CN1617733B - 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

The Therapeutic Method of gastrointestinal disease and the polymer composition that is used for wherein

Technical field

The present invention relates to treat or prevent gastrointestinal disease and promote the method for growth of animal and relate to the antimicrobial compositions that is used for the treatment of this class.

Background technology

Antimicrobial drug be kill and wound microorganism, such as the chemical compound of antibacterial.Antibiotic is the subclass antimicrobial drug that (usually) derives from other microorganism and work by the specific mechanism of disturbing in the target microorganism.The antibiotic first Application is in nineteen forties and the fifties and progressively increase of its application so far from that time.The generation of antibiotic resistance has become serious and potential life-threatening problem in the whole world.Some bacterial strain of staphylococcus has shown anti-nearly all antibiotic and mortality occurred in hospital and infected.Other medicines resistance organism comprises the streptococcus pneumoniae that causes pneumonia and causes diarrheal Cryptosporidium and escherichia coli.

Its application that the application of antibiotic in animal feed regarded extensively as to quicken reason that toleration takes place and result be many state controls.This has produced problem aspect animal feeding, cause being difficult to control disease and obtain the optimum growh rate.This problem is particularly raised the difficult problem in pig and the poultry.For example, gastrointestinal disease, may have destructive effect such as colibacillosis of pig and the coccidiosis of poultry.

Melrose etc. (International Patent Publication No. 96/38186) have described the application of acrylic aldehyde polymer formulations in the treatment gastrointestinal disease first.

These polymer have the repetitive of general formula I:

Or by this unit of its hydrated form, hemiacetal or the acetal form of the representative of following general formula:

Wherein R is that hydrogen and n are the integers of having described more than 1 or 1.Before this, Melrose etc. has described the kill livestock thing characteristic of acrylic aldehyde polymer in antibacterial applications in International Application No. WO 88/04671.German patent application P4404404 and patent families, such as the method that discloses polypropylene aldehyde in the sodium hydrate aqueous solution medium among EP667358 and the AU 11686/95 (at present with expired).The polyacrolein of the disclosure document record gained is dissolved in polyhydric alcohol and forms the polyhydric alcohol solutions of polyacrolein under 40-50 ℃.Just as explained below, the assignee of this German application finds these base polymer existing problems subsequently and have low-solubility in aqueous medium.

The European publication number EP 792895 (being equivalent to US 6060571) of Werle etc. relates to by acrylic aldehyde monomer and polyhydric alcohol being carried out the polymer of the release acrylic aldehyde that combined polymerization prepares.Werle etc. observe the polypropylene aldehydes existing problems described in the German application P4404404, and promptly productive rate is lower than desirable yield and these polymer are in fact water insoluble.Instructed among the European application EP792895 by overcoming these difficult problems through acrylic aldehyde monomer and polyhydric alcohol monomer being carried out the polymer that combined polymerization forms the release acrylic aldehyde.The structure of the copolymer that proposes is as follows:

Although free acrylic aldehyde can be used as antimicrobial drug and works its exciting eye, lung, tissue and skin.Existence to use in the certain limit, particularly there is demand in the application to stable, highly-water-soluble and gastrointestinal antimicrobial medication safe in utilization.Also exist the effective antimicrobial drug to treatment or prevention gastrointestinal disease to have demand, they can reduce the pressure that antibiotic resistance takes place.

This paper comprises that the discussion of background technology of the present invention is in order to explain context of the present invention.It is open when the priority date of present patent application, known or as the ingredient of general the common knowledge not to be seen as any related material.

Summary of the invention

If we have had been found that poly-(2-acrylic aldehyde at present, 2-acrylic acid) polymer and alcohol or polyol reaction and generate protected carbonyl, such as acetal and/or hemiacetal derivant, so their activity and the stability in the gastrointestinal disease obtains substantive the raising in treatment or prevention.Although we find that unexpectedly the content of free acrylic aldehyde in described polymer may extremely hang down maybe and can ignore, the activity of its derivant in treatment or prevention gastrointestinal disease obtains substantive the raising.The dissolubility of this polymer in water is also high.

The invention provides the method for the gastrointestinal disease of treatment or prevention animal (comprising the people), this method comprises the step that described animal is given poly-(2-acrylic aldehyde, 2-propanoic acid) derivant of effective dose, it is by poly-(2-acrylic aldehyde, 2-acrylic acid) and contain between the organic compound of one or more hydroxyls reaction such as alcohol like this and generate and protected carbonyl and form, the wherein said organic compound of one or more hydroxyls that contains is preferably from alkane alcohols, phenols, polyalcohols and composition thereof.

The present invention provides the antimicrobial drug that is used for the treatment of gastrointestinal disease in one aspect of the method, it comprises by poly-(2-acrylic aldehyde, 2-acrylic acid) and contain like this such as alcohol that reaction generates poly-(2-acrylic aldehyde, the 2-propanoic acid) derivant of being protected carbonyl and forming between the organic compound of one or more hydroxyls, the wherein said organic compound of one or more hydroxyls that contains is preferably from alkane alcohols, phenols, polyalcohols and composition thereof.

Term polyhydric alcohol used herein refers to the molecule that contains at least two hydroxyls.

The derivant that forms generally is selected from hemiacetal and acetal derivant.Do not wish to be subjected to theory constraint, we think that poly-(2-acrylic aldehyde, 2-acrylic acid) and the reaction of alcohol form hemiacetal and/or acetal by a certain proportion of at least aldehyde radical side chain, make the carbonyl of polymer that the alkaline degradation by Cannizaro reaction is kept stable thus.Have been found that the formation of acetal radical has has significantly reduced or eliminated the release of free acrylic aldehyde, improved the activity of gained derivant simultaneously unexpectedly.

Another embodiment of the invention provides above-mentioned antimicrobial drug to be used for the treatment of or to prevent application in the medicine of gastrointestinal disease in preparation.

In the description and claim of this description, word " comprises " and the version of this word, do not get rid of other additive or composition or integral body such as " containing " and " comprising ".

Detailed Description Of The Invention

Can prepare antimicrobial drug of the present invention by under the situation that alcohol, preferred polyol is arranged, exist, adding hot polymerization (2-acrylic aldehyde, 2-acrylic acid) such as Polyethylene Glycol.Always there is moisture content in the alcohol apoplexy due to endogenous wind, and should understand and exist at least one quantitative water to help necleophilic reaction, thereby makes hemiacetal or acetal formation.

Generally at 40 ℃-150 ℃, more preferably 40-115 ℃ and this solution of heating under the temperature of 70-115 ℃ of scope most preferably.

By poly-(2-acrylic aldehyde, 2-acrylic acid) polymer manufacture antimicrobial drug of the present invention.This base polymer and preparation method thereof is described in the International Patent Publication No. WO 96/38186 (PCT/AU96/00328), and the content of the document is incorporated herein by reference.Preferably by preferably in aqueous solution through anionic polymerisation come polypropylene aldehyde, autoxidation prepares poly-(2-acrylic aldehyde, 2-acrylic acid) polymer subsequently.These polymer contain the repetitive of at least a (and generally being mixture) in general formula I and hydration, hemiacetal and the acetal form.

Known different carbon-to-carbons and the carbon-oxygen flowcollector aggregation scheme FlowCollector generation of passing through hydration, hemiacetal and the acetal form of the formation of polypropylene aldehyde by acrylic aldehyde.For example, hydrated form is generally hydration glycol form, hemiacetal or acetal form can be by described glycol form and aldehyde or the condensations of glycol form and are formed, Pentamethylene oxide. or condense the Pentamethylene oxide. form and can be formed from the condensed forms condensation by described glycol form and aldol-Michael.

The representative instance of these forms is shown in following general formula (a)-(f):

Wherein R is a hydrogen and n is the integer more than 1 or 1.The ratio of general formula I repetitive generally is lower than 20% and be generally 5-15%.Although these unitary ratios are relatively low, we have found that they have remarkable effect to the stability of described polymer.

Poly-(2-acrylic aldehyde, 2-acrylic acid) generally contain by mole be no more than 10% from monomeric monomeric unit of non-acrylic aldehyde and acrylic aldehyde homopolymer (before the autoxidation) most preferably.If use other monomer, they can be selected from the group of acrylic acid and vinyl pyrrolidone composition so.The content of 2-acrylate moiety is generally 0.1-5 mole carboxyl/kilogram.Poly-(2-acrylic aldehyde, 2-acrylic acid) polymer generally has and surpasses 1000 and most preferably surpass 2000 number-average molecular weight.This molecular weight is generally less than 10,000.

Antimicrobial drug of the present invention is by generating the derivant of gathering (2-acrylic aldehyde, 2-acrylic acid) of being protected the carbonyl preparation with alcohol or phenol reaction.Form by the 2-acrylic aldehyde group that forms hemiacetal and acetal radical with alcohol reaction and to be protected carbonyl.Described alcohol is preferably polyhydric alcohol, and so-called polyhydric alcohol refers to it and preferably contains at least two hydroxyls.Can use such as C ₁-C ₁₀Such alkane alcohols.If described alcohol is polyhydric alcohol, this reaction can produce reaction formation acetals or the hemiacetal class by one or more alcohol radicals so.In addition, when two alcohol radicals participate in reaction, can make on their same carbonyls in polymer or the different carbonyl and react.

The present invention has produced the derivant that relates to above-mentioned general formula I and hemiacetal and acetal form, wherein there is the unit of less general formula I and forms a kind of group, wherein one or more radicals R derive from alcohol, maybe when this alcohol is polyhydric alcohol, two above radicals R can form bridging group together, such as the cyclic acetal base.

The tendency of polyalcohols generation inner annular group depends on the spacing and the configuration of this polyhydric alcohol.Preferred alcohols is that polyalkylene glycol class and preferred alcohols are polyethylene glycols.

The molecular weight of polyalkylene glycol class is preferably 200-2000 and more preferably 200-1000.

Be 50-99% weight preferably such as the such content of alcohol in the process of preparation anti-microbial polymer of Polyethylene Glycol.Preferred especially rare relatively acrylic aldehyde polymer composition, wherein when reducing the incidence rate of intermolecular cross-linking by dilution, described alcohol is polyhydric alcohol.

More preferably the content of Polyethylene Glycol in the process of the described polymer of preparation is 64-95% weight.

