MXPA04007005A - Method of treatment of gastrointestinal disease and polymeric composition for use therein. - Google Patents

Abstract

A method of treatment of gastrointestinal disease by administering polymeric antimicrobial comprising a derivative of poly(2-propenal, 2-propenoic acid) formed by reaction between a poly(2-propenal, 2-propenoic acid) and an alcohol or phenol to form protected carbonyl groups. The invention also relates to composition for use in treatment of gastrointestinal disease.

Description

METHOD FOR TREATMENT OF GASTROINTESTINAL DISEASE AND POLYMER COMPOSITION FOR USE IN THIS.

FIELD OF THE INVENTION The present invention relates to the treatment or prevention of gastrointestinal diseases and the promotion of animal growth and antimicrobial compositions for use in these treatments.

BACKGROUND OF THE INVENTION Antimicrobial drugs are compounds that kill microorganisms such as bacteria. Antibiotics are a subset of antimicrobial drugs that are (usually) derived from other microorganisms and that operate by interfering with specific mechanisms within the target microorganism. Antibiotics were used for the first time in the 1940s and 1950s and their use has been increasing since then without ceasing. The development of antibiotic resistance has become a serious and potentially life threatening event throughout the world. Some staphylococcal strains have shown resistance to almost all antibiotics and fatal infections have occurred in hospitals. Other drug-resistant organisms include pneumococci that cause pneumonia and cryptosporidium and E. coli that cause diarrhea. The use of antibiotics in animal feed is widely considered to be responsible for the accelerated development of resistance and as a result, many countries control its use. This has caused problems in livestock raising difficulties in controlling diseases and obtaining optimal growth rates. This is a particular problem in raising pigs and birds. For example, gastrointestinal diseases such as colibacillosis in pigs and coccidiosis in birds can have devastating effects. Melrose et al (International Patent Publication No. 96/38186) were the first to describe the preparation of acrolein polymers for use in the treatment of gastrointestinal diseases. These polymers have a repeating unit of formula I or this unit in its hydrated, semi-acetal or acetal formula, represented by the formulas: CH, (0 CH2 CK where R is hydrogen and n an integral of one or more, have been previously manifested. Prior to this, the biocidal properties of acrolein polymers in antiseptic applications were described by Melrose et al in International Application No. O88 / 04671. The German patent application P4404404 and equivalents such as EP667358 and AU 11686/95 (currently expired) show a method where acrolein is polymerized in an aqueous sodium hydroxide medium. The publication teaches that the resulting poly-acrolein is soluble in polyhydric alcohol at 40 to 50 ° C to form a solution of the poly-acrolein in a polyhydric alcohol. As explained below, the assignee of this German application subsequently found that such polymers are problematic and have a low solubility in aqueous medium. European publication No. 792895 erle et al (corresponding to US 6060571) relates to polymers that release acrolein produced by copolymerization of acrolein monomer and a polyhydric alcohol. Werle et al notes that the poly-acroleins described in the German application No. P4404404 have problems because the yield is less than desirable and the polymers are virtually insoluble in water. European application 792895 teaches that these problems can be overcome by forming a polymer that releases acrolein by copolymerization of an acrolein monomer and a polyhydric alcohol monomer. The proposed structure of the copolymer is as follows: While free acrolein has antimicrobial activity, it is also irritating to eyes, lungs, tissue and skin. There is a requirement for a range of applications, particularly in gastrointestinal treatments of antimicrobial agents that are stable, highly soluble in water and safe to use. There is also a requirement for an effective antimicrobial agent for the treatment or prevention of gastrointestinal diseases that can reduce the urge to develop resistance in the field of antibiotics. The description of the background of the invention has been included herein in order to explain the context of the invention. This should not be understood as admission that the material referred to has been published, has been known or part of the general public knowledge on the priority date of any of the claims. SUMMARY OF THE INVENTION We have found that the activity and stability of poly (2-propenal, 2-propenoic acid) polymers in the treatment or prevention of gastrointestinal diseases is substantially improved if they are reacted with an alcohol or polyol to form a protected carbonyl group, such as acetal and / or semi-acetal derivatives. Surprisingly we have found that the activity of the derivative in the treatment or prevention of gastrointestinal diseases substantially increases although the content of cold acrolein may be extremely low or negligible. The solubility of the polymer in water is also very high. The invention provides a method for the treatment or prevention of gastrointestinal diseases in animals (including humans) comprising administering to the animal an effective amount of a derivative of poly (2-propenal, 2-propenoic acid) formed by reaction between poly (2-) propenal, 2-propenoic acid) and an organic compound containing one or more hydroxyl groups as alcohol, preferably selected from alkanols, phenols, polyols and mixtures thereof, to form protected carbonyl groups. In a further aspect, the invention features an antimicrobial drug for the treatment of gastrointestinal diseases comprising a derivative of poly (2-propenal, 2-propenoic acid) formed by reaction between poly (2-propenal, 2-propenoic acid) and a compound organic containing one or more hydroxyl groups such as an alcohol, preferably selected from alkanols, phenols, polyols and mixtures thereof, to form protected carbonyl groups. The term polyol, as used herein, means a molecule containing at least two hydroxyl groups. The derivatives formed are typically selected from hemiacetal and acetal derivatives. Without wishing to restrict ourselves to a theory, we believe that the reaction of poly (2-propenal, 2-propenoic acid) with alcohol forms hemiacetal and / or acetal groups of at least a portion of the pendant aldehyde groups, thus stabilizing the carbonyl groups of the polymers against alkaline degradation by the Cannizzaro reaction. It has been verified that the formation of acetal groups significantly reduces or eliminates the release of free acrolein while surprisingly increasing the activity of the resulting derivative. In yet another embodiment, the invention offers the use of the above-described antimicrobial drug for the preparation of a medicament for the treatment or prevention of gastrointestinal diseases.

Throughout the present description and the claims of this specification, the word "comprise" and variations of the word such as "comprising" and "comprising" are not used with the intention of excluding other additives, components or ingredients. DETAILED DESCRIPTION OF THE INVENTION The inventive antimicrobial drug can be prepared by heating poly (2-propenal, 2-propenoic acid) in the presence of alcohol, preferably a polyol such as polyethylene glycol. Water is invariably present in the alcohols and it will be understood that the presence of at least some water aids in the nucleophilic substitution reaction that produces hemxacetal or acetal formation. The solution is generally heated to a temperature in the range of 40 ° C to 150 ° C, more preferably 40 to 115 ° C and more preferably 70 to 115 ° C. The inventive antimicrobial drug is prepared from poly (2-propenal, 2-propenoic acid) polymers. Such polymers and their preparation are described in International Patent Publication No. WO 96/38186 (PCT / AU96 / 00328) whose content is incorporated herein by reference. The poly (2-propenal, 2-propenoic acid) polymers are preferably prepared by polymerization of acrolein, preferably in aqueous solution by anionic polymerization, followed by autoxidation. The polymers contain the repeating unit of the formula I and at least one (and typically a mixture) of the hemiacetal and acetates hydrated forms. It is public knowledge that the hydrated hemiacetal and acétal forms, formed by polymerization of acrolein, are produced by various polymerization mechanisms of carbon-carbon and carbon-oxygen acrolein. For example, the hydrated form is typically the hydrated form of diol, the hemiacetal or acetal form can be formed by condensation of the diol form with the aldehyde or diol form, the fused tetrahydro pyran or tetrahydro pyran form can be formed by condensation of the diol form and the aldolic autocondensation form of Michaelis-Menten. Typical examples of these forms are shown in formulas (a) to (f) below: \ (I) CH2 (a) RO RO RO or CH = CH2 t-H CH2 (f) CH2 CH ^ where R is hydrogen and n is an integral of one or more. The part corresponding to the repetitive unit of formula I is typically less than 20% and frequently between 5 and 15%. Despite the relatively low proportion of these units, we have found that they have a significant effect on polymer stability. The poly (2-propenal, 2-propenoic acid) generally contains no more than 10% on a molar basis of monomer units of monomers other than acrolein and is, more preferably, an acrolein homopolymer (prior to autoxidation). Other monomers of the group consisting of acrylic acid and vinyl pyrrolidone can be selected where they are used. The 2-propenoic acid groups are present essentially in an amount of 0.1 to 5 moles of carboxylic groups per kilogram. The poly (2-propenal, 2-propenoic acid) polymers typically have a number average molecular weight greater than 1000 and more preferably 2000. Typically, the molecular weight is less than 10,000. The inventive antimicrobial drug is a derivative of poly (2-propenal, 2-propenoic acid) produced by reaction of an alcohol or phenol to form protected carbonyl groups. The protected carbonyl groups are formed with the 2-propenal groups, which react with the alcohol to form hemiacetal or acetal groups. The alcohol is preferably a polyol, which means that it preferably contains at least two hydroxyl groups. Alkanes can be used as Ci a Cio | If alcohol is a polyol, the reaction can produce acetals or hemiacetals formed by reaction of one or more of a group of alcohol. Additionally, when two alcohol groups react it is possible for them to react with the same carbonyl group or different carbonyl groups within the polymer. With reference to the preceding formula I and hemiacetal and acétal forms, the invention produces derivatives where fewer units of formula I are present and forms a group where one or more groups are derivatives of an alcohol, or, if the alcohol is a polyol, more than two R groups can together form a bridging group as , for example, a cyclic acetal group. The tendency of polyols to generate internal cyclic groups depends on the distribution and configuration of the polyol. Preferred alcohols are polyalkylene glycols and more preferred alcohols are polyethylene glycols.

