JP2012512955A - Method for producing antibacterial agent - Google Patents

Abstract

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, peracid, and mixtures thereof. Production method of poly (2-propenal, 2-propenoic acid).

Description

  The present invention relates to a method for producing an antibacterial agent from a 2-propenal polymer, such as poly-2-propenal, and a poly (2-propenal, 2-propenoic acid) polymer antibacterial agent obtained from the method.

  A process for the preparation of poly-2-propenal polymers and their use as biocides is described in US 5290894 (Melrose (I)). The use of the polymer in the treatment of gastrointestinal diseases is described in US6723336 (Melrose (II)). Melrose (II) further described in Example 1b that a poly 2-propenal was prepared by ionic initiation and the carboxyl group was carefully heated to a temperature of 80 ° C. to 85 ° C. with sufficient air to produce a dry polymer. Describes the method of introduction. The resulting poly (2-propenal, 2-propenoic acid) is reported to be soluble in aqueous media at duodenal pH.

  Heating solid poly 2-propenals with air is an effective method that results in improved efficacy of gastrointestinal applications, but we have found that this method is a large scale production and widespread use of antibacterial agents (e.g., cosmetics). Found that there are problems with preservatives, pharmaceutical formulations, and pesticides.

  The inventors have found that oxidation of poly-2-propenal, especially by heating, tends to color significantly when dissolved to use the polymer, resulting in a yellow-brown solution. This coloring is undesirable for consumer goods and is problematic in identifying and removing the coloring source.

  The inventors have attempted to overcome the problem by heating an organic solution of poly-2-propenal in the presence of an oxidant, such as a peroxide, but the oxidation is ineffective or has only a slight effect. There is a problem in recovering the product without decomposing it.

  Discussion of materials, statutes, materials, equipment, literature, etc. is included herein only to provide a background to the invention. Any or all of these matters form the basis of prior art or do not suggest or indicate that they are common general knowledge in the fields relevant to the present invention that exist before the priority date of the present application.

(wrap up)
The present invention forms an aqueous suspension of poly-2-propenal and oxidizes the suspension by mixing with a peroxide oxidant selected from the group consisting of hydrogen peroxide, peracid, and mixtures thereof. A process for producing poly (2-propenal, 2-propenoic acid) is provided.

  In a further aspect, the present invention provides a colorless poly (2-propenal, 2-propenoic acid) composition, preferably prepared according to the above method.

  In a further aspect, a composition comprising a physiologically active substance and a conservatively effective amount of the poly (2-propenal, 2-propenoic acid) is provided. The active substance can be cosmetics, pharmaceuticals, veterinary drugs and the like.

  In one aspect, a cosmetic composition for hair care or skin care comprising an effective amount of poly (2-propenal, 2-propenoic acid) is provided.

  Throughout this specification and claims, the term “comprise” and variations thereof (eg, “comprising” and “comprises”) are not intended to exclude other additives, ingredients, integers, or steps. .

(Detailed explanation)
The process for producing poly (2-propenal, 2-propenoic acid) comprises forming an aqueous suspension of poly-2-propenal. Aqueous suspensions can be made by dispersing poly-2-propenal in an aqueous liquor. A suspension can be formed by dispersing poly-2-propenal in water and mixing the solid of poly-2-propenal with an aqueous liquid. The solid poly-2-propenal may be dry or a mixture containing a solvent, but adding the composition to a liquid solution results in the formation of a suspension of poly-2-propenal. For example, in certain embodiments, the suspension is formed by mixing a composition of poly-2-propenal in a water miscible solvent with an aqueous liquid. The poly-2-propenal may be soluble or insoluble in the solvent, and when added to an aqueous solution, the composition results in a suspension of poly-2-propenal. The use of a solvent in which the poly-2-propenal is soluble can facilitate storage or manipulation of the poly-2-propenal prior to oxidation and / or convenient manipulation when mixed with a liquid, but the nature and proportion of the solvent is When added to an aqueous solution, a suspension of poly-2-propenal is obtained.