Preferably in polymer, add alkali (base) or alkaline matter (alkali), pH oxytropism pH direction is changed, the acidic-group neutralization of polymer takes place this moment, improve the antimicrobial acivity of polymer thus.Preferably adding alkali or alkaline matter at first makes the pH of poly-(2-acrylic aldehyde, 2-acrylic acid) polymer reach 7-9.More preferably the initial pH when adding alkali is about 8.Described alkali is preferably alkali metal hydroxide, carbonate, bicarbonate or its mixture.

In another kind of form of the present invention, the free monomeric release of acrylic aldehyde is suppressed from continuous release, and these polymer can produce tissue or skin irritation source hardly thus.

We have found that antimicrobial drug of the present invention significantly improves at the antimicrobial drug of specific activity poly-(2-acrylic aldehyde, the 2-acrylic acid) preparation aspect the control gastrointestinal disease.The derivant of superactivation of the present invention can be used for the treatment of extensive animal (comprising the people) and extensive infection by microorganisms.

Antimicrobial drug of the present invention can be used for the treatment of people's gastrointestinal disease, but, especially preferably uses it for other animal of treatment, particularly is selected from the animal of the group of Canis familiaris L., pig, sheep, horse, goat, cattle, cat, poultry, duck, turkey and Carnis Coturnicis japonicae composition.

Antimicrobial drug of the present invention can be prepared into the form of oral or rectally.Rectally can be used for ruminant especially.Can also use enteric-coating material to prepare oral formulations that ruminant uses so that provide optimum activity in the gastrointestinal tract bottom.

Antimicrobial drug of the present invention is specially adapted to treatment and prevention gastroenteritic ulcer, diarrhoea and human primary gastrointestinal cancers.Antimicrobial drug of the present invention can also be by improving feedstuff in the animal body improves weight increase rate from farm-animals to the conversion ratio of body weight.

We have found that antimicrobial drug of the present invention can be used to replace the antibiotic of present use as growth promoter and described polymer.The Drug resistance that exists in pathogenic bacterium is the main clinical important difficult problem in the human medicine.This problem is aggravated with the body weight that increases farm-animals, particularly poultry and pig because of use important antibiotic in animal feed.In fact, in some European countries, forbidden in animal feed, using common antibiotics.Antimicrobial drug of the present invention can be used for the treatment of animal so that obviously prolong the life-span of the common antibiotics that uses in people's autogenic therapy.

We have found that antimicrobial drug of the present invention is effective to microorganism widely, comprise protozoacide, gram positive bacteria and gram negative bacteria.Polymer of the present invention contains a plurality of structures of isomorphism type not and can find and the protein fit of finding that this structure has been quickened the destruction of described proteinic inactivation and pair cell on the target organisms cell wall.In gram negative bacteria, have been found that antimicrobial drug of the present invention is specially adapted to provide the broad spectrum of activity to coliform group or enterobacteria class.It is used in particular for treating the gastrointestinal disease that causes because of escherichia coli, such as enterotoxigenic Escherichia coli and beta hemolysis coli-infection.Colibacillosis is a kind of crushing disease in the industry of raising pigs.This disease is generally relevant with the beta hemolysis escherichia coli propagation in the small intestinal of wean back and cause high mortality and sickness rate in the immature porkling of wean.The wean porkling that infects can not obtain normal weight increase.

Coccidiosis is the protozoan disease of animal, particularly poultry, and if do not add control, then have crushing effect.We have found that antimicrobial drug of the present invention can be used for the treatment of or prevent the coccidiosis of birds, particularly poultry.In chicken, the typical disease of coccidiosis comprise lack cordiality, body weight descends fast, diarrhoea and dysentery.The most serious effect occurs in the intestinal, and wherein protozoacide is tended to encroach on mucosa and caused epithelial damage, infringement and hemorrhage.Attempted vaccine is used to prevent coccidiosis, but had side effect, comprised weight loss and anorectic tendency.

Antimicrobial drug of the present invention can knownly have an active drug combination of coccidiosis with other.This class medicine comprises nitro diphenylcarbamide, quinoline, pyridone, guanidine, quinoxaline, toltrazuril (toltrazural), toluamide (toluamide), compound sulfamethoxazole medicine and contains the ionophore of diphenylcarbamide.

Clostridium is to cause the certain limit animal that the gram positive bacteria of serious disease takes place.For example, the necrotic enteritis disease is the disease of known effect commodity poultry.The antibacterial of Clostridium produces some toxic extracellular toxin of tool in all known toxin.The sick chicken that influences the 14-42 age in days especially of necrotic enteritis.This disease cause sound dim, diarrhoea and can in a few hours, cause death.

The upper stomach intestinal diseases that comprises chronic gastritis, gastric ulcer and duodenal ulcer is significant health problem.Think that Helicobacterium is the reason that causes ulcer generation and human primary gastrointestinal cancers, particularly adenocarcinoma of stomach to take place.We have found that antimicrobial drug of the present invention be used in particular in anti-animal, particularly the people's gastrointestinal disease Helicobacterium, comprise helicobacter pylori.

In specific embodiments according to the present invention, wherein said gastrointestinal disease causes because of one or more microorganisms, and these microorganisms are selected from the group that coliform group, Salmonella, Pseudomonas aeruginosa, Helicobacterium, proteus, enterobacteria class, yeast, protozoacide, Clostridium, Shigella and Globidium are formed.

The stomach infections helicobacter pylori is one of modal infectious disease in the world.50% group infection helicobacter pylori is arranged approximately.In developing country, surpass 80% crowd according to estimates and just infected helicobacter pylori in childhood.

Helicobacter pylori is the little aerobic spiral type bacillus of Gram-negative that moves about by the flagellum on cell one end.Standard care to helicobacter pylori infections is so-called three antibiotherapies, and all these therapies include metronidazole or clarithromycin.Regrettably, the helicobacter pylorus bacteria strain has demonstrated these two kinds of antibiotic tolerations.

Helicobacter pylori is lived on the interface between gastric epithelial cell surface and the mucus gel layer above it.Find that in addition helicobacter pylori is arranged in the skin top, Weishang of duodenum and esophagus.There is its unique Helicobacterium kind in other animal species in its gastrointestinal tract, they have and the similar characteristic of helicobacter pylori.Outside the Pass having with human primary gastrointestinal cancers, helicobacter pylori also is formed with direct relation with intravital gastritis of people and peptic ulcer.

Helicobacterium kind generally and particularly helicobacter pylori is survived under the extreme condition of stomach by the secretion urase, and excretory urase hydrolysis urea and obtain ammonia and bicarbonate ion, and the pH of bacillus around contiguous raise.The change of this local condition has prevented that antibacterial is subjected to the influence of gastric acid bactericidal action.Preferred site under the stomach protectiveness rete malpighii also is favourable to survival and its motion makes it reach this position by this layer.

The epithelial cell that arrange on the Weishang is difficult to nature and sees through; This is to prevent that the remainder of health from contacting the part of the function of gastric juice and Digestive system.Thisly see through last difficulty and also make the natural defence of health be difficult to and reach the position of helicobacter pylori infections by coat of the stomach.There are two results in this: health is transported to the position of auxiliary leukocyte, T-cell and other defense structure with more nutrient, follows nutrient is offered bacillus; And defense cell is finally dead, discharges superoxides ion and other lethal chemical substance of its load, the epithelial cell around destroying.

Obvious this activity causes may being easy to develop into the gastritis of peptic ulcer.If infringement continues to carry out, adenocarcinoma of stomach takes place so will significantly be increased with the lymphadenomatous probability of lymphoid tissue (MALT) relevant with mucosa.It is that stomach is avoided self the reaction of helicobacter pylori infections taking place that first stage intestinal tissue that adenocarcinoma of stomach takes place and takes place from mucosa transforms.In addition, the research of carrying out in the UCL medical college has confirmed that the MALT lymphoma need obtain from the help of helicobacter pylori specificity T-cell and grows.It is very effective on healing MALT lymphoma to have confirmed to treat helicobacter pylori infections.World Health Organization (WHO) has been labeled as this pathogen I class carcinogen.

Therefore, the present invention also provides the method for the gastroenteropathy for the treatment of or preventing to be caused by helicobacter infection, this method comprises the step that gives the activating agent of therapeutic dose through gastrointestinal, wherein this activating agent comprises by poly-(2-acrylic aldehyde, 2-acrylic acid) and the reaction that contains between the organic compound of hydroxyl generate poly-(the 2-acrylic aldehyde that is protected carbonyl and form, 2-acrylic acid) derivant, the described organic compound that contains hydroxyl is selected from alkane alcohols, phenols, polyalcohols and composition thereof.Term polyhydric alcohol used herein refers to the chemical compound that contains at least two hydroxyls.The derivant that forms generally is selected from hemiacetal and acetal derivant.

Therefore, the application of the inventive method provides operation, radiotherapy or traditional chemotherapeutic treatment human primary gastrointestinal cancers outer another kind of method.

The present invention further provides the Therapeutic Method of the alimentary infection that the Helicobacterium bacterial species causes, described alimentary infection is all if any gastritis, gastric ulcer, duodenal ulcer, malignant lymphoma of stomach or gastric cancer, this method comprises the step that gives the activating agent of therapeutic dose through gastrointestinal, wherein this activating agent comprises by poly-(2-acrylic aldehyde, 2-acrylic acid) and contain the derivant that reaction between the organic compound of one or more hydroxyls generates poly-(2-acrylic aldehyde, the 2-acrylic acid) that protected carbonyl and form.

The invention provides the outer another kind of method of traditional remedies of helicobacter infection, in general, traditional remedies comprises so-called three antibiotherapies, and wherein all therapies include metronidazole or clarithromycin.The helicobacter pylori bacterial strain has occurred can effectively treating this class antibiotic-resistant bacteria to these two kinds of antibiotic tolerations and our verified method of the present invention.

Verified poly-(2-acrylic aldehyde, 2-acrylic acid) part that belongs to poly-(2-acrylic aldehyde, 2-acrylic acid) and contain the comparable corresponding non-superactivation of product of the reaction between the organic compound of one or more hydroxyls is more effectively treated helicobacter infection.

The derivant that the present invention further provides poly-(2-acrylic aldehyde, 2-acrylic acid) preparation be used for the treatment of or the medicine of the disease preventing to cause by helicobacter infection in application.

Method of the present invention can be used for the treatment of or prevent human primary gastrointestinal cancers.They can comprise: for example esophageal carcinoma, gastric cancer, intestinal cancer and colon cancer.The example of this class cancer is CCL188 HT-29.

