leaks at suture or staple lines. In embodi position, with or without other additives, can be done by any
ments, the composition can be used to seal or adhere delicate conventional means. By varying the selection of the compo
tissue together in place of conventional tools that may cause nents, the strength and elasticity of the adhesive and/or seal
mechanical stress. The composition can also be used to seal ant composition can be controlled, as can the gelation time.
air and/or fluid leaks in tissue. Additionally, the composition I0082. The compositions rapidly form a compliant gel
can be applied to tissue as a barrier to prevent adhesions, matrix, which insures stationary positioning of tissue edges or
provide a protective layer for delicate damaged tissue and/or implanted medical devices in the desired location where the
provide a drug delivery layer to a Surgical site. composition is utilized as an adhesive, and a tightly adherent
0077. When used as a sealant, the composition of the yet flexible seal where the composition is used as a sealant. In
present disclosure can be used in Surgery to prevent or inhibit either case, the rapidity of gelation lowers the overall required
bleeding or fluid leakage both during and after a Surgical Surgical/application time. Where delicate or spongy tissues
procedure. It can also be applied to prevent air leaks associ are involved and/or air or fluid leaks must be sealed, spray
ated with pulmonary Surgery. The sealant may be applied application of a composition may be utilized to avoid stress to
directly to the desired area in at least an amount necessary to the tissue and insure a uniform coating over the area.
seal off any defect in the tissue and seal off any fluid or air I0083. The compositions retain the positional integrity of
moVement. the tissue to which the composition is applied and/or location
0078. A variety of optional ingredients including medici of a medical device. The compositions form strong cohesive
nal agents may also be added to the compositions of the bonds. They exhibit excellent mechanical performance and
present disclosure. These agents may be added to adhesive strength, while retaining the necessary pliability to adhere
compositions of the present disclosure, Sealant compositions living tissue. This strength and pliability allows a degree of
of the present disclosure, or both. A phospholipid surfactant movement of tissue without shifting the Surgical tissue edge.
that provides antibacterial stabilizing properties and helps Additionally, the compositions are biodegradable, allowing
disperse other materials in the compositions may be added to the degradation components to pass safely through the Sub
the compositions of the present disclosure. Additional ject's body.
medicinal agents include antimicrobial agents, colorants, pre I0084. It will be understood that various modifications may
servatives, or medicinal agents such as, for example, protein be made to the embodiments disclosed herein. For example,
and peptide preparations, antipyretic, antiphlogistic and anal the compositions in accordance with this disclosure can be
US 2008/02939 10 A1 Nov. 27, 2008

blended with other biocompatible, bioabsorbable or non-bio tide linkages, polypropylene glycol-co-polyethylene oxide
absorbable materials. As another example, optional ingredi copolymers, polyethylene oxide/polypropylene oxide
ents such as dyes, fillers, medicaments or antimicrobial com copolymers, and combinations thereof.
pounds can be added to the composition. Therefore, the above 6. The biocompatible component of claim 1, wherein the
description should not be construed as limiting, but merely as isocyanate comprises a diisocyanate selected from the group
exemplifications of embodiments. Those skilled in the art will consisting of aromatic diisocyanates, aliphatic diisocyanates
envision other modifications within the scope and spirit of the and alicyclic diisocyanates.
claims appended hereto. 7. The biocompatible component of claim 6, wherein the
What is claimed is:
diisocyanate is selected from the group consisting of 2,4-
toluene diisocyanate, 2,6-toluene diisocyanate, 2,2'-diphe
1. A biocompatible component selected from the group nylmethane diisocyanate, 2,4'-diphenylmethane diisocyan
consisting of: ate, 4,4'-diphenylmethane diisocyanate,
diphenyldimethylmethane diisocyanate, dibenzyl diisocyan
ate, naphthylene diisocyanate, phenylene diisocyanate,
I-(X-Y-Z), and
(I) Xylylene diisocyanate, 4,4'-oxybis(phenyl isocyanate), 2.4.6-
trimethyl-1,3-phenylene diisocyanate, tetramethylxylylene
(II) diisocyanate, tetramethylene diisocyanate, hexamethylene
O
diisocyanate, lysine diisocyanate, 2-methylpentane-1,5-di
ls isocyanate, 3-methylpentane-1,5-diisocyanate, hexane-1,6-
diisocyanate, 2,2,4-trimethylhexamethylene diisocyanate,
isophorone diisocyanate, cyclohexane diisocyanate, hydro
wherein I comprises a core selected from the group con genated Xylylene diisocyanate, hydrogenated diphenyl
sisting of multifunctional polyols and multifunctional methane diisocyanate, hydrogenated trimethylxylylene
amines, diisocyanate, and combinations thereof.
8. A composition comprising the biocompatible compo
X is selected from the group consisting of carboxylic acids, nent of claim 1 in combination with a cross linker.
isocyanates, isothiocyanates, and combinations thereof, 9. The composition of claim 8, wherein the cross linker
Y is selected from the group consisting of polyalkylene comprises a polyfunctional amine cross linker selected from
oxides, polyether polyesters, polyether polyurethanes, the group consisting of primary amines, secondary amines,
polyether polyester urethanes, and combinations diamines, aromatic amines, polyamines, polyamidoamines,
thereof, and combinations thereof.
