U.S. patent application number 09/770561 was filed with the patent office on 2002-03-28 for bioadhesive compositions and wound dressings containing them.
Invention is credited to Munro, Hugh Semple, Yasin, Mohammed.
Application Number | 20020037270 09/770561 |
Document ID | / |
Family ID | 27269424 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020037270 |
Kind Code |
A1 |
Munro, Hugh Semple ; et
al. |
March 28, 2002 |
Bioadhesive compositions and wound dressings containing them
Abstract
A method for the treatment and/or prophylaxis of conditions
characterized by overstimulation of the tachykinin receptors, which
method comprises the administration to a mammal in need thereof of
an effective, non-toxic, pharmaceutically acceptable amount of a
compound of formula (I), or a pharmaceutically acceptable solvate
thereof, or a pharmaceutically acceptable salt thereof, wherein: Ar
is an optionally substituted phenyl, naphthyl or C 5-7
cycloalkdienyl group, or an optionally substituted single or fused
ring heterocyclic group, having aromatic character, containing from
5 to 12 ring atoms and comprising up to four heteroatoms in the or
each ring selected from S, O, N; R is linear or branched C 1-8
alkyl, C 3-7 cycloalkyl, C 4-7 cycloalkylalkyl, optionally
substituted phenyl or phenyl C 1-6 alkyl, an optionally substituted
five-membered heteroaromatic ring comprising up to four heteroatoms
selected from O and N, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, C
1-6 alkylaminoalkyl, di C 1-6 alkylaminoalkyl, C 1-6
acylaminoalkkyl, C 1-6 alkoxyalkyl, C 1-6 alkylcarbonyl, carboxy, C
1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkyl,
aminocarbonyl, C 1-6 alkylaminocarbonyl, di C 1-6
alkylaminocarbonyl, halogeno C 1-6 alkyl; or is a group --(CH 2)
p-- when cyclized onto Ar, where p is 2 or 3. R1 and R2, which may
be the same or different, are independently hydrogen or C 1-6
linear or branched alkyl, or together form a --(CH2)n-- group in
which n represents 3, 4 or 5; or R 1 together with R forms a group
--(CH 2)q--, in which q is 2, 3, 4 or 5; R 3 and R 4, which may be
the same or different, are independently hydrogen, C 1-6 linear or
branched alkyl, C 1-6 alkenyl, aryl, C 1-6 alkoxy, hydroxy,
halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C 1-6
alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono-
and di-C 1-6 alkylamino, --O(CH 2)r--NT 2, in which r is 2, 3 or 4
and T is hydrogen or C 1-6 alkyl or it forms with the adjacent
nitrogen a group (a) or (b), in which V and V 1 are independently
hydrogen or oxygen and u is 0, 1 or 2; --O(CH 2 ) s--OW in which s
is 2, 3 or 4 and W is hydrogen or C 1-6 alkyl; hydroxyalkyl,
aminoalkyl, mono- or di-alkylaminoalkyl, alkylamino,
alkylsulphonylamino, aminoacylamino, mono- or
di-alkylaminoacylamino; with up to four R 3 substituents being
present in the quinoline nucleus; or R 4 is a group --(CH 2 ) t --
when cyclized onto R 5 as aryl, in which t is 1, 2 or 3; R 5 is
branched or linear C 1-6 alkyl, C 3-7 cycloalkyl, C 4-7
cycloalkylalkyl, optionally substituted aryl, or an optionally
substituted single or fused ring heterocyclic group, having
aromatic character, containing from 5 to 12 ring atoms and
comprising up to four heteroatoms in the or each ring selected from
S, O, N; X is O, S, or N-CaN.
Inventors: |
Munro, Hugh Semple;
(Warwickshire, GB) ; Yasin, Mohammed; (Birmingham,
GB) |
Correspondence
Address: |
PALMER & DODGE, LLP
ONE BEACON STREET
BOSTON
MA
02108-3190
US
|
Family ID: |
27269424 |
Appl. No.: |
09/770561 |
Filed: |
January 26, 2001 |
Current U.S.
Class: |
424/78.17 |
Current CPC
Class: |
A61N 1/0452 20130101;
A61N 1/0496 20130101; A61N 1/046 20130101; A61B 2562/0215 20170801;
A61N 1/0428 20130101; A61L 24/06 20130101; A61F 13/0253 20130101;
A61B 2562/0217 20170801; A61N 1/0456 20130101; A61B 5/259 20210101;
A61L 24/0021 20130101; A61L 24/043 20130101; A61L 15/58 20130101;
A61L 15/585 20130101; A61N 1/0468 20130101; A61L 24/043 20130101;
C08L 3/02 20130101; A61L 24/043 20130101; C08L 33/14 20130101; A61L
24/06 20130101; C08L 33/26 20130101; A61L 24/06 20130101; C08L
33/14 20130101 |
Class at
Publication: |
424/78.17 |
International
Class: |
A61K 031/74 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 31, 1998 |
GB |
9816826.3 |
Mar 24, 1999 |
GB |
9906700.1 |
Apr 23, 1999 |
GB |
9909348.6 |
Jul 30, 1999 |
GB |
PCT/GB99/02524 |
Claims
1. A water unstable bioadhesive composition characterised in that
it has: (i) a water activity of from 0.4 to 0.9; (ii) an elastic
modulus at 1 rad/s of from 700 to 15,000 Pa; (iii) an elastic
modulus at 100 rad/s of from 2000 to 40,000 Pa; (iv) a viscous
modulus at 1 rad/s of from 400 to 14,000 Pa; (v) a viscous modulus
at 100 rad/s of from 1000 to 35,000 Pa; wherein the viscous modulus
is less than the elastic modulus in the frequency range of from 1
to 100 rad/s.
2. A bioadhesive composition according to claim 1 which comprises
an aqueous plasticiser, a copolymer of a hydrophilic unsaturated
water-soluble first monomer, a hydrophilic unsaturated
water-soluble second monomer together with a cross-linking agent,
the first monomer having a tendency preferentially to enhance the
bioadhesive properties of the composition.
3. A bioadhesive composition according to any one of the preceding
claims which is obtainable by polymerising an aqueous reaction
mixture comprising a hydrophilic unsaturated water-soluble first
monomer, a hydrophilic unsaturated water-soluble second monomer
together with a cross-linking agent, the first monomer having a
tendency preferentially to enhance the bioadhesive properties of
the composition.
4. A bioadhesive composition according to claim 2 or claim 3
wherein the first monomer has a tendency to enhance the mechanical
strength of the composition and/or the second monomer has a
tendency preferentially to increase the water activity of the
composition.
5. A bioadhesive composition according to claim 4 wherein the
second monomer has a tendency preferentially to lower the
electrical impedance and thereby enhance the electrical
conductivity of the composition.
6. A bioadhesive composition according to any one of claims 2 to 5
wherein the first monomer is a compound of formula 4wherein R.sup.1
is an optionally substituted hydrocarbon moiety, R.sup.2 is
hydrogen or optionally substituted methyl and ethyl, and M
represents hydrogen or a cation.
