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WO2003061672A1 - Procede de traitement de troubles gastro-intestinaux et composition polymerique a cet usage - Google Patents

Procede de traitement de troubles gastro-intestinaux et composition polymerique a cet usage Download PDF

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Publication number
WO2003061672A1
WO2003061672A1 PCT/AU2003/000039 AU0300039W WO03061672A1 WO 2003061672 A1 WO2003061672 A1 WO 2003061672A1 AU 0300039 W AU0300039 W AU 0300039W WO 03061672 A1 WO03061672 A1 WO 03061672A1
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WO
WIPO (PCT)
Prior art keywords
antimicrobial
propenal
polymer
poly
propenoic acid
Prior art date
Application number
PCT/AU2003/000039
Other languages
English (en)
Inventor
Graham John Hamilton Melrose
Andrew James Huxham
Damon Matthew Goadby Tilbrook
Vincent Leonard Wycoco
Original Assignee
Chemeq Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/053,088 external-priority patent/US7629002B2/en
Priority claimed from AUPS3271A external-priority patent/AUPS327102A0/en
Priority to CA2472685A priority Critical patent/CA2472685C/fr
Priority to AU2003201209A priority patent/AU2003201209B2/en
Priority to BR0306960-5A priority patent/BR0306960A/pt
Priority to CN038023873A priority patent/CN1617733B/zh
Application filed by Chemeq Ltd filed Critical Chemeq Ltd
Priority to EA200400965A priority patent/EA015165B1/ru
Priority to NZ533811A priority patent/NZ533811A/en
Priority to MXPA04007005A priority patent/MXPA04007005A/es
Priority to JP2003561616A priority patent/JP4732691B2/ja
Priority to KR1020047011132A priority patent/KR100971520B1/ko
Priority to EP03731608A priority patent/EP1474155A4/fr
Publication of WO2003061672A1 publication Critical patent/WO2003061672A1/fr
Priority to HK05108595.7A priority patent/HK1076602A1/xx

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • the present invention relates to treatment or prophylaxis of gastrointestinal disease and promotion of animal growth and to antimicrobial compositions for use in such treatments.
  • Antimicrobials are compounds which kill microorganisms, such as bacteria. Antibiotics are a subset of antimicrobials that are (usually) derived from other microorganisms and work by interfering with specific mechanisms within the target microorganism. Antibiotics were first used in the 1940s and 1950s and their use has increased ever since. The development of antibiotic resistance has become a serious and potentially life threatening event worldwide. Some strains of Staphylococcus have shown resistance to almost all antibiotics and have had fatal infection occurring in hospitals. Other drug resistant organisms include pneumococci that cause pneumonia and cryptosporidium and E.coli which cause diarrhoea.
  • antibiotics in animal feed is widely considered to be responsible for the accelerated development of resistance and as a result many countries control their use. This has lead to problems in animal farming resulting in difficulty in controlling disease and obtaining optimum growth rates. This is a particular problem in farming of pigs and poultry. For example, gastrointestinal diseases such as colibacillosis in pigs and coccidiosis in poultry can have a devastating effect.
  • European publication No. 792895 Werle et al. (corresponding to US 6060571) relates to acrolein releasing polymers prepared by copolymerisation of acrolein monomer and a polyhydric alcohol.
  • Werle et al. observes that the polyacroleins described in German Application No. P4404404 are problematic in that the yield is less than desired and the polymers are virtually insoluble in water.
  • European Application 792895 teaches that these problems are overcome by forming an acrolein releasing polymer by copolymerisation of acrolein monomer and a polyhydric alcohol monomer.
  • the proposed structure of the copolymer is as follows:
  • the invention provides a method of treatment or prophylaxis of gastrointestinal disease in an animal (including humans) comprising administering to the animal an effective amount of a derivative of poly(2-propenal, 2-propanoic acid) formed by reaction between poly(2-propenal, 2-propenoic acid) and an organic compound containing one or more hydroxyl groups such as an alcohol preferably selected from alkanols, phenols, polyols and mixtures thereof, to form protected carbonyl groups.
  • a derivative of poly(2-propenal, 2-propanoic acid) formed by reaction between poly(2-propenal, 2-propenoic acid) and an organic compound containing one or more hydroxyl groups
  • an alcohol preferably selected from alkanols, phenols, polyols and mixtures thereof, to form protected carbonyl groups.
  • the invention provides an antimicrobial for treatment of gastrointestinal disease comprising 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 such as an alcohol preferably selected from alkanols, phenols, polyols and mixtures thereof, to form protected carbonyl groups.
  • 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 such as an alcohol preferably selected from alkanols, phenols, polyols and mixtures thereof, to form protected carbonyl groups.
  • polyol as used herein means a molecule containing at least two hydroxyl groups.
  • the derivatives formed are typically selected from hemiacetal and acetal derivatives.
  • the reaction of the poly(2-propenal, 2-propenoic acid) with the alcohol forms hemiacetal and/or acetal groups from at least a proportion of the pendent aldehyde groups thereby stabilising the carbonyl groups of the polymers against alkaline degradation by the Cannizzaro reaction.
  • the formation of acetal groups has been found to significantly reduce or eliminate the release of free acrolein while surprisingly increasing the activity of the resulting derivative.
  • the invention provides the use of the above described antimicrobial for preparation of a medicament for treatment or prophylaxis of gastrointestinal disease.