The molecular weight of the polyalkylene glycols is preferably from 200 to 2000, and more preferably from 200 to 1000. Preferably, the alcohol such as polyethylene glycol is present during the preparation of antimicrobial polymers in an amount of 50 to 99% by weight. Relatively dilute compositions of the acrolein polymer are particularly preferred, if the alcohol is a polyol, since the occurrence of intermolecular crosslinking is reduced by dilution. More preferably, polyethylene glycol is present during the preparation of the polymers in an amount between 64 and 95% by weight. A base or alkali is preferably added to the polymers followed by a shift to an acidic pH before and / or during heating, since a neutralization of the acid groups of the polymer occurs, which improves the antimicrobial activity of the polymers. Preferably, the addition of the base or alkali adjusts the pH of the poly (2-propenal, 2-propenoic acid) polymers initially to between 7 and 9. Even more preferably, the initial pH upon addition of the base is approximately 8. The base is preferably an alkali metal hydroxide, carbonate, bicarbonate or a mixture thereof.

In yet another embodiment of the invention, the release of free-release acrolein monomers is inhibited, whereby the polymers are less likely to represent a source of tissue and skin irritation. We have found that the inventive antimicrobial drug has significantly improved activity to control gastrointestinal diseases as compared to the poly (2-propenal, 2-propenoic acid) with which it is produced. The superactivated derivative of the present invention can be used to treat a wide range of animals (including humans) and a broad range of microbial infections. The inventive antimicrobial drug can be used in the treatment of gastrointestinal diseases in humans, however, it is particularly preferred that it be used in the treatment of other animals, in particular animals selected from the group consisting of dogs, pigs, sheep, horses, goats, cattle. , cats, chickens, ducks, turkeys and quail. The inventive antimicrobial drug can be produced in preparations for oral or rectal administration. Rectal administration may be particularly convenient in ruminant animals. Oral preparations for ruminant animals can also be produced using enteric coatings to provide optimal activity in the posterior parts of the gastrointestinal tract. The inventive antimicrobial drug is particularly convenient for the treatment and prevention of gastrointestinal ulcers, diarrhea and gastrointestinal cancers. The inventive antimicrobial drug can also be used to improve the rate of weight gain in farm animals by improving the conversion of feed to weight in animals. We have found that the inventive antimicrobial drug can be used as a growth promoter and that the polymer can be used in place of antibiotics currently in use. Drug resistance is a problem of major clinical importance in human medicine. This problem is aggravated by the use of important antibiotics in animal feed in order to offer weight gain in farm animals, particularly in birds and pigs. In fact, in some European countries the use of conventional antibiotics in the feeding of animals has been banned. The inventive antimicrobial drug can be used in the treatment of animals to significantly prolong the lifespan of conventional antibiotics in human treatment. We have found that the inventive antimicrobial drug is active against a broad range of microbes comprising protozoa, gram-positive bacteria and gram-negative bacteria. The inventive polymers contain multiple structures of various configurations and can be linked to proteins found in the cell walls of target organisms, which accelerates the deactivation of the protein and the destruction of the cell. Among gram-negative bacteria it has been verified that the inventive antimicrobial drug is particularly useful for offering activity against a broad spectrum of coliform microbes or enterobacteria. It is particularly useful in the treatment of gastrointestinal diseases caused by infection with E. coli such as enterotoxigenic E. coli and β-hemolytic E. coli. Colioacilosis is a devastating disease in the pig breeding industry. The disease is generally associated with the proliferation of ß-hemolytic E. coli in the small intestine after weaning and causes high mortality rates and high incidence of disease in young weaning piglets. Infected weaning piglets do not register normal weight gains. Coccidiosis is a protozoan animal disease, particularly of poultry, and has a devastating effect if left unchecked. We have found that the inventive antimicrobial drug can be used in the treatment and prevention of coccidiosis in poultry, particularly in poultry. In chickens the typical clinical symptoms include lack of development, rapid weight loss, diarrhea and dysentery. The most serious effects occur in the intestine where the protozoa tend to invade the mucous membranes and cause epithelial damage, injury and bleeding. Vaccines have been used to try to prevent coccidiosis, but they have side effects including the tendency to lose weight and food efficiency. The inventive antimicrobial drug can be used in combination with other drugs with known activity against coccidiosis. These drugs include nitro-carbanilide, quinoline, pyridone, guanidine, quinoxaline, toltrazural, toluamide, enhanced sulfamide and ionophore with carbanilide. Clostridia are gram-positive bacteria responsible for serious diseases in a variety of animals. For example, necrotic enteritis is known as a disease that affects commercial poultry. Clostridia bacteria produce exotoxins that are among the most toxic of all known toxins. Necrotic enteritis particularly affects chickens at the age of 14 to 42 days. The condition causes pronounced apathy, diarrhea and can cause death in a matter of hours. Upper gastrointestinal diseases including chronic gastritis, gastric ulcer and duodenal ulcer, are important human health problems. It is assumed that Helicobacter is responsible for the development of ulcers and the development of gastrointestinal cancers, in particular of adenocarcinomas of the stomach. We have found that the inventive antimicrobial drug is particularly active against Helicobacter, including f. pylori, in gastrointestinal diseases in animals, particularly humans. Stomach infection with Helicobacter pylori is one of the most common infectious diseases in the world. Approximately 50% of the population are infected with H. pylori. It has been estimated that in developing countries more than 80% of the population is already infected with H. pylori during childhood. Helicobacter pylori is a gram-negative, microaerophilic, spiral-shaped bacillus that is mobile by flagella at one end of the cell. The standard treatments of infections with fí. pylori are the so-called triple antibiotic therapies that comprise either metronidazole or clarithromycin. Unfortunately, strains of H. pylori have emerged that are resistant to both antibiotics. H. pylori live in the stomach at the interface between the surface of gastric epithelial cells and the mucosal gel layer on top. H. Pylori can also be found above the gastric epithelium in the duodenum and esophagus. Other animal species have presence of their own Helicobacter species in their gastrointestinal tracts, which have properties similar to H. pylori. In addition to its association with gastrointestinal cancers, H. pylori has been directly related to gastritis and peptic ulcer formation in humans. The species of Helicobacter in general, and fí. pylori in particular survive extreme conditions in the stomach secreting urease that hydrolyzes urea to produce ammonia and bicarbonate ions, thus increasing the pH of the immediate environment of the bacillus. The local modification of the conditions protects the bacterium from the bactericidal effects of gastric acid. The preferred position below the mucosal protective layer of the stomach is also a survival advantage and its mobility allows it to penetrate the layer to obtain this position. The epithelial cells covering the stomach are naturally difficult to penetrate; this is part of its function to protect the rest of the body from gastric acid and digestive juices. This difficulty of penetration also makes it difficult for the body's natural defenses to pass through the stomach walls and reach the site of H. pylori infection. This has two consequences; the body sends more nutrients to the site to help white cells, T cells, and other defense mechanisms, simultaneously feeding the bacilli; and the defensive cells eventually die, releasing their charge of superoxide ions and other lethal chemicals, causing damage to nearby epithelial cells. It is obvious that this activity produces gastritis that can easily progress to peptic ulcers. If the attack continues, the possibility of the appearance of gastric adenocarcinomas and lymphoma of lymphoid tissue associated with mucosa (MALT) is increased significantly. Gastric adenocarcinoma begins in the mucosa and the first stage of its development, intestinal metaplasia, is a response of the stomach to get rid of H. pylori infection. Studies conducted at UCL Medical School have shown that MALT lymphoma requires the help of H. pylori-specific T cells for its growth. Treatment of H. pylori infection proved to be extremely efficient in curing MALT lymphoma. The World Health Organization has cataloged the pathogen as a group I carcinogen. Consequently, the present invention also provides a method for the treatment or prevention of diseases of the gastrointestinal tract caused by infections with Helicobacter comprising the gastrointestinal administration of a therapeutic amount of a agent wherein the agent comprises a derivative of poly (2-propenal, 2-propenoic acid) formed by reaction between a poly (2-propenal, 2-propenoic acid) and an organic compound containing hydroxyl groups selected from alkanols, phenols, polyols and mixtures of these, to form protected carbonyls groups. The term polyol, where it is used herein, means a compound containing at least two hydroxyl groups. The derivatives formed are typically selected from hemiacetal and acetal derivatives. Therefore, the use of the method of the present invention offers an alternative to the use of surgery, radiation therapy or traditional chemotherapy in the treatment of gastrointestinal cancers. The invention further provides a method for the treatment of gastrointestinal infections by a species of Helicobacter bacteria such as gastritis, gastric ulcer, duodenal ulcer, malignant gastric lymphoma or gastric cancer, comprising gastrointestinal administration of a therapeutic amount of an agent where the agent comprises a derivative of poly (2-propenal, 2-propenoic acid) formed by reaction between a poly (2-propene, 2-propenoic acid) and an organic compound containing one or more hydroxyl groups to form protected carbonyls. The present invention offers an alternative to standard treatments of infections with Helicobacter which, in general, comprise so-called triple antibiotic therapies, where all of them include either metronidazole or clarithromycin. Strains of H. pylori have appeared to be resistant to these two antibiotics and we have shown that the method of the present invention can effectively treat these antibiotic resistant bacteria. The agent that is a product of the reaction between poly (2-propenal, 2-propenoic acid) and an organic compound containing one or more hydroxyl groups has been shown to be more effective in the treatment of Helicobacter infections than the corresponding poly groups ( 2-propenal, 2-propenoic acid) not superactivated. The invention further provides the use of a poly (2-propenal, 2-propenoic acid) derivative in the production of a medicament for the treatment or prevention of a disease caused by infection with Helicobacter. The method of the present invention can be used in the treatment or prevention of gastrointestinal cancers. These can include, for example, cancers of the esophagus, stomach, intestine and colon. An example of this type of cancer is the HT-29 