  In some embodiments of the invention, poly-2-propenal is produced by polymerization of 2-propenal, and the resulting poly-2-propenal is filtered from the reaction mixture and the filtered product is used in the oxidation step without further processing. Sometimes. Alternatively, the filtered material may be dried, but it is preferred that the drying conditions not use a temperature above 60 ° C., as it has been found that the product is colored, possibly as a result of decomposition if a high drying temperature is used, It is more preferable not to use a temperature exceeding 50 ° C.

  A feature of the present invention is that when a peroxide oxidant selected from the group consisting of hydrogen peroxide, peracids, and mixtures thereof is mixed with the aqueous composition, the poly-2-propenal is present as a suspension in the aqueous composition. That is. Oxidation of poly-2-propenal as an aqueous suspension results in efficient oxidation, resulting in a colorless stable composition of poly (2-propenal, 2-propenoic acid), but non-volatile solvents (e.g. ethylene Glycol) or a corresponding step that attempts to oxidize a solution of poly-2-propenal in a volatile solvent (e.g. ethanol) does not result in a discernible change or to improve the solubility of the product in alkali. Brings changes that are almost ineffective.

  The poly (2-propenal, 2-propenoic acid) product resulting from the process can be isolated by filtering the aqueous liquid. Product recovery in some cases modifies the pH to a low or neutral pH so that the acid groups of poly (2-propenal, 2-propenoic acid) do not solubilize the product Can be improved. Alternatively or additionally, the product can be extracted into a suitable water-miscible medium.

  The present invention can of course be practiced with varying concentrations of poly-2-propenal in aqueous compositions that exist as suspensions rather than dissolve. Preferably, the concentration is 0.1% to 80% by weight based on the total weight of the aqueous composition (preferably 1% to 60%, more preferably 5% to 50%, most preferably 8% to 20%) Range.

  The method includes oxidizing a suspension of poly-2-propenal by mixing a suspension in an aqueous liquid with a peroxide oxidant selected from the group consisting of hydrogen peroxide and peracid.

  A peracid is an acid containing a peroxide group (—O—OH). The peracid may be organic or inorganic and the preferred peracid is a percarboxylic acid. Percarboxylic acids are substituted with a parent acid (RCOOH, where R is hydrogen, an alkali, e.g. a C1-C4 alkali that may be substituted with one or more hydrogens, e.g. perfluoroacetic acid, and halo. Can be produced by reacting with hydrogen peroxide to form highly reactive peracids. Preferred peracids are performic acid and peracetic acid and meta-chloroperbenzoic acid.

  The degree of oxidation, that is, the ratio of acid groups in poly (2-propenal, 2-propenoic acid) can be adjusted by the ratio of peroxide used for oxidation to 2-propenal, and the time and conditions for oxidation. it can. In general, the desired degree of oxidation can be determined by the solubility of the polymer in an alkaline solution (eg, sodium carbonate).

  The peroxide oxidant is preferably mixed with an aqueous suspension of poly-2-propenal in a weight ratio of peroxide: poly-2-propenal of 0.5: 1 to 2: 1, more preferably 0.5: 1 to 1.1: 1. To do.

  The time for performing the oxidation will depend on the nature and reactivity of the peroxide / peracid, the conditions used, and the desired solubility in the final product. In certain embodiments, the oxidation is performed for 10 minutes to 10 hours, preferably 30 minutes to 5 hours, and most preferably 30 minutes to 3 hours.

  Oxidation can be carried out at elevated temperatures depending on the particular peracid and concentration used, if desired, and the reaction mixture may be exothermic during the reaction procedure. Preferably, the reaction temperature is maintained at 60 ° C or lower, preferably 50 ° C or lower (eg, 45 ° C or lower, 40 ° C or lower, 35 ° C or lower, and 30 ° C or lower). The reaction medium can be at a temperature of at least 5 ° C, preferably at least 10 ° C. In certain embodiments, the temperature is maintained at about 25 ° C.

  The poly 2-propenal used in the process of the present invention is preferably formed by anionic polymerization, most preferably base catalyzed polymerization. In general, radical-initiated polymerization of 2-propenals using, for example, peroxide initiators, tends to result in the resulting product typically being an unwieldy and highly crosslinked solid that is not particularly useful as a preservative. It is best to avoid it. The base-catalyzed polymerization of 2-propenal results in a variety of monomer units generated by oxygen-carbon chain extension in addition to carbon chain extension from the head to the tail. Examples of the types of monomer units are described in US Pat. No. 6,723,336.