7. A bioadhesive composition according to claim 6 wherein R.sup.1
is an optionally substituted alkyl, cycloalkyl or aromatic moiety
containing from 3 to 12 carbon atoms.
8. A bioadhesive composition according to claim 6 or claim 7
wherein R1 represents 5wherein R.sup.3 represents hydrogen or an
optionally substituted straight or branched chain alkyl group
possessing from 1 to 6 carbon atoms and R.sup.4 represents an
optionally substituted straight or branched chain alkyl group
possessing from 1 to 6 carbon atoms.
9. A bioadhesive composition according to any one of claims 2 to 8
wherein the second monomer is a compound of formula 6wherein
R.sup.5 represents hydrogen or optionally substituted methyl or
ethyl, R.sup.6 represents hydrogen, a cation or R.sup.7SO.sub.3
wherein R.sup.7 represents an optionally substituted alkylene
moiety of 1 to 4 carbon atoms.
10. A water unstable bioadhesive composition substantially as
hereinbefore described in any one of Examples 1 to 10.
11. A wound dressing which comprises a carrier material and a
bioadhesive composition according to any one of the preceding
claims.
12. A wound dressing according to claim 11 which coated by the
bioadhesive compositions.
13. A wound dressing substantially as hereinbefore described in
Example 11.
14. A process for the preparation of a wound dressing as defined in
claim 11, 12 or 13 which process comprises either: (a) coating or
encapsulating a carrier material with an aqueous reaction mixture
as defined in claim 3, and curing the coating on the material; or
(b) coating a carrier material with a bioadhesive composition as
defined in any one of claims 1 to 10.
Description
[0001] This invention relates to bioadhesive compositions,
particularly wound dressings comprising hydrogel compositions
having bioadhesive properties.
BACKGROUND
[0002] One form of wound dressing commonly used comprises a
perforated carrier material and a layer of hydrophilic coating
which lies against the wound or sore. U.S. Pat. No. 5,352,508
(Cheong) discloses a net dressing in which the net is encapsulated
by a hydrophilic tacky resin and wherein the resin encapsulated on
the net leaves the majority of the apertures in the net substrate
unoccluded. The hydrophilic tacky resin used as the coating is said
to be a polymerised hydrogel.
[0003] An important feature for a wound dressing is that it should
not adhere to the wound. This is in order that it is allowed to
heal and to prevent damage to the wound on removal of the dressing.
At the same time the wound dressing needs to adhere strongly to
normal skin to prevent the wound dressing from coming off. Whilst
it has been appreciated in the past that these features are
important, there has been no understanding of how to achieve them
in a hydrogel system.
[0004] It is an object of this invention to provide hydrogel skin
adhesives possessing controlled and predictable adhesive properties
which may be readily varied to suit different uses and, in the case
of wound dressings or similar devices, different configurations or
applications. It is also an object of the invention to provide such
hydrogel skin adhesives which in addition may possess superior
adhesion characteristics as compared to those commonly associated
with bioadhesive hydrogels.
SUMMARY OF THE INVENTION
[0005] The performance of hydrogels as adhesives is related to the
surface energetics of the adhesive and of the adherend (for example
mammalian skin) and to the viscoelastic response of the bulk
adhesive. The requirement that the adhesive wets the adherend to
maximise the work of adhesion is well known. This requirement is
generally met when the adhesive has a similar or lower surface
energy to the adherend. The viscoelastic properties, in particular
the elastic or storage modulus (G') and the viscosity modulus (G")
are important. They are measured by dynamic mechanical testing at
different rad/s. Their values at low rad/s (approximately 0.01 to
Irad/s) and high rad/s (100 to 1000 rad/s) has been related to the
wetting/creep behaviour and peel/quick stick properties
respectively. The choice, assembly and processing of the
ingredients of the hydrogel adhesive are usually targetted at
making a material with a balance of properties suitable for
pressure sensitive adhesive applications. A balance between the
quantities and nature of polymer, plasticiser and the degree of
crosslinking/entanglement has to be achieved.
[0006] Whilst the presence of glycerol or other polyhydric alcohols
in other reported formulations has been quoted to provide humectant
properties to the hydrogel, it has been found that the most
important parameter to preventing water loss is the activity of the
water within the hydrogel which in turn depends on the nature and
proportions of the other components and manner of processing.
[0007] Water activity in the hydrogel adhesive is primarily
dependent on the water content and the nature of the polymeric
components and the way in which they are processed. Water activity
has been shown to have a better correlation with the growth of
bacteria and moulds than water content. It has been found that
organisms struggle to grow at water activities less than 0.8.
Enzyme activity has also been reported to decrease significantly
below activity of 0.8. Some wound dressings currently available not
only have high water contents but also high water activity, greater
than 0.99. Although these materials are sterilised, on opening the
pack they may become subject to encouraging microbial growth. Water
activity has also been found to influence the adhesivity of the
hydrogel adhesive in that at water activities above about 0.75,
they become less adhesive. A bioadhesive composition having a
suitable balance of the characteristics discussed above has now
surprisingly been found.
[0008] According to the invention there is provided a water
unstable bioadhesive composition characterised in that it has:
[0009] (i) a water activity of from 0.4 to 0.9;
[0010] (ii) an elastic modulus at 1 rad/s of from 700 to 15,000
Pa;
[0011] (iii) an elastic modulus at 100 rad/s of from 2000 to 40,000
Pa;
[0012] (iv) a viscous modulus at 1 rad/s of from 400 to 14,000
Pa;
[0013] (v) a viscous modulus at 100 rad/s of from 1000 to 35,000
Pa;
[0014] wherein the viscous modulus is less than the elastic modulus
in the frequency range of from 1 to 100 rad/s. Preferably the
surface energetics of the composition is from 25 to 40 dynes.
[0015] Examination of the rheological properties of the
compositions have been successfully used to characterise and
differentiate adhesive behaviour. Typically the elastic modulus
(G') and the viscous modulus (G") are measured over a range of
0.01-100 rad/s at a given temperature. For skin applications the
appropriate temperature is 37.degree. C. The moduli at low rad/s
values relate to the initial bonding of the adhesive to skin and
the higher to the changes in moduli values associated with
de-bonding. Methods of measuring G' and G" are well known; for
example a Rheometric Scientific RS-5 rheometer could be used.
[0016] The water activity of the composition can be measured using
impedance methods with devices such as the Rotronic AWVC
(manufactured by Rotronic). The activity of water may also be
determined by placing the composition in environments of controlled
humidity and temperature and measuring the changes in weight. The
relative humidity (RH) at which the composition does not change
weight corresponds to the activity of water in the gel (RH/100).
The use of saturated salt solutions to provide the appropriate
environmental conditions is well known. All compositions directly
exposed to relative humidities less than that corresponding to the
activity of water will be thermodynamically allowed to lose water.
Exposure to greater relative humidities and the composition will
gain weight.