  • the antimicrobial of the invention may be prepared by heating poly(2-propenal, 2-propenoic acid) in the presence of the alcohol, preferably a polyol such as polyethylene glycol.
  • the 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 assists in the nucleophilic reaction resulting in hemiacetal or acetal formation.
  • the solution is generally heated at a temperature in the range of from 40°C to 150°C, more preferably 40 to 115°C and most preferably 70 to 115°C.
  • the antimicrobial of the invention 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) the contents of which are herein incorporated by reference.
  • the poly(2-propenal, 2- propenoic acid) polymers are preferably prepared by polymerisation of acrolein preferably in aqueous solution by anionic polymerisation, followed by autoxidation.
  • the polymers contain the repeating unit of formula I and at least one (and typically a mixture) of the hydrated, hemiacetal and acetal forms.
  • the hydrated, hemiacetal and acetal forms formed by polymerisation of acrolein are known to arise from the various carbon-carbon and carbon-oxygen polymerisation mechanisms of acrolein.
  • the hydrated form is typically the hydrated diol form
  • the hemiacetal or acetal form may be formed from the condensation of the diol form with the aldehyde or diol form
  • the tetrahydropyran or fused tetrahydropyran form may be formed from condensation of the diol form and the aldol-Michael self condensation form.
  • Typical examples of these forms are shown in formula (a) to (f) below:
  • R is hydrogen and n is an integer of one or more.
  • the proportion of repeating unit of formula I is typically less than 20% and frequently from 5 to 15%. Notwithstanding the relatively low proportion of these units we have found that they have a significant effect on the stability of the polymer.
  • the poly(2-propenal, 2-propenoic acid) will generally contain no more than 10% on a molar basis of monomer units from monomers other than acrolein and is most preferably an acrolein homopolymer (before autoxidation). Where used other monomers may be selected from the group consisting of acrylic acid and vinyl pyrrolidone.
  • the 2-propenoic acid groups are typically present in an amount of from 0.1 to 5 moles of carboxyl groups per kilogram.
  • the poly(2- propenal, 2-propenoic acid) polymers typically have a number average molecular weight of over 1000 and most preferably over 2000. Typically the molecular weight is less than 10,000.
  • the antimicrobial of the invention is a derivative of poly(2-propenal, 2-propenoic acid) prepared by reaction with an alcohol or phenol to form protected carbonyl groups.
  • the protected carbonyl groups are formed from the 2-propenal groups, which react with the alcohol to form hemiacetal and acetal groups.
  • the alcohol is preferably a polyol by which is meant that it preferably contains at least two hydroxyl groups. Alkanols such as Ci to C ⁇ 0 may be used. Where the alcohol is a polyol the reaction may produce acetals or hemiacetals formed by reaction of one or more than one alcohol group. Furthermore when two alcohol groups react it is possible for them to react at the same carbonyl or different carbonyl groups within the polymer.
  • the invention produces derivatives in which there are fewer units of formula I and forms a group wherein one or more groups R are derived from an alcohol, or when the alcohol is a polyol, more than two groups R may together form a bridging group such as a cyclic acetal group.
  • the propensity for polyols to give rise to internal cyclic groups will depend on the spacing and configuration of the polyol.
  • the 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.
  • the alcohol such as polyethylene glycol is present during the preparation of the antimicrobial polymers in an amount of between 50 and 99% by weight.
  • Relatively dilute compositions of the acrolein polymer are particularly preferred where the alcohol is a polyol as the incidence of intermolecular cross- linking is reduced by dilution.
  • polyethylene glycol is present during preparation of the polymers in the amount of between 64 and 95% by weight.
  • Base or alkali is preferably added to the polymers followed by a drift to acidic pH before and/or during heating, as neutralization of the acid groups of the polymer occurs, thereby enhancing the antimicrobial activity of the polymers.
  • the addition of the base or alkali initially brings the pH of the poly(2- propenal, 2-propenoic acid) polymers to between 7 and 9. Still more preferably, the initial pH on addition of the base is about 8.
  • the base is preferably an alkali metal hydroxide, carbonate, bicarbonate or mixture thereof.
  • the release of free acrolein monomer is inhibited, from continuous release, whereby the polymers are less likely to present a source of tissue or dermal irritation.
  • the superactivated derivative of the present invention may be used to treat a wide range of animals (including humans) and a wide range of microbial infections.
  • the antimicrobial of the invention may be used in treatment of gastrointestinal disease in humans, however it is particularly preferred that it be used in treatment of other animals particularly animals selected from the group consisting of dogs, pigs, sheep, horses, goats, cattle, cats, poultry, ducks, turkeys and quail.
  • the antimicrobial of the invention may be formulated for oral or rectal administration. Rectal administration may be particularly useful in ruminant animals. Oral formulations for ruminant animals may also be prepared using enteric coatings to provide optimal activity in the later part of the gastrointestinal tract.
  • the antimicrobial of the invention is particularly useful in treatment and prophylaxis of gastrointestinal ulcers, diarrhoea and gastrointestinal cancers.
  • the antimicrobial of the invention may also be used to improve the rate of weight gain in farm animals by improving the feed to weight conversion in animals.
  • the antimicrobial of the invention may be used as a growth promotant and that the polymer may be used in place of the presently used antibiotics.
  • Drug resistance in pathogenic bacteria is a problem of major clinical importance in human medicine. This problem is exacerbated by the use of important antibiotics in animal feed to provide weight gain in farm animals particularly poultry and pigs. Indeed, in some European countries the use of conventional antibiotics in animal feeds has been banned.
