Note: Descriptions are shown in the official language in which they were submitted.
~079~6
BACKGROUND OF T~IE INVENTION
1. Field of the Invention
This invention relates to novel compositions which are
random interpolymers of a terminally quaternized derivative of
acrylic acid with an ~ olefinically unsaturated comonomer
polymerizable therewith, and to their preparation by polymer-
ization in an aqueous medium. More particularly, this invention
relates to hydrophilic interpolymer compositions having novel
- bacteriostatic properties which, in conjunction with their
high water ad~orbency, makes them especially suitable for
applications where the combination of such water adsorbency with
control of bacterial growth is desired.
2. Description of the Prior Art
; There has long been a need for polymers which can be
prepared by polymerization in aqueous systems and which can
be cast as self-supporting films having a large water adsorbent
capacity. There has also been a need for such compositions that
are bacteriostatic and can therefore control the growth of
bacteria on surfaces which they contact. Some polymeric compo-
sitions, such as polyvinyl alcohol and cellophane, are excellent
film formers yet are unable to adsorb water in appreciable
amounts. Other materials, exemplified by the so-called HXDRON*
, polymers, are more water adsorbent than the above films, but
cannot be converted to flexible films from aqueous dispersions,
Such materials, if they are to be converted into films, must
be polymerized in non-aqueous organic solvents which are termed
"syrups", as disclosed in U.S. Patent No. 3,520,949 dated July
21, 1970, inventors Ihomas H. Shepherd and Francis E. Gould, as-
signors to National Patent Development Corporation. Likewise,
* Trade Mark
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.. . .
10~9896
these polymers lack bacteriostatic properties. When the above
prior art compositions are bacteriostatic, they are rendered
so by the inclusion of an additional substance, which is not
an integral part of the polymer.
SUMMARY OF THE_INVENTION
~he present invention provides-a random interpolymer
that is bacteriostatic, i8 capable of adsorbing large multiples
of its own weight of water, and can be prepared by polymeriza-
tion in an aqueous polymerization medium. More particularly,
the bacteriostatic random interpolymers of this invention ex-
hibit the properties of having a water adsorbing capacity of
from about 10 to about 125 times their own weight or greater.
In accordance with one aspect of the invention, the
random interpolymers are provided in the form of an aqueous
colloidal dispersion or suspension which can be converted into
a gel, or a dry powder, which find uses as highly adsorbent
thickening agents. In addition, articles can be coated with
the interpolymers to give them a lubricious coating such, for
example, as medical instruments and devices which are to be
; 20 inserted into body openings e.g., proctoscopes and the like.
In accordance with ano~her aspect of the invention,
the random interpolymers may be prepared initially in the form
of a gel. In either event, the gelled material, when in a high-
ly cross-linked form, can be cut and shaped into various ~truc-
tures such as contact len~es where the bacteriostatic pro-
2-
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10'~9~3~6
J&J 7g6
perties of the interpolymer material can be advantageously
,
employed.
Further, the aqueous colloidal dispersion can be cast
into a self-supporting, transparent, conformable film which
is particularly useful as a wound dressing since it is highly
conforming to wound surfaces, and provides an occlusive
bacteriostatic dressing. As set forth in Hinman, C. D., and
Maibach, H. I. : Effect Of Air Exposure and Occlusion On
Experimental Human Skin Wounds, Nature 200:377, 1963, an~
Winter, G. D. & Scales, J. T.: Effect Of Air Drying & Dressings
On The Surface Of A Wound, Nature 197:91, 1963, it has been
shown that the healing of superficial wounds can be enhanced
by providing an occlusive dressing. But under such dressings
- bacteria often can proliferate. However, dressings prepared
~rom the interpolymers of this in~ention are not only
occ]u~ive, but also, because of their bacteriostatic
' propert~es, help prevent the proli~eration of bacteria.