[0017] The bioadhesive composition preferably comprises an aqueous
plasticiser, a copolymer of a hydrophilic unsaturated water-soluble
first monomer and a hydrophilic unsaturated water-soluble second
monomer and a cross-linking agent, the first monomer having a
tendency preferentially to enhance the bioadhesive properties of
the composition.
[0018] Preferably the first monomer has a tendency also to enhance
the mechanical strength of the composition according to the
invention and/or the second monomer has a tendency preferentially
to increase the water activity of the composition.
[0019] The bioadhesive composition is preferably obtainable by
polymerising an aqueous reactive mixture comprising the said first
monomer, the said second monomer and a crosslinking agent.
[0020] According to the invention, there is further provided a
wound dressing which comprises a carrier material and the
bioadhesive composition according to the invention. The carrier
material is either encapsulated or coated by either of the
bioadhesive compositions. Preferably it is coated, particularly on
only one side.
[0021] According to the invention there is also provided a process
for the preparation of a wound dressing according to the invention
which process comprises either:
[0022] (a) coating or encapsulating a carrier material with an
aqueous reaction mixture comprising the said first monomer, the
said second monomer and a crosslinking agent, and curing the
coating on the material; or
[0023] (b) coating a carrier material with the bioadhesive
composition according to the invention.
[0024] In preferred embodiments the first and second monomers will
be acrylate based monomers selected for their ability to polymerise
rapidly in water and having substantially the same molecular weight
whereby in a mixture of the two the relative proportions may be
varied without significantly altering the molar characteristics of
the composition.
[0025] The first monomer is preferably a compound of formula 1
[0026] wherein R.sup.1 is an optionally substituted hydrocarbon
moiety, R.sup.2 is hydrogen or optionally substituted methyl and
ethyl, and M represents hydrogen or a cation.
[0027] R.sup.1 is preferably an optionally substituted alkyl,
cycloalkyl or aromatic moiety. Preferably R.sup.1 represents a
saturated moiety or an aromatic moiety. R.sup.1 preferably contains
from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon
atoms. A preferred moiety which R.sup.1 represents is 2
[0028] wherein R.sup.3 represents hydrogen or an optionally
substituted straight or branched chain alkyl group possessing from
1 to 6 carbon atoms and R.sup.4 represents an optionally
substituted straight or branched chain alkyl group possessing from
1 to 6 carbon atoms.
[0029] The second monomer is preferably a compound of formula 3
[0030] wherein R.sup.5 represents hydrogen or optionally
substituted methyl or ethyl, R.sup.6 represents hydrogen, a cation
or R.sup.7SO.sub.3 wherein R.sup.7 represents an optionally
substituted alkylene moiety of 1 to 4 carbon atoms. Preferably
R.sup.7 represents optionally substituted n-propyl.
[0031] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.7 are
optionally substituted by a group which preferably has a tendency
to increase the water solubility of the compound. Suitable groups
will be well known to a person of skill in the art. A preferred
optional substituent is a hydroxyl, amino or ammonium group or a
halogen (e.g. chlorine, bromine, or iodine) atom. A suitable cation
is an alkali metal cation, especially sodium or potassium.
[0032] Most preferably the first monomer is
2-acrylamido-2-methylpropanesu- lphonic acid or an analogue thereof
or one of its salts, e.g. an alkali metal salt such as a sodium,
potassium or lithium salt. The second monomer preferably is acrylic
acid or an analogue thereof or one of its salts, e.g. an alkali
metal salt such as sodium, potassium or lithium or it preferably is
a polymerisable sulphonate or a salt, e.g. an alkali metal salt
such as a sodium, potassium or lithium salt, of acrylic acid
(3-sulphopropyl)ester or an analogue thereof. Particular preferred
examples of these respective monomers are the sodium salt of
2-acrylamido-2-methylpropanesulphonic acid, commonly known as
NaAMPS, and acrylic acid (3-sulphopropyl)ester potassium salt,
commonly known as SPA. NaAMPS is available commercially at present
from Lubrizol as either a 50% aqueous solution (reference code
LZ2405) or a 58% aqueous solution (reference code LZ2405A). SPA is
available commercially in the form of a solid from Raschig.
[0033] The total monomer content in the aqueous reactive mixture is
preferably from 15% to 60% by weight, preferably from 20% to 50% by
weight.
[0034] One advantage of the bioadhesives and wound dressings
according to the present invention is that they do not adhere to
wet skin. This is measured by the decrease in peel strength of a
hydrogel when it absorbs water, for example more than 3% by weight
water. It has been found that this decrease in peel strength is
optimal for certain weight ratios of monomers. A further advantage
of the composition according to the invention is that tests have
shown that such compositions are readily sterilisable. Consequently
they have particular application in products having medical uses,
such as wound dressings.
[0035] Where the first monomer is a salt of AMPS and the second
monomer is a salt of acrylic acid, the ratio by weight of the first
monomer to the second monomer is preferably not less than 2:1 and
preferably not less than 3:1. Where the first monomer is a salt of
AMPS and the second monomer is a salt of acrylic acid
(3-sulphopropyl)ester, the ratio by weight of the first monomer to
the second monomer is preferably not less than 1:10, preferably not
less than 1:1.
[0036] The first monomer is preferably included in an amount by
weight of from 1% to 60%, more preferably from 5% to 50%, most
preferably from 15% to 40%. The second monomer is preferably
included in an amount by weight of from 1% to 50%, preferably from
10% to 30%, most preferably from 10% to 20%. The crosslinker is
preferably included in an amount of from 0.01% to 2%, more
preferably from 0.1 to 2% by weight. The balance of the composition
preferably comprises an aqueous plasticiser.
[0037] One advantage of the first and second monomers is that it
has been found that high monomer content solutions can be achieved
(approximately 75%). It has also been found that the second monomer
is soluble in polyhydric alcohols such as glycerol, and addition of
glycerol to the first and second monomer mixture enhances the
solubilisation process. It has been found that the combination of
the two monomers enables a greater control over water content than
can be achieved otherwise. This can be important because it has
also been found that compositions made with the final water content
as an integral part of the pre-gel mix have different properties
from those made with an excess of water and then dried to the final
composition. For example, hydrogels with a final composition
obtained be the evaporation of water generally have lower elastic
or storage moduli than those made with no evaporation of water. To
obtain similar levels of elastic moduli, the amount of crosslinker
required in the former materials is higher. The evaporation of
water and extra crosslinker add to the cost of the process. This
problem is avoided by the present invention where a final drying
step is generally not required.
[0038] Conventional crosslinking agents are used to provide the
necessary mechanical stability and to control the adhesive
properties of the composition. Typical crosslinkers include
tripropylene glycol diacrylate, ethylene glycol dimethacrylate,
alkoxylated triacrylate, polyethylene glycol diacrylate (PEG400 or
PEG600), methylene bis acrylamide.
