Note: Descriptions are shown in the official language in which they were submitted.
2119232
-- 1 --
DESCRIPTION
METHOD FOR PRODUCING PROTEIN-SYNTHETIC POLYMER CONJUGATE
AND SAID CONJUGATE PRODUCED THEREBY
TECHNICAL FIELD
The present invention relates to a method for producing
a protein-synthetic polymer conjugate and the conjugate
produced thereby. More specifically, it relates to a method
for producing a protein-synthetic polymer conjugate, wherein
a protein-synthetic polymer conjugate is obtained by making
an alcohol having a functional group react with a carboxyl
group of amino acids constituting a protein to produce an
ester of the protein having a side chain lengthened by
esterification, or wherein the estex is further made to
react with a synthetic polymer material reactive to the
functional group after the lengthening of the side chain.
BACKGROUND ART
Protein, a hydrophilic polymer constituting the living
body, has various excellent functions, including
biocompatibility and bioactivities such as enzymatic action.
When a protein alone is used as a material, it fails to
fully offer its excellent function because its stability,
mechanical strength and workability are lower than those of
a synthetic polymer. To compensate for these drawbacks,
formation of a conjugate of protein with a synthetic polymer
has intensively been studied.
However, it is actually very difficult for a synthetic ~;
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2119232
2 -
polymer to form a conjugate with a hydrophilic protein
because it is usually hydrophobic. As an approach to this
problem, it may be possible to utilize a large number of
active side chains present in a protein, but protein-based
graft polymerization of a monomer requires the use of an
aqueous solvent because the reactivity in an organic solvent ~;~
is poor. Therefore this kind of polymerization has a limit
in itself.
With this in mind, the present inventors previously
developed a moisture absorbing/releasing material wherein a
small amount of natural polymer is bound to a synthetic ;~
polymer by milling gelatin to a fine powder and mechanically
kneading the powder in the absence of a solvent. However, -`~
its function was subject to limitation because this method ~
15 is limited to the process for producing a conjugate based on -~ ;
a synthetic polymer. ;~
However, if the content ratio of the protein and
synthetic polymer, which are mutually bound, can freely
adjusted and if free shaping is possible, development of ;
various conjugate materials with so far never obtained
totally new functions will be possible.
, For example, if it is possible to make a highly
hydrophilic protein form a conjugate with a synthetic
polymer, its affinity to other synthetic polymers becomes ;
high. This not only permits the combined use with other
synthetic polymers but also offers a useful material of good
touch or what is called "a moist touch." To achieve this, a ;
design of proteins with high reactivity even in organic ~ ~ ~
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2119232
solvents is required.
With these circumstances in mind, the present inventors
intensively investigated to obtain a protein highly reactive
in organic solvents.
Although esterification of a compound containing no
functional group other than the hydroxyl group, such as a
monohydric alcohol, with protein is well known so far,
protein esterification with an alcohol having a functional
group in addition to the hydroxyl group remains yet to be
fully clarified.
Directing the attention to the conventional method for
esterification of a protein with a monohydric alcohol, the
inventors esterified the side chain of protein with a
polyfunctional alcohol to lengthen the chain of the side
chain carboxyl group of the protein, and examined the
improvement in its reactivity in organic solvents.
As a result, the present inventors found that
polyfunctional alcohols, like monohydric alcohols, can also
easily be esterified with the carboxyl group in a protein
even in the absence of a catalyst, and further that this
ester can be used to obtain a protein-synthetic polymer
con;ugate, and developed the present invention.
DISCLOSURE OF INVENTION
Specifically, in order to synthesize a protein-
synthetic polymer conjugate in the present invention,
the first step to be taken is to prepare a protein ester
having a functional group derived from a polyfunctional
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~ 1 1 9 2 3 2
- 4 -
alcohol by making a polyfunctional alcohol react with the
side chain carboxyl group of amino acids constituting the
protein to lengthen its chain by esterification.