cell line of human colon cancer. When the inventive antimicrobial drug is integrated into animal feeds or water, this can be done in the usual manner. In a preferred embodiment, the inventive antimicrobial drug is integrated into a premix. The premix preferably will include the antimicrobial drug, a physiologically compatible carrier and optionally some food. The premix is generally in a relatively concentrated form and is ready to be diluted with another material such as one or more other vehicles, vitamins, mineral supplements and feed to form the finished animal feed. The premix preferably comprises the antimicrobial drug in a concentration in the range of 0.1 to 70% by weight, preferably 0.5 to 50% by weight. The optimal concentration depends on whether the treatment is preventive, for control or remedy and whether the inventive antimicrobial drug is the only active substance or if it is used in concomitant therapy with other antimicrobial materials or drugs. In a preferred embodiment, the concentrated composition of the antimicrobial drug is present in a controlled release form. The controlled release form comprises the antimicrobial drug and polymeric material to provide controlled release of the antimicrobial drug from the controlled release system, and is particularly convenient in additive compositions to solid food material. As a result of the controlled release formulation, the release of the antimicrobial drug can be retarded so that it occurs mainly in the duodenum. A controlled release polymer can also minimize the rejection of the composition due to taste, or it can be used for rectal suppositories. An inventive antimicrobial composition may be present in the form of pellets, pellets or similar solid compositions. The pellets containing the inventive antimicrobial drug can be prepared by the steps of: (i) dissolving the aforementioned antimicrobial drug in an alkaline or basic aqueous solution; (ii) neutralizing the aforesaid solution with acid; (iii) adding to said neutralized solution insoluble, crosslinked, absorbent acrylic acid polymers and / or copolymers of acrylamide and acrylic acid, to form wet swollen beads; and (iv) optioy, completely or partially drying the swollen wet pellets. The wet, swollen beads thus formed can be used wet, partially dry or completely dry, as a supplement to, for example, animal feed. The system is further designed so that the carboxyl-containing groups in the exterpolymer matrix make the referred polymers remain essentially contained in the matrix in the acidic environment of the stomach. However, in the alkaline environment of the duodenum, the carboxylic groups of the matrix become ionized and mutually repellent, and the pellet swells rapidly to allow the reference polymers, supported by repulsion cock between their own ionic groups, to be expelled in a diffusion process approximately synchronized with the speed of passage of the food through the duodenum. In the present invention, the term "controlled release system" is used in the same context as in, and comprises the same range of examples as cited in "Controlled Drug Delivery" (Robinson &Lee, 1987). Many other pH-sensitive controlled release systems known in the art (Robinson and Lee, 1987) can be used in place of the acrylic acid polymer or copolymer of acrylamide and acrylic acid. For example, systems of soluble and anionic cellulose, or insoluble, reticulated and anionic; or soluble and anionic, or insoluble, crosslinked and anionic polymers derived from any generic acrylic acid polymer and / or its derivatives. Such crosslinked and insoluble polymers are preferred, since they swell and are also less likely to be subjected to metabolism. It is preferred that the controlled release system comprises a pH sensitive, crosslinked, water absorbing bead, which is a gel when wet. The invention also provides a food composition for animals comprising the inventive antimicrobial drug and food. The antimicrobial drug is preferably present in an amount of 0.0001 to 25% of the total food composition and preferably 0.0001 to 5% of the total food composition. In another preferred embodiment, the inventive antimicrobial drug can be prepared for addition to the drinking water of the animals. The inventive antimicrobial drug is preferably administered in amounts of 0.05 to 5000 mg / kg of physical weight / day, more preferably 0.05 to 50 mg / kg / day. Examples of suitable inert carriers for use in compositions for administration of the inventive antimicrobial drug include water, olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, peanut oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides, polyvinyl alcohols, partially hydrolyzed polyvinyl acetate and mixtures thereof. Solid forms for oral or rectal administration may contain binders, sweeteners, disintegrating agents, diluents, flavorings, coating agents, preservatives, lubricants and / or retarding agents. Suitable binders include acacia gum, gelatin, starch, tragacanth gum, sodium alginate, carboxymethyl cellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose or flavor glycosides such as neohesperidin dihydrochalcone. Suitable disintegrating agents include corn starch, methyl cellulose, polyvinyl pyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavoring agents include peppermint oil, methyl salicylate, cherry, orange or raspberry flavors. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, and / or their amides, waxes, fatty alcohols, corn gluten, shellac or gluten. Convenient preservatives include sodium benzoate, vitamin E, α-tocopherol, ascorbic acid, methyl parabens, propyl parabens or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable retarding agents include glyceryl monostearate or glyceryl distearate. Suspensions for oral or rectal administration may further comprise dispersing agents and / or suspending agents. Suitable suspending agents include sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, sodium alginate or cetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters or fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate, and the like. The composition of the antimicrobial drug may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as mentioned by way of example in the foregoing or natural gums or gums such as acacia gum or tragacanth gum. Compositions for administration according to the inventive method can be prepared by means known in the state of the art for the preparation of compositions (cone in the state of the art of veterinary and pharmaceutical compositions) including mixing, grinding, homogenizing, suspending, dissolving, emulsifying, Disperse and, where applicable, mix the polymers in question together with excipients, diluents, vehicles and auxiliary substances. For oral administration, the pharmaceutical or veterinary composition may be present in the form of tablets, pills, pills, tablets, capsules, elixirs, powders, including lyophilized powders, solutions, granules, suspensions, emulsions, syrups and dyes. Slow release or delayed release forms can also be prepared, for example, in the form of coated particles, multilayer tablets or microgranules. It is generally preferred that poly (2-propenal, 2-propenoic acid) is prepared from poly (2-propenal) by oxidation of the solid to the air. The poly (2-propenal) polymer can be initially heated, in a predominantly dry state, to between 80 and 110 ° C. More preferably, the polymer is initially heated to about 85 ° C. The poly (2-propenal, 2-propenoic acid) is preferably heated in alcohol for a lapse in the range of 1 hour to 1400 hours and more preferably from 1 hour to 60 hours. According to the present invention, there is further provided a compound or a preservation composition comprising the inventive antimicrobial drug. According to the present invention, there is further provided a disinfectant or antiseptic composition or composition comprising the inventive antimicrobial drug. According to another inventive aspect we are offering a composition for the treatment of gastrointestinal diseases comprising an antimicrobial polymer as described above and additionally a chemotherapeutic agent where the additional chemotherapeutic agent is adsorbed on the antimicrobial drug. Adsorption typically reduces the membrane penetration of the additional chemotherapeutic agent. Suitable chemotherapy agents for use in this modality are those that show a significant reduction in membrane penetration when added by mixing with the polymer antimicrobial drug. Preferably, the penetration is inhibited by a factor of at least 50%. Suitable chemotherapeutic agents for use in this inventive embodiment include antibiotics for the treatment of gastrointestinal diseases and anticancer agents for the treatment of gastrointestinal cancers. The use of chemotherapy agents in combination with the antimicrobial polymer drug reduces the membrane penetration of the chemotherapy agent, thus reducing the systemic secondary effects and offering a more targeted therapy. In many cases the smell is also reduced. Examples of chemotherapy agents for the treatment of gastrointestinal diseases include antibiotics and anticancer agents. Examples of antibiotics that can be used in combination with the antimicrobial polymer include tetracyclines, penicillins, aminoglycosides, sulfonamides, cephalosporins and nitrofurans. Antibiotics may be conventional antibiotics used to treat infections of the gastrointestinal tract. Examples of anticancer agents that can be used in combination with the inventive polymer antimicrobial drug are alkylating agents, antimetabolics, anticancer antibiotics, plant alkaloids, hormones and other anticancer agents, in particular anticancer agents containing only carbon, hydrogen and oxygen. The inventive compositions may comprise one or more additional antimicrobial drugs selected from the group of phenol (preferably in an amount of 0.1 to 10% by weight), an isothiazolinone (preferably in an amount of 0.001 to 1% by weight), an albenic paraben ( preferably in an amount of 0.02 to 2%) and a low alcohol (preferably in an amount of 20 to 99%), wherein the amounts are based on weight on the weight of the composition. It has been verified that the poly (2-propenal, 2-propenoic acid) derivative used in the inventive method significantly increases the stability compared to poly (2-propenal, 2-propenoic acid) polymers. As the state of the art had recorded some instability of poly (2-propenal, 2-propenoic acid), as was shown by the loss of antimicrobial activity of its compositions, we have performed "accelerated aging" at elevated temperatures, ie at 40 ° C. However, as a major surprise to us, the "aging" at elevated temperatures of poly (2-propenal, 2-propenoic acid) in aqueous or aqueous-polyethylene solutions not only delayed the loss of antimicrobial activity, but actually increased activity antimicrobial of the poly (2-propenal, 2-propenoic acid), see example 2 (a) and (b). This result is totally contradictory and unexpected considering the state of the art which predicts that an increase in temperature should cause "accelerated aging", that is, accelerated loss of antimicrobial activity. In the present document, the process of procuring an increased antimicrobial activity by forming a new configuration of the polymer in question including poly (2-propenal, 2-propenoic acid), is termed "super-activation" and the polymers are mentioned as "super-activated polymers". Even more surprising, in view of the state of the art, the inventors have found that super-activation in aqueous polyethylene glycol solution is promoted by basic conditions, followed by acids. Heat and humidity are also favorable to super-activation. The super-activation is facilitated by the presence of polyethylene glycols or protected polyols or alkanols groups and stabilizes the carbonyl groups of the polymers by the formation of acetals, by alkaline degradation by the Cannizzaro reaction. An additional advantage of super-activation is that it reduces or eliminates contaminating acrolein as a source of tissue and skin irritation.

