EP1440078A1 - Utilisation antimicrobienne de derives d'anhydrofructose - Google Patents

Utilisation antimicrobienne de derives d'anhydrofructose

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Publication number
EP1440078A1
EP1440078A1 EP02772582A EP02772582A EP1440078A1 EP 1440078 A1 EP1440078 A1 EP 1440078A1 EP 02772582 A EP02772582 A EP 02772582A EP 02772582 A EP02772582 A EP 02772582A EP 1440078 A1 EP1440078 A1 EP 1440078A1
Authority
EP
European Patent Office
Prior art keywords
compound
independently selected
cyclic compound
formula
derivative
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02772582A
Other languages
German (de)
English (en)
Inventor
Aksel Buchter-Larsen
Andrew John Morgan
Shukun Yu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DuPont Nutrition Biosciences ApS
Danisco US Inc
Original Assignee
Danisco AS
Danisco US Inc
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 GBGB0126186.6A external-priority patent/GB0126186D0/en
Application filed by Danisco AS, Danisco US Inc filed Critical Danisco AS
Publication of EP1440078A1 publication Critical patent/EP1440078A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/3481—Organic compounds containing oxygen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A23L3/3562—Sugars; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/02—Monosaccharides

Definitions

  • the present invention relates to antimicrobial agents. More specifically, the invention relates to the antimicrobial activity of a series of anhydrofructose derivatives.
  • Bacillus anthracis is gram positive, aerobic, spore forming bacillus that is a major cause of disease in man and mammals. Numerous other species within the Bacillus genus are widely distributed in nature and are commonly found in soil, water and dust samples.
  • Bacillus anthracis Historically, considerable attention has focused on the genus Bacillus because of the significance of anthrax, the disease caused by Bacillus anthracis. Due to its ability to produce spores, Bacillus anthracis is extremely resistant to adverse chemical and physical environments.
  • Anthrax is primarily a disease of herbivorous animals but the disease may be contracted by humans that accidentally encounter this disease in an agricultural setting, usually with the development of a local skin infection that may become generalised. The disease may also be contracted in an industrial setting during the processing of hides or animal hair with the resultant inhalation of anthrax and the production of a virulant type of pneumonia. In rare cases, the disease may also be acquired by ingestion.
  • the present invention seeks to provide antimicrobial agents that are active against a range of microorganisms, and morg specifically, against Bacillus anthracis.
  • the invention seeks to provide antimicrobial agents that are useful in medicine.
  • the present invention relates to antimicrobial agents suitable for use in food/feedstuffs and in non-food applications.
  • a further aspect of the invention seeks to alleviate the problems associated with prior art chemical substances and to provide new antimicrobial compositions based on anhydrofructose derivatives. More specifically, the invention seeks to provide antimicrobial agents that are suitable for use in both foodstuffs/feed and in non-food applications.
  • the invention provides the use in medicine of a cyclic compound having Formula I,
  • a second aspect of the invention relates to the use of a compound having Formula I, or a derivative thereof,
  • treatment includes curative effects, alleviation effects, and prophylactic effects.
  • the medicament may be used to treat a condition associated with the presence of one or more microrganisms by preventing and/or inhibiting the growth of, and/or killing the microoganisms.
  • preparation of a medicament includes the use of a compound of formula I directly as the medicament in addition to its use in a screening programme for further antimicrobial agents or in any stage of the preparation of such a medicament.
  • the microorganism is selected from Listeria, Salmonella, Bacillus, Saccharomyces, Pseudomonas, Clostridium, Lactobacillus, Brochothrix, Micrococcus, Yersinia, Enterohacter, Escherichia, Zygosaccharomyces and Staphylococcus.
  • the microorganism is selected from Listeria monocytogenes, Listeria innocua, Salmonella Typhimurium, Salmonella sp., Bacillus cereus, Bacillus subtilis, Saccharomyces cerevisiae, Saccharomyces cerevisiae var. paradoxus, Saccharomyces carlsbergensis, Pseudomonas fluorescens, Clostridium sporogenes, Lactobac ⁇ llus sake, Brochothrix thermosphacta, Micrococcus luteus, Yersinia enterocolitica, Enterobacter aerogenes, E. coli, Staphylococcus aureus, Bacillus anthracis and Zygosaccharomyces bailii.