.j
In accordance with yet another aspect of this invention,
the random interpolymers of the invention are prepared by the
polymerization in aqueous medium of (A) a mixture of monomers
comprising (1) up to about 90% by weight of an ester of an
a,~-olefinically unsaturated carboxylic acid and a monohydric
10~79896 :
J&J 796
.
or polyhydric alcohol ha~ing a terminal quaternary ammonium
group ~nd (2) at lea~t one a,~-ole~inic~lly unsaturated co-
monomer, in the presence of (B) a cross-linking agent com-
prising a difunctional monomer derived from an ~,~-ole~inical-
ly unsaturated carboxylic acid
DESCRIPTION OF THE PREFERRED EMBODIMENTS
There ha~ now been dlscovered a novel compositlon com-
prising a random interpolymer derived ~rom the polymeri.zation
: of a mixture o~ monomer~ comprising: (A) (1) from about
:10 10 to about 9~0 by welght of said mixture of a flrst monomer
which is an e~ter of an a,~-olefinically unsaturated
: carboxylic acid and a monohydric or polyhydric alcohol
havlng ~ terminal quaternary ammonium group and (2), cor-
- respondingly, ~rom about 90 to about 10~ by weight of said
1~ mixture of at least one ~,~-olefinlcally unsaturated co-
monomer capable of being dispersed in aqueous media, in
the presence of (B) at least 0.02~ by weight, based on
the weight of sald mixture, o~ a cross-llnklng agent com-
prising a difunctlonal monomer which i8 capable of being : -
dispersed or dissolved in aqueous media and is an ester : .
or amide o~ an a,~-oleiinically unsaturated carboxylic . . :
, . . .
acid; sald comonomer (2) comprising (a) at least 10~ by
welght of sald mlxture o~ monomers of an acld comonomer,
or (b) at least 20% by weight of said mixture of monomers
o~ an amlde comonomer, or (c) at least lO~o by weight of sa~d
mixture of monomers of a comblnatlon o~ acid and amide co-
".
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1079896
J&J 79
-- monomers, said combination containing at least 5% by weight
of said mixture of an acid monomer. .-
The esters of an a,~-olefinically unsaturated carboxylic
acid and a monohydric or polyhydric alcohol having a terminal ~ .
quaternary ammonium group which may be suitably employed in
this invention include those having the structure:
H2C-f~ ORl- I (R2) 3
R O X
wherein R is selected from the group consisting of hydrogen
and Cl to C4 alkyl; Rl is selected from the group consisting
. .
of Cl to C4 alkylene and hydroxy substituted Cl to C4 alkylene;
each R2 is selected from the group consisting of Cl to C4
alkyl; and X represents an anion of an acid sufficiently
acidic to form a salt with amino nitrogen, for example Cl-,
Br , I , and CH3S04-. Such esters are exemplified by 2-
, methacryloyloxyethyltrimethylammonium methyl sulfate and ~ ~-
:hs 2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride,
¦ the latter being preferred.
!
, :
! Difunctional monomers suitable for use as a crosslinking
agent in accordance with this invention include the esters and
amides of a,~-olefinically unsaturated acids selected from the
:. ~ . ...
~079896 J&J 796
group consisting of the compounds defined by structural
formulas I, II and III below:
I H2C C - C - O -~R3~0]n- Cl - C = CH2
R O O R
wherein R is hydrogen or Cl to C4 alkyl; R3 is Cl to C6
alkylene; and n is an integer from 1 to 3;
H H
II H2C _ C - ICl - N - R3- N - IC - C - CH2
R O O R
wherein R is hydrogen or Cl to C4 alkyl; and R3 is Cl to C6
alkylene; and
III H2C = tC - ICl - N - Y
R O
wherein R is hydrogen or Cl to C4 alkyl; and Y is selected
from the group consisting of - CHOH and
R4
R O R :
15 11 15
- C C - C - R5
R5 5
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' ' '
6 - :
..
1 0 7 9 89 6 J&J 796
wherein R4 is selected from the group consisting of hydrogen
and Cl to C5 alkyl; and each R5 is selected from the group
consisting of hydrogen and -CH20H, provided, however, that at
least one R5 is -CH20H.
S Examples of such difunctional monomers include ethylene
glycol dimethacrylate and diacrylate, diethyleneglycol di-
, .
methacrylate and diacrylate, triethyleneglycol dimethacrylate
and diacrylate, 1,3-propanediol dimethacrylate and diacrylate,
. 2,2-dimethylpropanediol diacrylate, tripropylene glycol di-
methacrylate and diacrylate, 1,3-butylene glycol dimethacxylate
:~ and diacrylate, N,N'-propylenebisacrylamide, N,N'-methylenebis-
~ .