  Poly-2-propenals can be prepared in aqueous solution by base (preferably alkali metal hydroxides such as NaOH or KOH) catalysis, preferably at a temperature of 60 ° C. or lower, preferably 50 ° C. or lower, most Preferably, it is maintained at 40 ° C. or lower. The resulting poly-2-propenal can be filtered from the aqueous mixture used in the oxidation process by resuspension in water. In general, poly-2-propenals formed by base-catalyzed polymerization can disrupt polymer clumps and agglomeration, if desired, by particle size reduction methods, such as grinding, but without oxidizing the particle size. Precipitate from an aqueous solution in which 2-propenal is reacted as a finely divided solid that can be used in Although the filtered polymer can be dried, as described above, the polymer is preferably not subjected to temperatures of 60 ° C. or higher, preferably 50 ° C. or higher, more preferably 40 ° C. or higher.

  Poly (2-propenal, 2-propenoic acid) can be formulated as a preservative in cosmetics, pharmaceuticals, or veterinary drugs. Alternatively, the product can be used for the treatment of gastrointestinal diseases according to the disclosure of US6723336. The product is also useful for preservative, fungicide and antifungal formulations according to the general description of US 5290894.

  In some embodiments of the invention, the poly (2-propenal, 2-propenoic acid) is one or more of WO2005 / 044874, WO / 2001/060874, WO / 2000/003723, WO2002 / 026211, and PCT / Au2008 / 001032. Further processing is performed to improve the activity and solubility of the antimicrobial agent in the aqueous medium according to the methods disclosed above.

  For example, in certain embodiments, poly (2-propenal, 2-propenoic acid) is dissolved in an alcohol solution, particularly a polyalkylene glycol and / or an alkaline aqueous composition, such as an aqueous sodium carbonate or potassium carbonate solution. In another embodiment, the poly (2-propenal, 2-propenoic acid) is provided in the form of a nanoparticle composition as described in PCT / Au2008 / 001032.

  Poly (2-propenal, 2-propenoic acid) produced according to the present invention has various uses as an antibacterial agent as described in our earlier patent application. The gastrointestinal disease can arise from, for example, one or more microorganisms selected from the group consisting of coliforms, Salmonella, P. aeruginosa, Helicobacter, Proteus, enterobacteria, yeast, protozoa, Clostridium, Shigella, and Coccidium 14. Poly (2-propenal) formed by the reaction of poly (2-propenal, 2-propenoic acid) and organic compounds (including hydroxyl groups selected from alkanols, phenols, polyols, and mixtures thereof) , 2-propenoic acid), and a gastrointestinal disease caused by Helicobacter infection, comprising administering to the gastrointestinal a therapeutically effective amount of the polymer. For example, poly (2-propenal, 2-propenoic acid) can be administered to animals to treat gastrointestinal disorders such as porcine collibacilosis, poultry coccidiosis. Accordingly, in certain embodiments, a method of treating gastrointestinal disease is provided comprising administering to an animal in need of an effective amount of the antimicrobial agent.

  In addition, the carrier for gastrointestinal administration is water, controlled release polymer, olive oil, peanut oil, sesame oil, sunflower oil, peanut oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol An antibacterial agent for treating or preventing gastrointestinal diseases selected from the group consisting of fatty alcohols, triglycerides, polyvinyl alcohol, in particular hydrolyzed polyvinyl acetate, and mixtures thereof.

  In certain embodiments, an antimicrobial composition in the form of a food additive or a drinking water additive comprising 0.1-70% by weight antimicrobial agent is provided. In certain embodiments, the antimicrobial agent in the animal feed composition is present in an amount from 0.001 to 25% by weight of the total feed or water composition.

  The antibacterial agent can be used in surface cleaning antibacterial or cosmetic preparations to provide an antibacterial effect on the surface to be treated or to provide a preservative effect on the composition itself. The antimicrobial agent is typically present at a concentration in the range of 0.001 to 25% by weight in the use.

  The invention will now be described with reference to the following examples. It should be understood that the examples are illustrative of the invention and do not limit the scope of the invention.