[0039] The aqueous reactive mixture optionally further comprises a
surfactant, an additional monomer, an electrolyte, a processing aid
(which is preferably a hydrophobic polymer), a water soluble
polymer suitable for forming an interpenetrating polymer network, a
non-hydrophilic polymer, an antimicrobial agent (e.g. citric acid,
stannous chloride) and/or, for drug delivery applications,
pharmaceutically active agents, the latter being designed to be
delivered either passively (e.g. transdermally) or actively (e.g.
iontophoretically) through the skin.
[0040] The process used to prepare bioadhesive compositions in
accordance with the invention comprises mixing the ingredients to
provide a reaction mixture in the form of an initial pre-gel
aqueous based liquid formulation, which is then converted into a
gel by a free radical polymerisation reaction. This may be achieved
for example using conventional thermal initiators and/or
photoinitiators or by ionizing radiation. Photoinitiation is a
preferred method and will usually be applied by subjecting the
pre-gel reaction mixture containing an appropriate photoinitiation
agent to UV light after it has been spread or coated as a layer an
siliconised release paper or other solid substrate. The processing
will generally be carried out in a controlled manner involving a
precise predetermined sequence of mixing and thermal treatment or
history. One preferred feature of the process according to the
invention is that no water is removed from the hydrogel after
manufacture.
[0041] Additional Monomer
[0042] The composition according to the invention preferably
comprises one or more additional monomers. A suitable additional
monomer is an ionic monomer, preferably a cationic monomer.
Additional monomers, when present, are preferably included in an
amount of up to 10% by weight.
[0043] A preferred cationic monomer is a quaternary ammonium salt.
An especially preferred cationic monomer is
(3-acrylamidopropyl)trimethyl ammonium chloride or
[2-(acryloyloxy)ethyl]trimethyl ammonium chloride.
[0044] Plasticiser
[0045] The compositions according to the invention generally
comprise, in addition to a crosslinked polymeric network, an
aqueous plasticising medium. Plasticisers are generally used in the
invention to control adhesive properties.
[0046] The aqueous plasticising medium optionally additionally
comprises a polymeric or non-polymeric polyhydric alcohol (such as
glycerol), an ester derived therefrom and/or a polymeric alcohol
(such as polyethylene oxide). Glycerol is the preferred
plasticiser. An alternative preferred plasticiser is an ester
derived from boric acid and a polyhydric alcohol (such as
glycerol). The aqueous reactive mixture preferably comprises from
10% to 50%, preferably from 10% to 45%, of plasticiser (other than
water) by weight of the mixture.
[0047] One advantage of this invention is that it provides hydrogel
dressings that are adhesive to dry skin which have water activities
from 0.4 to 0.85, preferably from 0.65 to 0.8 and more preferably
from 0.7 to 0.8. The latter materials have a greater tendency to
wet (i.e. donate water to the skin) rather than to extract. These
materials do not encourage the growth of microbial agents and they
can be sterilised. Hydrogels based on the curing of ionic monomers
are preferred as they enable a greater control of the activity of
water. For materials with requirements for higher water activities,
e.g. from 0.75 to 0.85, monomers which are potassium salts are
preferred, e.g. SPA, K AMPS, and K acrylate.
[0048] The water activity of the bioadhesive composition is ideally
selected to suit the wound to which the dressing is to be applied.
Thus different compositions may be provided for application to
different kinds of wounds such as burns and cuts. The water
activity, and thus absorption characteristics, of the composition
are optimised to prevent drying of the wound or to absorb excess
exudate from the wound.
[0049] Interpenetrants
[0050] The compositions preferably additionally comprise a water
soluble polymer suitable for forming an interpenetrating polymer
network. Hydrogels based on interpenetrating polymer networks (IPN)
are well known. An IPN has been defined as a combination of two
polymers, each in network form, at least one of which has been
synthesised and/or crosslinked in the presence of the other. As
will be appreciated, this combination will generally be a physical
combination rather than a chemical combination of the two polymers.
IPN systems may be described by way of example as follows:
[0051] Monomer 1 is polymerised and crosslinked to give a polymer
which is then swollen with monomer 2 plus its own crosslinker and
initiator.
[0052] If only one polymer in the system is crosslinked the network
formed is called a semi-IPN. Although they are also known as IPN's,
it is only if there is total mutual solubility that full
interpenetration occurs. In most IPN's there is, therefore, some
phase separation but this may be reduced by chain entanglement
between the polymers. It has also been reported that semi IPN's can
be made in the presence of carrier solvents (for example water in
the case of hydrophilic components).
[0053] It has been found that polymerising and crosslinking water
soluble monomers in the presence of water soluble polymers, water
and polyhydric alcohols produces hydrogel materials with enhanced
rheological and consequently adhesive properties.
[0054] Suitable water soluble polymers for the formation of semi
IPN's include poly (2-acrylamido-2-methylpropanesulphonic acid) or
one of its salts and its copolymers, poly (acrylic
acid-(3-sulphopropyl) ester potassium salt), copolymers of NaAMPS
and SPA, polyacrylic acid, polymethacrylic acid, polyethylene
oxide, polyvinyl methyl ether, polyvinyl alcohol,
polyvinylpyrrolidone, its copolymers with vinyl acetate,
dimethylaminoethyl methacrylate, terpolymers with
dimethylaminoethyl methacrylate and vinylcaprolactam,
polysaccharides such as gum arabic, karaya gum, xanthan gum, guar
gum, carboxymethyl cellulose (CMC), NaCMC, hydroxypropylmethyl
cellulose (HPMC), hydroxyethyl cellulose (HEC) or combinations
thereof.
[0055] The amount of interpenetrant polymer used will be dependent
on the mechanical and rheological properties required as well on
consideration of processing conditions. If the interpenetrant
polymer used increases the viscosity of the pre-gel mix beyond 5000
centipoise it has been found that the monomers do not polymerise
and crosslink on an acceptable time scale (should be less than 60
seconds, preferably less than 10 seconds). The viscosity depends on
the nature and molecular weight of the interpenetrant and the
nature of pre-gel processing.
[0056] Of the natural polysaccharides, gum arabic or maltodextrin
is usually preferred due to its cold water solubility and lesser
effect on viscosity compared with, for example, karaya gum. A
higher concentration of gum arabic than karaya may therefore be
used if desired, enabling a wider control of hydrogel properties.
It has also been found that the processing steps for assembling the
pre-gel formulation can be critical with respect to the properties
of the manufactured hydrogel. For a given formulation, if the
components are assembled at 25.degree. C. and cured different
adhesive properties are obtained compared to those that have been
heated to 70.degree. C. Solutions containing natural
polysaccharides become less opaque indicative of improved
solubility. The activity of water in compositions prepared from
heat treated pre-gels generally is lower than in non heat treated
pre-gels.
[0057] Other Additives
[0058] The composition preferably comprises a hydrophobic polymer.
Hydrophobic polymers may be incorporated either in the presence or
absence of interpenetrant polymers to form phase separated
materials. The preparation of two phase composites consisting of a
hydrophilic polymer containing an ionically conducting continuous
phase and domains of a hydrophobic pressure sensitive adhesive
which enhance adhesion to mammalian skin have been reported in U.S.
