Note: Descriptions are shown in the official language in which they were submitted.
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Preparation of Antimicrobial
Field
[0001] The invention relates to a method of preparing an antimicrobial from
polymers of 2-propenal such as poly-2-propenal and to a poly(2-propenal, 2-
propenoic acid) polymeric antimicrobial resulting from the process.
Background
[00021 The preparation of polymers of poly 2-propenal and their use as
biocides
is described in US 5290894(Melrose (I)). The use of the polymers in treatment
of
gastrointestinal disease is described in US6723336 (Melrose (II)). Melrose
(II)
further describes in Example lb a method in which poly 2-propenal is prepared
by ionic initiation and carboxyl groups are introduced to the dried polymer by
careful heating with ample air at a temperature of 80 C-859C. The resulting
poly(2-propenal, 2-propenoic acid) is reported to be soluble in aqueous media
at
the pH of the duodenum.
[0003] The heating of solid poly 2-propenal in air is an effective way of
providing
improved efficacy in gastrointestinal application but we have found this
process
to have problems for large scale preparation of the antimicrobial and for a
wider
range of uses such as preservatives in cosmetics, pharmaceutical and
agrochemical formulations.
[00041 We have found that oxidation of the poly 2-propenal particularly with
heating tends to produce significant coloration resulting in a yellow to brown
solution when the polymer is dissolved for use. This coloration is undesirable
in
consumer products and causes difficulty in identifying and removing the source
of coloration.
100051 We have attempted to overcome the problem by heating organic solutions
of the poly 2-propenal in the presence of an oxidizing agent such as peroxide
but
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oxidation is ineffective or only poorly effective and recovery of the product
without
decomposition remains a problem.
[0006] The discussion of documents, acts, materials, devices, articles and the
like
is included in this specification solely for the purpose of providing a
context for
the present invention. It is not suggested or represented that any or all of
these
matters formed part of the prior art base or were common general knowledge in
the field relevant to the present invention as it existed before the priority
date of
each claim of this application.
Summary
[0007] The invention provides a method of preparation of poly(2-propenal, 2-
propenoic acid) comprising forming an aqueous suspension of poly 2-propenal
and oxidizing the suspension by mixing with a peroxide oxidant selected from
the
group consisting of hydrogen peroxide, peracids and mixtures thereof.
[0008] In a further aspect the invention provides a poly(2-propenal, 2-
propenoic
acid) composition which is colorless and preferably made according to the
above
process.
[0009] In a further aspect there is provided a composition comprising a
biologically active agent and a preservative effective amount of the above
described poly(2-propenal, 2-propenoic acid). The active agent may be a
cosmetic, pharmaceutical, veterinary agent or the like.
[0010] In one aspect there is provided a cosmetic composition for hair or
skincare
comprising an effective amount of the poly(2-propenal, 2-propenoic acid).
[0011] Throughout the description and the claims of this specification the
word
"comprise" and variations of the word, such as "comprising" and "comprises" is
not intended to exclude other additives, components, integers or steps.
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Detailed Description
[0012] The preparation of poly(2-propenal, 2-propenoic acid) comprises forming
an aqueous suspension of poly 2-propenal. The aqueous suspension may be
prepared by dispersing the poly 2-propenal in an aqueous liquor. The poly 2-
propenal may be dispersed in water to form a suspension by mixing the poly 2-
propenal solid with an aqueous liquor. The solid poly 2-propenal may be dry or
may be a mixture containing a solvent provided addition of the composition to
the
aqueous liquor results in formation of a suspension of the poly 2-propenal.
For
example in one embodiment the suspension is formed by mixing a composition
of poly 2-propenal in a water miscible solvent with an aqueous liquor. The
poly 2-
propenal may be soluble or insoluble in the solvent and when added to the
aqueous liquor the composition provides a suspension of the poly 2-propenal.
