[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

[0002] 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 1 b 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 ^Q C-85 ^Q C. 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.

[0004] 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.

[0005] 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 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. 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 60 ^Q C and more preferably not exceeding 50 ^Q C 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 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.

[0018] 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 Cito C ₄ alkyl optionally substituted with one or more halogen such as perfluoroacetic and aryl acetic optionally substituted with halo), with hydrogen peroxide to form a highly reactive peracid. The preferred peracids are perform ic 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).

[0020] 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.

[0021] 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.

[0022] 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 60 ^Q C and preferably no more than 50 ^Q C (such as no more than 45 ^Q C, no more than 40 ^Q C, no more than 35 ^Q C and no more than 30 ^Q C). The reaction medium may have a temperature of at least 5 ^Q C and preferably at least 10 ^Q C. In one embodiment the temperature is maintained at about 25 ^Q C. [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 ^Q C preferably below 50 ^Q C and most preferably below 40 ^Q 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 ^Q C, preferably not temperatures over 50 ^Q C and more preferably not temperatures over 40 ^Q 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. [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 WO2005/044874, WO/2001 /060874, WO/2000/003723, WO2002/026211 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.

[0028] 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. [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 polyvinylacetate 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

[0033] Freshly distilled acrolein (56 g; 70 ml_) was dissolved in de-ionised water (649.6 g) at about 2O ⁰ C. To this vigorously stirring solution, 0.2M sodium hydroxide solution (22.4 g) was added all at once. The temperature was controlled to stay below 3O ⁰ 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%). [0041] 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

[0042] 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 3O ⁰ C and the suspension was stirred for 2 hours after the complete addition of peroxide.

[0043] The suspension was transferred to a 5 L beaker and cooled to about 5 ⁰ 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.

[0045] Notes: • 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. coli ATCC 8739 were determined for the white oxidized product of Example 3 and also for hot air oxidized poly(2-propenal, 2-propenoic acid).

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 ^"1 compound. Table 1

[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 ^"1

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 7O ⁰ C for 4 hours.

[0053] 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. [0054] Sodium chloride was added to the aqueous solution and extracted with THF (2 x 15 ml_). The combined THF 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).