Note: Descriptions are shown in the official language in which they were submitted.
CA 02353436 2001-06-01
WO 00/33778 PCT/US99/29091
Ynains~suY bactcricWal Aosarbeat Drasdog nd biethod of F.ubricatioa
Fi~ ef he ++vrs+drnt
S Tivs iavontion seriwes ge=ally to absorbeat dressiags, and more Psraculatiy
hWy-
~sarbent syntiudc polymer drusiags having saamic:obial agents attaobud dereto.
Bscses3al gww in sbsorbent dmmngs for womds, ttaaary in1=ti2mce dispers, and
maastruatioa pads can lmd tb sesious me" aanpliatiosws si wdl as sodal
diffi=lti=. For
exampie, bacmial groa-th in ntiaary inmdsam dlapers or merssavation peds
uswlly
pt+oduces sanutg, uqpieaaaat odors ttat sra socWUy unooapabls and can cum
pexsaos to alter
ttuir lifwtyle. Caatveatioaasl abserbcat pads for uritny incootfaoum and
meostnurioa am not
inbecotttly bweriaidaL Conse~qumtly, tta only way to ivoid g,t+oath of becisda
In the
zbz orbent drasiags is to ch=aa them at figquent intaWs, evao 3f the -
ubsosbant aqmcity of
the pad ho not baa nuched. In the am of wound dreuin,p, hwtodmt couUminstipn
of acute
wonads and fnfiocdoa of cbroaic sicia wounds am msjor cliniaal problkms tdas
caa nsnlt ia
significant morbidity and, in wvae cs:es, marcaliti-. cAMMeaticcauy, wound
d:i;dogs have
baea designed to sbsorb wound flui,ds and yos provtde A ma3u eaviroomant tar
promoft
wound hatina. Iiovvara, such mdst eavuo~ cmts a aueriaau rich remvoir. for
bs,ct, " at Srowth in dc d:+asdng. Bsctoda growiag in ttx dtessiaS cm be sbod
back into de
wound, Wcsaiag the iish of wound iAbactiore, or respmso to toieins, and
prvdueiag :t:M,
fonl odors.
In aa etfon to addtnss these ptobleou, unn'biodcs or clismial dssmSotnft a=e
fre~ueatiy applled topiplly to wewsds priar to corrr.rW the wowd with a
drasing.
1
CA 02353436 2007-07-25
Alternatively, topical agents are sometimes applied directly to the surface of
the dressing. To
control foul odors, some known dressings incorporate charcoal powder to absorb
molecules
generating the foul odor. For some applications, topical application of
antibacterial agents is
not desirable. For instance, bactericidal agents applied topically to wound
dressings have a
tendency to seep into the wound being treated. Furthermore, many antimicrobial
drugs, such as
iodine, are cytotoxic and will retard wound healing if used repetitively or at
high
concentrations.
A composition comprising a superabsorbent polymer having a monolayer (or near
monolayer) of silane antimircobial agent in a covalent bonding relationship
with the base
polymer is disclosed in U.S. Patent No. 5,045,322. The composition may be in
the form of
flakes, strips, powders, filaments, fibers or films, and may be applied to a
substrate in the form
of a coating. The aforementioned composition is less apt to enter a wound vis-
a-vis
conventional topical treatment systems. In that respect, the disclosed
composition provides an
improvement over conventional topical treatment systems. However, silanes
contain siloxane
bonds which can be cleaved by acids and bases produced by infection or
bacterial growth. In
turn, these reactions may weaken or destroy bonds between the silane
antimicrobial agent and
the underlying polymer. Consequently, antimicrobial agent may seep into a
wound and retard
wound healing.
The need exists for an improved antimicrobial dressing composition having an
antimicrobial agent which can be maintained securely attached to a
superabsorbent polymer
upon exposure to acids and bases produced by infection and bacterial growth.
In addition to
reducing the propensity for detachment of the antimicrobial agent, it would be
desirable to
provide a surface area enhanced dressing structure for increasing the
effectiveness of the
antimicrobial agent.
2
CA 02353436 2001-06-01
WO 00/33778 PCT/US99/29091
SITMMry ef the ttyentee~
.
It is an object of the presmt invantion to provide an inhereatly b2ctericidal
='.~Fe.~abw.r'',,=t dressing :ta=r:r:g an sr.i=c--1 sutface a.-ci.
S It is aznothca object of the prusent invention to provide an inhereaclv
bacter_cida!
superabsorbant dressing having an improved bactericidal attachment strucutre
that resiists
degiada:~en upon exposure to :ci,ds or bases produced, far instance, during
bactezw growth.