  • the microorganism is Bacillus anthracis.
  • the invention provides an antimicrobial composition or compound for use against Bacillus anthracis, said compound is or said composition comprises a cyclic compound having Formula I,
  • R 4 and R 5 are each independently selected from a hydrocarbyl group, H, OH or
  • the invention relates to a process for preventing and/or inhibiting the growth of, and/or killing Bacillus anthracis in a material, the process comprising the step of contacting the material with a cyclic compound having Formula I,
  • the invention relates to the use of a compound having Formula I, or a derivative thereof,
  • the material may be a foodstuff or feed.
  • the present invention relates to antimicrobial substances that are suitable for use in foodstuffs and/or feed to inhibit food poisoning and spoiling bacteria contained therein.
  • the material is a nonfood material.
  • the present invention also relates to antimicrobial substances for use in non-food applications such as surface cleaning, cleaning of fabrics (laundry), and in cosmetic and/or pharmaceutical products.
  • the invention relates to a process for preventing and/or inhibiting the growth of, and/or killing a mico-organism in a non-food material, the process comprising the step of contacting the material with a cyclic compound having Formula I,
  • R is C 1-10 alkyl; wherein R is a substituent comprising an -OH group; wherein R 4 and R 5 are each independently selected from a hydrocarbyl group, H, OH or
  • the compounds of the invention are particularly advantageous in such non-food applications due to their biodegradability and instablility. Moreover, since many of the compounds of formula I may be derived from starch, they are ideally suited for cosmetic, medical and surface cleaning purposes in view of their low toxicity. We have also found that the compounds of the present invention may be active against caries (tooth decay).
  • antimicrobial refers to a substance that kills or prevents or inhibits the growth or reproduction of micro-organisms.
  • Antimicrobials are generally classified according to the type of micro-organism they are effective against. For example, antibacterial substances are effective against bacteria, antifungal substances are effective against fungi, including yeast, and antiviral substances are effective against viruses. Certain antimicrobials can be used internally, for example antibiotic medications, whereas other antimicrobials are for external use only, such as antiseptics.
  • the cyclic compound of the invention is a compound having Formula II
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above.
  • the cyclic compound of the invention is a compound having Formula III
  • R 4 and R 5 of the general formula may independently be a hydrocarbyl group.
  • hydrocarbyl group means a group comprising at least C and H and may optionally comprise one or more other suitable substituents.
  • substituents may include halo-, alkoxy-, nitro-, hydroxy, carboxyl, epoxy, acrylic, hydrocarbon, N-acyl, or cyclic group etc.
  • a combination of substituents may form a cyclic group.
  • the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group.
  • the hydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen.
  • the groups R 4 and R 5 of the general formula may independently be selected from alkyl, alkenyl, cycloalkyl and aryl or may together represent an al ylene.
  • the derivative of the compound of Formula I is an ester.
  • ester includes mono-, di-, tri- and poly-esters.
  • the derivative of the compound of formula I is an ester wherein an ester linkage is formed from the -OH group of the R 3 substituent.
  • the derivatised R 3 substituent is a group of the formula -(CH ) n -OC(O)-(CH 2 ) p CH 3 , wherein n and p are independently of each other from 1 to 24, preferably from 1 to 20, preferably from 1 to 10, preferably from 1 to 5, or preferably 1, 2, or 3.
  • the derivative of the compound of formula I is an ester wherein the R 1 substituent and/or the R 2 substituent is an -OH group and wherein an ester linkage is formed from the -OH group of the R 1 substituent and/or the R 2 substituent.
  • the derivatised R 1 substituent and/or the R 2 substituent is a group of the formula -(CH 2 ) n -OC(O)-(CH 2 ) p CH 3 , wherein n and p are independently of each other from 1 to 24, preferably from 1 to 20, preferably from 1 to 10, preferably from 1 to 5, or preferably 1, 2, or 3.