The use of a solvent in which poly 2-propenal is soluble may facilitate
storage or
handling of the poly 2-propenal prior to oxidation and/or convenient handling
during the mixing with the liquor but the nature and proportion of the solvent
is
such that when added to the aqueous liquor a suspension of the poly 2-propenal
is provided.
[0013] In one embodiment of the invention the poly 2-propenal is prepared by
polymerization of 2-propenal and the resulting poly 2-propenal is filtered
from the
reaction mixture and the filtered product used in the oxidation step
optionally
without further treatment. Alternatively, the filtered material may be dried
although it is preferable that the drying conditions not use a temperature
exceeding 609C and more preferably not exceeding 509C as we have found the
use of high temperature for drying results in coloration of the product
possibly as
a result of decomposition.
[0014] It is a feature of the invention that the poly 2-propenal be present as
a
suspension in an aqueous composition when the peroxide oxidant selected from
the group consisting of hydrogen peroxide, peracid and mixtures thereof is
mixed
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with the composition. We have found that oxidation of the poly 2-propenal as
an
aqueous suspension produces efficient oxidation leading to a colorless and
stable composition of poly(2-propenal, 2-propenoic acid) whereas the
corresponding process in which oxidation is attempted for a solution of poly 2-
propenal in non volatile solvent such as ethylene glycol or even a volatile
solvent
such as methanol results in no discernable change or a change which is
significantly less effective in improving solubility of the product in alkali.
[0015] The poly(2-propenal, 2-propenoic acid) product resulting from the
process
may be isolated by filtration of the aqueous liquor. The recovery of product
may
in some cases be improved by modification of the pH to provide a pH of neutral
or lower so that acid groups of the poly(2-propenal, 2-propenoic acid) do not
solubilise the product. Alternatively or in addition the product may be
extracted
into a suitable water immiscible solvent.
[0016] The invention may be conducted with the poly 2-propenal in a range of
concentrations in the aqueous composition provided, of course, that it is
present
as a suspension rather than dissolved. Preferable the concentration is in the
range of from 0.1% by weight to 80% by weight (preferably 1% to 60%, more
preferably from 5% to 50% and most preferably from 8% to 20%) based on the
total weight of the aqueous composition.
[0017] The method involves oxidizing the suspension of poly 2-propenal by
mixing the suspension in an aqueous liquor with a peroxide oxidant selected
from
the group consisting of hydrogen peroxide and peracid.
[00181 A peracid is an acid containing a peroxide group (-O-OH). The peracid
may be organic or inorganic and preferred peracids are per-carboxylic acids.
Percarboxylic acids may be prepared by reaction of the parent acid (RCOOH
where R can be hydrogen, alkyl such as C1to C4alkyl optionally substituted
with
one or more halogen such as perfluoroacetic and aryl acetic optionally
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substituted with halo), with hydrogen peroxide to form a highly reactive
peracid.
The preferred peracids are performic acid and peracetic acid and meta-
chloroperbenzoic acid.
[0019] The degree of oxidation and hence proportion of acid groups in the
poly(2-
propenal, 2-propenoic acid) can be controlled by the ratio of peroxide to 2-
propenal used in the oxidation and the period of time and conditions under
which
the oxidation is conducted. Generally speaking the desired extent of oxidation
can be determined by the solubility of the polymer in alkaline solution (e.g.
sodium carbonate).
[00201 The peroxide oxidant is preferably mixed with the aqueous suspension of
poly 2-propenal in a weight ratio of peroxide: poly2-propenal of 0.5:1 to 2:1
and
more preferably from 0.5:1 to 1.1:1.
100211 The period of time over which the oxidation is conducted will depend on
the nature and reactivity of the peroxide/peracid, the conditions used and the
degree of solubility desired in the final product. In one embodiment the
oxidation
is conducted for a period of from 10 minutes to 10 hours, preferably from 30
minutes to 5 hours and most preferably from 30 minutes to three hours.
[00221 The oxidation may be conducted at elevated temperature if desired and,
depending on the specific peracid and the concentration used the reaction
mixture may undergo a significant exotherm during the reaction procedure.