It is being emphasized that super-activation is completely distinct and in addition to any increase in antimicrobial activity that may result from merely greater availability of polymer, in any aqueous test medium, as a result of increased hydrophilicity, as demonstrated in the application of Australian patent expired AU-A-11686/95 (hereinafter "11686/95"). The inventors have exactly repeated the method described in 11686/95 and then found that further super-activation of the partially soluble polymer demonstrably generated another substantial additional increase in antimicrobial activity. It should be noted that even super-actuation did not return the fully soluble 11686/95 polymer, in contrast to super-activation starting with polymer first heated to between 80-85 ° C. The optimal time to achieve super-activation of solutions of poly (2-propenal, 2-propenoic acid) depends on the temperature in inverse proportion. It will be obvious that even aging at room temperature can be used for super-activation, particularly when supported by the presence of hydroxyl and / or base solvent followed by acidity, but obviously, this can be impractical due to the longer periods of time that can occur. they require. The inventors have found super-activated polymers as described herein, suitable for gastrointestinal therapy, preservatives in water-based products or methods, and active ingredients in disinfectants or antiseptics that have the advantage of improved antimicrobial activity. In addition, the inventors found that the antimicrobial activity of these disinfectants or antiseptics was increased by increasing their pH, for example, above pH 6. A common feature of the invention is the addition of a group capable of hydrophobic interaction to the inventive antimicrobial drug. , by hemiacetal / acetal formation, or by adsorption, in order to improve the antimicrobial activity. The invention will now be described with reference to several examples which should not be understood as limiting the scope thereof. Biocidal Test Dissolve sample with 1% by weight aqueous sodium bicarbonate to obtain the required concentration (unless otherwise specified, 0.125% by weight of the polymer). Weigh 19.9 g of the sample diluted in a sterile jar and inoculate with 0.1 ml of 107-108 cfu of Ps. aeruginosa and mix. Transfer at time intervals 1 ml of the inoculated sample to 9 ml of Letheen broth and place in a vortex. Distribute in plates in serial dilutions from 1 to 10. Pour into trypticase soy with agar. Incubate for 3 days at 37 ° C. Example 1 The example describes a method for preparing poly (2-propenal, 2-propenoic acid) by oxidation of a solid acrolein polymer to the air. This poly (2-propenal, 2-propenoic acid) is the preferred method for preparing a raw material for use in the inventive method. Water (720 ml at room temperature, approximately 20 ° C) and acrolein (60 g, freshly distilled, plus hydroquinone added at 0.25% w / w) were placed in an open-top cup inside a fume cupboard and mechanically agitated very vigorously. Then 0.2 M aqueous sodium hydroxide (21.4 ml) was added to adjust the pH to 10.5 - 11.0. The solution immediately turned a typical yellow for the hydroquinone anion and within one minute the color had disappeared and the clear solution became milky. Approximately 1 minute later, precipitation of a white, poisonous polymer began, and appeared complete within 15-30 minutes. The precipitate was filtered and washed with water (250 ml), dried at room temperature in paper filters for 2 days (yield 25 g), then sprayed as a thin layer in glass culture dishes and heated to 40 ° C. /8 hours. This heating was continued according to the following scheme: 50 ° C / 15 hours; 65 ° C / 4 hours; 75 ° C / 18 hours; 84 ° C / 24 hours. It is envisioned that this method can be scaled up to include, for example, the stepwise addition of acrolein in a closed container and followed by faster drying (compare Example 10). Typically, a solution of poly (2-propenal, 2-propenoic acid) obtained was prepared by adding 2 q of the respective polymer by stirring for 15 to 30 minutes to a 1% w / w solution of sodium carbonate (100 ml), and diluted then as required. These solutions were perfectly clear, in contrast to the solutions tried using alternatively polymer derived from Example 5 of 11686/95. Example 2 This example describes the formation of acetal of poly (2-propenal, 2-propenoic acid). (a) 5g of poly (2-propenal, 2-propenoic acid) was dissolved in 64g of polyethylene glycol ("PEG") 200 and combined with 31g of a 0.71% w / w solution of sodium carbonate. A part of the solution (apparent pH = 5.8) was maintained at room temperature while (b) the remainder of the sample from step (a) was heated to 60 ° C for periods of 12 to 25 days. Samples of (a) and (b) were diluted with 1% w / w of sodium bicarbonate and subjected to a biocide test at polymer concentrations of 0.125% w / w. Surprisingly, samples that had been subjected to "accelerated aging" showed improved antimicrobial activity, as can be deduced by reference to Table 1: Table 1 idades forming colonies (cfu) / ml lg of poly (2-propenal, 2-propenoic acid) was dissolved in 200 ml of 0.1% w / w Na2CO3 and allowed to stand overnight. Sodium lauryl sulfate was added at a level of 0.05% w / w and the solution was acidified with HC1 to a pH of 5.9. Portions were stored at room temperature as well as at 60 ° C. Biocidal assays were performed with 0.125% w / w polymer solutions, with 1% w / w of NaHCC > 3 employee as diluent. The "aged" sample showed a surprising improvement in performance, as can be seen by reference to table 2: Table 2 * units forming colonies (cfu) / rnl (c) A 5% w / w solution of super-activated polymer was prepared according to example 2 (a), but substituting PEG200 with PEG1000. A part of this solution was treated with concentrated NaOH with pH 8.1. Samples were heated to 60 ° C and subjected to biccid assay. The sample exposed to more basic conditions unexpectedly produced a higher biocidal activity, as can be seen by reference to Table 3: Table 3 * units forming colonies (cfu) / ml Example 3 This example analyzes the product obtained by reaction of the poly (2-) propenal, 2-propenoic acid) with polyethylene glycol.

The presence of acetals in the polymers of example 2 (b) can be determined by analysis of the remaining solid residue after dialysis and concentration of the polymer solution using proton nuclear magnetic resonance (NMR) spectroscopy (lti) and carbon (13C). Dialysis separates all material with molecular weight less than 1000. Table 4 shows proton NMR (1H) and carbon (13H) data. As can be seen from table 4, nuclear magnetic resonance spectroscopy of the residue showed peaks in d 3.58 and 3.56 in the 1H nuclear magnetic resonance spectrum and d 71.62, 69.48 and 60.25 in the 13C nuclear magnetic resonance spectrum. These peaks are indications of the adhesion of polyethylene glycol units as acetals. Table 4 Data of the nuclear magnetic resonance spectra of 600 MHz 1? and 125MHz 13C in D20 with 1% w / w Na2C03 of the super-activated polymer solid residue after dialysis and concentration.