The second step, which uses an organic solvent such as
toluene, dimethylformamide, ethyl acetate, tetrahydrofran,
cyclohexane and dimethylsulfoxide which have seldom been ;~
used as a solvent for protein itself because of its low
affinity to protein, is to produce a protein-synthetic ;~
polymer conjugate by combining existing, so called,
polymerization techniques such as addition polymerization of
epoxy resin, raw material compound of urethane resin or - -~
other polymerizable vinyl monomers to the ester obtained in
the first step and graft polymerization of a synthetic
polymer to the ester.
The present invention is based on the above findings,
and the gist relates to:
(1) A method for producing an ester of a protein,
characterlzed by conducting the esterification reaction of a
protein in the form of aqueous solution, fine powder or
20 suspension with an excess amount of a polyfunctional alcohol `
to lengthen the chain of the side chain carboxyl group of
the~protein;
(2) A method for producing a protein-synthetic polymer
conjugate, characterized by using a polyhydric alcohol as a
25 polyfunctional alcohol and conducting the urethanation :
: ~ ., :.
reaction of a compound having the isocyanate group with the -
hydroxyl group derived from the polyhydric alcohol present
in the lengthened side chain.
' ~
2119232
-- 5 --
( 3 ) A method for producing a protein-synthetic polymer
conjugate, characterized by using a polyhydric alcohol as a
polyfunctional alcohol and allowing the hydroxyl group
derived from the polyhydric alcohol present in the
lengthened side chain to react with a compound having the
epoxy group and then to undergo subsequent resinification.
(4) A method for producing a protein-synthetic polymer
conjugate, characterized by using an alcohol having an
unsaturated bond as a polyfunctional alcohol; and conducting
addition polymerization, in the presence of a polymerization
initiator, of a vinyl monomer to the unsaturated group of
the alcohol present in the lengthened side chain, graft
polymerization of a synthetic polymer to it, or graft
polymerization of the ester of a protein having the
unsaturated group to a synthetic polymer.
(5) The ester of a protein obtained in (1) above, and
various protein-synthetic polymer conjugates obtained by the
above production methods (2) to (4).
BEST MODE FOR CARRYING OUT THE INVENTION
Each embodiment of the present invention is described
below.
(1) The first embodiment (production of ester):
An ester of a protein can be produced by the reaction
of an aqueous solution, fine powder or suspension of the
protein with excessive amount of a polyfunctional alcohol to
thereby lengthen the chain of the side chain carboxyl group
of the protein.
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2 1 1 9 2 3 2
- 6 -
V ' ~ '
The protein used in the present invention is not
subject to particular limitation; various polypeptides can
~ ' ' ' - ':":
be exemplified, including gelatin, collagen, casein, etc.
Animal skins such as calf skin, pig skin and sheep skin,
like chrome-tanned leather, containing these polypeptides,
may be used as such.
In the present invention, an ester of a protein can be
obtained by adding a polyfunctional alcohol to an aqueous
solution, fine power or suspension of the protein and
conducting an esterification reaction.
The polyfunctional alcohols mentioned here are -
exemplified by polyhydric alcohols such as diethylene
glycol, triethylene glycol, polyethylene glycol, glycerol,
butanediol and propanediol, and alcohols having an
unsaturated bond such as allyl alcohol, 4-allyl catechol and
allyl carbinol. Alcohols having the epoxy group are also
acceptable.
Although the amount of these polyfunctional alcohols
used ls not subject to special limitation, it is common to
use them in an excessive amount relative to the carboxyl
groups in the protein, the appropriate amount being 0.0015
-. . :::
to 0.1 mole per gram of the protein as mentioned above.
Esterification can usually be carried out at a reaction
temperature optionally chosen in the range from 10 to 100C.
25 Reaction time is usually chosen in the range from 1 hour to `
4 days, though it does not depend on a single factor, since -~
the degree of esterification can be optionally chosen
according to the amount of polyfunctional alcohol used and -
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. . . .
2119232
-- 7 --
reaction temperature.
By the reaction of these polyfunctional alcohol with
the protein mentioned above, the side chain carboxyl group
of glutamic acid (Glu), aspartic acid (Asp), etc. in a
protein can be esterified, to yield the protein with the
chain being lengthened. In such a manner, protein esters
having various functional groups of polyfunctional alcohols
in the lengthened chain can be obtained. When a polyhydric
alcohol is used as a polyfunctional alcohol mentioned above,
for example, an ester of a protein having the hydroxyl group
on the lengthened chain can be obtained. When an alcohol
having an unsaturated bond is used, an ester of protein
having an unsaturated group in the lengthened chain can be
obtained.