Preparation of poly-2-propenal Freshly distilled acrolein (56 g; 70 mL) was dissolved in deionized water (649.6 g) at about 20 ° C. To this vigorously stirred solution was added 0.2 M sodium hydroxide solution (22.4 g) all at once. The temperature was adjusted to be kept below 30 ° C.

  After about 20 seconds, a polymer formed and was no longer in solution. After about 20 minutes, stirring was reduced sufficiently to keep the polymer in suspension and stirring was continued for about 2 hours.

  The suspension was filtered (Buchner funnel). The residue was washed with water (twice the cake volume) and repeated twice more.

  The cake was removed from the filter paper, spread as a layer (about 10 mm) and dried in a fume cupboard at ambient temperature.

Study scale for peroxide oxidation of poly-2-propenal Poly 2-propenal (2 g) prepared according to Example 1 was suspended in deionized water (20 mL) containing sodium carbonate (2 g). Hydrogen peroxide (0.606 g; 2.36 g of a 30% solution) was added and the suspension was stirred for 2 hours.

  The mixture was acidified to about pH 2 with aqueous HCl. Sodium chloride (5 g) was added and the suspension was extracted with tetrahydrofuran (THF 3 × 15 mL). The combined THF extract was dried over magnesium sulfate, filtered and then the THF was evaporated.

  Note: Under the above conditions, THF is a phase separated from water.

  The white viscous residue was air dried and the remaining solvent was removed (yield 100%).

  The white oxidation product was soluble in sodium carbonate solution and the FTIR was consistent with the carboxylic acid group containing product.

Scale-up Poly 2-propenal (100 g) prepared according to Example 1 was suspended in deionized water (1000 g) containing sodium carbonate (100 g). Hydrogen peroxide 30% w / w (118 g) was added dropwise so that the temperature did not rise above 30 ° C., and after the peroxide was completely added, the suspension was stirred for 2 hours.

The suspension was transferred to a 5 L beaker and cooled to about 5 ° C. The mixture was carefully acidified with HCl to about pH 2 (about 140 mL of 35% w / w HCl). Sodium chloride (239 g) was added and the suspension was stirred for about 30 minutes.
a. The white solid was collected by vacuum filtration and the cake was washed with ice cold deionized water (100 mL). The cake was air dried at room temperature to a constant weight.
b. The remaining filtrate was extracted with ethyl acetate (6 × 200 mL). The combined extract was washed with brine (2 × 20 mL). The filtrate was dried over magnesium sulfate, filtered and then evaporated to remove ethyl acetate. The residue was dried to give a constant weight of a colorless viscous oil.
c. The solid and oil fractions were mixed and the mixture was homogenized by trituration together until a fine white powder was obtained (yield about 70%).

  The white oxidation product was soluble in sodium carbonate solution and the FTIR was consistent with the carboxylic acid group containing product.

note:
Residual material (about 30%) was retained in the aqueous phase after ethyl acetate extraction.
The white solid is a higher molecular weight polymer, the ethyl acetate extract is an intermediate range of molecular weight material, and the non-extractable material is a more polar and lower molecular species.
• The ideal workup is a single extraction with THF. However, this was considered impractical to scale up, as residual peroxide may increase when THF is evaporated.

  The white oxidation product was soluble in sodium carbonate solution and the FTIR was consistent with the product produced by hot air oxidation of the poly-2-propenal (reference sample) prepared in Example 1b of US 6723336.

Minimum inhibitory and kill concentrations for E. coli ATCC 8739 were determined for the white oxidation product of Example 3 and hot air oxidized poly (2-propenal, 2-propenoic acid).

  The method of Example 2 was repeated using the various conditions described in Table 1 (contact time, amount of peroxide solution, and temperature).

The FTIR spectrum of the resulting product is shown as the spectrum of the product produced by hot air oxidation of the solid poly (2-propenal) described in Example 1b of US 6,723,336 and the intensity of the carboxylic acid signal at 1726 cm ^-1 of the compound. Compared.

  In each case, poly 2-propenal (2 g) was suspended in water (20 mL) containing 2 g sodium carbonate and the indicated amount of hydrogen peroxide solution.