Example 4 (a) solutions of 5% w / w of polymers range of super-activation degrees, apparent pH of 5.7, were prepared in a manner similar to example 2 (a), but varying the percentage of PEG200. Samples were heated to 60 ° C and the stabilities over time were observed. It was considered that the physical stability failed with the occurrence of precipitation or gelation. UV measurements were made at a concentration of 0.01% w / w of polymer in a 1% w / w solution of sodium carbonate. It is considered that a decrease in the absorption rate at 268 nm 230 nm means a decrease in chemical stability. The results are shown in table 5: Table 5: composition ABCD PEG 200 (% by weight) 0 50 64 95 physical stability time ABCD 4 days at 60 ° C failed happened spent spent 1 1 days at 60X failed failed passed chemical stability stability = 260-170 peak absorbance 228-238 peak absorbance time ABCD 0 days at 60 ° C 1 .38 1 .41 1.43 1.46 4 days at 60 ° C 0.98 1 .04 1.21 1.27 1 1 days at 60 ° C - 0.97 1.03 1.09 18 days at 60 ° C - 0.89 0.92 1.04 25 days at 60 ° C - 0.84 1.04 Both the physical and UV spectrum results demonstrate the positive effect of PEG on stability; Higher PEG content results in greater physical and chemical stability. (b) The following solutions A and B were prepared by dissolving 4g of poly (2-propenal, 2-propenoic acid) in 196 g of 1% w / w sodium bicarbonate and adjusting the pH to 7 (A) and 5.5 (B ) with diluted HC1. Solution C was prepared by dissolving 50 g of poly (2-propenal, 2-propenoic acid) in PEG 200 (640 g) at 65 ° to 70 ° C. Then a solution of 4 g of sodium carbonate in water (306 g) was added, the apparent pH being 7, and then 5.5 at the end of the 31 day treatment period. All samples were stored at 40 ° C. At different time intervals, samples containing the equivalent of 0.125% w / w were subjected to biocidal tests. The results are shown in table 6: Table 6 Example 5 1 g of poly (2-propenal, 2-propenoic acid) heated in a dry or wet closed chamber, in both cases at 60 ° C, for 3 days. Solutions of dry polymer and wet polymer, respectively, were prepared at 0.125% w / w (with correction for moisture content) and submitted for evaluation by biocidal assay: Table 7: * units forming colonies (cfu) / ml The polymers showed absorption of carbonyl and / or carboxyl under IR between 1700-1730 cm "1 in the carbonyls groups (for example, with Schiff's reagent) and have Mw = approximately 10000 and Mn = approximately 5000; titration shows carboxyl groups of approximately 5 mol% These parameters are similar (but not identical) to those of poly (2-propenal, 2-propenoic acid) Example 6 In a duplicate assay, a polymer sample was prepared and then dissolved in ethano-diol, Exactly as described in example 5 of 11686/95, half of this material was subsequently heated to 80 ° C for 24 hours (after which its solubility in aqueous medium was still incomplete) .The samples were compared with respect to their antimicrobial activity using the standard biocidal assay Both samples treated by heating, that is, super-activation, showed a clear improvement of the antimicrobial activity, as shown in table 8 : Table 8: * units forming colonies (cfu) / ml Example 7 50 g of poly (2-propenal, 2-propenoic acid) were dissolved in PEG200 (640 g) at 65 to 70 ° C. Then a solution of sodium carbonate (4g) in water (306g) was added. The sample was separated and rested at room temperature or heated at 80 ° C for 24 hours. The acrolein content of the solution was determined by periods using reverse phase HPLC and the results are shown in Table 9: Table 9 days stored at 20 ° C non-super-activated super-activated acrolein (pprn) content 0 274 144 7 - 126 16 34 103 30 13 80 Example 8 Solutions of poly (2-propenal, 2-propenoic acid) were prepared as in Example 7 and treated at temperatures of 40, 60, 80, 100 and 115 ° C per variable periods of time. Samples were subjected to standard biocidal assay to confirm the increased kill rate and the results are shown in the table .10: Table 10 It is observed that the period of time required for super-activation is proportional to the inverse to the temperature. All the polymer solutions derived from the super-activation process were completely miscible, in any proportion, with aqueous solvents. Example 9 (a) 540 g of poly (2-propenal, 2-propenoic acid) were dissolved in 2304 g of PEG200 at 65 ° C before mixing them with 43.2 g of sodium carbonate in 712 g of water. Then, the solution was heated at 100 ° C for 4 hours, and 36 g of sodium lauryl sulfate, 7 g of ECOTERIC T20 (non-ionic detergent) and 2 g of lemon fragrance were added. The formulation, pH6, was diluted 1:30 in hard water and tested against Staphylococcus aureus (a Gram-positive bacteria, of particular importance with respect to infections in hospitals) and Salmonella choleraesuis (a Gram-negative bacteria of particular importance with respect to infections in preparation areas). food), respectively using Association of Agricultural Chemists Official Methods of Analysis (1995) 991.47, 991.48, (Hard surface vehicle testing method). The results are shown in table 11: Table 11 Adjustments of this preparation to higher pH numbers, increases in antimicrobial activity, as observed in the biocidal assay. The results are shown in Tables 12 (a) and 12 (b): Table 12 (a) Activity against Staphylococcus aureus Initial Conreo, 3 x 106 cfu / mL; polymer 350 ppm. pH 10 20 30 45 60 minutes minutes minutes minutes cfu / ml cfu / ml cfu / ml cfu / ml cfu / ml 5.6 2.8 x 105 4.4 x 104 2.3 x 103 20 < 10 7.2 2.7 x 103 < 10 < 10 < 10 < 10 8.9 3.2 x 103 < 10 < 10 < 10 < 10 10.5 1 .1 x 102 < 10 < 10 < 10 < 10 Activity against Pseudomonas aeruginosa Initial count, 3.7 x 106 cfu / ml; polymer 350 ppm. (b) 1200 g of poly (2-propenal, 2-propenoic acid) were dissolved in 7680 g of PEG200 at 60 ° C and then 96 g of Na 2 CO 3 in 3024 g of water were added. The solution was heated at 100 ° C for 6 hours. The preparation was added to the tub of a circulating cooling tower induced in a concentration of 300 ppm (30 ppm polymer) 3 times / week. The dosage was made in the afternoon to leave contact periods of 8-12 hours before starting the operation; it was expected that the residual concentration would be reduced by half every 3 - 6 hours of operation. The recirculation water had on average a temperature of 27 ° C, pH 8.5, conductivity of 3000. The microbial count was determined and compared with the contiguous, identical tower that had been endowed daily with a biodispersion agent. The results are shown in table 13: Table 13 * units forming colony / mi The data indicate the treatment program maintained the microbial counts within the guidelines of the standard AS / NZ 3666.3 (Int): 1998 and below those of the adjacent tower containing biological dispersant (which proved to be unusually inadequate during the demanding conditions of the very hot summer period of the trial). Example 10 (a) Comparative example This example shows a method for preparing an acrolein polymer where the inventive method is not used. 1.0 0.8% weight / weight of sodium hydroxide Place 9.90 kg of deionized water in a 10 1 stainless steel tub and add 0.08 kg of sodium hydroxide to the water and shake until it has dissolved. 2.0 polymerization Place 100.1 kg of deionized water in a 200 1 stainless steel tub and add 4.99 kg of a 0.8% w / w solution of sodium hydroxide to the 200 tub 1. Equilibrate the solution at 15 - 20 ° C. Simultaneously, add 20 kg of acrolein monomer and the rest of the 0.8% w / w solution of sodium hydroxide to the 200 1 a tub in portions for 1 hour so that the pH remains at 10.5 - 11.0, and the temperature Do not rise above 30 ° C. Continue polymerization for another 90 minutes. 3.0 Washing Filter / centrifuge the polymerization mixture and wash the polymer with deionized water until the pH of the wash water is less than 7.0. The approximate yield is 8 kg. 4.0 Drying Dry the polymer to air, then heat it in an oven according to the following scheme: stage period temperature 1 2 hours 25 ° C 2 1 hour 40 ° C 3 1 hour 70 ° C 4 1 hour 75 ° C 5 2 hours 85 ° C 5.0 solution Place 400 1 of water in a 500 1 tub and add 4 kg of sodium carbonate and shake until dissolved. Slowly add 8 kg of dry polymer, heated and shake for 30 minutes. It was verified that the obtained polymer has an approximate solubility of 90-95% w / w in 1% w / w of sodium carbonate. Example 10 (b) This example describes a method for preparing an acrolein polymer wherein the polymer of the comparative example is super-activated according to the inventive method. 1.0 Base Production Dissolve 0.4 kg of sodium carbonate in 30.6 kg of water in a convenient container and place 64 kg of polyethylene glycol 200 in the mixing container. Start stirring with a mechanical stirrer and heat the PEG200 to 65 + 3 ° C. Add 5 kg of the dry acrolein polymer from example 10a to PEG200 and shake until a uniform mixture is obtained. Note: It is possible that the solid does not dissolve completely at this stage. Slowly add the sodium carbonate solution to the glycol mixture in portions that ensure that the pH of the solution remains in the range of 3.5 - 9.0. Shake the solution for 45 minutes at 65 ± 3 ° C. Note: The pH should be in the range of 7-9.