(2) The second embodiment (production of a protein-synthetic
polymer con;ugate):
In the first embodiment mentioned above, a protein-
synthetic polymer conjugate can be produced by using a
polyhydric alcohol as a polyfunctional alcohol to synthesize
a protein ester having the hydroxyl group derived from a
polyhydric alcohol on the lengthened side chain and then
making said hydroxyl group to react with a compound having
the isocyanate group to yield an urethane.
The polyhydri.c alcohols which can be used herein are
exemplified by diethylene glycol, triethylene glycol,
polyethylene glycol and glycerol among the above-mentioned
polyfunctional alcohols, and alcohols having two or more
hydroxyl groups in the molecule thereof such as butanediol
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2119232
- 8 -
:
and propanediol.
The hydroxyl group present in the lengthened side chain -
of the resulting ester can be urethanated by the reaction of ;~
the ester with a compound having the isocyanate group.
. , .
5 Specifically, for example, the ester may be made to react -~
with a compound having the isocyanate group and then
urethanated with a polyol or a diamine. Also, as a compound
having the isocyanate group, a prepolymer of a terminal
diisocyanate may be used to urethanate said ester to yield a --~
protein-synthetic polymer conjugate.
The compound having the isocyanate group, the polyol or
diamine used herein may be chosen according to the purpose,
usually from ordinary ones.
(3) The third embodiment (production of a protein-synthetic
polymer conjugate):
In the first embodiment mentioned above, a protein-
synthetic polymer con~ugate can be produced by using a ~ -~
: . ~:::.: .::: .:
polyhydric alcohol as a polyfunctional alcohol, forming a
proteln ester having an hydroxyl group derived from the,~
polyfunctional alcohol in the lengthened side chain, making
the hydroxyl group to react with a compound having the epoxy ~`
group and then resinifying.
The polyhydric alcohol used herein may be the same as
those used in the second embodiment. Compounds having the
epoxy group include epichlorohydrin, which may be used to
epoxidate the ester, followed by a reaction with, for
example, a polyhydric phenol, to cause sequential resin
formation, or a resin having an epoxidated end may be made
: : : :: : ;~:
2119232
g
to react with the hydroxyl group of the ester to yield a
protein-synthetic polymer conjugate.
(4) The fourth embodiment (production of a protein-synthetic
polymer conjugate):
In the above-described first embodiment, a
protein-synthetic polymer conjugate can be produced by
synthesizing an ester of a protein having an alcohol-derived
unsaturated group with an unsaturated bond in the lengthened
side chain using an alcohol having an unsaturated bond as a
polyfunctional alcohol, then carrying out addition
polymerization of a vinyl monomer in the presence of a - ;
polymerization initiator or graft polymerization of a
synthetic polymer to the unsaturated group or graft
polymerization of an ester of a protein having the
unsaturated group to a synthetic polymer.
The alcohols used hereinj which has an unsaturated
bond, are exemplified by allyl alcohol, 4-allyl catechol and
allyl carbinol as mentioned above.
Various methods can be used to produce a
protein-synthetic polymer conjugate using an ester having
such an unsaturated group, including 1) addition
polymerization with various polymerizable vinyl monomers in
the presence of a conventional polymerization initiator, 2)
graft polymerization of a synthetic polymer to the ester,
and 3) graft polymerization of the ester to a synthetic
polymer.
The polymerization initiators which can be used in the
above-described method 1) are exemplified by benzoyl
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2119232
.,
-- 10 --
peroxide and azoisobutyronitrile, and known polymerization
techniques based on radiopolymerization, ultraviolet
polymerization, polymerization by mechanochemical reaction,
etc. may also be used.
Polymerizable vinyl monomers which can be used include
vinyl chloride, ethylene, styrene, methyl methacrylate,
butadiene and chloroprene. Silicon monomers can also be
used.