When sneaking into antimicrobial drug of the present invention in animal feed or the water, can implement this step according to usual way.In preferred embodiments, antimicrobial drug of the present invention is sneaked into premix.This premix preferably includes described antimicrobial drug, physiologically acceptable carrier and optional food.This premix is generally relative conc forms and is suitable for other material dilution, such as being diluted to the finished product animal feed with one or more other carriers, vitamin and mineral additive and food.This premix preferably includes the antimicrobial drug of concentration at 0.1-70% weight, preferred 0.5-50% weight range.Optium concentration depends on that whether therapy is that antimicrobial drug preventative and of the present invention is uniquely to have active or do not use it for and other material or antimicrobial drug concomitant therapy linked together for control or treatment.

In preferred embodiments, the concentrate composition of antimicrobial drug is a controlled release forms.Controlled release form comprises the compositions that antimicrobial drug and being used for provides the polymer that antimicrobial drug discharges from controlled release system and is specially adapted to add to the solid feed material.As the result of controlled release preparation, antimicrobial drug can delay to discharge so that mainly occur in duodenum.Controlled release polymer can also be minimized the compositions discharge (rejection) that causes because of taste or be used for rectum suppository.

Antimicrobial compositions of the present invention can be solid composite forms such as pill, pill.Can prepare the pill that contains antimicrobial drug of the present invention through the following steps:

(i) described antimicrobial drug is dissolved in alkali or alkaline aqueous solution;

(ii) with the described solution of acid neutralization;

(iii) in described neutral solution, add insoluble crosslinked acrylic adsorbent polymer and/or acrylamide and acrylic copolymer to form moistening swellable pill; With

The (iv) optional described moistening swellable pill of all or part of drying.

So the moistening swellable pill that forms can be with the form of moistening, part drying or bone dry as for example such additive of animal feed.This system is further designed, thereby containing when carboxy moiety makes the polymer of theme of the present invention in the sour environment of stomach of outer polymer substrate keeps being included in the described substrate basically.Yet, in duodenal alkaline environment, the carboxylic ionsization of substrate and repulsion mutually, and the quick swelling of described pill, the auxiliary polymer of theme of the present invention that makes by the repulsion between owned ionic group is excluded outside diffusion process, and to cross duodenal speed very nearly the same with feed link basically.

In the present invention, the term of use " controlled release system " has and " controlled release transhipment " (" Controlled Drug Delivery ") (Robinson ﹠amp; Lee, 1987) identical meanings and comprising and " controlled release transhipment " (" Controlled Drug Delivery ") (Robinson ﹠amp in the context; Lee, 1987) the identical scope of example described in.Can be with many other pH-sensitivity controlled release system (Robinson and Lee, 1987) substitutional crylic acid polymer or acrylamide and acrylic copolymers as known in the art.For example, solubility and anionic or insoluble crosslinked and anionic, cellulose family system; Or solubility and anionic or derive from the insoluble crosslinked and anionic polymer of any common acrylate copolymer and/or its derivant.The preferred crosslinked and insoluble polymer of this class is because their swellables and almost can not be by metabolism.

Preferred described controlled release system comprises the cross-linking of water-absorbing pill of pH-sensitivity, and at this moment, wet pill is a gel.

The present invention also provides the animal feed composition that comprises antimicrobial drug of the present invention and feedstuff.The content of antimicrobial drug is preferably the 0.0001-25% of total fodder compound and is preferably the 0.0001-5% of total fodder compound.

In another preferred embodiment, can prepare antimicrobial drug of the present invention so that it is joined in the animal drinking water.

Preferably give 0.05-5000mg/kg body weight/day, the more preferably antimicrobial drug of the present invention of 0.05-50mg/kg/ days consumptions.

The example of suitable inert carrier that is used to give the compositions of antimicrobial drug of the present invention comprises polyvinylacetate of water, olive oil, Oleum Arachidis hypogaeae semen (peanut), Oleum sesami, Oleum helianthi, safflower oil, Oleum Arachidis hypogaeae semen (arachis oil), Oleum Cocois, liquid paraffin, ethylene glycol, propylene glycol, Polyethylene Glycol, ethanol, propanol, isopropyl alcohol, glycerol, aliphatic alcohols, triglyceride, polyvinyl alcohol, partial hydrolysis and composition thereof.

Oral or rectally can contain on the medicine with solid dosage forms or acceptable binding agent, sweeting agent, disintegrating agent, diluent, flavoring agent, coating materials, antiseptic, lubricant and/or time dilation agent on the veterinary drug.Suitable bonding comprises Radix Acaciae senegalis, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethyl cellulose or Polyethylene Glycol.Suitable sweeting agent comprises sucrose, lactose, glucose or such as the such flavonoid glycoside of neohesperidin dihydrochalcone.Suitable disintegrants comprises corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.Suitable diluent comprises lactose, sorbitol, mannitol, dextrose, Kaolin, cellulose, calcium carbonate, calcium silicates or dicalcium phosphate.Suitable flavoring agent comprises Oleum menthae, wintergreen oil, Fructus Pruni pseudocerasi, orange or Fructus Rubi spice.Suitable coating materials comprises polymer or copolymer, wax, aliphatic alcohols, zein, lac or the glutelin of acrylic acid and/or methacrylic acid and/or its esters and/or its amide-type.Suitable antiseptic comprises sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl parahydroxybenzoate, propyl p-hydroxybenzoate or sodium sulfite.Examples of suitable lubricants comprises magnesium stearate, stearic acid, enuatrol, sodium chloride or Talcum.Suitable time dilation agent comprises glyceryl monostearate or glycerol distearate.

The suspensoid that is used for oral or rectally may further include dispersant and/or suspending agent.Suitable suspending agent comprises sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, sodium alginate Huo Whale ceryl alcohol.Suitable dispersant comprise lecithin, polyoxyethylene esters or fatty acid, such as the list of stearic acid, polyoxyethylene sorbitol-or two-oleate ,-stearate or-list of laurate, polyoxyethylene sorbitol acid anhydride-or two-oleate ,-stearate or-laurate etc.

The antimicrobial drug composition may further include one or more emulsifying agents.Suitable emulsifying agent comprises the dispersant as above enumerated or such as Radix Acaciae senegalis or the such natural gum of Tragacanth.

Can comprise fusion by being used for the compositions of administration in mode (such as veterinary drug and field of medicinal compositions) preparation the inventive method that is used for preparing compositions known in the art, grind, homogenize, suspension, dissolving, emulsifying, dispersion; And if be mixed with each other the polymer of theme of the present invention and excipient, diluent, carrier and the adjuvant of selection suitable comprising.

For oral administration, described medicine or animal medicinal composition can be for tablet, lozenge, pill, lozenge, capsule, elixir, powder, comprise the form of lyophilized powder, solution, granule, suspensoid, Emulsion, syrup and tincture.Can also preparation example such as the slow release of coated granule, multilayer tablet or particulate form or delay release dosage form.

General preferably gather (2-acrylic aldehyde, 2-acrylic acid) by poly-(2-acrylic aldehyde) preparation by oxidation solid in air.Beginning can be heated to poly-(2-acrylic aldehyde) polymer that mainly is the dry state form under 80-110 ℃.When more preferably beginning described polymer is heated under about 85 ℃.Preferably will gather (2-acrylic aldehyde, 2-acrylic acid) heated 1 hour-1400 hours in alcohol and more preferably 1 hour-60 hours time bar.

The preservative compounds or the compositions that comprise antimicrobial drug of the present invention have been the present invention further provides.

The disinfectant or the antimicrobial composition that comprise antimicrobial drug of the present invention have been the present invention further provides.

We provide the compositions of treatment gastrointestinal disease in another aspect of the present invention, and it comprises aforesaid antimicrobial drug polymer and another kind of chemotherapeutics, and wherein said another kind of chemotherapeutics is adsorbed on the described antimicrobial drug.

The film that this absorption generally can reduce described another kind of chemotherapeutics sees through.The suitable chemotherapeutics that is used for this embodiment is that the performance membrane sees through those chemotherapeutics that significantly reduce when mixing with described polymeric anti-microbial medicine.Preferably described see through is suppressed to original 50% at least.

The chemotherapeutics that is used for this aspect of the present invention comprises the antibiotic that is used for the treatment of gastrointestinal disease and is used for the treatment of the human primary gastrointestinal cancers anticarcinogen.

The film that chemotherapeutics and the coupling of polymeric anti-microbial medicine have reduced described chemotherapeutics sees through, and has reduced systemic side effects thus and the more therapy of targeting is provided.In many cases, abnormal smells from the patient also obtains reducing.

The example that is used for the treatment of the chemotherapeutics of gastrointestinal disease comprises antibiotic and anticarcinogen.

Can comprise Tetracyclines, penicillins, aminoglycoside, sulfonamides, cephalosporins and itrofurans with the antibiotic example of antimicrobial drug polymer coupling.

Antibiotic can be the common antibiotics that is used for the treatment of gastrointestinal infection.

Can be alkylating agent, antimetabolite, antitumor antibiotic, plant alkaloid, hormone and other anticarcinogen with the example of the anticarcinogen of antimicrobial drug polymer coupling, particularly only contain the anticarcinogen of carbon, hydrogen and oxygen.

Compositions of the present invention can also comprise one or more other antimicrobial drugs, such as the group that is selected from following ingredients: phenol (preferable amount is a 0.1-10% weight); Isothiazolidine ketone (preferable amount is 0.001-1%); Alkyl paraben (preferable amount is 0.02-2%); And low-level chain triacontanol (preferable amount is 20-99%), wherein said consumption is the weight based on composition weight.

The derivant that has been found that poly-(2-acrylic aldehyde, the 2-acrylic acid) that is used for the inventive method has the stability of remarkable increase than poly-(2-acrylic aldehyde, 2-acrylic acid) polymer.Owing to write down some unstability of poly-(2-acrylic aldehyde, 2-acrylic acid) in the prior art, descending as the activity of antimicrobial drug in its compositions is confirmed, so we are heating up, promptly carrying out " accelerated ageing " under 40 ℃.Yet, what make that we feel surprised most is, poly-(2-acrylic aldehyde " wears out " in aqueous solution or in water-polyglycol solution under 40 ℃ of intensifications, 2-acrylic acid) not only slowed down the reduction of antimicrobial acivity, and in fact show poly-(2-acrylic aldehyde, 2-acrylic acid) antimicrobial acivity definitely increases, referring to embodiment 2 (a) and (b).Prior art estimates that intensification should cause " accelerated ageing ", be that active acceleration of antimicrobial drug descends that this discovery of the present invention contradicts fully with prior art and be unexpected.