; acrylamide; N-l-alkylol amides of a,~-olefinically unsaturated
carboxylic acid, which amides have from 4 to 8 carbon atoms,
j exemplified by N-methanol acrylamide, N-l-ethanolacrylamide, :
N-l-propanolacrylamide, N-methanolmethacrylamide, N-l-ethanol- :
I methacrylamide and hydroxymethyl diacetone acrylamide (available
i from Lubrizol Corporation). The preferred difunctional monomer
: is N,N'-methylenebisacrylamide. :
' :
The olefinically unsaturated monomers that are suitable -~
for employment as comonomers in the random interpolymers of
this invention include a,~-olefinically unsaturated monomers
.
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.
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1079896 J&J 7g6
.:
such as the vinyl monomers, as well as a,~-olefinically un-
saturated carboxylic acids of from 3 to 6 carbon atoms and the
lower alkyl esters and amides thereof, 2-(Cl-C4) alkyl sub-
stituted acrylic and crotonic acids and esters and amides there-
of, and N-substituted~amides of the above acids. Examples of
suitable ~,~-olefinically unsaturated ~onomers include sodium
vinyl sulfate, vinyl acetate, methyl vinyl ether, vinyl
chloride, crotonic acid, crotonamide, acrylic acid, methyl
acrylate, methyl crotonate, ethyl acrylate, ethyl crotonate,
methacrylic acid, 2-ethylacrylic acid, 2-methylcrotonic acid,
butyl methacrylate, ethyl methacrylate, ethyl 2-methylcrotonate,
- acrylamide, methacrylamide, 2-ethylcrotonamide, 2-ethylacryl~de., N-
isopropyl acrylamide, diacetone acrylamide, N-t-butyl acrylamide,
; N-2-ethanol acrylamide, N-3-propanol acrylamide and N-methyl
:15 methacrylamide. Of these, the preferred comonomers are acrylic
and methacrylic acids, acrylamide and methacrylamide.
! In a preferred embodiment of this invention, the mixture
of monomers comprises from about 10 to about 80% by weight of said
I mixture of said a,~-olefinically unsaturated carboxylic acid
;20 ester of a monohydric or polyhydric alcohol having a terminal
, .
~; quaternary ammonium group; and at least about 20% by weight of
the mixture of an olefinically unsaturated comonomer, from
: about 5 to about 35% by weight of the mixture (total monomers
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~079~96 J~J 796
in the prepolymer blend - excluding the crosslinking agent)
comprising a comonomer selected from the group consisting of
acrylic acid and methacrylic acid (acrylic acid being most
preferred), and from about 10 to about 85% by weight of the
mixture comprising acrylamide, or methacrylamide (acrylamide
being most preferred). Clearly the total amount of the
monomers employed will be 100% and therefore if an amount
equal to or approaching the maximum of one particular monomer
is employed, than the relative amounts of the remaining
monomers must be reduced accordingly. The amount of di-
functional monomer crosslinking agent employed in this pre-
ferred embodiment is from about 0.02 to about 5%, based on
the weight of the mixture, from about 0.05 to about 1% being
; particularly preferred. Generally, when the intended end use
;15 of the random interpolymer is as a film, the amount of cross-
linking agent will not exceed 0.5% although this may vary
depending on the particular crosslinking agent, as welL as
the composition of the monomer mixture. The selection of a
suitable concentration of crosslinking agent (as well as
monomer mixture) to meet a particular end use requirement
is, however, well within the skill of the art.
.1,
The random interpolymers of this invention are prepared,
in accordance with another embodiment of this invention, by
. . .
` - g _
1079896 - J&J 796
the free radical polymerization of the above monomers in an
aqueous medium using any suitable free radical initiator,
including high energy irradiation as well as photochemical
and chemical means.
- 5 Suitable chemical initiators are any of those which are
commonly known in the art to effect the polymerization of
acrylic monomers and which are dispersible or soluble in
aqueous medium. Such initiators are capable of generating a
sufficient number of free radicals to propagate the polymeri-
. . .
; 10 zation reaction, and include water soluble persulfated salts
such as sodium, potassium, and ammonium persulfate; t-butyl
peroxypivalate; the peroxycarbonate salts; hydrogen peroxide;
and water soluble oxidation and reduction couples such as the
combination of a water soluble persulfate and a water soluble
, 15 bisulfite.
`i In particular, there is preferred the use of the water
soluble persulfates, especially ammonium persulfate, and such
"redox" pairs as those comprising water soluble persulfates
as the oxidant and ammonium bisulfite as the reductant.
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0~79 89 6
J&J 796
These initiators are typically employed in a quantity
ranging from about 0.2 to about 2 parts by weight per hundred
parts of total monomers (phm). The pre~erred initiators and :~
especially ammonium persulfate are employed in amounts of
` 5 from 0.5 to 1 phm.