Pat. No. 5,338,490. The method of preparation described therein
involved casting a mixture (as a solution and or suspension)
consisting of the hydrophilic polymer containing phase and
hydrophobic components onto a substrate and then removing the
solvent. It has been found, however, that adhesive ionically
conducting hydrogels may be better prepared by combining the
hydrophobic polymer (preferably as an emulsion) with the components
of the pre-gel reaction mixture and casting these onto a substrate
and curing. In other words, there is no need to remove a solvent in
order to form useful materials. Furthermore, the hydrophilic phase
of the composition in addition to being a crosslinked network may
also be an IPN or semi IPN.
[0059] It is believed that when hydrophobic polymers are
incorporated in this way that the hydrophobic component segregates
to the surface (as determined by Fourier transform infrared
attenuated total reflectance spectroscopy, FTIR ATR, approximate
sampling depth 1 .mu.m using a ZnSe crystal or 0.25 .mu.m with a
Germanium crystal) and that it is the amount of the hydrophobic
component present in the surface that influences the adhesion to a
wide variety of materials. The greater the amount of the
hydrophobic component in the surface the greater the adhesion. In
U.S. Pat. No. 5,338,490 weight ratios of the hydrophilic phase to
the hydrophobic phase of 60:1 to 8:1 were claimed. In hydrogel
adhesives of between 100 to 2000 microns thick made in accordance
with the present invention, ratios of hydrophilic to hydrophobic
components ranging from 7:1 to 1:20 have been found to be
preferable, especially when these ratios are present in the surface
of the adhesive composition. In the process of the present
invention, however, it may take up to 72 hours from the initial
curing of the adhesive hydrogel for the segregation of the
hydrophobic materials to the surface, as defined by the ATR
sampling depth, to be complete.
[0060] Preferably, the hydrophobic pressure sensitive adhesive in
such embodiments is selected from the group consisting of
polyacrylates, polyolefins, silicone adhesives, natural or
synthetically derived rubber base and polyvinyl ethers or blends
thereof. Preferably the hydrophobic pressure sensitive adhesive in
these embodiments is an ethylene/vinyl acetate copolymer such as
that designated DM137 available from Harlow Chemicals or vinyl
acetate dioctyl maleate such as that designated Flexbond 150 and
sold by Air Products. Those skilled in the art will also know that
the molecular weight and comonomer ratios may be altered to control
the properties of hydrophobic pressure sensitive adhesives. In
general, the degree of surface segregation exhibited by such
hydrophobic pressure sensitive adhesive (HPSA) will be dependent on
factors such as composition of the HPSA, viscosity of the pre-gel
mixture, temperature and rate of curing.
[0061] The bioadhesive composition according to the invention
preferably is such that the relative amount of hydrophobic polymer
(which is the amount of hydrophobic polymer relative to the amount
of monomer) is preferably at least four times greater, more
preferably at least eight times greater, at the surface of the
composition compared to what it is in the bulk of the composition.
The relative amount at the surface is preferably the relative
amount in the composition at a depth of up to 1 micron (as measured
using FTIR ATR using a ZnSe crystal), preferably up to 0.25 micron
(as measured using FTIR ATR using a Germanium crystal). The
relative amount is measured by obtaining the ratio of the peak
height of the peak in the carbonyl region for the hydrophobic
polymer to the peak height of the peak in the carbonyl region for
the first monomer, using the relevant FTIR ATR technique. The wave
number values for the relevant peaks for the hydrophobic polymer
and the monomer are well known.
[0062] More preferably, the ratio of the relative amount in the
surface of the composition at a depth of up 0.25 micron to the
relative amount in the surface of the composition at a depth of up
1 micron is more than 1:1, more preferably more than 1.25:1, most
preferably more than 1.5:1.
[0063] Surfactant
[0064] The composition according to the invention optionally
includes a surfactant.
[0065] Any compatible surfactant may be used. Nonionic, anionic and
cationic surfactants are preferred, either alone or in combination.
The surfactant is preferably included in an amount from 0.1% to 20%
by weight, more preferably 0.1% to 10% by weight.
[0066] Carrier Material
[0067] The carrier material used in the wound dressings according
to the invention is preferably perforated. Generally any
conventional carrier material known for use in dressings can be
used as the carrier material. It is preferable that the carrier
material is made from inelastic fibres, preferably continuous
inelastic fibres. The carrier material is generally either knitted,
extruded, woven or non-woven. It is optionally in the form of, for
example, a foam or a film. The smallest dimension of each
perforation in the carrier material is preferably from 0.5 to 5.0
mm, more preferably from 1.0 to 3.0 mm. The fibres are made from
cotton, rayon, polyester, polyamide, polypropylene, polyamide or
wool or a mixture thereof.
[0068] Preparation of Wound Dressing
[0069] There are a variety of possible ways in which the process of
the invention may be carried out.
[0070] Examples of ways in which process (a) may be performed
include extruding the aqueous reaction mixture onto a web which, in
the case of an automated process, is preferably moving. The web is
preferably made from paper, polyester, polyolefin or any other
material commonly used in the art. The carrier material is either
laid on top of the aqueous reaction mixture after it has been
extruded or is laid on top of the web and the aqueous reaction
mixture is extruded over it. The assembly is then cured. Where the
carrier material is perforated, it may be necessary to blow air
through the assembly before curing to ensure that the perforations
are free from the bioadhesive composition.
[0071] An alternative way in which process (a) according to the
invention may be carried out is by coating the carrier material
with the aqueous reaction mixture by, for example, dipping the
carrier material in a bath of the aqueous reaction mixture and then
passing the coated carrier material over or round a single roller
or through a nip roller. The assembly is then cured. Again, if the
carrier material is perforated, it may be necessary to blow air
through the assembly before curing to ensure that the perforations
are free from the bioadhesive composition.
[0072] Process (b) according to the invention may be performed, for
example, by laminating a sheet of the bioadhesive composition with
the carrier material. The sheet of bioadhesive composition is
preferably supported by a plastic or coated material to act as a
protective release sheet.
[0073] In both processes according to the invention, the aqueous
reaction mixture is preferably coated in an amount of from 0.1 to 2
kg/m.sup.2.
[0074] The wound dressing according to the invention is optionally
coated on one or both sides with at least one release sheet. The
release sheets are generally either made of plastic or coated paper
e.g. siliconised paper.
[0075] The invention will be further described with reference to
FIGS. 1 to 5 of the accompanying drawings and the following
Examples in connection with bioadhesive compositions suitable for
use in wound dressings.