This paper comprises that by formation method that poly-(2-acrylic aldehyde, 2-acrylic acid) increases antimicrobial acivity at the polymer of the theme of the present invention of interior new configuration is called " superactivation " and these polymer are called " polymer of superactivation ".

Compared with prior art, more surprisingly the present inventor has been found that and uses alkali condition, uses acid condition can promote superactivation in the Polyethylene Glycol aqueous solution subsequently.In addition, promote superactivation by heating and moisture.

The existence of polyethylene glycols or polyalcohols or alkane alcohols can promote superactivation; we think, because Polyethylene Glycol that exists or polyhydric alcohol or alkane alcohols are by the alkaline bleach liquor degradation that forms acetals and prevented that Cannizaro reaction from causing and protection and stablized the carbonyl of described polymer.

Other advantage of superactivation is to have reduced or eliminated and can causes tissue and skin irritant pollutant acrylic aldehyde.

It is emphasized that superactivation with only very different and be, as result such as the polymer hydrophobic increase that confirms among the out of date Australian patent application AU-A-11686/95 (below be referred to as " 11686/95 ") to they replenish because of any antimicrobial acivity increase of in any moisture tested media, using more polymer to cause.Present inventor's strictness has repeated the method described in 11686/95, finds that then the superactivation subsequently of part soluble polymer has obviously increased other quite significant antimicrobial acivity.Also can't give from 11686/95 polymer solubility completely even should note superactivation, this result is opposite with the result who at first begins superactivation at 80-85 ℃ of following heated polymerizable thing.

The Best Times and the temperature that realize the superactivation of poly-(2-acrylic aldehyde, 2-acrylic acid) are inversely proportional to.Even obviously can be used for superactivation with at room temperature wearing out, especially when hydroxylic solvent and/or alkali being arranged, following the following time of situation that exists by acidity, these means may be unrealistic because of time limit needs long period.

The present inventor has been found that the superactivation polymer that is suitable for the gastrointestinal therapy described herein, has the advantage of the antimicrobial acivity of raising based on the product of water or the active component in the antiseptic in the method and disinfectant or the antibacterial.In addition, the present inventor finds that the antimicrobial acivity of this class disinfectant or antibacterial is being improved more than 6 by increasing its pH, for example pH.

General features of the present invention is to combine with antimicrobial drug of the present invention by hemiacetal/acetal formation or by the group that absorption allows to take place hydrophobic interaction and improves antimicrobial acivity.

Describe the present invention referring now to several embodiment, but these embodiment should not regard and are used for limiting scope of the present invention as.

The specific embodiment

The thing of killing livestock test

With the sodium bicarbonate aqueous solution sample dissolution of 1% weight to obtain desired concn (except as otherwise noted, concentration is the polymer of 0.125% weight).The 19.9g dilute sample is weighed into aseptic bottle also to wherein inoculating 10 of 0.1mL ⁷-10 ⁸The Pseudomonas aeruginosa of cfu (colony-forming units) also mixes.Change the sample that 1mL inoculates over to 9mL Letheen meat soup and vortex at concrete interval.Pave plate by 1: 10 serial dilution.To wherein toppling over tryptone bean peptone agar.Be incubated 3 days down at 37 ℃.

Embodiment 1

Present embodiment has been described the method by oxidation solid acrylic aldehyde polymer manufacture in air poly-(2-acrylic aldehyde, 2-acrylic acid).This poly-(2-acrylic aldehyde, 2-acrylic acid) is the raw material that preparation is used for the inventive method method for optimizing.In fume hood with water (720mL, under the ambient temperature, about 20 ℃) and acrylic aldehyde (60g; Recently distillatory, added hydroquinone to 0.25%w/w) put into the opening beaker and carry out mechanical agitation very tempestuously.Add 0.2M sodium hydrate aqueous solution (21.4mL) then and reach 10.5-11.0 to pH.

This solution becomes the anionic yellow of typical hydroquinone immediately and this color disappeared in a few minutes and this settled solution becomes emulsus.

After about 1 minute, white cotton-shaped polymer begins precipitation and just looks in 15-30 minute precipitation fully.With the washing of sedimentation and filtration and water (250mL), dry 2 days (output 25g) on filter paper at room temperature, then at glass dish upper berth straticulation and with heating down in 40 ℃/8 hours.Continue this heating according to following scheme: 50 ℃/15 hours; 65 ℃/4 hours; 75 ℃/18 hours; 84 ℃/24 hours.

Expectation can be amplified this method in proportion to comprise and for example progressively add acrylic aldehyde and dry more apace (comparing embodiment 10) subsequently in sealed container.

In general, in 15-30 minute time, in 1%w/w aqueous sodium carbonate (100mL), add the polymer of 2g theme of the present invention and dilute the solution for preparing gained poly-(2-acrylic aldehyde, 2-acrylic acid) then as required by stirring.This class solution is preferably clarifying-and opposite with the dissolving of using the polymer that derives from 11686/95 embodiment 5 to attempt to carry out.

Embodiment 2

Present embodiment has been described by poly-(2-acrylic aldehyde, 2-acrylic acid) and has been formed acetal.

(a) 5g poly-(2-acrylic aldehyde, 2-acrylic acid) is dissolved in 64g Polyethylene Glycol (" PEG ") 200 and merges with 31g 0.71%w/w sodium carbonate liquor.This solution of part (apparent pH=5.8) is kept at room temperature; Simultaneously

(b) will be from the remainder of the sample of part (a) 60 ℃ of following time limits of 12 or 25 days of heating.

Dilute from (a) and sample (b) and the thing of under the polymer concentration of 0.125%w/w, killing livestock test with the 1%w/w sodium bicarbonate.Surprisingly, the sample that carries out " accelerated ageing " shows the antimicrobial acivity of improvement, as can be viewed with reference to table 1:

Table 1

* colony-forming units/mL

1g poly-(2-acrylic aldehyde, 2-acrylic acid) is dissolved in 200mL 0.1%w/wNa ₂CO ₃And make that this system is stable spends the night.Add the sodium lauryl sulphate of 0.05%w/w concentration and this solution is acidified to pH 5.9 with HCl.Sample segment is stored under room temperature and 60 ℃.With the kill livestock thing test of 0.125%w/w polymer solution, use 1%w/w NaHCO ₃As diluent." wearing out " sample shows unexpected improvement on performance, as can be viewed with reference to table 2:

Table 2

* colony-forming units/mL

(c) polymer solution of the superactivation of preparation 5%w/w described in embodiment (2a), but replace PEG200 with PEG1000.To this solution-treated of part to pH 8.1 with dense NaOH.In 60 ℃ of following heated sample and the thing of killing livestock test.Make the more alkaline condition of sample contact, obtained the good thing characteristic of killing livestock unexpectedly, as can be viewed with reference to table 3;

Table 3

* colony-forming units/mL

Embodiment 3

The product that present embodiment has been checked poly-by making (2-acrylic aldehyde, 2-acrylic acid) obtains with the Polyethylene Glycol reaction.

Can be by check dialysis and concentrate the solid residue left over behind the described polymer solution, use proton ( ¹H) and carbon ( ¹³C) acetals that exists in NMR spectroscopic assay embodiment 2 (b) polymer.Dialysis has been removed all molecular weight and has been lower than 1000 material.Table 1 provide proton ( ¹H) and carbon ( ¹³C) NMR data.As can be viewed from table 1, the NMR (Nuclear Magnetic Resonance) spectrum of residue exists ¹The δ 3.58 of H NMR (Nuclear Magnetic Resonance) spectrum and 3.56 places and ¹³The δ 71.62,69.48 and 60.25 places of C NMR (Nuclear Magnetic Resonance) spectrum demonstrate the peak.These peaks represent that Polyethylene Glycol unit is combined into acetals.

Table 4

1%w/w Na from dialysis and concentrated back superactivation polymer solids residue ₂ CO ₃ Solution is at D ₂ 600MHz among the O ¹ H-and 125MHz ¹³ The data of C-NMR (Nuclear Magnetic Resonance) spectrum

Embodiment 4

(a) according to embodiment 2 (a) similarly mode prepare the polymer solution of 5%w/w of the apparent pH 5.7 of certain limit superactivation degree, but change the percentage ratio of PEG 200.

Monitor stability in time limit 60 ℃ of following heated sample and at certain hour.Think that because of precipitation or gelling occurring physical stability is defective.To the concentration that is dissolved in the 1%w/w sodium carbonate liquor is that the polymer of 0.01%w/w carries out UV and measures.With 268nm: the assimilation ratio at 230nm place reduces that to regard the implication that descends with chemical stability as identical.The result is as shown in table 5:

Table 5

Physics and UV spectral results confirm that PEG has positive effect to stability; PEG content is high more, and physics and activity stability are high more.

(b) by 4g poly-(2-acrylic aldehyde, 2-acrylic acid) is dissolved in 196g 1%w/w sodium bicarbonate and with rare HCl pH regulator to 7 (A) and 5.5 (B) is prepared following solution A and B.Prepare solution C by under 65-70 ℃, 50g poly-(2-acrylic aldehyde, 2-acrylic acid) being dissolved in PEG 200 (640g).Add the resulting solution of 4g sodium carbonate water-soluble (306g) then, apparent pH is 7, and handled at 31 days subsequently the time limit when finishing apparent pH be 5.5.

Whole samples are stored under 40 ℃.Make at interval at different time and to contain kill livestock thing test of the sample that equals the 0.125%w/w polymer.The result is as shown in table 6:

Table 6

Embodiment 5

In the dry or moist sealing chamber under 60 ℃ 1g poly-(2-acrylic aldehyde, 2-acrylic acid) was heated 3 days.The dry polymeric for preparing 0.125%w/w (moisture is calibrated) is respectively assessed them with the solution that adds wet polymer and by the thing test of killing livestock:

Table 7

* colony-forming units/mL

These polymer are at I.R.1700-1730cm ^-1Between demonstrate carbonyl and/or carboxyl and absorb, carbonyl (for example using Schiff (Schiff ' s) reagent) and have Mw=about 10000 and M _n=about 5000; Titration shows that carboxyl is about 5mol%.These parameters and the parameter similar (but inequality) of gathering (2-acrylic aldehyde, 2-acrylic acid).