  • the derivative of the compound of formula I is an ester wherein the R 1 substituent and/or the R 2 substituent is an -OH group and wherein an ester linkage is formed from the -OH group of the R 1 substituent and/or the R 2 substituent.
  • the derivatised R substituent and/or the R substituent is a group of the formula -OC(O)-(CH 2 ) p CH 3 , wherein p is from 1 to 24, preferably from 1 to 20, preferably from 1 to 10, preferably from 1 to 5, or preferably 1, 2, or 3.
  • the compound of formula I is a diester wherein the R 1 substituent is an -OH group and wherein the ester linkages are formed from the -OH group of the R 4 substituent and from the -OH group of the R 3 substituent.
  • a derivative of the compound of formula I is a compound of the formula
  • This compound (3,6-di-O-acetyl-l ,5-anhydro-4-deoxy-D-g )vcero-hex-3-enopyranose- 2-ulose) may be prepared in accordance with the teaching of Andersen et al. (1998), Structure of 1,5-anhydro-D-fructose: X-ray analysis of crystalline acetylated dimeric forms, J. Carbohydr. Chem. 17: 1027-1035.
  • I is an ester is particularly preferred because the compound may be lipophilic and/or may have both hydrophobic and hydrophilic properties. When the compound has both hydrophobic and hydrophilic properties the compound readily resides at a water/oil interface of an emulsion.
  • the residence of the compound at a water/oil interface of an emulsion may allow it to act as an emulsifier.
  • the present invention may further provide compounds having a dual functional effect.
  • the compounds may act both as an antimicrobial and as an emulsifier.
  • the cyclic compound is selected from Ascopyrone P, Ascopyrone M, Ascopyrone T, Ascopyrone Ti, Ascopyrone T 2 , and Ascopyrone T 3 , and mixtures thereof, the structures of which are shown below.
  • the cyclic compound is ascopyrone P.
  • Ascopyrone is a known compound.
  • 1978 and 1981 a group of American scientists prepared Ascopyrone P by pyrolysis of amylopectin, amylose and cellulose at the Wood Chemistry laboratory in Montana, with the intention of using Ascopyrone P as a starting material for organic synthesis [Shafizadeh, F., Fumeaux R.H., Stevenson, T.T., and Cochran, T.G., l,5-Anhydro-4-deoxy-D-g/j ⁇ cero-hex-l-en-3-ulose and other pyrolysis products of cellulose, Carbohydr. Res.
  • 1,5-anhydrofructose is monoketo sugar found in bacteria, red algae, fungi and mammals.
  • red algae and fungi 1,5-anhydrofructose is produced by the action of -l,4-glucan lyase [EC 4.2.2.13] from floridean starch and glycogen, respectively.
  • the 1,5-anhydro-D-fructose is prepared in accordance with GB-A-2296717.
  • the 1,5-anhydro-D-fructose is prepared by a method comprising treating an -l,4-glucan with the enzyme ⁇ -l,4-glucan lyase characterised in that enzyme is used in substantially pure form.
  • Ascopyrone P and Ascopyrone T can be produced enzymatically from 1,5-anhydro-D- fructose using cell-free extract prepared from the fungi of the order Pezizales, such as Plicaria leiocarpa and Anthracobia melaloma, and the order of Tuberales, such as, Tuber melanosporum.
  • Ascopyrone T_ is the dihydrate form of Ascopyrone T
  • Ascopyrone T 2 and T 3 are the tautomeric monohydrate forms of Ascopyrone T.
  • Ascopyrone M can be produced from 1,5-anhydro-D-fructose by EDTA-sensitive dehydratases isolated from the fungi Morels, such as Morchella vulgaris, Gyromitres, pezizes, such as Peziza echinospora.
  • Ascopyrone M, P and T can also be produced chemically by treating 1,5-anhydro-D- fructose with alkali under mild conditions [Studies on the degradation of some pentoses and of 1,5-anhydro-D-fructose, the product of the starch-degrading enzyme a-1,4- glucan lyase; Thesis, Ahmad, T., The Swedish University of Agricultural Sciences, Sweden, 1995].
  • the compound of the present invention is prepared by chemical means, it may be prepared in accordance with one of the following methods:
  • Ascopyrone P may be produced by treating 1,5-anhydro-D-fructose with non- aqueous acid at elevated temperature, for example at 70 °C.