FTIR code: Comparison with poly (2-propenal, 2-propenoic acid) produced by hot air oxidation:
1: Low carboxylic acid strength at 1726cm ^-1
2: Similar carboxylic acid strength at 1726cm ^-1
3: High carboxylic acid strength at 1726cm ^-1

(Comparative Example)
Poly 2-propenal (2 g) prepared 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.

  The solution was then oxidized to about pH 2 with HCl. Methanol was evaporated under reduced pressure. The residue was diluted with water (33 mL) to give a viscous solid that was separated from the aqueous solution and air dried. FTIR showed that the residue was consistent with unchanged poly 2-propenal.

  Sodium chloride was added to the aqueous solution and extracted with THF (2 × 15 mL). The combined THF extract was dried (magnesium sulfate), filtered and then evaporated to give a colorless viscous gel. The FTIR of this product was also consistent with unchanged poly (2-propenal).

Claims (17)

  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, peracid, and mixtures thereof. (2-propenal, 2-propenoic acid) production method.   2. The method of claim 1, wherein the aqueous suspension is prepared by dispersing poly-2-propenal in an aqueous liquid.   2. The method of claim 1, wherein a solution of poly-2-propenal in a water miscible solvent is dispersed in the aqueous composition to form an aqueous suspension of poly 2-propenal.   The concentration of poly-2-propenal is 0.1% to 80% by weight based on the total weight of the aqueous composition (preferably 1% to 60%, more preferably 5% to 50%, most preferably 8% to 20% A method according to any of the preceding claims which is in the scope of   The peroxide oxidant is hydrogen peroxide, organic or inorganic peracids, and percarboxylic acids, and mixtures thereof, preferably hydrogen peroxide, percarboxylic acids of formula R (CO) OOH, where R is hydrogen , An alkali, such as a C1-C4 alkali that may be substituted with one or more halogens, such as perfluoroacetic acid, and aryl that may be substituted with halo), and mixtures thereof A process according to any preceding claim, preferably selected from the group consisting of hydrogen peroxide, performic acid, peracetic acid, and permetachlorobenzoic acid.   The process according to any of the preceding claims, wherein the reaction temperature is maintained at 60 ° C or lower, preferably 50 ° C or lower (eg 45 ° C or lower, 40 ° C or lower, 35 ° C or lower, 30 ° C or lower).   Where the peroxide oxidant is mixed with an aqueous suspension of poly-2-propenal at a peroxide: poly-2-propenal weight ratio of 0.5: 1 to 2: 1, more preferably 0.5: 1 to 1.1: 1. A method according to any of the claims.   A method according to any of the preceding claims, wherein the time for performing the oxidation is 10 minutes to 10 hours, preferably 30 minutes to 5 hours, most preferably 30 minutes to 3 hours.   Poly 2-propenal is prepared in an aqueous solution by catalysis of a base (preferably an alkali metal hydroxide such as NaOH or KOH), preferably at a temperature of 60 ° C. or less, preferably 50 ° C. or less, most preferably 40 A method according to any preceding claim, wherein the method is maintained at or below C.   10. The process of claim 9, wherein the resulting poly-2-propenal is filtered from the aqueous mixture used in the oxidation process, resuspended in water.   As a preservative comprising poly (2-propenal, 2-propenoic acid) in the range of 0.001 to 75% by weight, preferably 0.01 to 25%, more preferably 0.01 to 10% by weight, based on the total weight of the composition A composition comprising a poly (2-propenal, 2-propenoic acid) antimicrobial agent or solution or derivative for use.   Use of the acrolein polymer produced by the method according to any one of claims 1 to 11 as an antibacterial agent.   13. Use according to claim 12, which is administered to an animal for treating or preventing a gastrointestinal microbial infection.   Use of an acrolein polymer produced by the method according to claim 1 for producing a medicament for oral administration to an animal in the treatment or prevention of gastrointestinal infections.   A colorless poly (2-propenal, 2-propenoic acid) composition produced according to the above method.   A composition comprising a preservatively effective amount of poly (2-propenal, 2-propenoic acid) prepared according to the method of any of claims 1 to 11 and a bioactive substance or cosmetic.   A cosmetic composition for hair or skin care comprising an effective amount of poly (2-propenal, 2-propenoic acid) produced according to the method of any of claims 1-11.