  • the antimicrobial of the invention may be used in treatment of animals to significantly extend the useful life of conventional antibiotics in human treatment.
  • the antimicrobial of the invention to be effective against a wide range of microbes including protozoa, Gram positive bacteria and Gram negative bacteria.
  • the polymers of the invention contain multiple structures of diverse configurations and can find a fit with the proteins found in the cell wall of target organisms, this speeds up the inactivation of the protein and the destruction of the cell.
  • the antimicrobial of the invention has been found to be particularly useful in providing broad spectrum activity against conforms or Enterobacteria. It is particularly useful in treatment of gastrointestinal diseases resulting from infection by E. coli such as enterotoxigenic E. coli and ⁇ -haemolytic E. coli. Colibacillosis is a devastating disease in the pig-rearing industry.
  • the disease is generally associated with proliferation of ⁇ -haemolytic E. coli. in the small intestine after weaning and gives rise to high mortality rates and morbidity rates in young weaner piglets. Infected weaner piglets fail to make normal weight gains.
  • Coccidiosis is a protozoal disease of animals particularly poultry and if left uncontrolled has a devastating effect.
  • the antimicrobial of the invention may be used in the treatment or prevention of coccidiosis in birds particularly in poultry. In chickens typical clinical signs of coccidiosis include lack of thriving, rapid loss of weight, diarrhoea and dysentery.
  • Vaccines have been used in an attempt to prevent coccidiosis but have side effects including the tendency to reduce weight and feed efficiency.
  • the antimicrobial of the invention may be used in combination with other drugs known to have activity against coccidiosis.
  • drugs include nitro-carbanilide, quinoline, pyridon, guanidine, quinoxaline, toltrazural, toluamide, potentiated sulfa drugs and ionophore with carbanilide.
  • Clostridia are Gram positive bacteria responsible for serious disease in a range of animals.
  • necrotic enteritis is a disease known to affect commercial poultry.
  • Clostridia bacterial produce exotoxins which are some of the most toxic of all known toxins.
  • Necrotic enteritis particularly effects broilers of between 14 and 42 days of age. The condition causes pronounced apathy, diarrhoea and can cause death within hours.
  • Upper gastrointestinal disease including chronic gastritis, gastric ulcer and duodenal ulcer are significant human health problems.
  • Helicobacter is understood to be responsible for the development of ulcers and the development of gastrointestinal cancers particularly adenocarcinoma of the stomach.
  • H. pylori The infection of the stomach with Helicobacter pylori is one of the most frequent infectious diseases in the world. About 50% of the population are infected with H. pylori. In developing countries it has been estimated that more than 80% of the population is already infected with H. pylori during childhood.
  • Helicobacter pylori is a Gram-negative, microaerophilic, spiral-shaped, bacilli that is motile by way of flagella at one end of the cell.
  • the standard treatments of H. pylori infections are the so-called triple antibiotic therapies all of which include either metronidazole or clarithromycin. Unfortunately strains of H. pylori have emerged, which are resistant to both these antibiotics.
  • H. pylori live in the stomach at the interface between the surface of gastric epithelial cells and the overlying mucus gel layer. H. pylori can additionally be found on top of the gastric epithelium in the duodenum and oesophagus. Other animal species have their own unique Helicobacter species present in their gastrointestinal tracts, which have similar properties to H. pylori. In addition to its association with gastrointestinal cancers, H. pylori has been directly linked in humans to gastritis and peptic ulcer formation.
  • H. pylori Helicobacter species in general, and H. pylori in particular, survive the extreme conditions of the stomach by secreting urease, which hydrolyses urea to give ammonia and bicarbonate ion, thus raising the pH of the immediate surroundings of the bacilli. This local alteration of the conditions protects the bacteria from the bactericidal effect of the gastric acid.
  • the preferred position underneath the stomach's protective mucus layer is also a survival advantage and its motility allows it to burrow through the layer to attain this position.
  • the epithelial cells lining the stomach are naturally difficult to penetrate; this is part of their function to protect the rest of the body from gastric acid and digestive juices. This difficulty in penetration also makes it difficult for the body's natural defences to pass through the stomach wall and reach the site of H. pylori infection. This has two consequences; the body sends more nutrients to the site to aid the white cells, T-cells, and other defence mechanisms, concomitantly supplying the bacilli; and the defence cells eventually die, releasing their cargo of superoxide ion and other lethal chemicals, damaging the surrounding epithelial cells. It is apparently this activity that leads to gastritis, which can easily progress to peptic ulcers.
  • gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma are greatly increased.
  • Gastric adenocarcinoma begins in the mucosa and the first stage of development, intestinal metaplasia, is a response of the stomach to rid itself of the H. pylori infection.
  • studies performed in UCL Medical School have shown that the MALT lymphoma requires help from H. pylori specific T-cells to grow. Treatment of H. pylori infection has been shown to be extremely effective in curing MALT lymphoma.
  • the World Health Organisation has labelled the pathogen a Group I carcinogen.
  • the present invention also provides for a method for the treatment or prophylaxis of diseases of the gastrointestinal tract caused by Helicobacter infection comprising the gastrointestinal administration of a therapeutic amount of an agent wherein the agent comprises a derivative of poly(2-propenal, 2- propenoic acid) formed by the reaction between a poly(2-propenal, 2-propenoic acid) and an organic compound containing hydroxyl groups selected from alkanols, phenols, polyols and mixtures thereof, to form protected carbonyl groups.