As used herein, the term "aqueous medium" is meant to
include water, as well as a fluid comprising water, and one or
more water-miscible organic solvents. In general, the aqueous
medium may comprise water alone, especially deionized water,
10 and may further comprise, in instances where it is desirable
to increase the tolerance of the aqueous medium for various
; monomers otherwise poorly dispersible in water at their higher
levels within the foregoing description so as to achieve
homogeneous polymerization, a water-miscible solvent, e.g.
methanol, ethanol, isopropanol, N,N-dimethylformamide, N,N-
j dimethylacetamide and acetonitrile. The amount of this in-
;l cluded organic solvent can be from 0 to about 60% by weight,
based on the weight of the aqueous medium, and, in preferred
embodiments, is from 0 to about 15% by weight.
., . ,~ .
The amount of aqueous medium employed should ~ sufficient
to achieve a uniform solution of the monomers. Generally,
` this amount of aqueous medium will be in the range of 9 to
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- 11_
~
.
. :-' ' - , ' . ' . - ~ ~ .' .
1079896 J&J 796
20 times by weight of aqueous medium based on the total weight
of the monomers. In general, if larger quantities of aqueous
medium are employed, the polymerization reaction proceeds less
rapidly, and there is the further disadvantage of having an
additional quantity of aqueous medium which must eventually be
removed.
Generally, the order of addition is immaterial when
admixing the monomers and aqueous medium. However, in those
instances where a monomer is insoluble or poorly soluble in
water and is only sparingly soluble in the aqueous medium,
such monomer is preferably first dissolved in the water-
miscible organic solvent and the resulting solution is then
added to the aqueous medium.
. , .:
In general, the temperature at which the polymerization
is carried out is limited only by the stirrability of the
reaction mixture. Thus, at too high a reaction temperature,
the viscosity of the reaction mixture rapidly increases to
; a point where the reaction mixture is too viscous to be stirred
and the reaction is then difficult to control and must be
terminated. The polymerization rate, however, depends both
upon the polymerization initiator employed and the temperature
at which the reaction is run.
- 12 -
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. .,: , : : :. -
1079896
J&J 796
In the preferred embodiment of this invention in which
ammonium persulfate is used as the initiator, the reaction is
suitably conducted at a temperature range of about 55 to 75C.
Preferably, when less than 60% by weight of the monomer
S mixture is a terminally quaternized monomer, the reaction
temperature should not exceed about 68C. It is also preferred
that the time at the elevated temperature be limited to about
20 to 45 minutes, so as to limit the viscosity of the reaction
mixture (at the reaction temperature) to no more than about
3,000 centipoise. After the reaction has proceeded for this
period, it is preferred to rapidly cool the reaction mixture
to below 30C. It has been found that when the duration at
elevated temperature is thus limited, a random interpolymer
is produced that will remain as a stable (uniform) hydro-
colloidal dispersion, having a viscosity at 25C. of from
~- about 40 to about 10,000 centipoise, for a period of from
1 to 24 months or longer at room temperature.
~'
Once the polymerization reaction has proceeded to the
point where the random interpolymerized product exists as a
gel rather than a hydrocolloidal dispersion, smooth films
can no longer be cast. A~ter the hydrocolloidal dispersion
has formed a gel, the gelled random interpolymer may be
dried and pulverized into a powder. In this powder form,
- 13 -
.: :
. , . - , . . ..
~0~9896 J&J 796
it does retain its highly hydrophilic and bacteriostatic
properties, but cannot be readily redispersed in water as
a colloidal dispersion.
Of course, a dry product or a gel may be preferred for
various applications. In such instances the hydrocolloidal
dispersion of random interpolymer can be converted into a
- gel by storing at elevated temperatures, e.g. 30 - 40C.,
for ~rom one to eight weeks. If desired, this gel can be
used as is or dried and pulverized into a powder as discussed
above. Alternatively, the hydrocolloidal dispersion can
be dried directly by well-known means, for example drum
drying or spray drying, to form substantially dry hydrophilic
particles of the interpolymer.
. , .
` In a less preferred alternative method, the interpolymers
can be prepared by the quaternization of corresponding inter-
~,
polymers prepared with monomer having the free amino group instead o.f
the quaternary monomer, using well-known techniques. One dis~
advantage of this procedure, particularly for medical or other
end uses where the ultimate product may contact people or
2a animals, is that incomplete quaternization may leave some
; ~ free amino groups in the end product, and these tend to be
~ irritating and cause undesirable side effects.