Z is selected from the group consisting of N-hydroxysuc 10. The composition of claim 8, wherein the cross linker
cinimide, N-hydroxysulfoSuccinimide, pentafluorophe comprises an amine cross linker selected from the group
nol, p-nitrophenol, and combinations thereof, consisting of poly(allylamine), poly(L-lysine), polyalkylene
R is selected from the group consisting of alkyl, aryl, ether, oxides having two or more amine functional groups, spermi
and combinations thereof, and dine, spermine, 1,4-bis(3-aminopropyl)piperazine, diamino
w is a number from about 3 to about 250. bicyclooctane, triethylamine, diisopropylethylamine, ethyl
2. The biocompatible component of claim 1, wherein the ene diamine, 1,4-butane diamine, hexamethylene diamine,
multifunctional polyol is selected from the group consisting diethylene triamine, triethylene tetramine, lysine, lysine con
of polyether polyols, polyester polyols, branched chain taining polypeptides, arginine, arginine containing polypep
ethoxylated alcohols, alkoxylated alcohols, polyvinyl alco tides, tetraethylene pentamine, bishexamethylene triamine,
hols, polyhydric alcohols, carboxylic acid esters of polyhy N,N'-Bis(3-aminopropyl)-1,2-ethane diamine, N-(3-Amino
dric alcohols, polyglycols, polylactone polyols, and combi propyl)-1,3-propane diamine, N-(2-aminoethyl)-13 propane
nations thereof. diamine, cyclohexane diamine, 4,4'-methylene biscyclohex
3. The biocompatible component of claim 1, wherein the ane amine, 4'4'-methylene bis(2-methylcyclohexane amine),
multifunctional polyol is selected from the group consisting isophorone diamine, phenalkylene polyamines, di-(4-ami
of hexane-1,2,6-triol, polycaprolactone triol, glycerol, pen nophenyl)sulfone, di-(4-aminophenyl)ether, 2.2-bis(4-ami
taerythritol, sorbitol, mannitol, trimethylol propane, diethyl nophenyl)propane, 4,4'-diamino diphenylmethane, 3,3'-dim
ene glycol, pentaerythritol ethoxylate, pentaerythritol pro ethyl-4,4'-diaminodiphenyl methane, m-phenylene diamine,
poxylate, dipentaerythritol, and combinations thereof. p-phenylene diamine, m-xylylene diamine, toluene diamine,
4. The biocompatible component of claim 1, wherein the 4,4'-methylene dianiline, benzidine, 4,4'-thiodianiline,
multifunctional amine is selected from the group consisting 4-methoxy-1,3-phenyldiamine, 2,6-diaminopyridine, diani
of poly(allyl amine), poly(L-lysine), polyalkylene oxides sidine, 4.9-dioxadodecane-1,12-diamine, 4,7,10-trioxamide
having three or more amine groups, polyethylene oxide/ cane-1,12-diamine, bis(3-amino propyl)polytetrahydro
polypropylene oxide copolymers possessing three or more furans, Bis(3-aminopropyl)amine, 1.2-Bis(3-
amine groups, trilysine, diethylene triamine, di(heptamethyl aminopropylamino)ethane, polyoxyalkylene amines, and
ene)triamine, di(trimethylene)triamine, bis(hexamethylene) combinations thereof.
triamine, triethylene tetramine, tripropylene tetramine, tetra 11. The composition of claim8, wherein the biocompatible
ethylene pentamine, hexamethylene heptamine, component of claim 1 is present in an amount from about 50
pentaethylene hexamine, dimethyl octylamine, dimethyl to about 90 percent by weight of the composition, and the
decylamine, rh-collagen, rh-gelatin, chitosan, and combina cross linker is present in an amount from about 10 to about 50
tions thereof. percent by weight of the composition.
5. The biocompatible component of claim 1, wherein the 12. A method for closing a wound comprising:
polyalkylene oxide is selected from the group consisting of applying the composition of claim 8 to said wound; and
polyethylene glycols, polypropylene glycols, polyethylene allowing the composition to set thereby closing said
oxides, polypropylene oxides, polyethylene glycols with lac wound.
US 2008/02939 10 A1 Nov. 27, 2008

13. A method for sealing a leak in animal tissue compris polypropylene oxides, polyethylene glycols with lactide link
1ng: ages, polypropylene glycol-co-polyethylene oxide copoly
applying the composition of claim 8 to said leak; and mers, polyethylene oxide/polypropylene oxide copolymers,
allowing the composition to set thereby sealing said leak. and combinations thereof.