  • polyol where used herein means a compound containing at least two hydroxyl groups.
  • the derivatives formed are typically selected from hemiacetal and acetal derivatives
  • the use of the method of the present invention provides an alternative to the use of surgery, radiation therapy or traditional chemotherapy in the treatment of gastrointestinal cancers.
  • the invention further provides a method of treatment for gastrointestinal infection by a species of Helicobacter bacteria such as gastritis, gastric ulcer, duodenal ulcer, gastric malignant lymphoma or gastric cancer, comprising the gastrointestinal administration of a therapeutic amount of an agent wherein the agent comprises 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 carbonyl groups.
  • a species of Helicobacter bacteria such as gastritis, gastric ulcer, duodenal ulcer, gastric malignant lymphoma or gastric cancer
  • the present invention provides an alternative to standard treatments of Helicobacter infections, which, in general, comprise the so-called triple antibiotic therapies all of which include either metronidazole or clarithromycin. Strains of H. pylori have emerged which are resistant to both these antibiotics and we have shown that the method of the present invention can effectively treat such antibiotic resistant bacteria.
  • the agent which 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 non-superactivated poly(2-propenal, 2- propenoic acid) groups.
  • the invention further provides the use of a derivative of poly(2-propenal, 2- propenoic acid) in manufacture of a medicament for treatment or prophylaxis of a disease caused by Helicobacter infection.
  • the method of the present invention may be used in treatment or prophylaxis of gastrointestinal cancers.
  • gastrointestinal cancers may include, for example, cancers of the oesophagus, stomach, intestine and colon.
  • An example of such a type of cancer is the human colon cancer cell line HT-29.
  • the antimicrobial of the invention is incorporated in a premix.
  • the premix will preferably include the antimicrobial, a physiologically acceptable carrier and optionally a feedstuff.
  • the premix is generally in a relatively concentrated form and is adapted to be diluted with other material such as one or more of the other carriers, vitamins and mineral supplements and feedstuff to form the final animal feed.
  • the premix preferably includes the antimicrobial in a concentration in the range of from 0.1 to 70% by weight, preferably 0.5 to 50% by weight. The optimum concentration will depend on whether the treatment is preventative, for control or remedial and whether the antimicrobial of the invention is the only active or whether it is used in concomitant therapy with other materials or antimicrobials.
  • the concentrated composition of the antimicrobial is in a controlled-release form.
  • the controlled release form will include the antimicrobial and a polymeric material for providing controlled release of the antimicrobial from the controlled-release system and is particularly useful in compositions for addition to solid feed material.
  • the release of the antimicrobial may be delayed so as to occur mainly in the duodenum.
  • a controlled release polymer may also minimise rejection of the composition due to taste or be used for rectal suppositories.
  • An antimicrobial composition in accordance with the invention may be in the form of pellets, pills or like solid composition.
  • the pellets containing the antimicrobial of the invention may be prepared by the steps of:
  • the so-formed wet, swollen pellets may be used either wet, partially dried or wholly dried, as an additive to, for example, animal feed.
  • This system is further designed so that the carboxyl-containing groups of the outer polymeric matrix cause the Subject Polymers to remain essentially contained within the matrix when in the acidic environment of the stomach.
  • the carboxyl groups of the matrix become ionised and mutually-repelling, and the pellet rapidly swells to allow the Subject Polymers, aided by repulsion among their own ionic groups, to be excluded by a diffusion process, approximately matching the speed of passage of feed through the duodenum.
  • controlled release system is used in the same context as that in, and includes the same range of examples as quoted in “Controlled Drug Delivery” (Robinson & Lee, 1987).
  • Many other pH-sensitive controlled-release systems which are known in the art (Robinson and Lee, 1987) may be substituted for the polymer of acrylic acid or copolymer of acrylamide and acrylic acid.
  • Such cross-linked and insoluble polymers are preferred since they swell and also are less likely to be metabolised.
  • the controlled release system comprises a pH-sensitive, cross-linked, water-absorbent pellet, which when wet is a gel.
  • the invention also provides an animal feed composition comprising the antimicrobial of the invention and a feedstuff.
  • the antimicrobial is preferably present in an amount of from 0.0001 to 25% of the total feed composition and preferably from 0.0001 to 5% of the total feed composition.
  • the antimicrobial of the invention may be formulated for addition to the drinking water of animals.
  • the antimicrobial of the invention is preferably administered in amounts of from 0.05 to 5000 mg/kg of bodyweight/day more preferably from 0.05 to 50 mg/kg/day.
  • suitable inert carriers for use in compositions for administration of the antimicrobial of the invention include water, olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides, polyvinyl alcohol, partially hydrolysed polyvinyl acetate and mixtures thereof.
  • Solid forms for oral or rectal administration may contain pharmaceutically or veterinarally acceptable binders, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents.
  • Suitable binders include gum acacia, gelatine, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol.
  • Suitable sweeteners include sucrose, lactose, glucose or flavonoide glycosides such as neohesperidine dihydrochalcone.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavourings.
  • 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, zein, shellac or gluten.
  • Suitable preservatives include sodium benzoate, vitamin E, ⁇ -tocopherol, ascorbic acid, methyl parabens, propyl parabens or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay 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 carboxylmethylcellulose, methylcellulose, hydroxypropylmethylcellulose, poly- vinyl-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 may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as gum acacia or gum tragacanth.