Tbeae and other objocts are achievcd by the inh=tly baat,ericldal polymer
compoddoa of the premt invendon. In the preferrad embodfinens, the composition
comprises
a polymer matsix haviti$ 4uaternasy ammoniata groups athered to its surfacx
throagh non-
siEoxaae bonds. The surfaca araa of the polymer matrix is enhanced, for
instance, by
electroat;ticsliy apiuniag a 5ber-forming syndade polymer to fozni a&ayed
fiber or Slameat.
Altesuqivtly, the PoIY>ver solutior can be wat- or dry-spua to crem a
rottgheoed fibet surface
by oontioalft the choim of solvent and tbs polyatar salution tdrpe=re. AMtioW
sarface
erea mba:,ceQUat is p:onrided by wlming md1=9ar cWns of quemrnary unmoniun
pmdatt
gwups to dte surhca of the polyme,r mauix. Terbacrnag anay be acoomplished by
lanown
tiedusiquas wch as Vmfftg and sel4ctive ad:orptiaa.
In an altabue embodimatt of the iavention, non iotuc Momiadal moleotles. Are
caouplad to the surlacx of the polymer matdx, in lieu of iontcally-cbarged
moWCUles.
Yoaicaily-chuged atdleCules aY+e prau to being neutniized upon ascountering
opposiody-
cbarged molmdes. Foe instance, positivety.cbarged quammay ammoniuas gz+onps
may be
steutrailmed by suqptivveiy-dur=ed chloridk ioos psatatt in phydaftiptl
tluids. In instances
werb such neu~suion is significant enough to reduce die bacbesiadal propesties
of tbe
exos:iag helow sa aeaeptable level, nen-ioaic suiface groups may be prdesable.
3
CA 02353436 2001-06-01
WO 00/33778 PCT/US99/29091
rimmilcd b
A novel antibacternipolymer oomposition is fabriamd to have an enhaaced wrcacc
arM sad superabsozbent capacity for biologicil fluids, iaclndiag arine, blood,
and wound
eC::c.
S In the prefcrred cmSodiment of dw present ir,vention, dw composition
iaclvdzs a
polymer matrix having quamuary amrnoniam compauoda atrchcd to the surlace of
dw
polymer matrfx. Thc polymer mamix is comprised of a plur4ity of hydrephaic
fibars or
&]aznesYts which can be fabrfcated in any suitable manner. For examplc,
:uitable fibers or
filamants aan be fabrioated by wet- or dry-spinning a fYber-formiag synmt!wtic
polymcr from a
spmning soivmt. Tise resulting polymer has svperabsaabent cxpacity. GeoeaIly,
poiymecs
c.apable of absoacDing from about thircy co sixry grrmi of wataa per gram of
polymer ub
caosidand oo be wpmabsorbent. kAMplea of auperabsaabcnt polymrss wb3cb can be
fabriptu+d iti this maaAaz mr,iude polyacrylic wids+ IolyethYloo oacSdes ared
potyvi,nyl
atcohols. For "ample, mstbods for spinning polyetl-Ykae oxide using loetooe
solvwt aro
wttllrnow+n.
Sigalficantly, do pWYuw matrix is fabricabod to bave an eQEianced rafae =VL
Enhaoc.itig the surtue uea of tfie polymer manix s+ewlts in impmed aluorptiaa
of bielogicsl
tluids, snd ieanmses dw avafilability of sites for amchment of the
sntiiaicmbial qeiaaernsury
ammanium eomapouads. A cornspondi:tg ia=usa in the qmrttiry and Qensiry of
antlsaiarobial
siua, in turn, a>ianm the efflday of the composidca in ]dlling oWnisnns such
as bactesia
and viruses.
It may o=tr m one sldaled in the art of polyjm sCieace tl>at a vatlay of
inerbods are
avaflable for accomposhing wriitse am moQfiicadon. Pfetessbly, arface uat
enbancment
is aocomplishod by a modifled spinning or cuttag memod. For iAstaoce,
electrosUdc sp~.~ning
is a eroWfed spinaimg teahnique which results in lmying of the Sbw as it Wts
the spineretre.
AUM=dVely, a poly= sdntton caa be wet or dry-spun to craats s rougbeaod fiber
sur"
by coutroliing tha solve,ut typs and the polymer solution M%M=re. This
aechnology is weU
]caown and has been appifed, for exatnple, ia the manubcxute of asymmecic
membranes
haviag rotlghened pores for dialysis. ?he siae of thn mugheaad pores is
pzfmauily cmbroll,ed
4
CA 02353436 2007-07-20
by the speed of precipitation which, in turn, is controlled by solvent
interaction parameters,
temperature, etc.