~ .. , . .:
~ 14 -
"
.. . . . . .
~079896 J&J 796
The interpolymers of this invention are useful in the
form of a hydrocolloidal dispersion, as a film, as a gel and
in the form of particles prepared by the pulverization of
the dried interpolymer. The particulate form can be used
as a thickening agent in the so-called "water base" paints,
or interspersed within a fibrous material, for example, paper
products or other woven or nonwoven fabric materials (used,
for example, as towels, disposable diapers and the like)
where its combination of water adsorbency and antibacterial
properties can be employed to special advantage. The hydro-
colloidal dispersion itself can be used Per se in impreg-
nating and coating operations for direct application to an
article. Examples of such uses include the application
~,
of a hydrophilic lubricious coating to a medical instrument
that is intended for insertion into a body opening such,
for example, as a disposable rectal thermometer, or to the
surfaces of latex gloves used by physicians in carrying out
physical examinations of such body cavities,
ç The interpolymers are especially useful when cast into
a tough, integral film. As a film, the interpolymers are
particularly well-suited for covering minor wounds such
as cuts, scratches, and other irritated skin areas where
a dressing is indicated.
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1079896 J&J 796
The interpolymers have been shown to have in vitro
bacteriostatic properties, and in vivo studies on intact skin
have also established such activity. Thus, the cast films
prepared from these interpolymers are well-suited as occlusive
dressings for minor wounds such as cuts, scratches, and irri-
tated areas.
: To cast a film of the interpolymer of this invention,
an aqueous dispersion of the interpolymer, preferably a dis-
persion of the interpolymer in the aqueous polymerization
medium,is disposed on a smooth, non-adherent surface such
as polyethylene, polytetrafluoroethylene or silicone-treated
surfaces.
. ~ .
The films can be cast in a variety of thicknesses. The
details for film casting are well-known in the art, and such
well-known procedures can be advantageously employed in
preparing the interpolymer films of this invention. When
a film is to be prepared from the interpolymers of this -
invention, increased film flexibility can be achieved by
including in the polymeric dispersion prior to casting from
5 to 40% by weight of a plasticizer such for example as
glycerol, carbitol or methyl carbitol, glycerol being pre-
lerred.
- 16 -
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;,. . . . , .. :
10~9896 J.~J 796
The ~ollowing examples will further serve to illustrate
the preparation and use o~ the interpolymers of this inven-
tlon.
Example I
A 5-liter ~ulti-neck flask, equipped with a nitrogen
inlet, mechanical stirrer, thermometer, reflux condenser and
an addition funne~ was charged with the fol]owing reagents:
2-hydroxy-3-methacryloyloxypropyl-
trimethylammonium chloride,
Sipomer Q-l, Alcolac Chemical
Corporation 108 g
~crylic acid 24 g
Acrylamide 108 g
N,N'-methylenebisacrylamide 0 12 g
Water ~7oo g
~fter purging the system wlth nitrogen ~or 100 minutes, the
contents were heated until the temperature reached 55C,
Then a solution o~ ammonium persulfate, (2.4 g ) in 10 ml,
o~ water was added, When the temperature reached 68, flnd
the viscosity o~ the reaction mixture became such that the
stirrer began to labor, then 240.0 g o~ methanol were
added over a 10 min. period anA the reaction mixture cooled
The colloidal dispersion obtained had a solids content o~
; 7,76%, equivalent to 100% conversion. A ~ilm is obtained
by drying down, in a polyethylene lined tray having a
surface area o~ about 40 cm2 and containing a piece o~
~auze or simllar fabric to act as a reinforcement, 200 g
o~ the above dispersion to whlch is added 5 g. of glycerol,
at 100F ~or 48 hours. A weighed sample of the film is
. .
,'. .
-17-
.. .
,
1079896
J~cJ '~6
.~ .
placed in 150 g of deionized water for 24 hours. The - -
mixture is then Qtrained through 40 mesh screening.
Example II
A 5-liter, multi-necked flask, equipped with a nitrogen
; 5 inlet, mechanical stirrer, thermometer and reflux condenser
was charged with the following reagents:
2-hydroxy-3-methacryloyloxypropyl-
trimethylammonium chloride 126 g.
Acrylamide 126 g
; 10 N,N'-Methylenebisacrylamide 0.14 g.