The temperature should be in the range of 65 ± 3 ° C. 2.0 Super-activation Cover the mixing bowl and heat at 100 ° C for four (4) hours. It was found that the resulting polymer has an approximate solubility of 99.5-100% w / w in water. Example 11 This example analyzes the antimicrobial activity of poly (2-propenal), 2-propenoic acid) dry, activated normally, of example 10a and the antimicrobial activity of the super-activated acetal derivative described in example 10b. Chicks treated with each of the antimicrobial drugs were compared to a control group according to the following method: In each trial 20 swan chicks (line 53), from one day were purchased from a commercial hatchery. They were weighed, their sex was determined and they were randomly distributed in adjacent cages in a room of an isolated animal house. There was a uniform distribution of male and female chicks. Water and food were available to taste. The diet was a commercial mixture (Chick Starter, Milne Feeds: 18% crude protein) with the presence of a coccidiostat (125 ppm dinitolmide). Ten chicks received the 0.1% w / w preparation of the normally activated antimicrobial drug of Example 10a in water for 14 days through static drinkers; the dosage was 30 mg / kg / day. The other ten chicks were the control group. Both groups of chicks were weighed in the days 0, 4, 7, 11 and 14. At the end of the trial, all the chicks were euthanized, and the treated chicks were post-mortem autopsied. A detailed total examination of the thoracic and abdominal cavities was performed. Results: Table 14a Weight gain during the test with normally activated antimicrobial drug of example 10a At the completion of the trial, in the post-mortem, there was no evidence of pathological signs of toxicity in this total examination in the group of treated chicks. Table 14b Weight gain in the test with super-activated antimicrobial acetal of example 10b day control group treated group difference between (average weight in g) (average weight in g) groups (%) 0 42.5 42.5 0 4 62.5 67.5 8 7 97.5 103 6 1 1 130 145 1 1 .5 14 1 8 219 23 In the post mortem at the end of the trial, no clinical or pathological signs were observed in the remaining chicks during the total examination in both groups. Conclusion: There was a significant difference in weight increases in the treated group compared to the control group (? 2; P <0.015). The treated group was 23% heavier than the control group at the completion of the trial. The significant improvement in weight gain of the super-activated acetal derivative compared to the control, and in the following example, when compared to the poly-2-propenal, 2-propenoic acid activated normally, demonstrates significant improvement in enteric antimicrobial activity of the acetal derivative. Example 12 This example evaluates the polymeric antimicrobial drug of Example 10b under conditions of application for the control of porcine colibacillosis after weaning (PWC, for its acronym in English).

Method: 146 young [weaning] pigs, either receiving several preparations of super-activated antimicrobial drug in their food or water, APRALAN® (Elando) orally, autogenous vaccine, or none of this, were exposed to stress related to weaning in a large commercial pig breeding that had a long history of problems with PWC. Their responses regarding the development of diarrhea, weight gain and mortality were evaluated and are shown in Table 15. Table 15 Notes: 1. Coding of treatments: i. group 1 = 0.1% weight / weight of super-activated polymer antimicrobial drug in food ii. group 2 = 0.02% w / w of polymer antimicrobial drug in water. 2. Percentage of the group that died of PWC during the trial 3. Average number of days of each pig in the group where a faecal score of 1 or 2 was recorded; Fecal score is a measure of the intensity of diarrhea. 4 The sum of the fecal score divided by the number of samples observed per pig. 5 F = Fisher's exact test. Conclusion: The food trial underlines the following points that positively demonstrate the efficacy of the acetal derivative of poly (2-propenal, 2-propenoic acid) (super-activated antimicrobial drug) for use in piglets in commercial pig farming when they are exposes to ß-hemolytic Escherichia coli after weaning: 1. Mortality: Lower mortality rates for any of the groups treated with super-activated polymer antimicrobial drug to any of the untreated, vaccinated or Apralan® groups. 2. Days of diarrhea: Significantly fewer days of diarrhea in any of the groups treated with super-activated antimicrobial drug [F; P < 0.0001] than in any of the untreated, vaccinated or Apralan® groups. 3. Fecal score: Significantly lower fecal score in any of the groups treated with super-active antimicrobial drug [F; P < 0.0001] than in any of the untreated, vaccinated or Apralan® groups. Example 13 This example analyzes the effect of using certain supplements with the inventive antimicrobial drug. Method: Verification culture broths were prepared during the night and the total viable count (TVC) of the cultures of the night was estimated. The samples were serially diluted 1 to 1 using sterile saline (5 ml). Sterile hard water (SWH), for its acronym in English) was used as a diluent when verifying samples containing EDTA. 1 part of each overnight culture was diluted in 9 parts of diluent. The diluted suspensions thus obtained were used to inoculate. Inoculate each dilution sample with 100 μ? of diluted night culture. (One culture per test tube). Mix well. The tubes were incubated for = 24 hours at 37 ° C (A. niger was incubated at 28 ° C for = 24 hours). From each test piece, 1 ml was re-cultivated in 9 ml of recovery broth and mixed well (recovery broth: nutrient broth + 3% Tween 80 (NBT) for polymer antimicrobial drug and EDTA); nutrient broth + 3% Tween 80 + 0.1% ammonia (NBTA) for glutaraldehyde and, Letheen broth (LB) for methyl parabens). The samples were incubated at 37 ° C for others = 48 hours. (28 ° C = 5 days for A. niger). Each test piece was examined for growth. All the specimens were then cultured in selective agar and incubated for = 24 hours at 37 ° C. (28 ° C for = 5 days for A. niger). It was judged that growth in selective agar confirms the growth of the test organism. Positive tests were performed using 5 ml of diluent inoculated with culture and subjected to incubation, recovery and confirmation. Negative tests were performed using 5 ml of diluent without inoculation and subjected to incubation, recovery and confirmation.