The surface area of the polymer composition is further enhanced by tethering
chains of
antimicrobial groups to the outer surface of the individual polymer fibers.
Preferably,
molecular chains of quaternary ammonium pendent groups are fabricated to have
at least one
end adapted for attachment to a fiber surface. For instance, surface grafting
may be
accomplished by creating surface free radicals as initiation sites from
peroxide generation
(ozone or microwave). Alternatively, surface attachment of an interpenetrating
network may
be achieved using a monomer which swells the substrate polymer. The
incorporation of
tethered antimicrobial chains has the further benefit of enhancing the
functionality of the
composition. In particular, the tethered antimicrobial chains extend into the
particular
biological solution to bind to harmful bacterial and viral organisms. In
contrast to known
dressing compositions in which a monolayer (or near monolayer) of bactericidal
compound is
directly attached to a fiber surface, the chain structures of the present
invention, which function
like arms extending outwardly from the fiber surface, more effectively bind
the antimicrobial
sites to harmful organisms. Preferably, tethering is accomplished by grafting
the antimicrobial
chains directly to the matrix surface, or by selective adsorption of a
copolymer to the matrix
surface.
Grafting techniques are well known in the art. For example, quaternary
ammonium
compound grafting using the monomer trimethylammonium ethyl methacrylate to
graft
polymerized to a modified polyethylene surface is described by Yahaioui
(Master's Thesis,
University of Florida, 1986). Yahaioui describes a grafting technique in which
a plasma
discharge is used to create free radicals which initiate polymerization of
appropriate monomers.
Selective adsorption of appropriate block copolymers can also be used.
In contrast to known compositions in which an antimicrobial structure is
achieved by
covalently bonding silane groups to the surface of the base polymer, the
present invention
incorporates a chemical structure which is based on polymerization (i.e.,
surface grafting) of
monomers containing all carbon-carbon, carbon-oxygen and carbon-nitrogen main
bonds, such
as the dialkyl, diallyl, quaternary ammonium compounds. Consequently, the
composition of
5
CA 02353436 2006-12-13
the present invention results in a structure which is less prone to reacting
with acids and bases
produced by bacterial growth. As previously mentioned, such reactions can
degrade the
attachment between the matrix and antimicrobial groups. In instances where the
composition
is applied to a wound dressing, such degradation could result in antimicrobial
agents
detaching from the polymer matrix and entering a wound site. In some cases,
this can have
the deleterious effect of retarding wound healing.
In an alternate embodiment of the present invention, anionic antibactericidal
groups
are immobilized on the surface of a superabsorbant dressing to improve the
antibactericidal
efficacy of the dressing. The positive charge associated with quaternary
ammonium groups,
for example, can be neutralized by negative ions, such as chloride ions
present in
physiological fluids such as urine and plasma. For applications where the
degree of
neutralization will significantly reduce the effectiveness of the
antibactericidal agent, anionic
surface groups can be substituted for quaternary ammonium groups. Examples of
chemical
compounds that can be used to produce immobilized anionic surface groups
include
TritonTM-100, TweenTM 20 and deoxycholate. For instance, Triton-100 contains a
free
hydroxyl group which can be derivatized into a good leaving group, such as
tosyl or chloride,
and subsequently reacted with a base-treated polymer, such as methyl
cellulose, to yield a
surface immobilized non-ionic surfactant.
Dimethyldiallyl ammonium chloride is one example of a suitable monomer which
may be used with the present invention. This monomer, commonly referred to as
DMDAC or
DADMAC, is used in the fabrication of commercial flocculating polymers.
Modifications of
trialkyl(p-vinylbenzyl) ammonium chloride or the p-trialkylaminoethyl styrene
monomers are
also suitable. One such example is trimethyl(p-vinyl benzyl) ammonium
chloride; the methyl
groups of this monomer can be replaced by other alkyl groups to impart desired
properties.
Alternatively, methacrylate-based monomers may be used; however, they may
suffer from
hydrolytic instability under acidic and basic conditions in a fashion similar
to the silane-based
treatments of the prior art. Consequently, methacrylate-based monomers are not
preferred.
While the preferred embodiments of the invention have been illustrated and
described,
it will be clear that the invention is not so limited. Numerous modifications,
changes,
6
CA 02353436 2001-06-01
WO 00/33778 PCT/US99/29091
vaziad,oas, mbsdmr>ans VA equEv.iats wilt cwur to thoae skilled in the art
withauc depar6n8
fTCDI ttbE si7tlZt aC1d 9COpC of the PrCSmt iAYlSLiCn a4 df.SQ'l'3bM in 1M
cWI!!s.
7