Acrylic acid 28 g.
Methanol 280 g.
Water 3175 g.
The system was purged with nitrogen for approximately 60
minutes. The reaction mixture wa~ then heated until the
, ~e temperature reached 55C. At this time a solution of 1.4 g.
of ammonium persulfate in 25 ml. o~ water was added. When
the temper~ture reached 63.5C, heating was discontinued,
l and the te~perature was maintained between 63 and 64C
-~20 for 10 minutes, The reaction mixture was cooled to 24.5C
and filtered air was bubbled through the ~tirred reaction
mixture for 2 hours. The colloidal dispersion so obtained
had a solids content of 7.37% and a viscosity of 80 cP.
~¦ A film was obtained by drying down, in a polyethylene lined
~5 tray having a surface area of about 40 cm2, and containing
a piece o~ gauze or similar fabric to act as a reinforce~
ment, 200 g. of the above dispersion to which was added
., . ~ '~
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18-
` . ~ ~ ;. - - :
1079896 J&J 796
5 g. of glycerol, at 100 F for 4~ hours. A weighed sample
of the ~ilm was placed in 150 g. of deionized water for
24 hours. The mixture was then strained through 40 mesh
screening and the amount of water ad~orbed calculated.
For this polymer there was adsorbed 35.5 g. of H20 per g.
of hydrocolloid.
Example III
Using the polymerization procedure described in
Examples I or II, the monomers listed in the following
table were polymerized under the conditions and with the
results indicated to give colloidal dispersions of inter-
polymers in accordance with the present invention. The
amount of ingredients in the table is in grams.
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-19-
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~79896 J~J 796
Example IV
An aqueous dispersion of the interpolymer prepared from
12 g. of acrylic acid, 54 g of acrylamide, o.o6 g. Or N,N'-
methylenebisacrylamide and 54 g. of 2-hydroxy-3-methacryloyloxy-
propyltr~methylarnmonium chloride in 1520 g. of water and
120 g. of methanol was prepared using 1.2 g. ar~nonium per-
sulfate as the initiator The polyrnerization was carried
out at 55 to 63C for 0.8 hours. The resulting hydro-
colloidal dispersion had a solids content of 6.4~ and a
vlscosity of 193 cP. 4.3 g of glycerol plasticlzer were
added to ~00 g. of the dispersion and the interpolymer cast
as films having thicknesses in the range 20 to 30 mils.
From these films hydrocolloiflal film dressln~s were
prepared in the following manner. A 3x3 inch, 1/16 inch thick
polyester urethanefoam was coated on one side thereof with a
pressure sensitlve adhesive A 2-1/4 x 2-1/4 inch portion
o~ the film prepared as described above was affixed to the
center area of the coated side of the foarn by means of the
pressure sensitive adhesive, leaving a 3/8 inch border
about the perimeter of the foam to serve as a mesns for
flttaching the h~drocolloidal ~ilm dressing to the desired
skln are~.
Example V
To illustrate the irl vitro bacteriostatic pro~erties
of the hydrocolloid film against specific organisrns, 2cm x
~cm portions o~ a film of Example IV, without any L oam
. .
~ -22-
1079~96
J~J 79
backing, were placed in the center of test plates containing
a 10 ml base layer of nutrient agar overlaid wlth 4 ml agar
containing approximately 2,000,000 viable cells of test
organism per ml. The plates were then incubated for 24 hours
at 3~C. The average zone of inhibition of triplicate trials
is set forth below.
Staph aureus 2 3mm (from the edge of the dressing)
Staph, epi-
dermidis 3 mm (~rom the edge o~ the dressing)
0 Similar acti~ity can be demonstrated against Ps
aeroginosa, K. pneumoniae, and E. coli Por films produced
with 2-hydroxy-3-methacryloyloxypropyltrimethylammonlum
chloride
Exam~le VI
Hydrocolloid fllm dressings of Example IV were attached
to a human subject's skin and occluded with Saran film.
After 48 hours the dressings were removed, and a sample
taken by washing the treated area with 1.5 milliliters of
physiological saline in a 28 millimeter diameter cylinder.
0 The area was gently scraped for 30 seconds with a sterile
pipette. One milliliter of the wash solution was trans- -
ferred to a tube containing 9 milliliters of peptone w~ter.
These suspensions, and dilutions made from them, were
plated in Brain Heart Infusion Agar. After incubation for
48 hours, colonies on the plates were counted and the
numbers of bacteria per square centimeter of skin calcu-
lated~
,' , '
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~ . . .