  • compositions for administration in the method of the invention may be prepared by means known in the art for the preparation of compositions (such as in the art of veterinary and pharmaceutical compositions) including blending, grinding, homogenising, suspending, dissolving, emulsifying, dispersing and where appropriate, mixing of the Subject Polymers together with selected excipients, diluents, carriers and adjuvants.
  • the pharmaceutical or veterinary composition may be in the form of tablets, lozenges, pills, troches, capsules, elixirs, powders, including lyophilised powders, solutions, granules, suspensions, emulsions, syrups and tinctures.
  • Slow-release, or delayed-release, forms may also be prepared, for example in the form of coated particles, multi-layer tablets or microgranules.
  • poly(2-propenal, 2-propenoic acid) is prepared from poly(2-propenal) by oxidation of the solid in air.
  • the poly(2-propenal) polymer may be initially heated, predominantly in the 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 the alcohol for a period in the range of from 1 hour to 1400 hours and more preferably from 1 hour to 60 hours.
  • a preservative compound or composition comprising the antimicrobial of the invention.
  • a disinfectant or antiseptic compound or composition comprising the antimicrobial of the invention.
  • a composition for treatment of gastrointestinal disease comprising an antimicrobial polymer as hereinbefore described and a further chemotherapeutic agent wherein the further chemotherapeutic agent is adsorbed onto the antimicrobial.
  • the adsorption will typically reduce membrane penetration of the further chemotherapeutic.
  • the suitable chemotherapeutics for use in this embodiment are those which exhibit a significant reduction in membrane penetration when admixed with the polymeric antimicrobial. Preferably the penetration is inhibited by a factor of at least 50%.
  • the useful chemotherapeutic agents for use in this aspect of the invention include antibiotics for treatment of gastrointestinal disease and anticancer agents for treatment of gastrointestinal cancers.
  • chemotherapeutics in combination with the polymeric antimicrobial reduces membrane penetration of the chemotherapeutic thereby reducing systemic side effects and providing more targeted therapy. In many cases odour is also reduced.
  • chemotherapeutics for treatment of gastrointestinal disease include antibiotics and anticancer agents.
  • antibiotics which may be used in combination with the antimicrobial polymer include tetracyclines, penicillins, aminoglycosides, sulfa drugs, cephalosporins and nitrofurans.
  • the antibiotics may be conventional antibiotics used to treat infections of the gastrointestinal tract.
  • anticancer agents which may be used in combination with the polymeric antimicrobial of the invention are alkylating agents, antimetabolites, anticancer antibiotics, plant alkaloids, hormones and other anticancer agents, particularly anticancer agents containing carbon, hydrogen and oxygen only.
  • the compositions of the invention may also comprise one or more further antimicrobials such as those selected from the group of a phenol (preferably in an amount of 0.1 to 10% by weight), an isothiazolinone (preferably in an amount of fromk 0.001 to 1%), an alkyl parabens (preferably in an amount of from 0.02 to 2%) and a lower alcohol (preferably in an amount of from 20 to 99%) wherein the amounts are on the basis of weight by weight of the composition.
  • the derivative of poly(2-propenal, 2-propenoic acid used in the method of the invention has been found to have significantly increased stability compared with of poly(2-propenal, 2-propenoic acid) polymers. Since the prior art recorded some instability of poly(2-propenal, 2-propenoic acid), as evidenced by loss of antimicrobial activity of its compositions, we conducted "accelerated ageing" at elevated temperature, ie. at 40°C.
  • An added advantage of super-activation is that it reduces or eliminates, contaminant acrolein which is a source of tissue and dermal irritation.
  • the inventors have found polymers super-activated as described herein, suitable for gastrointestinal therapy, preservatives in water-based products or processes, and active ingredients in disinfectants or antiseptics having the advantage of enhanced antimicrobial activity. Furthermore, the inventors found that the antimicrobial activity of such disinfectants or antiseptics was increased by increase in their pH, for example above pH 6.
  • a common feature of the invention is the attachment of a group capable of hydrophobic interaction, to the antimicrobial of the invention, by way of hemiacetal/acetal formation or by way of adsorption, in order to enhance antimicrobial activity.
  • the example describes a method of preparing poly(2-propenal, 2-propenoic acid) by oxidation of a solid acrolein polymer in air.
  • This poly(2-propenal, 2- propenoic acid) is the preferred method of preparing a starting material for use in the method of the invention.
  • Water (720 mL at ambient temperature, about 20°C) and acrolein (60g ; freshly distilled, plus hydroquinone added to 0.25% w/w) were placed in an open beaker, within a fume cupboard, and very vigorously stirred, mechanically. Then, 0.2 M aqueous sodium hydroxide (21.4 mL) was added to bring the pH to 10.5-11.0.
  • a solution of the resulting poly(2-propenal, 2-propenoic acid) was prepared by adding 2g of the subject polymer, with stirring over 15-30 minutes, to a 1 % w/w aqueous sodium carbonate solution (100 mL), and then diluted as required.
  • Such solutions were perfectly clear-in contrast to attempted dissolutions, using alternatively, polymer derived from Example 5 of 11686/95.
  • This example describes acetal formation from poly(2-propenal, 2-propenoic acid).
  • (a) 5g of poly(2-propenal, 2-propenoic acid) was dissolved in 64g polyethylene glycol ("PEG") 200 and combined with 31 g of a 0.71 % w/w solution of sodium carbonate. A portion of the solution (apparent pH 5.8) was retained at room temperature while
  • This example examines the product produced by reaction of the poly(2- propenal, 2-propenoic acid) with polyethylene glycol.