In the above-described methods 2) or 3), the reaction
10 is carried out by cleaving the unsaturated group of the ~ ~-
ester on a synthetic polymer or on a shaped synthetic
polymer in the presence of a polymerization initiator to
graft the ester to the synthetic polymer, or by grafting a
synthetic polymer to the ester. The polymerization
initiator used here may be the same as those specified for
method 1) above. Synthetic polymers include polyvinyl ~
chloride, polyethylene, polyamide resin, silicon rubber, ;
polybutadiene rubber, polychloroprene rubber and
thermoplastic rubber. It should be noted, however, that
vulcanized rubbers can be used but are less effective than
unvulcanized ones, though they permit grafting.
, The protein-synthetic polymer conjugate of the present
invention is obtained in the second through fourth
embodiments with the ester obtained in the above-described ~ -
first embodiment as an intermediate. The protein-synthetic
polymer conjugate thus obtained is structurally
~characterized by the presence of an urethane bond in the
side chain of the protein (obtained in the second
: , : . .. . , .-
2119232
-- 11
embodiment), epoxidation of the side chain of the protein
(obtained in the third embodiment) and binding of the
synthetic polymer to the side chain of the protein (obtained
in the fourth embodiment).
The present invention is hereinafter described in more
details by means of the following working examples, but the
present invention is not limited by them.
The presence of an ester bond in the esters obtained in
Examples was confirmed as follows:
Qualitative determination: Determined by detection of an
ester bond by FT-IR or by a coloring reaction with
hydroxamic acid-iron (III).
In the hydroxamic acid-iron (III) coloring reaction,
0.6 ml of an aqueous solution of hydroxylamine (2 mol/1/3.5
N NaOHag = 1/1) is added to 0.2 ml of an about 2wt% aqueous
sample solution, and the mixture is kept standing at 30C
for 5 minutes. Then, 0.4 ml of 4 N HClaq and 0.4 ml of an
FeCl3aq solution (10wt% FeCl3-6H2O/O.l N HClaq) are added.
If an ester is present, the solution develops a
red-purple color.
Quantitative determination: Determined by the weight method
or the NMR method.
In the weight method, the resultant protein was washed
with water and dried, after which the weight increment was
measured to obtain the percent degree of esterification. In
the NMR method, the percent degree of esterification was
calculated from the area ratio of the phenylalanine nuclear
substitution H in the protein and the =CH2 group H in the
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21~232
- 12 -
allyl alcohol by NMR at 200 MHz.
Example 1
4.489 g (dry weight) of an alkali-treated gelatin - ~`
(produced by Konica Gelatin K.K., a-gelatin of about 100,000
molecular weight) was placed in a glass-stoppered conical
flask and dissolved in 10 ml of distilled water. After 5 ml
of allyl alcohol was added, the flask was tightly stoppered
and a reaction was carried out at 50C for 24 hours. To
recover the ester, the solvent water and the excessive `
unchanged allyl alcohol were evaporated in an oven at 50C
and subsequently completely removed by drying at 80C under
reduced pressure for 24 hours.
The resulting ester was again dissolved in 10 ml of
distilled water and subjected to three cycles of the same
procedure as above; the yield of the ester became constant,
reaching a final yield of 4.774 g. The resulting fine
powder was confirmed to contain an ester bond by absorption
at 1724 cm~1 in diffusion reflection FT-IR and by color
development from yellow to red-purple in the coloring
reaction with hydroxamic acid-iron (III). Also, NMR
analysis at 200 MHz identified the fine powder with an
gelatin ester (gelatin/allyl alcohol) wherein about 91~ of
the carboxyl groups of the gelatin was esterified.
Example 2
A dry weight of 5.105 g of a chrome-tanned leather - ;-~
(calf skin) powder, milled to not greater than about 10 ~m, ;
was placed in a glass-stoppered conical flask together with
5 ml of allyl alcohol to make a suspension, followed by a
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.. : . : :, .~. :.. :. . . ~ ~ ;: .
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- 13 - 2119232
reaction at 50C for 24 hours while stirring the suspension
using a magnetic stirrer. Next, the excessive allyl alcohol
was removed using a rotary evaporator and then completely
removed at 40C under reduced pressure for 24 hours.