RESULTS: The results are reflected in the following table: Table 16 MKC of selected addivators and synkertic index note: all proportional values are expressed as proportion of polymer antimicrobial drug: conservative Legend: 1) Polymer antimicrobial drug 0.025% weight / weight 2) Polymer antimicrobial drug 0.2% weight / weight 3) Glutaraldehyde 0.025% weight / weight 4) Polymer antimicrobial drug 0.025% w / w + glutaraldehyde 0.025% w / w 5) Drugs antimicrobial polymer 0.2% weight / weight + glutaraldehyde 0.025% w / w 6) polymer antimicrobial drug 0.2% w / w 7) EDTA 0.1% w / w 8) polymer antimicrobial drug 0.2% w / w + EDTA 0.1 w / w 9) Polymer antimicrobial drug 0.2% w / w (in 80% w / w glycerol) 10) Methyl paraben 1% w / w (in 80% w / w glycerol) 11) Polymer antimicrobial drug 0.2% w / w (in 80% w / w) / weight glycerol) + methyl paraben 1% w / w (in 80% w / w glycerol). Table 17 synergistic index with polymer antimicrobial drug Culture glutaraldehyde EDTA methyl paraben A. niger < 0.6 < 0.5 0.2 C. albicans 0.3 0.1 0.5 E. coli 0.5 < 0.3 0.3 P. aeruginosa 0.6 0.4 0.2 S. aureus 0.3 < 0.7 0 2 Note: synergy < 1.0, supplement = 1.0, antagonist > 1.0 where SI = CD / A + CE / BA = Polymer antimicrobial drug MKC B = conservative MKC C = mixture MKC D = Proportion of A with BE = Proportion of B with A Conclusion: It was shown that the poly (2-) acetal derivative propenai, 2-propenoic acid) was synergistic with glutaraldehyde, EDTA, and methyl paraben, respectively against A. niger, C. albicans, E. coli, P. aeruginosa, S. aureus. Example 14 This example demonstrates the activity of the inventive polymer antimicrobial drug in combination with the polymer antimicrobial drug brand "Dettol". The sample was diluted by series 1 to 1 in sterile normal saline (5 ml). Each sample dilution was inoculated with ??? μ? of diluted night culture (one culture per test piece). The samples were mixed well. They were incubated at 37 ± 2 ° C for = 24 hours (specimens inoculated with Aspergillus niger were incubated at 28 ± 2 ° C for <24 hours). From each test tube it was returned and incubated 1 ml in 9 ml of recovery broth and processed well in vortex (NBT, or Sabouraud + 3% Tween (SABT) for A. niger). They were incubated at 37 ± 2 ° C for = 48 hours. { A. niger was incubated at 28 ± 2 ° C for another 5 days). The recovery broths were examined for turbidity (growth) and blotted on selective agar to check growth. Table 18 MKC results in ppm of super-activated polymer antimicrobial drug and / or "Dettol" Legend 1) 0.1% weight / weight polymer antimicrobial drug 2) 0.2% weight / weight polymer antimicrobial drug 3) "Dettol" 4.8% weight / volume (diluted 1:20) 4) 0.1% weight / weight polymer antimicrobial drug + "Dettol "(diluted 1:20) 5) 0.2% weight / weight polymer antimicrobial drug +" Dettol "(diluted 1:20) Table 19 synergistic index of polymer antimicrobial drug and Dettol Note: Antagonist if YES > 1, supplement if YES = 1, synergetic if YES < 1 SI = CD / A + CE / B A = MKC polymer antimicrobial drug (ppm). B = MKC antimicrobial drug polymer C = MKC of antimicrobial drug polymer / mixture of "Dettol" (ppm) D ratio of antimicrobial drug polymer in relation to Dettol E = ratio of "Dettol" in relation to antimicrobial drug polymer Note: The antimicrobial drug active in "Dettol" is chloroxylenol. Conclusion: The inventive polymer antimicrobial drug was shown to be synergistic with "Dettol" against E. coli, S. aureus, P. aeruginosa, C. albicans and A. niger. This demonstrates that "Dettol" and the polymer antimicrobial drug, when used together as a mixed solution, will be more effective than when used alone. Example 15 Antiseptic qualities of poly (2-propenal, 2-propenoic acid) [super-activated] Poly (2-propene), 2-propenoic acid) [super-activated] antimicrobial was investigated regarding its antiseptic qualities. The amount of bacteria present in the hands of people was determined before and after the application of antimicrobial drug followed by putting on surgeon's gloves. The antiseptic effect of poly (2-propenal, 2-propenoic acid) [super-activated] was compared with the commonly used surgical antiseptic, 4% surgical soap chlorhexidine (produced by Orion Laboratories, in Perth, Western Australia). * Aqueous solutions of 3% w / w of poly (2-propenal, 2-propenoic acid) [super-activated] reduced base counts of bacterial populations in gloved hands after 3 hours. * A 2% w / w solution of poly (2-propenal, 2-propenoic acid) with 70% ethanol showed a sustained reduction in base bacterial count after 3 hours in gloved hands, as well as 4% chlorhexidine. * A 3.2% w / w solution of poly (2-propenal, 2-propenoic acid) [super-activated] with 3-1% sodium lauryl sulfate, followed by a 4% w / w solution of poly (2-) propenal, 2-propenoic acid) [super-activated] in 70% ethanol, applied to hands before putting them in surgeon's gloves, produced a significant reduction of the base bacterial count after 3 hours. The results indicate that poly (2-propenal, 2-propenoic acid) [super-activated] has a good antibacterial residual activity that is required for the sustained control of quantities of bacteria in surgical asepsis. The inclusion of 70% ethanol in the preparation helps the rapid initial decrease in the quantities of bacteria. Example 16 The. biocidal activity of 0.125% w / w and 0.05% w / w of super-activated polymer against the reference strain H. pylori NCTC 11673 with pH 7 and pH 4. The in vitro efficacy of the super-activated polymer is first established against the reference strain H. pylori, H. pylori NCTC11637. As variables, two concentrations were selected; one was a 40-fold dilution of the 5% solution of the super-activated polymer prepared in Example 2, yielding a concentration of 0.125% w / w of the super-activated polymer, mimicking the dilution in the stomach; the other was a 100-fold dilution yielding a 0.05% w / w concentration of the super-activated polymer. Two pH, pH 7 as base and pH 4 were selected to mimic conditions in the stomach. Cultures of H. pylori NCTC11637 were grown under microaerophilic conditions in selective agar plates at 37 ± 2 ° C until sufficient growth was observed. The growth was aseptically separated from the plates and prepared as a standardized 10% T cloudy suspension, as shown in the Vitek colorimeter, performing the dilution with saline? Pp .; sterile. 19.9 g of the sample were weighed and inoculated with ??? μ? of crop suspension. 1 ml of the sample was immediately transferred to the deactivation / recovery broth (nutrient broth plus 3% Tween 80) and then diluted in series. Aliquots of ??? μ? were placed on selective agar plates and spread using a disposable sterile separator. The transfer steps were repeated at time intervals of 5, 10, 15 and 20 minutes. All plates were incubated under microaerophilic conditions at 37 ± 2 ° C until sufficient growth had been achieved (approximately 5 to 7 days). All the colonies were counted and the population decline was determined over time. The test was repeated using normal sterile saline as a sample to determine the natural rate of extinction under atmospheric conditions. Legend: Culture 1. Super-activated polymer, pH 7.0, 0.125% weight / weight Culture 2. Super-activated polymer, pH 7.0, 0.05% weight / weight Culture 3. Super-activated polymer, pH 4, 0.125% w / w Culture 4. Super-activated polymer, pH 4, 0.05% w / w Culture 5. Normal sterile saline, pH 7. Culture 6. Normal sterile saline, pH 4. Table 20 Biocidal activity of CHEMEQR ™ antimicrobial drug on H. pylori (NCTC 11637) Note: I count in colony forming units (cfu) for my deactivation broth. The results against the reference strain (Table 20) show that the super-activated polymer was active at pH 7 with both 0.125% w / w and 0.05% w / w, and was also active at pH 4 and 0.125% w / w. weight . Example 17 In addition to example 16, three other strains of H. pylori were examined with pH 7 and pH 4: H. pylori 01/303, which is resistant to clarithromycin and metronidazole; H. pylori SS1, a clinical strain isolated in Sydney with a high colonizing capacity of interest for possible animal models, and H. pylori ATCC 700392, a strain whose genome has been sequenced and which comes from the United Kingdom. Table 21 Super-activated polymer biocidal activity, 0.125% pH 7 When treated with the super-activated polymer with 0.125% w / w at pH 7, all strains were rapidly killed, with the antibiotic-resistant strain being particularly vulnerable, since its extinction occurred in less than 10 minutes (Table 21). . The control strain was not treated. Example 18 The method of Example 3 was repeated by verifying the biocidal activity of 0.125% w / w super-activated polymer (pH 4) against all strains of H. pylpri. Table 22 Biocidal activity of CHEMEQR ™ polymer antimicrobial drug at 0.125% and pH 4.

Verifying the super-activated polymer in the stomach by imitating pH of 4 and 0.125% w / w resulted in all the strains being killed within 20 minutes (table 3). This result is significant because this period of time to kill H. pylori is less than the period of passage through the stomach (40 min - 1 hour). This demonstrates the effectiveness of the super-activated polymer at a pH, a concentration and in the period of time consistent with the treatment of an H. pylori infection in the stomach. The control strain was untreated. Example 19 This example demonstrates the enteric antimicrobial activity of the acetal derivative of poly (2-propenal, 2-propenoic acid) prepared according to the method of Example 10b. Material and methods: Sixteen weaning pigs (age: 18 days ± 2 days and weight 5.5 kg ± 1.0 kg) were purchased in a commercial pig farm. They were assigned to roast in 2 groups of 8 pigs (uniform distribution of sexes) and were housed in a house of isolation of animals with controlled environment. Water and food were available without restriction upon entering the animal house, and the diet consisted of croquettes for commercial weaning pigs free of antimicrobial drugs [19% crude protein]. All the weaning pigs were euthanized by intravenous injection of sodium barbiturate and then autopsy. DNA was extracted from gastric and esophageal regions of the stomach of twenty-four weaning pigs during autopsy using Qiagen Dneasy tissue equipment according to the included instructions. 3μ1 of the extracted DNA was used to verify the presence of Helicobacter species in tissue samples from the biopsy. Polymerase chain reaction (PCR) was performed twice in each sample with seven control DNA samples included in each PCR run. No discrepancies were found between the PCRs performed. Results: Coding of treatments: Group 1: No treatment (negative control) Group 2: 0.1% weight / volume of superimposed polymer antimicrobial drug according to example 10b; 30 mg / kg / day. Table 23 PCR results of Helicobacter species using primer specific to the previously optimized genus, where + represents a positive detection of Helicobacter species and - represents no detection.

In group 1 (without treatment) there were five positive results regarding Helicobacter species (1 - gastric, 4 - in the esophagus), while group 2 (0.1% weight / volume of polymeric antimicrobial drug) did not give positive results for the PCR. Conclusion: The acetal derivative of poly (2-propenal, 2-propenoic acid) at 0.1% w / v significantly reduces (?: P <0.025) the incidence of porcine Helicobacter species in the gastric and esophageal mucosa in pigs of weaning Example 20 Comparative Example 20 (a) This example shows a method for preparing non-super-activated poly (2-propenal, 2-propenoic acid). 0.8% weight / weight of sodium hydroxide Place 9.90 kg of deionized water in a 10 1 stainless steel tub and add 0.08 kg of sodium hydroxide to the water and shake until it has dissolved. Polymerization Place 100.1 kg of deionized water in a 200 1 stainless steel tub and add 4.99 kg of the 0.8% w / w solution of sodium hydroxide to the 2001 tub. Keep the solution at 15-20 ° C. Add simultaneously 20 kg of acrolein monomer and the rest of the solution of 0.8% w / w of sodium hydroxide to the tub of 200 1 in portions for more than 1 hour so that the pH remains at 10.5 - 11.0, and the temperature Do not rise above 30 ° C. Continue polymerization for another 90 minutes. Washing Filter / centrifuge the polymerization mixture and wash the polymer with deionized water until the pH of the wash water is less than 7.0. The approximate yield is 8 kg. Drying Dry the polymer to air, then heat it in an oven according to the following scheme: stage period temperature 1 2 hours 25 ° C 2 1 hour 40 ° C 3 1 hour 70 ° C 4 1 hour 75 ° C 5 2 hours 85 ° C Solution Place 400 1 of water in a 500 1 tub and add 4 kg of sodium carbonate and shake until dissolved. Slowly add 8 kg of dry polymer, heated and stir for thirty minutes. It was verified that the obtained polymer has an approximate solubility of 90 to 95% w / w in 1% w / w of sodium carbonate. Example 20 (b) This example describes a method for preparing an acrolein polymer where the polymer of Comparative Example 20 (a) is super-activated Base Production Dissolves 0.4 kg of sodium carbonate in 30.6 kg of 7 water in a convenient container and place 64 kg of polyethylene glycol 200 in the mixing container. Start stirring with a mechanical stirrer and heat the PEG200 to 65 ± 3 ° C. Add 5 kg of the dry acrolein polymer from Example 10a to PEG200 and shake until a uniform mixture is obtained. Note: It is possible that the solid does not completely dissolve at this stage. Slowly add the sodium carbonate solution to the glycol mixture in portions that ensure that the pH of the solution remains in the range of 3.5 - 9.0. Shake the solution for 45 minutes at 65 ± 3 ° C. Note: The pH should be in the range of 7-9. The temperature should be in the range of 65 ± 3 ° C. Super-activation Cover the mixing container and heat at 100 ° C for four (4) hours. It was found that the resulting polymer is miscible with water in any proportion.