EXAMPLE 1
[0076] In 20 parts of polyethylene glycol diacrylate (pEG600)
(product of UCB Chemicals marketed under the trade name designation
of Ebacryl 11) were dissolved 6 parts of 1-hydroxycyclohexyl phenyl
ketone (product of Ciba and marketed under the trade name
designation of Iracure 184). The solution so produced is herein
designated solution A (XL/PI). Separately, 50 parts of the
potassium salt of 3-sulphopropyl acrylate (SPA) (product of
Raschig) were dissolved in 50 parts water to form solution B. A
further solution designated solution C consisted of 50 parts water,
50 parts of the sodium salt of 2-acrylamido-2-methylpropane
sulphonic acid (NaAMPS) product of the Lubrizol Corporation and
marketed as a 50% aqueous solution under the trade name LZ2405).
Mixtures of solutions B and C in the ratios of 100:0, 90:10, 60:40,
50:50, 40:60, 10:90 and 0:100 were made to form pre-gel solutions.
To 80 parts of each of these pre-gel solutions, 0.15 parts of
solution A, 5 parts potassium chloride and 20 parts distilled water
were added. The pre-gel solutions were coated onto siliconised
release paper at a coat weight of 0.8 kilograms per square meter
and exposed to ultraviolet radiation by being passed under a medium
pressure mercury arc lamp at a speed of 5 meters per minute to form
clear self supporting gels. The residence time under the lamp was 4
seconds. The storage moduli(G') of 20 mm diameter discs stamped
from the gels were recorded on a Rheometric Scientific RS-5
rheometer at 37.degree. C. The G' values at lrad are recorded in
Table 1. With the exception of the gels containing 90 and 100 parts
SPA, the gels produced had acceptable tack and peel properties on
the skin. From the data in Table 1 relatively linear changes in
storage modulus are obtained on increasing or decreasing the SPA to
NaAMPS ratio.
[0077] The gels were found to lose adhesion on water uptake and are
thus suitable for use in wound dressings.
[0078] In the above Example, and in the following Examples wherever
parts are mentioned they are meant as parts by weight unless
otherwise specified.
1 TABLE 1 NaAMPS 80 72 48 40 32 8 0 Solution C SPA 0 8 32 40 48 72
80 Solution B Distilled 20 20 20 20 20 20 20 Water XL/PI 0.15 0.15
0.15 0.15 0.15 0.15 0.15 Solution A KCl 5 5 5 5 5 5 5 G'(Pa) @
4,198 3,389 2,471 2,205 1,759 703 492 1 rad/s
EXAMPLE 2
[0079] In 20 parts of polyethylene glycol diacrylate (pEG600)
(product of UCB Chemicals marketed under the trade name designation
of Ebacryl 11) 6 parts of 1-hydroxycyclohexyl phenyl ketone
(product of Ciba and marketed under the trade name designation of
Irgacure 184) were dissolved. (This solution is designated solution
A) (XL/PI). Separately 58 parts of the potassium salt of
3-sulphoproylacrylate (SPA) (product of Raschig) were dissolved in
58 parts distilled water to form solution D. A further solution
designated solution E consisted of 42 parts water, 58 parts of the
sodium salt of 2-acrylamido-2-methylpropane sulphonic acid (NaAMPS)
(a product of the Lubrizol Corporation marketed as a 58% aqueous
solution under the trade name LZ2405A). Mixtures of solutions D and
B in the ratios 100:0, 90:10, 60:40, 50:50, 40:60, 10:90 and 0:100
were made to form pre-gel solutions. To 100 parts of each of these
pre-gel solutions, 0.17 parts of solution A and 3 parts potassium
chloride were added. The pre-gel solutions were coated onto
siliconised release paper at a coat weight of 0.8 kilograms per
square meter and passed under a medium pressure mercury arc lamp at
a speed of 5 meters per minute to form clear self-supporting gels.
Storage moduli were measured as in Example 1 and are recorded in
Table 2. As in the gels described in Example 1 the changes in the
elastic or storage modulus G'(Pa) are linear with respect to the
increasing or decreasing ratio of NaAMPS to SPA. All the gels
produced possess acceptable tack and peel strength against skin.
The gels with NaAMPS:SPA ratios in the range of 60:40 to 40:60,
however, have a better balance of reusability and peel
strength.
[0080] The gels were found to lose adhesion on water uptake and are
thus suitable for use in wound dressings.
2TABLE 2 NaAMPS 100 90 60 50 40 10 0 Solution E SPA 0 10 40 50 60
90 100 Solution D XL/PI 0.17 0.17 0.17 0.17 0.17 0.17 0.17 Solution
A KCl 3 3 3 3 3 3 3 G'(Pa) @ 15,142 14,333 11,073 10,672 9,920
6,280 5,199 1 rad/s
[0081] Upon varying the amount of the cross-linking agent a
substantially linear change in the elastic modulus G' can also be
obtained, as illustrated by the graph of FIG. 1.
EXAMPLE 3
[0082] To 57 parts of a 58% solution of the sodium salt of
2-acrylamido-2-methylpropane sulphonic acid (NaAMPS) (LZ2405A) 10
parts of a 58% solution of the potassium salt of 3-sulphopropyl
acrylate (SPA) were added along with 5 parts potassium chloride and
stirred until the potassium chloride has dissolved. This solution
was then mixed with 30 parts glycerol for 30 minutes. To the latter
solution were added 0.15 parts of a solution containing 20 parts of
polyethylene glycol diacrylate (pEG600) (product of UCB Chemicals
marketed under the trade name designation of Ebacryl 11) in which 6
parts of 1-hydroxycyclohexyl phenyl ketone (product of Ciba and
marketed under the trade name designation of Irgacure 184) were
dissolved. The so-formed pre-gel solution was then cured as in
Example 1. The gels were found to lose adhesion on water uptake and
are thus suitable for use in wound dressings. Good skin adhesion
properties were obtained for this gel.
EXAMPLE4
[0083] The method of Example 3 was repeated with 1 part citric acid
being added with the potassium chloride. The adhesion to skin and
reusability characteristics for this gel of Example 4 containing
citric acid and SPA were better than the gel described in Example
3.
EXAMPLE 5
[0084] The formulations listed in Table 4 were prepared using the
following method which is for formulation 5a. To 58 parts of a 50%
aqueous solution of the sodium salt of 2-acrylamido-2-methylpropane
sulphonic acid (NaAMPS) (LZ2405) 2 parts of the potassium salt of
3-sulphopropyl acrylate (SPA) were added along with 1.575 parts of
acrylic acid and stirred. This solution was then mixed with 37
parts glycerol for 30 minutes. To the latter solution were added
0.175 parts of solution (F). Solution F contains 20 parts of an
alkoxylated triacrylate (product of UCB Chemicals marketed under
the trade name designation of IRR 210) in which 1.4 parts of
1-hydroxycyclohexyl phenyl ketone (product of Ciba and marketed
under the trade name designation of Irgacure 184) are dissolved.
The so-formed pre-gel solution was then cured as in Example 1. The
G' and G" moduli were measured from 20 mm diameter discs of the gel
using a Rheometric Scientific RS-5 rheometer at 37.degree. C.
[0085] To prepare formulation 5b, the same method was repeated
except that 0.15 parts of solution F were used instead of 0.175
parts.