, - - . . . .
~079896
.: J&J 796 ~ .
'
As shown in the Table below, the dressings of thi.s .Ln-
~ention inhlbited bacterial growth on intact skin o.f all o~
10 sub~ects,
TABLE
Bacteria per cm2 recovered ~rom treated and control sites
Saran Film
Saran Film Occluded
Occluded *Dialyzed
Hydrocolloid Hydrocollold Saran Film Skin
Sub~ect Film Dressing Film DresQing Control Control
46xlO~ 79x103 14x105 19x102
13X102 62 50x105 22
3 ~ 13 8 22x105 17
4 ~ 13 802 21x105 74
~i 5 768 29xlo2 34x104 43
6 142 24 97x104 l4g
7 89 12 84x104 14
8 29xlo2 34x105 106
9 17x103 74xlo2 48x104 36
: ~ 10 l8xlo2 46X102 31x104 70
-~ *Dialyzed hydrocolloid ~ilm was cast ~rom
; hydrocolloid dlspersion that had been sub-
Jected to dialysis to remove any impurities
(e.g. unreacted monomer) that may have been
i present.
Example VII
..
The volar aspect o~ the left forearm o~ a human ..
volunteer was shaved and then prepped with a 70~ ethanol
, swab. Three super~icial incisions 15 mm. long and approxi-
.) mately 300 microns deep were made with a sterile scalpel
(blade No. 11).
The incisions were then dressed with sterile hydro-
colloid film with ~oam backing descrlbed in Example IV.
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1079~96
The control portions of the wounds were biopsied once to yield
information at 1, 2 and 3 days post wounding. The biopsies are
small, elliptical samples obtained after infiltration of these
areas with ca. 0.3 - 0.4 cc of 2% lidocaine hydrochloride. The
fresh tissue was quick-frozen for cryotomy (Slee HR Cryostat).
Eight micron thick sections were cut, fixed in Wolman's solution
and stained with hematoxylin and eosin.
Gross observations of the incisions reveal that a
moderate scab formation is present on day 1 and this decreases
slightly by the third day. mere is no apparent infection,
hemorrhage, edema or excessive tenderness. A slight amount of
dried serosanguinous exudate is present on the film when
removed from the wound.
From the standpoint of histology, day 1 reveals slight
inflammation and the wound wa~ re-epithelialized. A fibrin
network i9 present below the hyperplastic epidermis. Differ-
entiation of the epidermis starts at that time.
; By day 2, a slight perivascular inflammatory response
.~ i9 seen in a re-epithelialized wound. A few fibroblasts can
be seen in the perivascular areas. The epidermis has a hyper-
plastic appearance and is differentiated. A few necrotic
cells are present in the lifting scab. A dermal fibrin net-
work is present.
By the third day a moderate polymorphonuclear inflam-
matory response is seen. The wound, as before, is re-
epithelialized and hyperplastic. No fibroplasia are
noticed. A fibrin network is seen in the dermis and the
.-, ., ~:
. ~ . . , ' .
~079896
J&J 79~
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- stratum granulosum is prësent. A lifting scab is seen and
contains only a few necrotic cells.
These studles reveal a well-healed wound by day 2.
This is equivalent to saran dressed wounds of the same age,
In addition to preventing free evaporatlon ~rom wound tis-
sues, the foam hydrocolloid dressing probably stabllize~
the wound mechanically, i.e., reducing shear ~orces, This
might also be the reason the wound is re-epithelialized and
differentiated by day 2. No evidence of any primary irrita
0 tion or damage to tis~ue is observed.
Example VIII
Cantharidin induced blister wounds were dressed with
(a) a sample o~ hydrocolloid film as prepared in Example IV,
(b) another sample of the same hydrocolloid film occluded
"j wlth Saran fllm and (c) a Saran film occluded control. The
Saran ~ilm drecsings were a~fixed by means o~ 6urgical tape.
After the dressings were in place for 48 hours, the wounds,
together with a skin control, were sampled ~or bacterial
growth. Sampllng was done by washing the treated area with
j3 2,5 milliliters physiological saline in a 12.7 mm. diameter
; cylinder. The area was not scraped as with intact skin, `
Saline was agitated in the cylinder by swl~hing a pipette
back and ~orth for 60 seconds. One ml. of the wash solution
was then transferred to a tube contalning 9 ml. of peptone
water. These suspensions and dilutions made from them were
;` plated in Brain Heart Infusion Agar. A~ter incubation for
48 hours, colonies on the plates were counted and the numbers
~; o~ ~acteria per square centimeter of skin calculated.