Embodiment 6

In duplicate experiment, preparation polymer samples and then they are dissolved in second-glycol, definite step is as described in the embodiment 5 in 11686/95.With half of this material further 80 ℃ of following 24 hours (after this, the dissolving in aqueous medium are still incomplete) of heating.The kill livestock antimicrobial acivity of thing test comparative sample of use standard.By heating, be that the antimicrobial acivity that sample that superactivation is handled shows significantly improves, just as shown in table 8:

Table 8

* colony-forming units/mL

Embodiment 7

Under 65-70 ℃, 50g poly-(2-acrylic aldehyde, 2-acrylic acid) is dissolved in PEG200 (640g).Add the resulting aqueous solution of sodium carbonate (4g) water-soluble (306g) then.With sample separately and make them or keep at room temperature or 80 ℃ of heating 24 hours down.It is as shown in table 9 to measure the content and the result of acrylic aldehyde in this solution by reversed-phase HPLC within a certain period of time:

Table 9

Embodiment 8

Preparation gathers the solution of (2-acrylic aldehyde, 2-acrylic acid) and handles the different time time limit under 40,60,80,100 and 115 ℃ temperature as described in example 7 above.Make sample carry out standard kill livestock thing test with confirm killing rate and increase and the result as shown in table 10:

Table 10

The superactivation temperature (℃)	The Best Times scope (hour)	Always kill the time (minute)
			Room temperature	＞1400	＜10
40	1400	＜10
			60	120-170	＜10
80	16-24	＜10

The superactivation temperature (℃)	The Best Times scope (hour)	Always kill the time (minute)
			100	4-7	＜10
115	1-3	＜10

Observing required time of superactivation and temperature is inversely proportional to.The whole polymer solutions that derive from the superactivation method are fully easily miscible with aqueous solvent under all proportions.

Embodiment 9

(a) under 65 ℃, 540g poly-(2-acrylic aldehyde, 2-acrylic acid) is dissolved in 2304g PEG200, after this in 712g water, mixes with the 43.2g sodium carbonate.Then this solution is heated to 100 ℃ following 4 hours and add 36g sodium lauryl sulphate, 7g ECOTERIC T20 (non-ionic detergent) and 2g Fructus Citri Limoniae essence.Diluted by 1: 30 and use Association of Agricultural Chemists Official Methods of Analysis (1995) 991.47 with hard water these goods pH6,991.48, (Hard Surface Carrier Test Method) attacks staphylococcus aureus (Staphylococcus aureus) (gram positive bacteria respectively, infection in hospital is had particular importance) and Salmonella choleraesuls (Salmonella choleraesuis) (gram negative bacteria has particular importance to the infection in the food article field).The result is as shown in table 11:

Microorganism	Positive pipe	The result
			Staphylococcus aureus	2/60	By
Salmonella choleraesuls	1/60	By

As what monitored by the thing test of killing livestock, these goods are adjusted to higher pH has increased antimicrobial acivity.The result is as shown in table 12 (a) and 12 (b):

Table 12 (a)

Activity to staphylococcus aureus

Initial counting 3 * 10 ⁶Cfu/mL; Polymer 350ppm.

pH	10 minutes cfu/mL	10 minutes cfu/mL	30 minutes cfu/mL	45 minutes cfu/mL	60 minutes cfu/mL
						5.6	2.8×10 5	4.4×10 4	2.3×10 3	20	＜10
7.2	2.7×10 3	＜10	＜10	＜10	＜10
						8.9	3.2×10 3	＜10	＜10	＜10	＜10
10.5	1.1×10 2	＜10	＜10	＜10	＜10

Table 12 (b)

Initial counting 3.7 * 10 ⁶Cfu/mL; Polymer 350ppm.

pH	10 minutes cfu/mL	10 minutes cfu/mL	30 minutes cfu/mL	45 minutes cfu/mL	60 minutes cfu/mL
						5.6	2.9×10 5	8.6×10 4	6.2×10 2	40	＜10
7.2	5.8×10 5	9.1×10 4	4.3×10 3	＜10	＜10
						8.9	9.5×10 5	8.2×10 4	4.6×10 2	＜10	＜10
10.5	1.1×10 2	3.0×10 3	＜10	＜10	＜10

(b) under 60 ℃, 1200g poly-(2-acrylic aldehyde, 2-acrylic acid) is dissolved in 7680gPEG200 and adds 96g Na then ₂CO ₃Solution in 3024g water.This solution was heated 6 hours down at 100 ℃.

These goods are joined in the basin of forced draught formula cooling tower to concentration be 300ppm (30ppm polymer), 3 times/week.Before the operation of recommending, carry out administration at night so that be 8-12 hour time of contact; Estimate that the every operation of residual concentration then reduced by half in 3-6 hour.The mean temperature of recirculation water is 27 ℃, pH 8.5, electrical conductivity 3000 μ S.Measure microorganism count and compare with the adjacent tower that gives biological dispersant identical every day.The result is as shown in table 13:

Table 13

* colony-forming units/mL

Tables of data is managed step in the open microorganism count has been maintained AS/NZ standard 3666.3 (Int): in 1998 guides, and be lower than microorganism count in the adjacent towers that contains biological dispersant (not enough singularly in the condition of finding to require in very hot experimental period in summer).

Embodiment 10

10 (a) comparative example

Present embodiment has represented not use the preparation method of the acrylic aldehyde polymer of the inventive method.

1.0 0.8%w/w sodium hydroxide

The 9.90kg deionized water put into the 10L stainless steel cask and the 0.08kg sodium hydroxide is added to the water and is stirred to till the dissolving.

2.0 polymerization

The 100.1kg deionized water is put into the 200L stainless steel cask and the 0.8%w/w sodium hydroxide solution of 4.99kg is joined the 200L bucket.This solution of balance is to 15-20 ℃.Add 20kg acrylic aldehyde monomer simultaneously and in 1 hour, remaining 0.8%w/w sodium hydroxide solution is joined in the 200L bucket, make pH remain on 10.5-11.0 and temperature is no more than 30 ℃ with certain speed.Continue polymerization 90 minutes again.

3.0 washing

Filtration/centrifugal polymerization mixture also washs this polymer to the pH of washings with deionized water and to be lower than 7.0.Approximate output is 8kg.

4.0 it is dry

At the described polymer of air drying, use following steps then at the baking oven internal heating.

The step time-temperature

12 hours 25 ℃

21 hours 40 ℃

31 hours 70 ℃

41 hours 75 ℃

52 hours 85 ℃

5.0 dissolving

400L water is put into the 500L bucket and add the 4kg sodium carbonate and be stirred to dissolving.The polymer of slow adding 8kg dry heat also stirred 30 minutes.

Find that resulting polymers has the dissolubility of about 90-95%w/w in the 1%w/w sodium carbonate.

Embodiment 10 (b)

Present embodiment has been described the method for preparing the acrylic aldehyde polymer, wherein makes comparative example's polymer superactivation by method of the present invention.

1.0 the preparation of alkali

In appropriate vessel, the 0.4kg sodium carbonate is dissolved in 30.6kg water and the 64kg Macrogol 200 is put into this mixer.Use mechanical agitator to begin to stir and PEG200 is heated to 65 ± 3 ℃.To join among the PEG200 and be stirred to till the thing that is uniformly mixed by dried acrylic aldehyde polymer from the 5kg of embodiment 10a.

Attention: this solid may and not exclusively dissolve in this stage.

The speed that remains on the 3.5-9.0 scope with the pH that guarantees solution slowly joins sodium carbonate liquor in the ethylene glycol mixture.

Under 65 ± 3 ℃ with this solution stirring 45 minutes.

Attention: pH should be in the scope of 7-9.Temperature should be 65 ± 3 ℃ scope.

2.0 superactivation

Cover mixer and be heated to 100 ℃ to descend four (4) hours.Find that resulting polymers has the dissolubility of about 99.5-100%w/w in water.

Embodiment 11

Present embodiment has been checked the drying of embodiment 10a, the antimicrobial acivity of normal activatory poly-(2-acrylic aldehyde, 2-acrylic acid) polymer and the antimicrobial acivity of the superactivation acetal derivant described in the embodiment 10b.

Chicken and the matched group that to treat with described antimicrobial drug each time according to the following step compare:

In each test, 20 1 age in days Cob chickens (strain 53) are available from the commerce place of hatching.Weigh, tell sex and be randomized in the indoor adjacent fence in isolating animal room to them.Male and female chicken uniform distribution.Can arbitrarily obtain water and feedstuff.Meals are for containing the delicatessen food bits (Chick Starter, Milne Feeds:18% crude protein) of decoquinate (125ppm Whitsyn T).

Give aqueous solution preparation to 10 chickens by fixed water fountain, continue 14 days from the normal activatory antimicrobial drug of 0.1%w/w of embodiment 10a; Dosage is 30mg/kg/ days.Other 10 chickens are matched group.

Weighed for two groups of chickens at the 0th, 4,7,11 and 14 day.When this test is finished, whole chickens are implemented euthanasia and the chicken for the treatment of is carried out obduction after death.Thoracic cavity and abdominal cavity are totally checked completely.

The result:

Table 14a

In process of the test, use the body of the normal activatory antimicrobial drug increase of embodiment 10a Heavy

My god	Matched group (by the average weight of g)	Treatment group (by the average weight of g)	Difference between two groups (%)
				0	42.5	42.5	0
4	65.0	72.5	11.5
				7	98.5	98.0	-0.5
11	145.5	148.5	2.4
				14	185.5	200.5	8.1

When 14 day time limit finished, the weight increase that treatment group after measured has was greater than matched group.

When this test was finished, after the execution, this overall inspection of carrying out in chicken treatment group was found, does not observe toxic clinical or pathology disease.

Table 14b

The body weight that the antimicrobial drug of the superactivation of use embodiment 10b increases in process of the test

My god	Matched group (by the average weight of g)	Treatment group (by the average weight of g)	The difference of two groups of preparations (%)
				0	42.5	42.5	0
4	62.5	67.5	8

My god	Matched group (by the average weight of g)	Treatment group (by the average weight of g)	The difference of two groups of preparations (%)
				7	97.5	103	6
11	130	145	11.5
				14	178	219	23

When this test is finished, the overall inspection that two groups of after death remaining chickens carry out is found, do not observe clinical or the pathology disease.

Conclusion:

There is significant difference (χ in weight increase between treatment group and matched group ²P＜0.015).When this test was finished, the body weight of treatment group was higher than matched group 23%.

The acetal derivant of superactivation significantly improves aspect the weight increase than matched group, and in next embodiment, when comparing with normal activatory poly-(2-acrylic aldehyde, 2-acrylic acid), the remarkable improvement that shows acetal derivant intestinal antimicrobial acivity.