  • the presence of acetals in the polymers of Example 2(b) may be determined by examining the solid residue left after dialysis and concentration of the polymer solution using proton ( 1 H) and carbon ( 13 C) NMR spectroscopy. Dialysis removes all material of molecular weight less than a 1000. Table 1 provides proton ( 1 H) and carbon ( 13 C) NMR data. As can be seen from Table 1, Nuclear Magnetic Resonance spectroscopy of the residue showed peaks at ⁇ 3.58 and 3.56 in the 1 H Nuclear Magnetic Resonance spectrum and ⁇ 71.62, 69.48 and 60.25 in the 13 C Nuclear Magnetic Resonance spectrum. These peaks are indicative of the attachment of polyethylene glycol units as acetals.
  • Example 9 (a) 540 g of poly(2-propenal, 2-propenoic acid) was dissolved in 2304 g PEG200 at 65° C, prior to mixing with 43.2 g of sodium carbonate in 712 g of water. Then, the solution was heated to 100° C for 4 hours, and 36g sodium lauryl sulphate, 7 g ECOTERIC T20 (non-ionic detergent) and 2 g lemon fragrance were added.
  • This example demonstrates a method of preparing an acrolein polymer in which the method of the invention is not used.
  • This example describes a method of preparing an acrolein polymer in which the polymer of comparative example is super activated by the method of the invention.
  • Example 10a This example examines the antimicrobial activity of the dry, normally activated poly(2-propenal, 2-propenoic acid) polymer of Example 10a and the antimicrobial activity of the superacfivated acetal derivative described in Example 10b. Chickens treated each of the antimicrobials were compared with a control group according to the following procedure:
  • Cob chickens (Line 53), day old were purchased from a commercial hatchery. They were weighed, sexed and randomly assigned into adjacent pens in a room of an isolated animal house. There was an even distribution of male and female chickens. Water and feed were available ad libitum. The diet was a commercial crumble (Chick Starter, Milne Feeds: 18% crude protein) with a coccidiostat present (125 ppm Dinitolmide).
  • Ten chickens were administered the formulation of 0.1% w/w of normally activated antimicrobial from Example 10a in the water for 14 days through static drinkers; dose rate of 30 mg/kg/day.
  • the other ten chickens were the Control Group.
  • the treatment group had measurably greater weight gains at the end of the 14- day period in comparison to the control group.
  • At the completion of the trial at post-mortem, no clinical or pathological signs of toxicity were evident at this gross examination in the treated group of chickens.
  • Example 10b evaluates the polymeric antimicrobial of Example 10b under field conditions for the control of porcine post weaning colibacillosis (PWC).
  • PWC porcine post weaning colibacillosis
  • faecal score is a measure of the intensity of diarrhoea.
  • This example examines the effect of using certain additives with the antimicrobial of the invention.
  • the samples were serially diluted 1 to 1 using sterile normal saline (5mL). Sterile Hard Water (SHW) was used as diluent when testing samples containing EDTA.
  • SHW Sterile Hard Water
  • Positive controls were performed using 5mL of diluent inoculated with culture and subject to incubation, recovery and confirmation.
  • Negative controls were performed using un-inoculated 5 mL of diluent and subject to incubation, recovery and confirmation.
  • A MKC polymeric antimicrobial
  • CONCLUSION It was shown that the acetal derivative of poly(2-propenal, 2-propenoic acid) was synergistic with Glutaraldehyde, EDTA, and Methyl Paraben, respectively versus A. niger, C. albicans, E. coli, P. aeruginosa, S. aureus.
  • the sample was serially diluted 1 to 1 using sterile normal saline (5mL).
  • Each sample dilution was inoculated with 100 ⁇ L of the diluted overnight culture. (One culture per tube). The samples were mixed well.
  • the recovery broths were examined for turbidity (Growth) and streaked onto selective agars to confirm growth.
  • A MKC polymeric antimicrobial (ppm)
  • B MKC Dettol (ppm)
  • the number of bacteria present on the hands of subjects was determined before and after application of antimicrobial followed by donning of surgical gloves.
  • the antiseptic effect of poly(2-propenal, 2-propenoic acid) [superactivated] was compared to the commonly used surgical antiseptic, 4% Chlorhexidine Surgical Scrub (manufactured by Orion Laboratories, in Perth, Western Australia).
  • the efficacy in vitro of the Superactivated Polymer was first established against the H. pylori reference strain, H. pylori NCTC11637. As variables, two concentrations were chosen; one was a 40-fold dilution of the 5% solution of the Superactivated Polymer prepared in Example 2 giving a 0.125% w/w concentration of the Superactivated Polymer, mimicking the dilution in the stomach; the other was a 100-fold dilution giving 0.05% w/w concentration of Superactivated Polymer. Two pHs were chosen, pH 7 as the baseline and pH 4 to mimic conditions in the stomach.
  • Cultures H. pylori NCTC11637 were grown microaerophilically on selective agar plates at 37 ⁇ 2°C until sufficient growth was observed. Growth was asepfically removed from the plates and prepared as a standardized turbid suspension of 10%) T, as displayed on a Vitek colorimeter, diluting with sterile normal saline. 19.9g of sample was weighed out and inoculated with 100 ⁇ L of culture suspension. 1mL of sample was immediately transferred into the Deactivation/Recovery broth (Nutrient Broth plus 3% Tween 80) and then serially diluted. 100 ⁇ L aliquots were placed onto selective agar plates and spread using a sterile disposable spreader.