Preferably the temperature of the reaction will be maintained at no more than
609C and preferably no more than 500C (such as no more than 459C, no more
than 409C, no more than 35 C and no more than 30 C). The reaction medium
may have a temperature of at least 5 C and preferably at least 10 C. In one
embodiment the temperature is maintained at about 259C.
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[0023] The poly 2-propenal used in the process of the invention is preferably
formed by anionic polymerization and most preferably by base catalysed
polymerisation. Generally speaking radical initiated polymerization of 2-
propenal
using for example a peroxide initiator is best avoided as the resulting
product
tends to be an intractable highly cross linked solid that is typically not
particularly
useful as a preservative. Base catalysed polymerization of 2-propenal provides
a
range of monomeric units resulting from oxygen-carbon chain extension in
addition to head to tail carbon chain extension. Examples of the types of the
monomeric units are illustrated in US 6723336.
[0024] The poly 2-propenal may be prepared in aqueous solution by base
(preferably alkali metal hydroxide such as NaOH or KOH) catalysis and
preferably the temperature maintained below 60 C preferably below 50 C and
most preferably below 40 C. The resulting poly 2-propenal may be filtered from
the aqueous mixture used in the oxidation method by resuspending it in water.
Generally the poly 2-propenal formed by base catalysed polymerization will
precipitate from the aqueous solution in which 2-propenal in reacted as a fine
particulate solid so that it can be used in the oxidation process without
particle
size reduction although a process of particle size reduction such as milling
may
be used if desired to disrupt agglomerates or clumps of polymer. The filtered
polymer may be dried although as previously described the polymer is
preferably
not subject to temperatures over 60 C, preferably not temperatures over 50 C
and more preferably not temperatures over 40 C.
[0025] The poly(2-propenal, 2-propenoic acid) may be formulated in cosmetic,
pharmaceutical or veterinary products as a preservative. Alternatively the
product
may be used in the treatment of gastrointestinal disease in accordance with
the
disclosure of US6723336. The product is also useful in formulated antiseptic,
disinfectant and antifungal preparations according to the general description
in
US 5290894.
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[0026) In one embodiment of the invention the poly(2-propenal, 2-propenoic
acid)
is subject to further processing to improve antimicrobial activity and/
solubility in
aqueous media in accordance with the methods disclosed in one or more of
W02005/044874, WO/2001 /060874, WO/2000/003723, W02002/026211 and
PCT/Au2008/001032.
[0027] For example in one embodiment the poly(2-propenal, 2-propenoic acid) is
dissolved in an alcohol solution particularly a polyalkylene glycol and/or
alkaline
aqueous composition such as sodium or potassium carbonate aqueous solution.
In another embodiment the poly(2-propenal, 2-propenoic acid) is provided in
the
form of a nanoparticulate composition as described in PCT/Au2008/001032.
[00281 The poly(2-propenal, 2-propenoic acid) prepared in accordance with the
invention has a range of uses as an antimicrobial as described in our previous
patent applications. The gastrointestinal disease may for example result from
one
or more microbes selected from the group consisting of Coliforms, Salmonella,
P.
aeruginosa, Helicobacter, Proteus, Enterobacteria, Yeasts, Protozoa,
Clostridia,
Shigella and Coccidia 14. A method for the treatment or prophylaxis of
diseases
of the gastrointestinal tract caused by Helicobacter infection comprising the
gastrointestinal administration of a therapeutic amount of a polymer
comprising a
derivative of poly (2-propenal, 2-propenoic acid) formed by the reaction
between
a poly (2-propenal, 2-propenoic acid) and an organic compound containing
hydroxyl groups selected from alkanols, phenols, polyols and mixtures thereof,
to
form protected carbonyl groups. For example the poly(2-propenal, 2-propenoic
acid) may be administered to animals to treat gastrointestinal diseases such
as
collibacilosis in pigsand coccidiosis in poultry. In one embodiment there is
therefore provided a method of treatment of gastrointestinal disease in
animals
comprising administering animals in need thereof an effective amount of the
above described antimicrobial.