[0086] To prepare formulations 5c and 5d, the same method used for
formulation 5a was repeated except that the parts by weight were
changed to the figures given in Table 4A. The potassium chloride
was added instead of the acrylic acid; for formulation 5d,
deionised water was also added.
3 TABLE 4 Composition in parts by weight Formulation 5a 5b 5c 5d
50% NaAMPS 58 58 75 75 KCl 5 5 Acrylic Acid 1.575 1.575 SPA 2 2 2 2
Glycerol 37 37 25 25 DI WATER 3 PI/XL (Solution) 0.175 (F) 0.15 (F)
0.15 (A) 0.15 (A) G" (Pa) @ 1 rad/s 1455 1054 G" (Pa) @ 100 5174
4613 rad/s G" (Pa) @ 1 601 488 rad/s G" (Pa) @ 100 2906 2640
rad/s
EXAMPLE 6
[0087] The formulations listed in Table 5 were prepared using the
following method which is for formulation 6a. To 67 parts of a 58%
aqueous solution of the sodium salt of 2-acrylamido-2-methylpropane
sulphonic acid (NaAMPS) (LZ2405A) 2 parts of the potassium salt of
3-sulphopropyl acrylate (SPA) were added along with 5 parts of
potassium chloride and 1 part of citric acid and stirred until the
potassium chloride had dissolved. This solution was then mixed with
30 parts glycerol for 30 minutes. To the latter solution were added
0.13 parts of solution A prepared as described in Example 1. The
so-formed pre-gel solution was then cured as in Example 1. The G'
and G" moduli were measured from 20 mm diameter discs of the gel
using a Rheometric Scientific RS-5 rheometer at 37.degree. C.
[0088] To prepare formulation 6b, the same method was repeated
except that the potassium chloride and citric acid were omitted,
0.06 parts by weight of solution G were used instead of solution A
and the amounts of the other ingredients were changed to the
amounts given in Table 5. Solution G contains 20 parts of
polyethylene glycol diacrylate (molecular weight 400) (product of
UCB Chemicals marketed under the trade name designation of IRR 280)
in which 6 parts of 1-hydroxycyclohexyl phenyl ketone (product of
Ciba and marketed under the trade name designation of Irgacure 184)
are dissolved.
[0089] To prepare formulations 6c and 6d, the same method used for
formulation 6a was repeated except that citric acid was omitted,
0.06 parts of solution G were used instead of solution A and the
parts by weight were changed to the figures given in Table 5.
[0090] To prepare formulation 6e, the same method used for
formulation 6a was repeated except that gum arabic and the
ethylene/vinyl acetate copolymer designated DM137 and sold by
Harlow Chemicals were added instead of citric acid and the parts by
weight were changed to the figures given in Table 5.
[0091] To prepare formulation 6f, the same method used for
formulation 6a was repeated except that the ethylene/vinyl acetate
copolymer designated DM137 and sold by Harlow Chemicals,
polyethylene glycol (molecular weight 400) and sodium nitrate were
added with the citric acid and the parts by weight were changed to
the figures given in Table 5.
4TABLE 5 Composition in parts by weight Formulation 6a 6b 6c 6d 6e
6f 58% NaAMPS 67 57 57 57 67 50 KCl 5 5 5 5 1 Citric Acid 1 1 SPA 2
10 10 10 2 18 Glycerol 30 33 33 28 30 20 Gum Arabic 2 DM 137 2 3
PEG 400 10 Sodium 0.05 Nitrate PI/XL 0.13(A) 0.06 0.06(G) 0.075
0.25(A) 0.175 (Solution) (G) (G) (A) G'(Pa) @ 1 2973 4326 3019 4637
rad/s G'(Pa) @ 100 9800 13986 9763 8789 rad/s G"(Pa) @ 1 1265 1914
1200 1029 rad/s G"(Pa) @ 100 4597 6707 4537 3952 rad/s
EXAMPLE 7
[0092] To 34.7 parts of a 58% aqueous solution of the sodium salt
of 2-acrylamido-2-methylpropane sulphonic acid (NaAMPS) (LZ2405A)
34.7 parts of a 58% aqueous solution of the potassium salt of
3-sulphoproyl acrylate (SPA) were added along with 4.6 parts
potassium chloride and 3 parts distilled water and stirred until
the potassium chloride has dissolved. This solution was then mixed
with 23.2 parts glycerol for 30 minutes. To the latter solution
were added 0.15 parts of solution A prepared as described in
Example 1. The so-formed pre-gel solution was then cured as in
Example 1. The gels were found to lose adhesion on water uptake and
are thus suitable for use in wound dressings.
EXAMPLE 8
[0093] To 20 parts glycerol, 3 parts of a hydrophobic
ethylene/vinyl acetate copolymer emulsion (50% solids) (product of
Harlow Chemicals marketed under the trade name DM137) and 10 parts
polyethylene glycol (molecular weight 600) were added and stirred
until a uniform colour was obtained. To this mixture were added 50
parts of a 58% solution of the sodium salt of
2-acrylamido-2-methylpropane sulphonic acid (NaAMPS) (LZ2405A), 16
parts potassium salt of 3-sulphopropyl acrylate (SPA) and 5 parts
potassium chloride, and the solution was heated with stirring to
60.degree. C. for one hour. The mixture had changed from an opaque
off white to a translucent off white appearance. The turbidity of
the solutions as measured in a portable turbidity meter, product
code H193703 marketed by Hanna had changed from 254 ftu to 107 ftu.
The solution was cooled to 20.degree. C. and then there was added
0.13 parts of solution A prepared as described in Example 1. This
final solution was stirred for one hour and then cured as in
Example 1. The resulting gel had a G' value at 1 rad of 5328 Pa.
The activity of water in the gel, as determined by placing the gel
into cabinets at varying levels of humidity at 40.degree. C. (40,
52, 64 and 80% RH) and measuring weight uptake or loss and
extrapolating to zero weight chance, was 0.62. The adhesion to skin
of this gel was significantly greater than those described in the
previous examples. The gels were found to lose adhesion on water
uptake and are thus suitable for use in wound dressings. Analysis
of the gel by attenuated total reflectance infra-red spectroscopy
revealed that in the surface regions (about 1 micron or less),
either the air surface or the surface in contact with the release
paper, the concentration of the ethylene/vinyl acetate copolymer
relative to the NaAMPS was significantly enhanced compared to the
bulk composition.
EXAMPLE 9
[0094] The method of Example 8 was carried out except that with the
glycerol were added 3 parts of gum arabic. The resulting gel had a
G' value at 1 rad of 5406 Pa. The activity of water as determined
by the method in Example 8 was 0.55. The adhesion to skin of this
gel was significantly greater than those described in the previous
examples. The gels were found to lose adhesion on water uptake and
are thus suitable for use in wound dressings. Analysis of the gel
by attenuated total reflectance infra-red spectroscopy revealed
that in the surface region (about 1 micron or less), either the air
surface or the surface in contact with the release paper, the
concentration of the ethylene/vinyl acetate copolymer relative to
the NaAMPS was significantly enhanced compared to the bulk
composition.