  • Ascopyrones for example, Ascopyrone P, T and M
  • Ascopyrone P, T and M may be produced from 1,5- anhydro-D-fructose by alkaline treatment according to Ahmad, T., 1995.
  • the compound of the present invention is prepared by enzymatic means as disclosed in M.-A. Baute et al, [Phytochemistry, 33 (1993): 41-45).
  • ascopyrones such as, Ascopyrone P, T and M
  • ascopyrone P, T and M may be produced from 1,5-anhydro-D- fructose using enzymatic methods as disclosed in M.-A. Baute et al.
  • the cyclic compound of the invention is of Formula IV,
  • the cyclic compound of the invention is of formula V,
  • R , R , R , R , R and R are as defined above.
  • the cyclic compound of the invention is selected from one or more of the following:
  • R is or comprises a CH 2 OH group.
  • the cyclic compound of the invention comprises a five or a six membered ring.
  • the cyclic compound may be used alone, or in combination with other components, for example, one or more chelators (such as EDTA sodium salt, polyphosphate or citrate) and/or one or more antioxidants (such as ascorbate, isoascorbate, ascorbate palmitate, BHA or BHT).
  • one or more chelators such as EDTA sodium salt, polyphosphate or citrate
  • one or more antioxidants such as ascorbate, isoascorbate, ascorbate palmitate, BHA or BHT.
  • the compound is used in combination with one or more preservatives.
  • preservative is intended to encompass all substances which inhibit the development of, or kill, micro-organisms.
  • preservatives are used in concentrations of 0.5 % or less.
  • Food additives which are allowed to be used as preservatives are listed in the Regulation No. 95/2/EG of the European Parliament and Council of 20 February 1995, relating to food additives other than colouring agents and sweeteners.
  • Typical food preservatives permitted in the EU which are suitable for use in combination with the compounds of the invention include sorbic acid, benzoic acid, PHB ester (p-hydroxybenzoate), and sulphur dioxide.
  • sorbic acid benzoic acid
  • PHB ester p-hydroxybenzoate
  • sulphur dioxide sulphur dioxide
  • Mode of action inhibits different enzymes in the cells of the micro-organisms. Range of effects: mainly against yeasts and moulds as well as catalase-positive bacteria. Catalase-negative bacteria as well as lactic acid bacteria and clostridia are not inhibited. Effective concentration: 500 - 3000 ppm.
  • Permitted maximum quantities in food up to 2000 ppm in potato dough, processed cheese, packed bread, fine bakery products, emulsified sauces etc.
  • Benzoic Acid (E210 to 213): Mode of action: inhibits exchange of oxygen through the cellular membrane and affects the enzymatic structure.
  • Mode of action damages the bacterial membrane because of the surface activity, poisonous to protoplasm because of protein denaturation.
  • Range of effects mainly inhibits yeasts and fungi, but also Gram-positive bacteria in a pH range between 3.0 and 8.0.
  • Effective concentration sensorical influence at concentrations beyond approx. 0.08 %.
  • Mode of action depends on pH to a great extent, in practice it is only effective at acidic pH values ( ⁇ 4,0). Very complex mechanisms.
  • Range of effects mainly antibacterial, above all against Gram-negative, aerobic bacteria.
  • Effective concentrations 250 - 500 ppm for inhibition of aerobic, Gram-negative bacteria, 800 - 2000 ppm against Gram-positive bacteria, yeasts, and moulds.
  • Permitted maximum quantity in food products max. 2000 ppm in dry fruits, grape juice concentrate for home production of wine, in some cases only max. quantities of
  • the compounds of the present invention may also be used in combination with the following preservatives: biphenyl, diphenyl, orthophenylphenol, thiabendazol, nisin, natamycin, hexamethylentetramine, dimethyldicarbonate, boric acid, sodiumtetraborate, nitrite, propionic acid and propionate, and lysozyme.
  • preservatives biphenyl, diphenyl, orthophenylphenol, thiabendazol, nisin, natamycin, hexamethylentetramine, dimethyldicarbonate, boric acid, sodiumtetraborate, nitrite, propionic acid and propionate, and lysozyme.