  • the transfer steps were repeated at .time intervals of 5, 10, 15 and 20 minutes. All plates were incubated microaerophilically at 37 ⁇ 2°C until sufficient growth was achieved (approximately 5 to 7 days). All colonies were counted and the population decline over time was determined. The test was repeated using sterile normal saline as the sample to determine the natural die-off rate at atmospheric conditions.
  • H. pylori 01/303 which is resistant to clarithromycin and metronidazole
  • H. pylori SS1 a clinical strain isolated in Sydney with a high colonising ability of interest for possible animal models
  • H. pylori ATCC 700392 a strain whose genome has been sequenced and comes from the UK.
  • Example 3 The method of Example 3 was repeated in testing the Biocidal Activity of 0.125% w/w Superactivated polymer (pH 4) against all strains of H. pylori.
  • Example 19 This example demonstrates the enteric antimicrobial activity of the acetal derivative of poly(2-propenal, 2-propenoic acid) prepared according to the procedure of Example 10b.
  • MATERIAL AND METHODS Sixteen weaner pigs (age: 18 days ⁇ 2 days and weight: 5.5 kg ⁇ 1.0 kg) were purchased from a commercial piggery. They were randomly assigned into 2 groups of 8 pigs (equal distribution of sexes) and housed in an environmentally controlled isolation animal house.
  • Group 1 No treatment (negative control)
  • Group 2 0.1% w/v of superactivated polymeric antimicrobial according to Example 10b; 30 mg/kg/day.
  • CONCLUSION The acetal derivative of poly(2-propenal, 2-propenoic acid) at 0.1 % w/v significantly ( ⁇ 2 : P ⁇ 0.025) reduces the incidence of porcine Helicobacter spp in the gastric and oesophageal mucosa in weaner pigs.
  • Example 20 The acetal derivative of poly(2-propenal, 2-propenoic acid) at 0.1 % w/v significantly ( ⁇ 2 : P ⁇ 0.025) reduces the incidence of porcine Helicobacter spp in the gastric and oesophageal mucosa in weaner pigs.
  • This example demonstrates a method of preparing non-superactivated poly(2- propenal, 2-propenoic acid).
  • Washing Filter/centrifuge the polymerisation mixture and wash the polymer with deionised water until the pH of the wash water is less than 7.0.
  • the approximate yield is 8 kg.
  • Drying Dry the polymer in air, then heat in an oven using the following program.
  • the resulting polymer was found to have an approximate solubility of 90 - 95% w/w in 1 % w/w sodium carbonate.
  • Example 20(b) This example describes a method of preparing an acrolein polymer in which the polymer of comparative example 20(a) is super activated
  • Example 14 of PCT/AU9600328 it was demonstrated that poly(2-propenal,2- propenoic acid) polymer in 0.5% w/w sodium carbonate solution possessed anticancer activity against the Ehrlich ascites cell line in a mouse model.
  • Example 20(a) The anticancer activity of poly(2-propenal,2-propenoic acid) polymer [Example 20(a)] against that of the Superactivated Polymer [Example 20(b)].
  • An in vitro model of a gastrointestinal cancer was carried out on the human colon cancer cell line, HT-29. Poly(2-propenal, 2-propenoic acid) was used in a 5% w/w concentrate. The test used incubates the cancer cells with varying concentrations of polymer to give a plot from which an IC50 can be established.
  • HT-29 cells human colon cancer cells
  • the polymer poly(2-propenal,2-propenoic acid) polymer in Comparative Example 20(a) and the Superactivated Polymer in Example 20(b)] was dissolved in water and then diluted in medium to 10 concentrations spanning a 4-log range. 100 ⁇ l of each solution was then added to each of 5 wells. The plates were incubated for a further 72 hr after which viable cells were measured using the sulforhodamine B assay (Skehan et al., (1990) J. Nat.
  • the poly(2-propenal,2-propenoic acid) polymer of Comparative Example 20(a) gave an average IC5 0 over two tests of 0.030%; the poly(2-propenal,2-propenoic acid) polymer being assigned the value of 100%. This translates to 0.0015%) w/w of active polymer.
  • Example 20(b) gave an average IC5 0 over four tests of 0.025%. This translates to 0.00125% w/w of the Superactivated Polymer and indicates that the Superactivated Polymer has potent anticancer activity.
  • IC 50 is the concentration required to inhibit cell growth by 50%.

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Abstract

L'invention porte sur un procédé de traitement de troubles gastro-intestinaux par administration d'un antimicrobien polymérique comprenant un dérivé d'un poly(acide 2-propénol, 2-propénoïque) formé par réaction d'un poly(acide 2-propénol, 2-propénoïque) et d'un alcool ou d'un phénol de manière à former des groupes carbonyle protégés. L'invention porte également sur des compositions de traitement desdits troubles.