After the ester obtained was washed with 10 ml of
distilled water, a small amount of alcohol contained was
removed in the same manner as in Example 1. After this
procedure is repeated three times, the yield of the ester
(chrome-tanned leather/allyl alcohol) reached a constant
amount. The final yield obtained was 5.237g, and the
percent degree of esterification based upon weight increment
was 37%.
Example 3
In a glass-stoppered conical flask, 5 ml of diethylene
glycol, 5.256 g of casein (first grade reagent) and 5 ml of
0.1 N HCl were placed, followed by a reaction at 50C while
stirring the mixture using a stirrer. The reaction was
stopped 24 hours later, and the reaction product was
precipitated in methanol and repeatedly washed with water to
completely remove the unbound diethylene glycol. After air
drying, the mixture was further dried under reduced pressure
to remove the remaining trace amount of water. As a result,
5.358 g of an ester (casein/diethylene glycol) was obtained.
Example 4
After 0.793 g of the ester (gelatin/allyl alcohol)
obtained in Example 1 and 2 ml of a 2 mmol/l solution of the
radical polymerization initiator benzoyl peroxide
(hereinafter referred to as BPO) in toluene were placed in a
,.i .; -, :
2119232
- 14 -
reaction vessel, 0.762 g of a styrene monomer and 5 ml of
toluene were further added, followed by nitrogen replacement
and 3 hours of reaction at 80C, and methanol was added to ~ -
stop the reaction. The resulting graft product was washed -
5 with acetone to remove the styrene monomer and the unbound ~-
polystyrene contained therein and 0.860 g of a
protein-synthetic polymer conjugate (gelatin/polystyrene
graft product) was obtained.
Example 5
Onto a 2 x 4 cm plasticizer-free transparent vinyl -
chloride resin plate, 0.225 g of the ester (gelatin/allyl
alcohol) obtained in Example 1 was applied in the form of a
powder as such, and several drops of a 3 mmol/l solution of
BPO in dimethyl sulfoxide were added to wet the powder,
after which the plate was transferred to a desiccator,
followed by a reaction at 80C for 3 hours while maintaining
a reduced pressure using an aspirator. The reaction product
formed a film on the vinyl chloride resin plate. After the
plate was boiled in water for 1 hour, an about 80~ insoluble
protein remained on the vinyl chloride resin plate as a
protein-synthetic polymer conjugate (gelatin/vinyl resin
plate graft product) as bound to the plate.
As a control experiment, gelatin which had not been ~ ~ -
chemically modified was applied onto a resin plate as a
BPO-free dimethyl sulfoxide solution in the same manner as
above. To the resulting product, water was added, which was
then boiled for 15 minutes. As a result, all the gelatin on
the vinyl chloride resin plate dissolved.
::
, : .:.. . . . .
2119232
- 15 -
Example 6
An 86% ester of gelatin (gelatin/butanediol) was
obtained in the same manner as in Example 3 except that
diethylene glycol was replaced with butanediol and casein
replaced with gelatin. This ester was dried at 80C under
reduced pressure for 24 hours to remove water therefrom,
after which 0.102 g of the ester was dissolved in dimethyl
sulfoxide to yield an about 15~ solution. While stirring
this solution, tolylene diisocyanate was added at an -NCO/OH
equivalence ratio of 1.02. After vigorous stirring, the
mixture was casted on a glass plate. About 30 minutes
later, the glass plate was immersed in water to remove the
solvent. As a result, obtained was a transparent flexible
tough film-like protein-synthetic polymer conjugate
(protein/urethane compound conjugate) which does not
dissolve even in 3 hours of boiling in water.
Example 7
5 g of an ester (gelatin/butanediol) obtained in the
same manner as in Example 6 and 0.2 g of caustic soda were
dissolved in 25 ml of distilled water. Separately, 2 ml of
epichlorohydrin was placed in a three-mouthed flask equipped
with a dripping funnel containing 5 ml of dimethyl sulfoxide
and a condenser. Next, a solution of the ester in caustic
soda was added drop by drop using the dripping funnel over a
period of about 10 minutes, followed by a reaction for 5
hours while stirring the mixture. After completion of the
reaction, the mixture was poured into an excessive amount of
acetone, filtered and washed, after which it was dried in a
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2119232
- 16 -
vacuum to yield an epoxidated intermediate of the ester.