Embodiment 12

The polymeric anti-microbial medicine that present embodiment has been estimated embodiment 10b under the condition of farm to the control of the colibacillosis of pigs (PWC) after the wean.

Method:

Use at large-scale commerce pig house and to attack oral acceptance with the relevant pressure that weans and mix superactivation antimicrobial formulation in feedstuff or the water with long-term PWC problem history

(Elanco), autoinoculation or 146 young pigs [wean person] that both all do not carry out.

Estimate they suffer from diarrhoea, reaction aspect weight increase and the mortality rate and being recorded in the table 15.

Table 15

Attention:

1. treatment group #:

I.1 the polymeric anti-microbial medicine of the superactivation in the group=0.1%w/w feedstuff.

Superactivation polymeric anti-microbial medicine in the ii.2 group=0.02%w/v water.

2. die from the group percentage ratio of PWC in this process of the test.

3. the average natural law of every pig in when the feces of record must be divided into 1 or 2, organizing; Feces must be divided into the standard of measurement of the intensity of suffering from diarrhoea.

4. the feces score summation of every pig is divided by the quantity of observation sample.

5.F=Fisher accurately test.

Conclusion:

Following viewpoint has been given prominence in the test of this farm: the front reflection that the effect of the acetal derivant (antimicrobial drug of superactivation) of poly-(2-acrylic aldehyde, 2-acrylic acid) has when using the beta hemolysis escherichia coli to attack after wean to the piglets that is used for commercial pig house:

1. mortality rate:

With the mortality rate of the group of the polymeric anti-microbial medicine of superactivation treatment be lower than untreated, vaccination or

Group.

2. diarrhoea natural law:

The diarrhoea natural law of the polymeric anti-microbial medicine treatment group of superactivation significantly is less than [F; P＜0.0001] untreated, vaccination or Group.

3. feces score:

The average feces score of the group of the polymeric anti-microbial medicine treatment of superactivation significantly is lower than [F; P＜0.0001] untreated, vaccination or Group.

Embodiment 13

Present embodiment has been checked the effect of the antimicrobial drug of the present invention that uses some additive.

Method:

The meat soup and estimate viable count total in the overnight culture (TVC) of spending the night of culture is attacked in preparation.

Use physiological saline solution (5mL) by 1: 1 serial dilution sample.When specimen contains EDTA, aseptic hard water (SHW) is used as diluent.

With 1 part of each overnight culture of 9 parts of diluent dilutions.The dilution suspension of gained is used as inoculum.

Give the overnight culture of the dilution of each sample diluting liquid inoculation 100uL.(a kind of culture/pipe).Fully mix.

Test tube is incubated≤24 hours down at 37 ℃ (black aspergillosis (A.niger) is incubated≤24 hours down at 28 ℃).

Getting 1mL from every test tube goes down to posterity and cultivates into 9mL and recover (revovery) meat soup and fully mix and (recover (revovery) meat soup: polymeric anti-microbial medicine and EDTA are nutrient broth+3%Tween 80 (NBT); Glutaraldehyde is nutrient broth+3%Tween 80+0.1% ammonia (NBTA); And methyl parahydroxybenzoate is Letheen meat soup (LB)).

Sample further is incubated≤48 hours down at 37 ℃ (black aspergillosis is incubated≤5 days down for 28 ℃).

Check the growing state of every test tube.Upload to be commissioned to train at selection agar then and support whole test tube inclusions and be incubated≤24 hours down at 37 ℃.(black aspergillosis is incubated≤5 days down for 28 ℃).To select the growth on the agar to be used to confirm the test organisms bulk-growth.

The 5mL diluent that culture has been inoculated in use carries out positive control and is incubated, reclaims and verify.

Use nonvaccinated 5mL diluent to carry out negative control and be incubated, reclaim and verify.

Result: the result is depicted as following table.

Illustrate:

1) polymeric anti-microbial medicine 0.025%w/w

2) polymeric anti-microbial medicine 0.2%w/w

3) glutaraldehyde 0.025%w/w

4) polymeric anti-microbial medicine 0.025%w/w+ glutaraldehyde 0.025%w/w

5) polymeric anti-microbial medicine 0.2%w/w+ glutaraldehyde 0.025%w/w

6) polymeric anti-microbial medicine 0.2%w/w

7)EDTA 0.1％w/w

8) polymeric anti-microbial medicine 0.2%w/w+EDTA 0.1%w/w

9) polymeric anti-microbial medicine 0.2%w/w (being dissolved in 80%w/w glycerol)

10) methyl parahydroxybenzoate 1%w/w (being dissolved in 80%w/w glycerol)

11) polymeric anti-microbial medicine 0.2%w/w (being dissolved in 80%w/w glycerol)+methyl parahydroxybenzoate 1%wlw (being dissolved in 80%w/w glycerol).

Table 17

Index of cooperation with the polymeric anti-microbial medicine

Culture	Glutaraldehyde	EDTA	Methyl parahydroxybenzoate
				Black aspergillosis	＜0.6	＜0.5	0.2
The white candida mycoderma	0.3	0.1	0.5
				Escherichia coli	0.5	＜0.3	0.3
Pseudomonas aeruginosa	0.6	0.4	0.2
				Staphylococcus aureus	0.3	＜0.7	0.2

Attention: synergism＜1.0, adduction=1.0, antagonism＞1.0

SI=CD/A+CE/B thus

A=MKC polymeric anti-microbial medicine

The B=MKC antiseptic

The C=MKC mixture

The ratio of D=A and B

The ratio of E=B and A

Conclusion:

The acetal derivant of verified poly-(2-acrylic aldehyde, 2-acrylic acid) has synergism with glutaraldehyde, EDTA and methyl parahydroxybenzoate to black aspergillosis, white candida mycoderma, escherichia coli, Pseudomonas aeruginosa, staphylococcus aureus respectively.

Embodiment 14

Present embodiment confirms the activity of the antimicrobial drug coupling of antimicrobial drug of the present invention and " Dettol " trade mark.

Use physiological saline solution (5mL) by 1: 1 serial dilution sample.

Give the dilution overnight culture of each sample diluting liquid inoculation 100uL.(a kind of culture/pipe).Abundant biased sample.

They are incubated≤24 hours down at 37 ± 2 ℃.(will inoculate the aspergillar test tube of black and be incubated≤24 hours down) at 28 ± 2 ℃.

Getting 1mL from every test tube goes down to posterity and cultivates 9mL and reclaim meat soup and abundant vortex (for black aspergillosis NBT or Sabouraud+3% Tween 80 (SABT)).

They are incubated≤48 hours down at 37 ± 2 ℃.(black aspergillosis is incubated 5 days again under 28 ± 2 ℃).

Check is reclaimed the turbidity (growth) of meat soup and is rule to confirm growth on selection agar.

Table 18

MKC result in superactivation polymeric anti-microbial medicine and/or " Dettol " of ppm

Culture	Inoculum is (cfu/mL) approximately	Polymeric anti-microbial medicine MKC scope (ppm)	1	2	3	4	5
								Black aspergillosis	4.1×10 7	2000-500	N/A	1000	300	N/A	125∶150
The white candida mycoderma	5.2×10 6	100-250	N/A	500	75	N/A	62.5∶75
								Escherichia coli	7.6×10 8	125-31	125	N/A	75	31∶75	N/A
Pseudomonas aeruginosa	1.8×10 9	250-62.5	N/A	250	600	N/A	125∶150
								Staphylococcus aureus	2.0×10 9	31-7	N/A	15	75	N/A	15∶19

Explanation

1) 0.1%w/w polymeric anti-microbial medicine

2) 0.2%w/w polymeric anti-microbial medicine

3) " Dettol " 4.8%w/v (by dilution in 1: 20)

4) 0.1%w/w polymeric anti-microbial medicine+" Dettol " (by dilution in 1: 20)

5) 0.2%w/w polymeric anti-microbial medicine+" Dettol " (by dilution in 1: 20)

Table 19

The index of cooperation of polymeric anti-microbial medicine and Dettol

Culture	Index of cooperation (SI)
		Black aspergillosis	0.3
The white candida mycoderma	0.6
		Escherichia coli	0.6
Pseudomonas aeruginosa	0.4
		Staphylococcus aureus	0.6

Attention: if SI＞1 then is an antagonism; If SI=1 then is adduction; If SI＜1 then is a synergism.

SI＝CD/A+CE/B

A=MKC polymeric anti-microbial medicine (ppm)

B＝MKC Dettol(ppm)

The MKC (ppm) of C=polymeric anti-microbial medicine/" Dettol " mixture

The ratio of D=polymeric anti-microbial medicine and Dettol

The ratio of E=" Dettol " and polymeric anti-microbial medicine

Attention: using the active antimicrobial drug of " Dettol " trade name is to chloroxylenol

Conclusion:

Verified polymeric anti-microbial medicine of the present invention has synergism with " Dettol " to escherichia coli, staphylococcus aureus, Pseudomonas aeruginosa, white candida mycoderma and black aspergillosis.This result shows that " Dettol " and polymeric anti-microbial medicine role as the mixed solution coupling time are better than their roles separately basically.

Embodiment 15

The antibacterial characteristics of poly-(2-acrylic aldehyde, 2-acrylic acid) [superactivation]

Follow the tracks of the antibacterial characteristics of antimicrobial drug poly-(2-acrylic aldehyde, 2-acrylic acid) [superactivation].

Before and after using antimicrobial drug, measure the bacterial number that the experimenter exists on hand, be with the operation glove subsequently.The antibacterial action that will gather (2-acrylic aldehyde, 2-acrylic acid) [superactivation] compares with operation antibacterial 4% chlorhexidine surgical scrub commonly used (by being positioned at Perth, the Orion Laboratories of Western Australia produces).

Poly-(2-acrylic aldehyde, 2-acrylic acid) [superactivation] aqueous solution of 3%w/w has reduced the band glove baseline counts of flora on hand after 3 hours.

Contain poly-(2-acrylic aldehyde, 2-acrylic acid) [superactivation] aqueous solution of 70% alcoholic acid 2%w/w made the band glove after 3 hours the slow continuous decrease of baseline count of bacteria on hand, as using 4% chlorhexidine role.

Operation is with using poly-(the 2-acrylic aldehyde of the 3.2%w/w that contains 3.1% sodium lauryl sulphate on hand before the glove on tape, 2-acrylic acid) [superactivation] aqueous solution, the 70% alcoholic acid aqueous solution of following by 4%w/w poly-(2-acrylic aldehyde, 2-acrylic acid) [superactivation] made the baseline count of bacteria significantly reduce after 3 hours.