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[0029] There is further provided an antimicrobial for treating or preventing
gastrointestinal disease wherein the carrier for gastrointestinal
administration is
selected from the group consisting of water, controlled release polymers,
olive
oil, peanut oil, sesame oil, sunflower oil, arachis oil, coconut oil, liquid
paraffin,
ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol,
isopropanol, glycerol, fatty alcohols, triglycerides, polyvinyl alcohol,
partially
hydrolyse polyvinyl acetate and mixtures thereof.
[0030] There is provided in one embodiment an antimicrobial composition in the
form of a feed additive or drinking water additive comprising from 0.1 to 70%
by
weight of the antimicrobial. In one embodiment the animal of the feed
composition the antimicrobial is present in an amount of from 0.001 to 25% by
weight of the total feed or water composition.
[0031] The antimicrobial may be used in a surface cleaner antiseptic or
cosmetic
formulation to impart and antimicrobial effect on the surface to be treated or
provide a preservative effect on the composition itself. The antimicrobial
will
typically be present in such uses at a concentration in the range of from
0.001 to
25%by weight.
[0032] The invention will now be described with reference to the following
examples. It is to be understood that the examples are provided by way of
illustration of the invention and that they are in no way limiting to the
scope of the
invention.
Examples
Example 1: Preparation of Poly 2-propenal
10033] Freshly distilled acrolein (56 g; 70 ml-) was dissolved in de-ionised
water
(649.6 g) at about 20 C. To this vigorously stirring solution, 0.2M sodium
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hydroxide solution (22.4 g) was added all at once. The temperature was
controlled to stay below 30 C.
[0034] After about 20 seconds, polymer formed and fell out of solution. After
about 20 minutes, the stirring was reduced sufficiently to keep the polymer in
suspension and stirring continued for about 2 hours.
[0035] The suspension was filtered (Buchner funnel). The residue was washed
with water (twice the volume of the cake) and repeated 2 more times.
[0036] The cake was removed from the filter and spread out as a layer (about
10
mm) and dried in the fume cupboard at ambient temperature.
Example 2: Peroxide oxidation of Poly 2-propenal
Investigation Scale
[0037] Poly 2-propenal (2 g), produced according to example 1, was suspended
in de-ionised water (20 mL) containing sodium carbonate (2 g). Hydrogen
peroxide (0.606 g; 2.36 g of 30% solution) was added and the suspension
stirred
for 2 hours.
[0038] The mixture was acidified with aqueous HCI to about pH 2. Sodium
chloride (5 g) was added and the suspension extracted with tetrahydrofuran
(THF
3 x 15 mL). The combined THF extracts were dried with magnesium sulfate,
filtered and the THF evaporated.
[0039] Note: Under the conditions above, THF is phase separated from water.
[0040] The white sticky residue was air dried to remove residual solvent
(Yield
100%).
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[00411 The white oxidized product was soluble in sodium carbonate solution and
the FTIR consistent with a product containing carboxylic acid groups.
Example 3: Scale-up
[00421 Poly 2-propenal (100 g), produced according to example 1, was
suspended in deionised water (1000 g) containing sodium carbonate (100 g).
Hydrogen peroxide 30% w/w (118 g) was added drop wise such that the
temperature did not rise above 30 C and the suspension was stirred for 2 hours
after the complete addition of peroxide.
[00431 The suspension was transferred to a 5 L beaker and cooled to about 5 C.