Subseguently, 4 g of this epoxidated intermediate was
dissolved in 25 ml of dimethyl sulfoxide. This solution was
placed in a three-mouthed flask equipped with a condenser
5 and a dripping funnel, and heated to 50C, and 8.5 mmol of ~ -
bisphenol A was added. After the bisphenol A was dissolved,
an equivalent molar amount of a 40~ caustic soda solution
was gradually added, followed by a reaction for 6 hours.
After the reaction was stopped, the reaction product was
filtered with an excessive amount of acetone and repeatedly
washed. -~
Next, to remove the caustic soda from the reaction
product, the reaction product was placed in a Visking tube - -
and dialyzed in a sodium borate solution of pH 7.2 for 2
days, after which it was dried, to yield about 5.3 g of a
product. To modify this 5.3 g to a setting resin, the same
procedure as for the above-described epoxidated intermediate
was repeated, and was obtained a protein-synthetic polymer
conjugate (protein/epoxy compound conjugate) whose terminal
hydroxyl group was epoxidated.
The epoxidated protein thus obtained could be
crosslinked with an ordinary setting agent for epoxy resin
. . .::: . :.-
setting.
-: . .
Example 8 -
4.683 g of the ester (casein/diethylene glycol) of -
Example 3, previously dried at 60C under reduced pressure
for 24 hours to remove water therefrom and 10 ml of dimethyl
sulfoxide were placed in a reaction vessel. Next, while
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2119232
- 17 -
stirring this solution using a stirrer, 0.952 g of
butanediol and 10 ml of a dimethyl sulfoxide solution were
added, and subsequently a solution of 0.363 g of
diphenylmethane diisocyanate in 5 ml of dimethylformamide
was added. Next, the reaction vessel was heated to 50C,
followed by a reaction for about 2 hours, after which the
reaction product was precipitated in methanol, the polymer
was recovered, and the unchanged mixture remaining in the
polymer was removed by 24 hours of Soxhlet extraction with
ethyl acetate.
The protein-synthetic polymer conjugate
(protein/urethane compound conjugate) thus obtained was a
powder, whose surface condition was analyzed by FT-IR based
on the diffusion method. An absorption assigned to an
urethane bond was noted at 1740 cm~l, and other absorptions
each assigned to an ester bond, at 1320 cm~1 and 1230 cm~l.
Example 9
5 ml of a 3 mmol/l solution of BP0 in toluene was
placed in a polymerization tube, and 5.25 g of the ester
(gelatin/allyl alcohol) (fine powder state) of Example 1,
previously dried at 60C under reduced pressure for 24 hours
to remove water therefrom, was added. 1.0 ml of a
chloroprene monomer purified by a conventional method was
further dissolved in this toluene mixture, the air in the
polymerization tube was replaced with nitrogen, the tube was
sealed, and polymerization was initiated at 60C.
: .,: .
After 6 hours of polymerization, the tube was opened,
the reaction mixture was poured into methanol, and the ~;
2119232
- 18 -
polymer was recovered.
The resulting polymer was subjected to 24 hours of
Soxhlet extraction with benzene to remove the residual -
monomer and homopolymer.
Drying under reduced pressure yielded about 5.5 g of a
polymer. This polymer was identified to be in a state (a
protein-synthetic polymer conjugate) wherein the rubber was
bound to the protein surface by detection of a chloroprene `~
double bond at 1640 cm~1 in the differential spectrum ~ ~ ;
obtained by the diffusion method (FT-IR analysis).
: :.
INDUSTRIAL APPLICABILITY
According to the present invention, it is possible not ~ - -
only to modify synthetic polymers or proteins by covering
the synthetic polymer surface with a protein or by covering
the protein surface with a synthetic polymer but also to
produce protein-synthetic polymer conjugates of various
compositions. - -~
The present invention is therefore applicable to new
functional products, such as functional separatiDn
membranes, biocompatible materials, biodegradable polymers,
protein-based water-resistant adhesives and protein-based
flame resistant materials.
The present invention is expected to be widely used in
various fields from food industry producing protein
materials to plastic, rubber and fine chemical industries. -
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