~ j ;
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.~' .
-26-
- . . ~ - . :
107~8~6
J~cJ 7~36
The f`ollowing Table shows the numbers of bacteria cul-
tured from the blister wounds.
TABLE
-
Hydrocolloid Hydrocolloid SARANR Skin
~ ilm Film Occluded Control Control
1 23X106 58 94x105 35xlo2
2 23 23 89x104 35
3 lOxiO7 37x105 62x104 173
4 115 35 37x105 104
O 5 104 17x103 39x105
6 299 23 11x106
7 391 12 l6xlo6 37x103
8 39xlo6 23 15X106 35x102
9 50X106 34X106 15X106 460
llxlo6 llxlo6 l2xlo6 24Xlo2
ExamPle IX
A 3-liter, multinecked ~lask, equipped with a nitrogen
inlet, mechanical stirrer, thermometer and reflux condenser
w~s charged with the ~ollowing reagents:
2-Hydroxy-3-methacryloyloxypropyl-
trlmethylammonium chloride 135 g ~ :
Acrylamide 7 5 g.
Acrylic acid 7.5 g.
N,N~-Methylenebisacrylamide o.o75 g
3 Water 1775 ~.
The system was purged with nitrogen for approximately
60 minutes. The reaction mlxture was then heated until the ~ -
temperature reached 55 C. At thl~ time, a solution of am-
monium persulfate (0.75 g.) in 25 ml. o~ water was added
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: ~.
1079896 J&J '796 ,
and heating continued. Heatin~ was dlscontinued when the
temperature reached 65C; and the temperature was maintained
between 62 and 66C for 30 minutes. The reaction mixture
was then cooled rapldly to below 30C and ~iltered air then
bubbled through the reaction mixture ~or 1 - 2 hour~, The
colloidal disperæion so obtained had a solids content of 7,7%
and a viscosity of 140 cP. A sample of the dispersion was
dried in a convection oven at 100C for 3 hours, yielding
0,6763 g, of polymer, The dried polymer was then immersed
0 in 150 g. of distilled water for 24 hrs, The mixture was
stralned through 40 mesh screening and the amount of water
absorbed by the polymer calculated, This interpolymer
absorbed 40 g, of water per gram of polymer, When another
sample was drled at 100F for 48 hours, the interpolymer
showed no water absorption, When the drying was performed
at 100C for 19 hours, the water absorption was 8 g, of
water per g, of polymer,
Example X
Using the polymerization procedure described in Example
~'1 IX, the monomers listed in the following table were poly-
; merized, dried and tested under the conditions and with
the results set forth in the following table, From the
drying and water retention data set forth therein, it can
be seen that for certain interpolymers within the scope
of the present in~ention, proper selection of drying con-
ditions may be necessary to achieve the desired water
,1 retention properties. The amount o~ ingredients in the
table is in grams.
~ .
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.s
' ~ : , ,;.
~7~896 ~ ~
J&J 796
Polymer A B C D
Acrylamide - 30 126 120
Acrylic Acid 10 - 28 30
Sipomer Q-l 1 go 120 126 150
N,N'-Methylenebis-
acrylamide 0,05 0.o75 0.14 o.o6
Ammonium persulfate 0.5 0.75 1.4 1.5
Water 1200 1800 3025 3600
i o Polymerization Temp, C 55-66 55-66 55-65 55-65
% Solids 7,7 7.8 ~.3 7.6
Viscosity, cP 70 265 120 375
Absorptlon~ g.H20/g
Polymer
~L5 a, Sample dried 2 2
at 100F N,R. N.R. 32.4 21,1
b, Sample drled
at 100C, 3 hr. 84.9 18,3 36.6 35.1
c. Sample dried at
'0 100C, 19 hr.67.3 134.6 13.4 27,8
' ' "
1. Sipomer Q-l = 2-hydrox~-3-methacryloyloxypropyltrimethyl-
ammonium chloride - Alcolac Chemical Corp,
~ 2, N.R. = no water retention
.
Now, ha~ing described the novel interpolymers of this
~5 inventlon, together with their preparation and use, those -
skilled in the art will have no difficulty in making changes
and modificationæ which do not depart from the scope or spirlt
o~ the ~nventlon,
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