EXAMPLE 10
[0095] The formulations shown in Tables 6 and 7 were prepared using
the following method which is for formulation 10a. To 20 parts
glycerol, 15 parts of a hydrophobic vinyl acetate/dioctyl maleate
copolymer emulsion (product of Air Products marketed under the
trade name Flexbond 150) were added and stirred until a uniform
colour was obtained. To this mixture were added 44 parts of a 58%
solution of the sodium salt of 2-acrylamido-2-methylpropane
sulphonic acid (NaAMPS) (LZ2405A), 20 parts potassium salt of
3-sulphopropyl acrylate (SPA) and 4 parts potassium chloride, and
the solution was heated with stirring to 60.degree. C. for one
hour. The solution was cooled to 20.degree. C. and then there was
added 0.13 parts of solution G prepared as described in Example 6.
This final solution was stirred for one hour and then cured as in
Example 1. The G' and G" moduli were measured from 20 mm diameter
discs of the gel using a Rheometric Scientific RS-5 rheometer at
37.degree. C.
[0096] Fourier transform infrared attenuated total reflectance
spectra (FTIR ATR) were taken of both the pregel mixture and of the
gel formed after polymerisation using a ZnSe crystal (approximate
sampling depth 1 .mu.m). The results obtained are shown in FIGS. 2
and 3, respectively. The peak at around 1740 cm.sup.-1 corresponds
to the hydrophobic polymer whereas the peak at around 1550
cm.sup.-1 corresponds to NaAMPS. It can be seen that before
polymerisation the ratio in height of the former peak to the latter
peak is about 0.25:1 whereas after polymerisation, the ratio is
about 2.9:1. This shows a twelve-fold increase in the concentration
of the hydrophobic polymer at the surface of the gel after
polymerisation indicating that the hydrophobic polymer surface
segregates. A further FTIR ATR spectrum was taken of the gel formed
after polymerisation using a germanium crystal (approximate
sampling depth 0.25 .mu.m). It was found that the ratio in the
height of the former peak to the latter peak is 3.9:1 showing a
sixteen fold increase in the concentration or the hydrophobic
polymer on the surface of the gel.
[0097] To prepare formulation 10b, the same method used for
formulation 10a was repeated except that a hydrophobic
ethylene/vinyl acetate copolymer emulsion (50% solids) (product of
Harlow Chemicals marketed under the trade name DM137) was used
instead of Flexbond 150, 3 parts polyethylene glycol (molecular
weight 600) were added with the hydrophobic copolymer DM137 and the
parts by weight were changed to the figures given in Table 6.
[0098] FTIR ATR were taken of the gel formed after polymerisation
using a ZnSe crystal (approximate sampling depth 1 .mu.m) and a
germanium crystal (approximate sampling depth 0.25 .mu.m). The
results obtained are shown in FIGS. 4 and 5, respectively. As for
formulation 10a, the peak at around 1740 cm.sup.-1 corresponds to
the hydrophobic polymer whereas the peak at around 1550 cm.sup.-1
corresponds to NaAMPS. The ratio of the former peak to the latter
peak for FIG. 4 (the ZnSe FTIR ATR spectrum) is about 21:1 whereas
the ratio for FIG. 5 (the germanium FTIR ATR spectrum) is about
11:1. This again demonstrates the hydrophobic polymer segregates to
the surface of the gel.
[0099] To prepare formulation 10c, the same method used for
formulation 10a was repeated except that a hydrophobic
ethylene/vinyl acetate copolymer emulsion (50% solids) (product of
Harlow Chemicals marketed under the trade name DM137) was used
instead of Flexbond 150, 0.05 parts of sodium nitrate were added
with the potassium chloride and the parts by weight were changed to
the figures given in Table 6.
[0100] To prepare formulations 10d and 10e, the same method used
for formulation 10b was repeated except that solution A as
described in Example 1 was used instead of solution G and the parts
by weight were changed to the figures given in Table 6.
[0101] To prepare formulations 10f and 10g, the same method used
for formulation 10d was repeated except that potassium chloride was
omitted and the parts by weight were changed to the figures given
in Table 6.
5TABLE 6 COMPOSITION by WEIGHT Formulation 10a 10b 10c 10d 10e 10f
10g 58% NaAMPS 44 44 65 35 35 35 37 KCl 4 5 5 5 5 SPA 20 20 10 25
25 15 18 Glycerol 20 20 23 20 20 30 30 Gum Arabic DM 137 15 2 15 15
15 10 Flexbond 150 15 PEG 600 3 10 10 5 5 Sodium Nitrate 0.05 PI/XL
0.13 0.13 0.15 0.12 0.13 0.15 0.15 (Solution) (G) (G) (G) (A) (A)
(A) G'(@ 1 rad/s) 6156 4756 G'(@ 100 rad/s) 15219 15412 G"(@ 1
rad/s) 1775 1840 G"(@ 100 5748 7743 rad/s)
[0102] To prepare formulations 10h, 10i and 10j, the same method
used for formulation 10g was repeated except that the parts by
weight were changed to the figures given in Table 7.
[0103] To prepare formulations 10k, 10l and 10m, the same method
used for formulation 10j was repeated except that a propylene
oxide/ethylene oxide block copolymer surfactant (designated PE/F127
and manufactured by BASF) was added with the glycerol and the parts
by weight were changed to the figures given in Table 7.
6TABLE 7 COMPOSITION by WEIGHT Formulation 10h 10i 10j 10k 10l 10m
58% 37 35 35 35 35 35 NaAMPS SPA 18 15 25 25 25 25 Glycerol 30 33
20 20 20 20 DM 137 10 10 15 15 15 15 PEG 600 10 5 10 10 10 10
PE/F127 1 5 9 PI/XL 0.15(A) 0.15(A) 0.14(A) 0.14(A) 0.14(A) 0.14(A)
(Solution)
EXAMPLE 11
[0104] An aqueous reaction mixture (or so-called pregel) was
prepared as described in Example 3 and coated onto a siliconised
release paper at a coat weight of 0.8 kilograms per square meter.
The aqueous reaction mixture was cured by passing the assembly
under a medium pressure mercury arc lamp at a speed of 5 meters per
minute. The residence time under the lamp was 4 seconds. The cured
bioadhesive composition was then laminated by a polyurethane film
(sold under the trade name SRF076 part number 93034 by Advanced
Medical Solutions) to form a wound dressing.
[0105] As will be seen, the invention presents a number of
different aspects and it should be understood that it embraces
within its scope all novel and inventive features and aspects
herein disclosed, either explicitly or implicitly and either singly
or in combination with one another. Also, many detail modifications
are possible and, in particular, the scope of the invention is not
to be construed as being limited by the illustrative example(s) or
by the terms and expressions used herein merely in a descriptive or
explanatory sense.
* * * * *