14. A method for adhering a medical device to a surface of 19. The method of claim 15, wherein the anhydride is
animal tissue comprising: selected from the group consisting of Succinic anhydride,
applying the composition of claim 8 to said device, said glutaric anhydride, phthalic anhydride, maleic anhydride,
surface or both; and combinations thereof.
bringing the device, composition and Surface into contact 20. A method comprising:
with each other; and providing a polyol possessing a functionality of at least 3:
allowing the composition to set thereby adhering the contacting the polyol with a diisocyanate to form an iso
device and Surface to each other. cyanate functionalized polyol;
15. A method comprising: contacting the isocyanate functionalized polyol with a
providing a multifunctional amine possessing a function polyalkylene oxide to form a polyalkylene oxide capped
ality of at least 3: polyol;
contacting the multifunctional amine with a diisocyanate contacting the polyalkylene oxide capped polyol with an
to form an isocyanate functionalized polyamine; anhydride to form a carboxylic acid group at the termi
contacting the isocyanate functionalized polyamine with a nus of the polyalkylene oxide; and
polyalkylene oxide to form a polyalkylene oxide capped reacting the carboxylic acid group at the terminus of the
polyamine; polyalkylene oxide with N-hydroxysuccinimide.
contacting the polyalkylene oxide capped polyamine with 21. The method of claim 20, wherein the polyol is selected
an anhydride to form a carboxylic acid group at the from the group consisting of polyether polyols, polyester
terminus of the polyalkylene oxide; and polyols, branched chain ethoxylated alcohols, alkoxylated
reacting the carboxylic acid group at the terminus of the alcohols, polyvinyl alcohols, polyhydric alcohols, carboxylic
polyalkylene oxide with N-hydroxysuccinimide. acid esters of polyhydric alcohols, polyglycols, polylactone
16. The method of claim 15, wherein the multifunctional polyols, and combinations thereof.
amine is selected from the group consisting of poly(allyl 22. The method of claim 20, wherein the diisocyanate is
amine), poly(L-lysine), polyalkylene oxides having three or selected from the group consisting of 2,4-toluene diisocyan
more amine groups, polyethylene oxide/polypropylene oxide ate, 2,6-toluene diisocyanate, 2,2'-diphenylmethane diisocy
copolymers possessing three or more amine groups, trilysine, anate, 2,4'-diphenylmethane diisocyanate, 4,4'-diphenyl
diethylene triamine, di(heptamethylene)triamine, di(trimeth methane diisocyanate, diphenyldimethylmethane
ylene)triamine, bis(hexamethylene)triamine, triethylene tet diisocyanate, dibenzyl diisocyanate, naphthylene diisocyan
ramine, tripropylene tetramine, tetraethylene pentamine, ate, phenylene diisocyanate, Xylylene diisocyanate, 4,4'-oxy
hexamethylene heptamine, pentaethylene hexamine, dim bis(phenyl isocyanate), 2,4,6-trimethyl-1,3-phenylene diiso
ethyl octylamine, dimethyl decylamine, rh-collagen, rh-gela cyanate, tetramethylxylylene diisocyanate, tetramethylene
tin, chitosan, and combinations thereof. diisocyanate, hexamethylene diisocyanate, lysine diisocyan
17. The method of claim 15, wherein the diisocyanate is ate, 2-methylpentane-1,5-diisocyanate, 3-methylpentane-1,
selected from the group consisting of 2,4-toluene diisocyan 5-diisocyanate, hexane-1,6-diisocyanate, 2,2,4-trimethyl
ate, 2,6-toluene diisocyanate, 2,2'-diphenylmethane diisocy hexamethylene diisocyanate, isophorone diisocyanate,
anate, 2,4'-diphenylmethane diisocyanate, 4,4'-diphenyl cyclohexane diisocyanate, hydrogenated Xylylene diisocyan
methane diisocyanate, diphenyldimethylmethane ate, hydrogenated diphenylmethane diisocyanate, hydroge
diisocyanate, dibenzyl diisocyanate, naphthylene diisocyan nated trimethylxylylene diisocyanate, and combinations
ate, phenylene diisocyanate, Xylylene diisocyanate, 4,4'-oxy thereof.
bis(phenyl isocyanate), 2,4,6-trimethyl-1,3-phenylene diiso 23. The method of claim 20, wherein the polyalkylene
cyanate, tetramethylxylylene diisocyanate, tetramethylene oxide is selected from the group consisting of polyethylene
diisocyanate, hexamethylene diisocyanate, lysine diisocyan glycols, polypropylene glycols, polyethylene oxides,
ate, 2-methylpentane-1,5-diisocyanate, 3-methylpentane-1, polypropylene oxides, polyethylene glycols with lactide link
5-diisocyanate, hexane-1,6-diisocyanate, 2,2,4-trimethyl ages, polypropylene glycol-co-polyethylene oxide copoly
hexamethylene diisocyanate, isophorone diisocyanate, mers, polyethylene oxide/polypropylene oxide copolymers,
cyclohexane diisocyanate, hydrogenated Xylylene diisocyan and combinations thereof.
ate, hydrogenated diphenylmethane diisocyanate, hydroge 24. The method of claim 20, wherein the anhydride is
nated trimethylxylylene diisocyanate, and combinations selected from the group consisting of Succinic anhydride,
thereof. glutaric anhydride, phthalic anhydride, maleic anhydride,
18. The method of claim 15, wherein the polyalkylene and combinations thereof.
oxide is selected from the group consisting of polyethylene
glycols, polypropylene glycols, polyethylene oxides, c c c c c