These results show poly-(2-acrylic aldehyde, 2-acrylic acid) [superactivation] has the required good residue antimicrobial acivity of bacterial number in the Sustainable Control aseptic operation.Comprise in the preparation when 70% ethanol helps bacterial number to begin and reduce fast.

Embodiment 16

0.125%w/w and 0.05%w/w superactivation polymer are in pH 7 and 4 times biocidal activity to reference bacterial strain helicobacter pylori NCTC 11637 of pH.

At first set up the external effect of superactivation polymer to helicobacter pylori reference bacterial strain helicobacter pylori NCTC11637.As variable, select two kinds of concentration; A kind of is 40 times of diluents of 5% superactivation polymer solution of preparation among the embodiment 2, obtains the superactivation polymer of 0.125%w/w concentration, the diluent in the simulation stomach; Another kind is a 100-times of diluent, obtains the superactivation polymer of 0.05%w/w concentration.Select two kinds of pH, as the pH 7 of baseline and the pH 4 that simulates condition in the stomach.

Culture helicobacter pylori NCTC11637 is being grown on the selection agar plate, up to observing the capacity growth under 37 ± 2 ℃ in little aerobic mode.Take out growth-gen and make muddy suspension from flat board with sterile manner, as what on the Vitek tintometer, show with the standardization 10%T of physiological saline solution dilution.Weigh up the 19.9g sample and inoculate 100 μ L culture suspensions.Immediately the 1mL sample is changed over to inactivation/recovery meat soup (nutrient broth+3%Tween80) and serial dilution then.100 μ L aliquots are placed select on the agar plate and use disposable sterilized spreader to be coated with exhibition.Interval repetitive displacement step at 5,10,15 and 20 minutes.To all dull and stereotypedly under 37 ± 2 ℃, be incubated to obtaining enough growths (about 5-7 days) in little aerobic mode.To all colony countings and measure the minimizing quantity of flora to the time.Use physiological saline solution to repeat this test so that be determined at the ratio of death progressively naturally air conditions under as sample.

Illustrate:

The polymer of culture 1. superactivations, pH 7,0.125%w/w.

The polymer of culture 2. superactivations, pH 7,0.05%w/w.

The polymer of culture 3. superactivations, pH 4,0.125%w/w.

The polymer of culture 4. superactivations, pH 4,0.05%w/w.

Culture 5. physiological saline solution, pH7.

Culture 6. physiological saline solution, pH4.

Table 20

CHEMEQ ^RTM The polymeric anti-microbial medicine is to helicobacter pylori (NCTC 11637) Biocidal activity

Culture	T=0 minute	T=5 minute	T=10 minute	T=15 minute	T=20 minute
						1	1.0×10 5	8.6×10 3	1.0×10 2	＜1.0×10 2	＜1.0×10 2
2	1.6×10 5	2.0×10 3	4.0×10 2	1.0×10 2	＜1.0×10 2
						3	1.0×10 5	3.2×10 4	1.1×10 4	4.0×10 2	＜1.0×10 2
4	3.0×10 4	1.7×10 4	1.1×10 4	8.2×10 3	3.6×10 3
						5	2.0×10 5	1.0×10 5	9.2×10 5	8.0×10 4	7.9×10 4
6	2.0×10 4	1.4×10 4	8.0×10 3	6.0×10 3	6.0×10 3

Attention: in the counting of colony-forming units (cfu)/mL inactivation meat soup

The polymer that result's (table 20) of reference bacterial strain is confirmed superactivation under pH 7 and 0.125%w/w and 0.05%w/w effectively and also under pH 4 and 0.125%w/w effectively.

Embodiment 17

For embodiment 16 is further analyzed, check other three kinds of helicobacter pylorus bacteria strains for 4 times at pH 7 and pH: Nike draws the helicobacter pylori 01/303 of mycin and metronidazole; Isolating clinical strains helicobacter pylori SS1 with ability that the influential height of possible animal model is settled down in Sydney; Sequenced genes group and derive from the bacterial strain helicobacter pylori ATCC 700392 of UK.

Table 21

The biocidal activity of the polymer of superactivation under 0.125%pH 7

Culture	T=0 minute	T=5 minute	T=10 minute	T=15 minute	T=20 minute
						Matched group helicobacter pylori 11637	2.0×105	1.0×105	9.2×105	8.0×104	7.9×104
Helicobacter pylori 11637	1.0×105	8.6×103	1.0×102	＜1.0×102	＜1.0×102
						Helicobacter pylori 01/303	3.6×105	2.8×103	＜1.0×10	＜1.0×102	＜1.0×102
Helicobacter pylori SS1	2.8×105	1.4×103	2.0×102	＜1.0×102	＜1.0×102
						Helicobacter pylori 700392	2.0×106	1.3×106	1.8×105	8.8×103	＜1.0×102

When with the polymer of superactivation when 0.125%w/w and pH handle for 7 times, all bacterial strains are all killed fast, wherein strains is easy at 10 minutes especially with interior death (table 21).The matched group bacterial strain is unprocessed.

Embodiment 18

Repeat the method for embodiment 3 and test the biocidal activity of the polymer (pH 4) of 0.125%w/w superactivation all bacterial strains of helicobacter pylori.

Table 22

The biocidal activity of the polymer of superactivation under 0.125%pH 7

Culture	T=0 minute	T=5 minute	T=10 minute	T=15 minute	T=20 minute
						Matched group helicobacter pylori 11637	2.0×10 4	1.4×10 4	8.0×10 3	6.0×10 3	6.0×10 3

Culture	T=0 minute	T=5 minute	T=10 minute	T=15 minute	T=20 minute
						Helicobacter pylori 11637	1.0×10 5	3.2×10 4	1.1×10 4	4.0×10 2	＜1.0×10 2
Helicobacter pylori 01/303	4.2×10 6	1.1×10 6	5.0×10 4	2.0×10 4	2.0×10 2
						Helicobacter pylori SS1	4.9×10 6	1.0×10 6	1.0×10 5	2.8×10 4	2.0×10 2
Helicobacter pylori 700392	5.5×106	1.9×10 6	1.2×10 5	3.6×10 4	＜1.0×10 2

Test superactivation polymer under the condition of pH 4 that simulates stomach and 0.125%w/w, all bacterial strains were killed (table 3) in 20 minutes as a result.This result is significant, because this time range that kills and wounds helicobacter pylori is than the time short (40 minutes-1 hour) by stomach.The effectiveness of the polymer that this result confirms superactivation under the pH consistent, concentration and in the time range with helicobacter pylori infections in the treatment stomach.The matched group bacterial strain is undressed.

Embodiment 19

Present embodiment confirms the intestinal antimicrobial acivity according to poly-(2-acrylic aldehyde, 2-acrylic acid) acetal derivant of the step preparation of embodiment 10b.

Material and method:

The pig of 16 wean (age: 18 days ± 2 days; And body weight is: 5.5kg ± and 1.0kg) available from commercial pig house.They are divided into 2 groups at random, and 8 every group pigs (sex is evenly distributed) are also closed in the isolating animal housing of controlled environment.

But the pill [19% crude protein] that animal ad libitum access and drinking-water and meals when entering animal housing are used for the commodity wean person who does not contain antimicrobial drug.

By the intravenous injection barbital sodium pig of whole wean is implemented euthanasia and carries out obduction then.Use Qiagen Dneasy to organize test kit, from the harmonization of the stomach esophagus district of the stomach of 24 wean pigs, extract DNA according to the explanation that provides.The DNA that 3uL is extracted is used for testing the kind that there is Helicobacterium in the biopsy sample.Each sample is carried out twice polymerase chain reaction (PCR), in PCR test each time, comprise 7 parts of contrast DNA samples.Discovery is zero difference between the PCR that carries out.

The result:

The numbering of treatment:

Group 1: not treatment (negative control)

The superactivation polymeric anti-microbial medicine of group 2:0.1%w/v embodiment 10b; 30mg/kg/ days.

Table 23

The PCR knot that uses optimized in advance genus Auele Specific Primer that the Helicobacterium kind is carried out Really, wherein+representative is to the positive test symbol of Helicobacterium kind, and-representative detects.

Group number	The gastric area	The esophagus district
			1	-	-
1	-	+
			1	-	+
1	+	-
			1	-	-
1	-	+
			1	-	-
1	-	+
			2	-	-
2	-	-
			2	-	-
2	-	-
			2	-	-
2	-	-
			2	-	-
2	-	-

In group 1 (not treatment), there are 5 positive PCR result (1-stomaches in the Helicobacterium kind; The 4-esophagus), in group 2 (the polymeric anti-microbial medicines of 0.1%w/v), there is not positive PCR result.

Conclusion:

The acetal derivant of 0.1%w/v poly-(2-acrylic aldehyde, 2-acrylic acid) is (x significantly ²: P＜0.025) reduced the incidence rate of pig Helicobacterium in the harmonization of the stomach mucous membrane of esophagus of wean pig.

Embodiment 20

Comparative example 20 (a)

Present embodiment is represented the not preparation method of poly-(2-acrylic aldehyde, the 2-acrylic acid) of superactivation.

The 0.8%w/w sodium hydroxide

The 9.90kg deionized water is put into 10L stainless steel cask and Xiang Shuizhong to add the 0.08kg sodium hydroxide and is stirred to dissolving.

Polymerization

The 100.1kg deionized water put into the 200L stainless steel cask and add the 0.8%w/w sodium hydroxide solution of 4.99kg to the 200L bucket.This solution of balance is to 15-20 ℃.Add 20kg acrylic aldehyde monomer simultaneously and in 1 hour, remaining 0.8%w/w sodium hydroxide solution is joined in the 200L bucket, make pH remain on 10.5-11.0, and temperature is no more than 30 ℃ with certain speed.Continue polymerization 90 minutes again.

Washing

Filtration/centrifugal polymerization mixture also washs this polymer to the pH of washings with deionized water and to be lower than 7.0.Output is about 8kg.

Dry

At the described polymer of air drying, use following steps then at the baking oven internal heating.

The step time-temperature

12 hours 25 ℃

21 hours 40 ℃

31 hours 70 ℃

41 hours 75 ℃

52 hours 85 ℃

Dissolving

400L water is put into the 500L bucket and add the 4kg sodium carbonate and be stirred to dissolving.The polymer of slow adding 8kg dry heat also stirred 30 minutes.

Find that resulting polymers has the dissolubility of about 90-95%w/w in the 1%w/w sodium carbonate.