  • Substance for treatment of fruits surface treatment of citrus fruits.
  • Mode of action Disturbance of membrane functions.
  • Mode of action specifically attacks cell membrane, where - in general - an interaction with sterines occurs which increases the permeability of the membrane.
  • Range of effects Moulds and yeasts, not effective against bacteria. Usual dosage rates are below approx. 50 mg / 1. Maximum level is 1 mg/dm 2 on the surface, with a maximum penetration of 5 mm.
  • Hexamethylentetramine is formed by adding ammonia to formaldehyde in an aqueous solution.
  • the microbicidal effect is due to the formaldehyde. Permitted only for Provolone cheese (25 ppm residual quantity).
  • the antimicrobial effectiveness of chemical substances in food and feed products is thus determined by a range of different factors.
  • the composition of the population of micro-organisms, the composition of the food product (ingredients, pH, water activity, content of salt, etc.), the packaging, time-temperature-conditions, etc. are key factors that influence the inhibitory activities of the antimicrobial agent.
  • a further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I admixed with a pharmaceutically acceptable diluent, excipient or carrier, or a mixture thereof.
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise as - or in addition to - the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and
  • Suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, com sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the pharmaceutical composition of the present invention may be formulated to be administered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route.
  • the formulation may be designed to be administered by a number of routes.
  • the compounds of the present invention may be administered alone but will generally be administered as a pharmaceutical composition - e.g. when the components are is in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the composition can be administered (e.g. orally or topically) in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the tablet may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropyl- methylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compound may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the routes for administration include, but are not limited to, one or more of: oral (e.g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e.g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracere- broventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, vaginal, epidural, sublingual.
  • oral e.g. as a tablet, capsule, or as an ingestable solution
  • mucosal e.g. as a nasal spray or aerosol for inhalation
  • nasal parenteral (e.g. by an injectable form)
  • gastrointestinal intraspinal, intraperitone
  • the composition comprises more than one compound of Formula I. In this case, it is to be understood that not all of the components of the pharmaceutical need be administered by the same route. Likewise, if the composition comprises more than one active component, then those compon administered by different routes.
  • a compound of the present invention is administered parenterally, then examples of such administration include one or more of: intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the component; and/or by using infusion techniques.
  • the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • the compound(s) of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134ATM) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EATM), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134ATM)
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • a lubricant e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the agent and a suitable powder base such as lactose or starch.
  • the compound(s) of the present invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compound(s) of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route.
  • the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
  • a preservative such as a benzylalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • the compound(s) of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition is administered orally.
  • the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • composition is to be administered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.
  • compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously.
  • compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • Figure 1 shows the effect of APP on the growth of B. anthracis at 30 °C over a period of 24 h (optical density versus time in hours).
  • Micro-organisms are taken from storage at -80 °C. Bacillus species are tested as endospore suspensions prepared earlier and stored at 4 °C. For Bioscreen testing the bacteria are grown in Brain Heart Infusion (BHI, Oxoid, pH 7.4) and cultured at 30 °C.
  • BHI Brain Heart Infusion
  • Oxoid pH 7.4
  • Sample E002012 is a dry powder that was dissolved in sterile de-ionised water. It is tested without filtration and used in the mini well diffusion test, initial Bioscreen runs (BS1211200; BS131200), and mini cidal experiment. The concentration of this sample is 49.3 mg/ml.
  • Further APP samples are prepared as follows: 3.84 g of batch number APP20010213, as 5 x 4 ml volumes, is made up to a concentration of 169 mg APP/ml, and 5.5 g of batch number APP20010215, as 4 x 10 ml volumes, is made up to a concentration of 138 mg APP/ml. All samples are kept at -20 °C until use. Stock solutions are made up in de-ionised water and filter sterilised. These samples are used in Bioscreen run BS010411 and BS010420. APP20010215 is used in Bioscreen run BS010510.
  • An automated Microbiology Reader Bioscreen C is used to measure growth curves of the strains in the presence and absence of APP.