Example 21 In Example 14 of PCT / AU9600328 it was shown that poly (2-propenal, 2-propenoic acid) polymer in 0.5% w / w solution of sodium carbonate possesses anti-cancer activity against the Ehrlich ascites cell line in a mouse model. The anti-cancer activity of poly (2-propenal, 2-propenoic acid) polymer [example 20 (a)] compared to that of the super-activated polymer [example 20 (b)]. An in vitro model of a gastrointestinal cancer was performed in the human colon cancer cell line, HT-29. Poly 2-propenal, 2-propenoic acid) was used in a concentration of 5% w / w. The assay used incubates cancer cells with various concentrations of polymer to obtain a graph that allows establishing an IC50. Methodology HT-29 cells (human colon cancer cells) were seeded (in 100 μ?) In wells of 96-well culture plates and incubated overnight at 37 ° C in a humid atmosphere with 5% C02, 95% air The polymer [poly (2-propene, 2-propenoic acid) polymer from comparative example 20 (a) and the super-activated polymer from example 20 (b)] was dissolved in water and then diluted in medium to 10 concentrations covering a 4-log interval. 100 μ? of each solution was then added to each of b wells. The plates were incubated for another 72 hours after which viable cells were measured using the sulforhodamine B assay (Skehan et al., (1990) J. Nat. Cancer Inst. 82: 1107-1112; Monks et al., (1991) J. Nat. Cancer Ins. 83: 757-766.). The cells were then fixed with 10% cold trichloroacetic acid for 1 hour at 4 ° C and the plates were rinsed with distilled water, left in the air to dry and then stained with 0.4% sulforhodamine B (Aldrich) in 1% acetic acid (volume / volume) for 30 minutes. Unbound dye is then removed by washing twice with distilled water and finally with 1% acetic acid. Protein-linked dye is dissolved in 10 mM Tris base without buffer and taken from the absorbance at 550 nm using an automatic plate reader. The average absorbance for each dose of active substance is expressed as a percentage of the absorbance of the untreated control well. The results are shown in Table 24. Poly (2-propenal, 2-propenoic acid) polymer from comparative example 20 (a) produced an average IC50 during two 0.030% tests; the polymer poly (2-propenal, 2-propenoic acid) was assigned the value of 100%. This translates to 0.0015% w / w of active polymer. The super-activated polymer of example 20 (b) produced an average IC50 in four 0.025% tests. This translates to 0.00125% w / w of the super-activated polymer and indicates that the super-activated polymer has a potent anti-cancer activity. Table 24 IC50- of CHEMEQR ™ antimicrobial polymer against HT-29 human colon cancer cells.

IC50 is the concentration needed to inhibit cell growth by 50%. Finally, it is understood that other modifications and / or changes may be made without deviating from the spirit of the present invention as detailed herein.

Claims (32)

1. CLAIMS 1. Method for the treatment or prevention of gastrointestinal diseases in an animal (including human) comprising gastrointestinal administration to the animal of an effective 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 one or more hydroxyl groups to form protected carbonyls.
2. 2. Method according to claim 1, characterized in that the polymer is administered orally.
3. 3. Method according to claim 1, characterized in that the animal suffers from at least one gastrointestinal disease selected from the group consisting of gastroenteritis, ulcer, diarrhea and gastrointestinal cancer and inadequate weight gain promoted by dysentery.
4. 4. Method according to claim 1, characterized in that the animal suffers at least one between diarrhea, gastroenteritis and dysentery.
5. Method according to claim 1, characterized in that the animal is selected from the group consisting of dogs, pigs, sheep, horses, cattle, cats, chickens, ducks, turkeys and quail.
6. Method according to claim 1, characterized in that the animal is selected from ruminant animals and the polymer is administered rectally.
7. Method according to claim 1, characterized in that the animal is selected from chickens and pigs.
8. 8. Method according to claim 1, characterized in that the animal is a partially grown pig.
9. 9. Method for the treatment or prevention of post-weaning porcine colibacillosis comprising oral administration to young pigs after weaning of an antimicrobial effective amount of the polymer according to claim 1.
10. Method according to claim 1, characterized in that the derivative of poly (2-propenal, 2-propenoic acid) mentioned is administered in a dose of 0.05 to 5000 mg / kg / day.
11. The method according to claim 1, characterized in that the aforementioned poly (2-propenal, 2-propenoic acid) derivative is administered in a dose in the range of 0.5 to 500 mg / kg / day.
12. The method according to claim 9, characterized in that the poly (2-propene, 2-propenoic acid) derivative mentioned is administered to young pigs in a dose in the range of 0.05 to 50 mg / kg / day.
13. Method according to claim 1, characterized in that the gastrointestinal diseases are caused by one or several microbes selected from the group consisting of Coliforms, Salmonella, P. aeruginosa, Helicobacter, Proteus, Enterobacteria, yeasts, protozoa, clostridia, Shigella and Coccidia.
14. 14. Method for the treatment or prevention of diseases of the gastrointestinal tract caused by infection with Helicobacter comprising the gastrointestinal administration of a therapeutic amount of a polymer comprising a derivative of poly (2-propenal, 2-propenoic acid) formed by 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.
15. 15. Method according to claim 1, characterized in that the gastrointestinal disease is caused by at least one of E. coli and enterotoxigenic β-hemolytic E. coli.
16. 16. Method according to claim 1 characterized in that it is used in the treatment or prevention of necrotic enteritis in chickens comprising the administration to chickens of an effective amount of poly (2-propene, 2-propenoic acid) derivative mentioned.
17. The method according to claim 1, characterized in that the poly (2-propene, 2-propenoic acid) derivative mentioned is administered in combination with another chemotherapeutic drug adsorbed therein to thereby reduce the membrane penetration of the additional chemotherapeutic drug.
18. 18. Method for the treatment or prevention of coccidiosis in chickens comprising administering to chickens an antimicrobial effective amount of a poly (2-propenal, 2-propenoic acid) derivative formed by the reaction between a poly (2-propene) , 2-propenoic acid) and an organic compound containing one or more hydroxyl groups to form protected carbonyls.
19. 19. The method according to claim 1, characterized in that the derivative comprises a multiplicity of protected carbonyl groups selected from at least one of hemiacetal and acetal groups.
20. 20. Method according to claim 19, characterized in that the protected carbonyls include acétal groups.
21. The method according to claim 1, characterized in that the alcohol is selected from alkanols, phenols, polyols and mixtures thereof.
22. 22. Method according to claim 21, characterized in that the alcohol is selected from at least one polyol.
23. 23. Method according to claim 22, characterized in that the polio comprises a polyalkylene glycol.
24. 24. Method according to claim 23, characterized in that the polyol comprises a polyethylene glycol.
25. Method according to claim 23, characterized in that the polyol is a polyethylene glycol with a molecular weight between 200 and 2000.
26. 26. Antimicrobial drug for the treatment or prevention of gastrointestinal diseases in animals by gastrointestinal administration of the aforementioned antimicrobial composition comprising a poly (2-propenal, 2-propenoic acid) and an organic compound containing one or more hydroxyl groups to form protected carbonyl groups and a pharmaceutically or veterinarily compatible inert carrier for gastrointestinal administration to animals.
27. 27. Antimicrobial drug for the treatment or prevention of gastrointestinal diseases according to claim 26, characterized in that the vehicle for gastrointestinal administration is selected from the group consisting of water, controlled release polymers, olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides, polyvinyl alcohol, partially hydrolyzed polyvinyl acetates and their mixtures.
28. 28. The antimicrobial composition according to claim 27 in the form of a food supplement or drinking water, wherein the supplement comprises between 0.1 and 70% by weight of the poly (2-propene, 2-propenoic acid) derivative mentioned.
29. 29. Animal feed (including human) or composition of drinking water comprising food material or water and an antimicrobial effective amount of an antimicrobial drug according to claim 1.
30. 30. Feed for animals according to claim 29, characterized in that the antimicrobial drug is present in an amount of between 0.001 to 25% by weight of the complete water food composition.
31. 31. An antimicrobial composition comprising an antimicrobial drug according to claim 26 and another active agent selected from the group consisting of antimicrobial and chemotherapeutic agents.
32. 32. The composition according to claim 31, characterized in that the additional antimicrobial drug comprises (based on the weight of the composition) at least one of (a) a phenol in an amount of 0.1 to 10%; (b) an isothiazolinone in an amount of 0.001 to 1%; (c) alkyl parabens in an amount of 0.02 to 2% and (d) alkanol of low molecular weight in an amount of 20 to 99.9%.