Embodiment 20 (b)

Present embodiment has been described the preparation method of acrylic aldehyde polymer, and wherein comparative example's 20 (a) polymer is by superactivation.

The preparation of alkali

In appropriate vessel, the 0.4kg sodium carbonate is dissolved in 30.6kg water and the 64kg Macrogol 200 is put into this mixer.Use mechanical agitator to begin to stir and with PEG200 heat to 65 ± 3 ℃.To join among the PEG-200 and be stirred to till the thing that is uniformly mixed by dried acrylic aldehyde polymer from the 5kg of embodiment 20a.

Attention: this solid may and not exclusively dissolve in this stage.

The speed that remains on the 3.5-9.0 scope with the pH that guarantees solution slowly joins sodium carbonate liquor in the ethylene glycol mixture.

Under 65 ± 3 ℃ with this solution stirring 45 minutes.

Attention: pH should be in the scope of 7-9.Temperature should be 65 ± 3 ℃ scope.

Superactivation

Cover the container of contain mixtures and be heated to 100 ℃ to descend four (4) hours.Find that gained superactivation polymer can be miscible with all proportions and water.

Embodiment 21

In the embodiment 14 of PCT/AU9600328, confirm that poly-(2-acrylic aldehyde, 2-acrylic acid) polymer is dissolved in the resulting solution of 0.5%w/w sodium carbonate liquor the Paul Ehrlich in the mouse model (Ehrlich) ascites cells cording is had active anticancer.

The active anticancer of the active anticancer of poly-(2-acrylic aldehyde, 2-acrylic acid) polymer [embodiment 20 (a)] and the polymer [embodiment 20 (b)] of superactivation.CCL188 HT-29 is set up external human primary gastrointestinal cancers model.Form with the 5%w/w concentrate is used poly-(2-acrylic aldehyde, 2-acrylic acid).Used test is incubated the polymer of cancerous cell with variable concentrations and obtain determining IC ₅₀Curve.

Method

HT-29 cell (human colon cancer cell) inoculation (with 100ul) is gone in each holes of 96 hole culture plates and down and humidification 5%CO at 37 ℃ ₂, incubated overnight in 95% air.Polymer [polymer of superactivation among poly-(2-acrylic aldehyde, 2-acrylic acid) polymer among the comparative example 20 (a) and the embodiment 20 (b)] is water-soluble and become 10 concentration of 4-log scope then with medium.Subsequently each solution of 100ul is joined in each in 5 holes.Flat board is incubated 72 hours again, after this uses cell (Skehan etc., the 82:1107-1112 of (1990) " international cancer EASD " (J.Nat.Cancer Inst.) of sulforhodamine B test determination survival; Monks etc., the 83:757-766 of (1991) " international cancer EASD " (J.Nat.Cancer Inst.).)。With 10% cold trifluoroacetic acid cell is fixed 1 hour and used the distilled water flushing flat board under 4 ℃ then, keep air-dry and use 1% acetic acid (v/v) solution-dyed 30 minutes of 0.4% sulforhodamine B (Aldrich) then.Then by with twice of distilled water wash and finally wash and remove unconjugated dyestuff with 1% acetic acid.Dyestuff with protein bound is dissolved in the not buffered Tris alkali of 10mM and uses automatic plate reader to read trap at the 550nm place subsequently.The average absorption of each drug dose is expressed as the percentage ratio that accounts for trap in the untreated control wells.

Test result is as shown in Table 24.

The average IC that poly-(2-acrylic aldehyde, 2-acrylic acid) polymer of comparative example 20 (a) obtains in twice test ₅₀Be 0.030%; To gather (2-acrylic aldehyde, 2-acrylic acid) polymer and be decided to be 100% value.Convert thereof into the living polymer of 0.0015%w/w.

The average IC that the polymer of comparative example's 20 (b) superactivation obtains in four tests ₅₀Be 0.025%.Convert thereof into the superactivation polymer of 0.0015%w/w and show that the polymer of superactivation has active anticancer.

Table 24

CHEMEQ ^RTM The polymeric anti-microbial medicine is to the IC of HT-29 human colon cancer cell ₅₀

Test compounds	Medicine time of contact (hour)	IC 50(％)	Average IC 50(％ w/w)	Average IC 50(being the %w/w of living polymer)
					Comparative example 20 (a)	72	0.037，0.023	0.030	0.0015
Comparative example 20 (b)	72	0.017，0.034， 0.025，0.023	0.025	0.00125

IC ₅₀Be that cell growth inhibiting reaches 50% required concentration.

At last, should understand the essence of the present invention that to carry out various other modifications and/or change and can not break away from this paper general introduction.

Claims (29)

1. following polymers is used for the treatment of or prevents to comprise application in people's the medicine of amimal gastroenteropathy in preparation, described polymer comprises by poly-(2-acrylic aldehyde, 2-acrylic acid) generate the derivant of gathering (2-acrylic aldehyde, 2-acrylic acid) of being protected carbonyl and forming with the organic compound reaction that contains one or more hydroxyls.

2. the application of claim 1, wherein said medicine are oral drugs.

3. the application of claim 1, wherein said animal suffer from the gastrointestinal disease of the not enough group of forming of at least a weight increase that is selected from gastroenteritis, ulcer, diarrhoea and human primary gastrointestinal cancers and causes because of dysentery.

4. the application of claim 1, wherein said animal suffer from least a disease in diarrhoea, gastroenteritis and the dysentery.

5. the application of claim 1, wherein said animal are selected from the group that Canis familiaris L., pig, sheep, horse, cattle, cat and poultry are formed.

6. the application of claim 1, wherein said animal are selected from ruminant and described medicine is the rectal application thing.

7. the application of claim 1, wherein said animal is selected from poultry and pig.

8. the application of claim 1, wherein said animal are the pig of part growth.

9. the application of claim 1 is the application in the oral drugs of colibacillosis after the pig wean that is used for the treatment of in preparation or prevents to take place in the young piglet of wean back.

10. the application of claim 1, wherein said gastrointestinal disease causes because of one or more microorganisms, and these microorganisms are selected from the group that coliform group, Salmonella, Pseudomonas aeruginosa, Helicobacterium, proteus, enterobacteria class, yeast, protozoacide, Clostridium, Shigella and Globidium are formed.

11. following polymers preparation be used for the treatment of or the medicine of the gastroenteropathy that prevents to cause because of helicobacter infection in application, described polymer comprises by poly-(2-acrylic aldehyde, 2-acrylic acid) and the reaction that contains between the organic compound of one or more hydroxyls generate poly-(the 2-acrylic aldehyde that is protected carbonyl and form, 2-acrylic acid) derivant, the described organic compound that contains one or more hydroxyls is selected from alkane alcohols, phenols, polyalcohols and composition thereof.

12. the application of claim 1, wherein said gastrointestinal disease are because of at least a the causing in enterotoxigenic Escherichia coli and the beta hemolysis escherichia coli.

13. the application of claim 1, described medicine are used for the treatment of or prevent avian necrotic enteritis.

14. the application of claim 1, wherein said polymer comprise absorption thereon another kind of chemotherapeutic and the film that reduces this another kind chemotherapeutic thus see through.

15. following poly-(2-acrylic aldehyde, 2-acrylic acid) derivant is used for the treatment of or prevents application in the medicine of coccidiosis of domestic fowls in preparation, described poly-(2-acrylic aldehyde, 2-acrylic acid) derivant is protected carbonyl by poly-(2-acrylic aldehyde, 2-acrylic acid) with the organic compound reaction generation that contains one or more hydroxyls to form.

16. the application of claim 1, the derivant of wherein said poly-(2-acrylic aldehyde, 2-acrylic acid) contains a plurality of at least a quilts that are selected from hemiacetal group and the acetal radical and protects carbonyl.

17. the application of claim 16 is wherein saidly protected carbonyl and is comprised acetal radical.

18. the application of claim 1, wherein said organic compound is selected from alkane alcohols, phenols, polyalcohols and composition thereof.

19. the application of claim 18, wherein said organic compound is selected from least a polyhydric alcohol.

20. the application of claim 19, wherein said polyhydric alcohol comprises poly alkylene glycol.

21. the application of claim 20, wherein said polyhydric alcohol comprises Polyethylene Glycol.

22. the application of claim 20, wherein said polyhydric alcohol are the Polyethylene Glycol of molecular weight at 200-2000.

23. be used for by give the antimicrobial compositions of described antimicrobial compositions treatment or prevention amimal gastroenteropathy through gastrointestinal, comprise by poly-(2-acrylic aldehyde, 2-acrylic acid) and contain reaction between the organic compound of one or more hydroxyls and generate the derivant of poly-(2-acrylic aldehyde, the 2-acrylic acid) that protected carbonyl and form and be used for animal is carried out acceptable inert carrier on the medicine of gastrointestinal administration or the veterinary drug.

24. the antimicrobial compositions that is used for the treatment of or prevents gastrointestinal disease of claim 23, the carrier that wherein is used for the gastrointestinal administration is selected from the group that polyvinylacetate of water, controlled release polymer, olive oil, Oleum Arachidis hypogaeae semen, Oleum sesami, Oleum helianthi, Oleum Arachidis hypogaeae semen, Oleum Cocois, liquid paraffin, ethylene glycol, propylene glycol, Polyethylene Glycol, ethanol, propanol, isopropyl alcohol, glycerol, aliphatic alcohols, triglyceride, polyvinyl alcohol, partial hydrolysis and composition thereof is formed.

25. the antimicrobial compositions of claim 24 is the form of feed additive or drinking water, described additive comprises the derivant of described poly-(2-acrylic aldehyde, the 2-acrylic acid) of 0.1-70% weight.

26. animal feed or human food or drinking water composition comprise the antimicrobial compositions of the claim 23 of feedstuff or food substance or water and antimicrobial effective dose.

27. the animal feed composition of claim 26, wherein the content of antimicrobial compositions is the 0.0001-25% of total feedstuff or food or water composition weight.

28. antimicrobial compositions comprises the antimicrobial compositions of claim 23 and the activating agent that another kind is selected from the group of antimicrobial drug and chemotherapeutics composition.

29. the compositions of claim 28, wherein said another kind of antimicrobial drug comprise at least a (in the weight of said composition) in the following ingredients:

(a) phenol of 0.1-10% consumption;

(b) the isothiazolidine ketone of 0.001-1% consumption;

(c) alkyl paraben of 0.02-2% consumption; With

(d) low-level chain triacontanol of 20-99.9% consumption.