PCT/AU2003/000039 2002-01-18 2003-01-17 Procede de traitement de troubles gastro-intestinaux et composition polymerique a cet usage WO2003061672A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EP03731608A EP1474155A4 (fr) 2002-01-18 2003-01-17 Procede de traitement de troubles gastro-intestinaux et composition polymerique a cet usage
KR1020047011132A KR100971520B1 (ko) 2002-01-18 2003-01-17 위장 질환의 치료방법 및 이에 유용한 중합체 조성물
AU2003201209A AU2003201209B2 (en) 2002-01-18 2003-01-17 Method of treatment of gastrointestinal disease and polymeric composition for use therein
BR0306960-5A BR0306960A (pt) 2002-01-18 2003-01-17 Uso de composição polimérica no tratamento de doença gastrintestinal
CN038023873A CN1617733B (zh) 2002-01-18 2003-01-17 胃肠疾病的治疗方法和用于其中的聚合物组合物
CA2472685A CA2472685C (fr) 2002-01-18 2003-01-17 Procede de traitement de troubles gastro-intestinaux et composition polymerique a cet usage
EA200400965A EA015165B1 (ru) 2002-01-18 2003-01-17 Способ производства лекарственного средства из поли(2-пропеналя, 2-пропеновой кислоты) для лечения или профилактики желудочно-кишечных заболеваний и антимикробная композиция
NZ533811A NZ533811A (en) 2002-01-18 2003-01-17 Method of treatment of gastrointestinal disease and polymeric composition for use therein
MXPA04007005A MXPA04007005A (es) 2002-01-18 2003-01-17 Metodo para tratamiento de enfermedad gastrointestinal y composicion polimera para su uso en este.
JP2003561616A JP4732691B2 (ja) 2002-01-18 2003-01-17 胃腸疾患の治療方法およびそれに使用するためのポリマー組成物
HK05108595.7A HK1076602A1 (en) 2002-01-18 2005-09-29 Method of treatment of gastrointestinal disease and polymeric composition for use therein

Applications Claiming Priority (4)

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US10/053,088 2002-01-18
US10/053,088 US7629002B2 (en) 2000-02-16 2002-01-18 Antimicrobial polymeric compositions and method of treatment using them
AUPS3271 2002-06-28
AUPS3271A AUPS327102A0 (en) 2002-06-28 2002-06-28 Method of treatment or prophylaxis of gastrointestinal diseases

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1800713A1 (fr) 2005-12-22 2007-06-27 Basf Aktiengesellschaft Utilisation d'alcoxylates d'alcools monovalents et polyvalents ou d'un dérivé pour remplacer les antibiotiques dans les aliments pour animaux
EP1274749B1 (fr) * 2000-02-16 2008-05-21 Chemeq Ltd. Compositions polymeres antimicrobiennes
WO2016077879A1 (fr) * 2014-11-18 2016-05-26 Recce Limited Copolymère et procédé de traitement d'infection bactérienne
WO2017139849A1 (fr) 2016-02-19 2017-08-24 Recce Limited Agent antiviral et méthode de traitement d'une infection virale

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ES2556732T3 (es) * 2007-11-07 2016-01-19 Recce Limited Polímeros anti-microbianos y sus composiciones
KR20190070457A (ko) 2017-12-13 2019-06-21 주식회사 오투파워 이산화염소를 포함하는 닭 대장균증 예방을 위한 음용수 첨가용 조성물

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WO1996038186A1 (fr) * 1995-05-30 1996-12-05 Chemeq Pty. Limited Compositions chimiotherapiques
WO2000003723A1 (fr) * 1998-07-17 2000-01-27 Chemeq Limited Composes polymeres et leurs procedes de formulation

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WO1988004671A1 (fr) * 1986-12-23 1988-06-30 Biopolymers Limited Compositions biostatiques biocides
WO1996038186A1 (fr) * 1995-05-30 1996-12-05 Chemeq Pty. Limited Compositions chimiotherapiques
WO2000003723A1 (fr) * 1998-07-17 2000-01-27 Chemeq Limited Composes polymeres et leurs procedes de formulation

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HAMPSON D.J. ET AL.: "Evaluation of a novel antimicrobial polymer for the control of porcine post weaning colibacillosis", AUST. VET. J., vol. 78, no. 2, February 2000 (2000-02-01), pages 117 - 120, XP008092727 *
See also references of EP1474155A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1274749B1 (fr) * 2000-02-16 2008-05-21 Chemeq Ltd. Compositions polymeres antimicrobiennes
EP1800713A1 (fr) 2005-12-22 2007-06-27 Basf Aktiengesellschaft Utilisation d'alcoxylates d'alcools monovalents et polyvalents ou d'un dérivé pour remplacer les antibiotiques dans les aliments pour animaux
WO2016077879A1 (fr) * 2014-11-18 2016-05-26 Recce Limited Copolymère et procédé de traitement d'infection bactérienne
US10226482B2 (en) 2014-11-18 2019-03-12 Recce Pharmaceuticals Limited Copolymer and method for treatment of bacterial infection
WO2017139849A1 (fr) 2016-02-19 2017-08-24 Recce Limited Agent antiviral et méthode de traitement d'une infection virale
EP3416656A4 (fr) * 2016-02-19 2019-11-13 Recce Pharmaceuticals Ltd Agent antiviral et méthode de traitement d'une infection virale
US11045491B2 (en) 2016-02-19 2021-06-29 Recce Pharmaceuticals Ltd Anti-virus agent and method for treatment of viral infection

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EP1474155A1 (fr) 2004-11-10
CN1617733B (zh) 2010-04-07
MXPA04007005A (es) 2005-06-17
BR0306960A (pt) 2004-11-23
CA2472685C (fr) 2010-07-20
NZ533811A (en) 2005-07-29
KR100971520B1 (ko) 2010-07-21
CA2472685A1 (fr) 2003-07-31

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