The mixture was cautiously acidified with HCI to about pH 2 (about 140 mL of
35% w/w HCI). Sodium chloride (239 g) was added and the suspension stirred
for about 30 minutes.
a. The white solid was collected by vacuum filtration and the cake washed
with ice-cold de-ionised water (100 mL). The cake was air dried to
constant weight at room temperature.
b. The remaining filtrate was extracted with ethyl acetate (6 x 200 mL). The
combined extracts were washed with brine (2 x 20 mL). The filtrate was
dried with magnesium sulfate, filtered and evaporated to remove the ethyl
acetate. The residue was dried to constant weight giving colorless viscous
oil.
c. The solid and oil fractions were combined and the mixture homogenized
by grinding together until a fine white powder is obtained (Yield about
70%).
[0044] The white oxidized product was soluble in sodium carbonate solution and
the FTIR consistent with a product containing carboxylic acid groups.
1,00451 Notes:
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= The remaining material (about 30%) is retained in the aqueous phase after
ethyl acetate extraction.
= The white solid has the higher molecular weight polymer; the ethyl acetate
extract has mid range molecular weight material and the non-extractable
material is more polar lower molecular weight species.
= The ideal work up is to do a single extraction using the THF. However, this
was considered non-practical in scale-up due to the potential residual
peroxide build up when evaporating the THF.
[0046] The white oxidised product was soluble in sodium carbonate solution and
the FTIR consistent with a product produced by hot air oxidation of poly 2-
propenal as produced in example 1 b of US 6723336 (Reference sample).
[0047] Minimum Inhibitory Concentrations and Minimum Kill Concentrations
against E. co/iATCC 8739 were determined for the white oxidized product of
Example 3 and also for hot air oxidized poly(2-propenal, 2-propenoic acid).
Sample MIC MKC
ppm
Example 3 peroxide product 15.6 31.2
Reference Sample 15.6 31.2
Example 4
[0048] The procedure of Example 2 was repeated using different conditions (of
contact time, amount of peroxide solution and temperature) as set out in Table
1.
[0049] The FTIR spectra of the resulting products were compared with the
spectra of product prepared by hot air oxidation of the solid poly(2-propenal)
as
detailed in US 6,723, 336 Example 1 b and the intensity of the carboxylic acid
signal at 1726 cm-' compound.
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Table 1
----- -- - ------ ---- --- Example Contact Poly 2- Hydrogen Temp. Product FTIR
time propenal peroxide Solubility Code
(25.7%) (Na2CO3 soln)
4a 1 (2 h) 2 g 0.47 g 25 C Relatively poor 1
4b 2 (2h) 2 g 2.36 g 25 C Soluble 2
4c 3 (2h) 2 g 4.72 g 25 C Soluble 3
2 4 (2h) 2 g 2.36 g 25 C Soluble 2
4d 5 (36 h) 2 g 2.36 g 25 C Soluble 3
4e 6 (2h) 2 g 0.47 g 60 C Relatively poor 2
[0050] In each case, poly 2-propenal (2 g) was suspended in water (20 mL)
containing 2 g of sodium carbonate and the indicated amount of hydrogen
peroxide solution.
[0051] FTIR Code: Compared with Poly(2-propenal, 2-propenoic acid) prepared
by hot air oxidation: 1: low carboxylic acid intensity at 1726 cm-'
2: Similar carboxylic acid intensity at 1726 cm-1
3: Higher carboxylic acid intensity at 1726 cm-1
Example 5 (Comparative Example)
[0052] Poly 2-propenal (2 g), produced according to example 1, was dissolved
in
methanol (10 mol). Hydrogen peroxide 30% w/w (4.72 g) was added to the
solution and heated at 70 C for 4 hours.
[00531 The solution was then acidified with HCI to about pH.2. The methanol
was
evaporated under reduced pressure. The residue was diluted with water (33 mL)
giving a sticky solid that was separated from the aqueous solution and air
dried.
The FTIR showed that the residue was consistent with unchanged poly 2-
propenal.
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100541 Sodium chloride was added to the aqueous solution and extracted with
THE (2 x 15 mL). The combined THE extracts were dried (magnesium sulfate),
filtered and evaporated to dryness to give a colourless sticky gel. The FTIR
of
this product was also consistent with unreacted poly(2-propenal).