  • the Bioscreen C measures the development of turbidity (i.e. growth) kinetically by vertical photometry in 200 wells of a honeycomb microtitre plate, simultaneously.
  • the system consists of a Bioscreen C analyser, which is an incubator and measurement unit, integrated with a PC, software (BioLink v 5.30), printer and a 'Honeycomb 2' cuvette multiwell plate. Growth curve data can be analysed within the BioLink software or exported to programs such as Excel.
  • Broth culture media are dispensed in 270 ⁇ l volumes into the wells as directed. Serial dilutions of a filter-sterilised APP stock solution are then dispensed into the same wells, as appropriate.
  • the wells are inoculated with 30 ⁇ l of an appropriately diluted spore suspension, to give a final inoculum level of ca. 10 3 cfu/ml.
  • the tests are incubated in the Bioscreen C for either 24 h at 30 °C, or 72 h at 25 °C with readings taken every 20 minutes after the trays are shaken. After the incubation period is complete the data are exported to Excel for analysis.
  • Bioscreen test results in vitro sensitivity of Bacillus anthracis The Bioscreen test results are summarised in Tables 1 below and Figure 1.
  • cream samples were prepared by the recipe above. Cream samples were added either a normally used preservative (methyl paraben) in sufficient amount or APP or AF-ester or AF in the concentrations: 250 or 2000 ppm. The results showed that APP, AF-ester and AF in both concentrations were as good preservatives as the commonly used preservative. Addition of APP, AF-ester and AF to the cream showed no irritation effect on the skin.
  • a normally used preservative methyl paraben
  • Citric Acid (to pH 6.5) q.s.
  • a shampoo according to the above-mentioned recipe were prepared. Samples of shampoo were added respectively a normally used preservative in sufficient amount and APP or AF- ester or AF in the concentration 2000 ppm.
  • Toothpaste samples were added respectively a normally used preservative (sodium benzoate) in sufficient amount and APP or AF-ester or AF in the concentration 2000 ppm.

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Abstract

La présente invention concerne l'utilisation en médecine d'un composé cyclique de formule (I), ou un dérivé de ce dernier, dans laquelle R1 et R2 sont indépendamment sélectionnés dans -OH, =O, et OR', dans laquelle R' représente H ou -COR'', et R'' représente alkyle C1-10; dans laquelle R3 représente un substituant comprenant un groupe OH; dans laquelle R4 et R5 sont chacun indépendamment sélectionnés dans un groupe hydrocarbyle, H, OH ou =O, ou représentent une liaison avec un atome adjacent présent sur le noyau du composé cyclique. L'invention concerne également un antimicrobien destiné à être utilisé contre le Bacillus anthracis d'un composé cyclique de formule (I).
EP02772582A 2001-10-31 2002-10-30 Utilisation antimicrobienne de derives d'anhydrofructose Withdrawn EP1440078A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GBGB0126186.6A GB0126186D0 (en) 2001-10-31 2001-10-31 Use
GB0126186 2001-10-31
US34336801P 2001-12-21 2001-12-21
US343368P 2001-12-21
PCT/GB2002/004914 WO2003037906A1 (fr) 2001-10-31 2002-10-30 Utilisation antimicrobienne de derives d'anhydrofructose

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EP1440078A1 true EP1440078A1 (fr) 2004-07-28

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GB0306312D0 (en) * 2003-03-19 2003-04-23 Danisco Composition

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GB9906457D0 (en) * 1999-03-19 1999-05-12 Danisco Anti-oxidant
GB2348423B (en) * 1999-03-19 2003-10-22 Danisco Novel anhydrofructose antioxidant
GB2358137B (en) * 2000-01-14 2004-06-09 Danisco Compound
EP1252827B1 (fr) * 2000-01-31 2007-05-23 Nihon Starch Co., Ltd. Procedes de production d'aliments presentant de bonnes qualites de conservation et agents de conservation d'aliments
JPWO2002020061A1 (ja) * 2000-09-07 2004-01-15 東京瓦斯株式会社 膵外分泌機能診断のための製剤
EP1322189A1 (fr) * 2000-09-27 2003-07-02 Danisco A/S Agent anti-microbien

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