WO2017147958A1 - 含氧碳氢衍生物作为多粘菌素的协同增效剂的应用 - Google Patents

含氧碳氢衍生物作为多粘菌素的协同增效剂的应用 Download PDF

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WO2017147958A1
WO2017147958A1 PCT/CN2016/077921 CN2016077921W WO2017147958A1 WO 2017147958 A1 WO2017147958 A1 WO 2017147958A1 CN 2016077921 W CN2016077921 W CN 2016077921W WO 2017147958 A1 WO2017147958 A1 WO 2017147958A1
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polymyxin
linear
carbon atoms
acid
use according
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PCT/CN2016/077921
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French (fr)
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彭险峰
覃宗华
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广州英赛特生物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/105—Aliphatic or alicyclic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/02—Local antiseptics
    • 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

Definitions

  • the invention belongs to the field of biomedicine and feed additives, and particularly relates to the application of an oxygenated hydrocarbon derivative as a synergistic synergist of polymyxin.
  • Polymyxin is a peptide antibiotic extracted from the fermentation broth of polymyxa, which mainly includes five different components such as polymyxin A, B, C, D and E.
  • polymyxin B is used in human medicine clinical practice and is considered to be the ultimate weapon for humans to deal with carbapenem-resistant Enterobacteriaceae bacteria.
  • Polymyxin E is the most widely used animal antibiotic growth promoter. one. With the wide application of antibiotics, bacterial resistance has become a global medical problem, especially the multidrug resistance (MDR) problem of Gram-negative bacteria.
  • MDR multidrug resistance
  • the object of the present invention is to provide an oxygen-containing hydrocarbon derivative containing 4 to 18 carbon atoms as a synergistic synergist of polymyxin in the preparation of a disease caused by infection of a polymyxin-sensitive or drug-resistant bacteria. Used in medicines or animal feed additives.
  • the polymyxin synergist of the present invention is a novel non-antibiotic polymyxin synergist, which is an oxygenated hydrocarbon derivative containing 4 to 18 carbon atoms.
  • the oxygen-containing hydrocarbon derivative containing 4 to 18 carbon atoms of the present invention is used as a synergistic synergist of polymyxin in the preparation of a medicament for treating diseases caused by polymyxin-sensitive bacteria or drug-resistant bacteria, or for animals. Application in feed additives.
  • the oxygenated hydrocarbon derivative having 4 to 18 carbon atoms is a linear or branched saturated or unsaturated fatty alcohol having 4 to 18 carbon atoms.
  • the structure is as shown in formula I:
  • R 1 is selected from a C 3-17 linear or branched saturated alkyl group, a C 3-17 linear or branched unsaturated alkyl group.
  • the R 1 is preferably a C 9-11 linear or branched saturated alkyl group, a C 9-11 linear or branched unsaturated alkyl group.
  • the oxygenated hydrocarbon derivative having 4 to 18 carbon atoms is a linear or branched saturated or unsaturated fatty aldehyde having 4 to 18 carbon atoms.
  • R 2 is selected from a C 3-17 linear or branched saturated alkyl group, a C 3-17 linear or branched unsaturated alkyl group.
  • the fatty aldehyde is preferably a linear or branched saturated or unsaturated fatty aldehyde having 10 to 12 carbon atoms.
  • the oxygenated hydrocarbon derivative having 4 to 18 carbon atoms is a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms. Structure as shown in Formula III:
  • R 3 is a C 3-17 linear or branched saturated alkyl group or a C 3-17 linear or branched unsaturated alkyl group.
  • the R 3 is preferably a C 9-11 linear or branched saturated alkyl group or a C 9-11 linear or branched unsaturated alkyl group.
  • the oxygenated hydrocarbon derivative having 4 to 18 carbon atoms is a linear or branched chain having 4 to 18 carbon atoms as shown in Formula IV.
  • R 4 is selected from C 3-17 straight or branched saturated alkyl, C 3-17 straight or branched unsaturated alkyl
  • R 5 is selected from C 1-18 straight or branched saturated An alkyl group, a C 1-18 linear or branched unsaturated alkyl group, a C 1-18 linear or branched hydroxy group substituted alkyl group.
  • esterified derivative of the linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms is a glyceride thereof.
  • the linear or branched saturated or unsaturated group having 4 to 18 carbon atoms is preferably a monoglyceride of the fatty acid.
  • the glyceride of a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms is preferably a diglyceride of the fatty acid.
  • the glyceride of a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms is a triglyceride of the fatty acid.
  • the carbonyl end of the esterified derivative of a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms preferably has 10 to 12 carbon atoms.
  • the carbonyl group preferably has 10 to 12 carbon atoms.
  • the present invention can be used in combination with an oxygen-containing hydrocarbon derivative having 4 to 18 carbon atoms and polymyxin to form a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described polymyxin synergist and polymyxin having an oxygen-containing hydrocarbon derivative of 4 to 18 carbon atoms.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or any combination thereof.
  • the pharmaceutical composition further comprises polymyxin.
  • the polymyxin is selected from the group consisting of polymyxin A, polymyxin B, polymyxin C, polymyxin D, polymyxin E, and the like.
  • the polymyxin is preferably polymyxin B.
  • the polymyxin is preferably polymyxin E.
  • the present invention also provides an oxygen-containing hydrocarbon derivative having 4 to 18 carbon atoms as a synergistic synergist of polymyxin in the preparation of a medicament for treating a disease caused by a polymyxin-sensitive or drug-resistant infection. application.
  • the pharmaceutical composition of the pharmaceutical composition comprising the polymyxin synergist is a polymyxin synergist, a pharmaceutically acceptable carrier, an excipient, and a vehicle. And adjuvants.
  • the pharmaceutical composition prepared by the pharmaceutical composition comprising the polymyxin synergist is one of polymyxin, a polymyxin synergist, and pharmaceutically Acceptable carriers, excipients, vehicles, and adjuvants.
  • the medicament prepared by the pharmaceutical composition comprising the polymyxin synergist can be used orally for treating diseases caused by polymyxin-sensitive bacteria or drug-resistant bacteria. Administration by injection or topical administration.
  • the medicament for treating diseases caused by polymyxin-sensitive bacteria or drug-resistant bacteria is used for treating diseases caused by infection of polymyxin-sensitive bacteria or drug-resistant bacteria in humans, including wounds and urine.
  • the medicament for treating a disease caused by a polymyxin-sensitive or drug-resistant bacteria is used for treatment Diseases caused by infection of polymyxin-sensitive or resistant bacteria in farmed animals.
  • the invention also provides the use of an oxygenated hydrocarbon derivative containing 4 to 18 carbon atoms as a synergistic synergist of polymyxin in the preparation of animal feed additives.
  • the animal feed additive is used to increase animal performance to promote animal growth.
  • the animal feed additive further comprises other nutritive feed additives and non-nutritive feed additives.
  • the animal feed additive is suitable for livestock and poultry at various stages of growth.
  • the livestock includes the cultivation of herbivorous or non-grass animals such as pigs, cattle, sheep, horses, rabbits, donkeys, deer, cats, dogs, foxes, crickets or crickets at various stages of growth.
  • herbivorous or non-grass animals such as pigs, cattle, sheep, horses, rabbits, donkeys, deer, cats, dogs, foxes, crickets or crickets at various stages of growth.
  • the livestock includes the cultivation of poultry such as chicken, guinea fowl, duck, goose, pigeon or cockroach at various stages of growth.
  • the results of the animal breeding experiments show that the oxygen-containing hydrocarbon derivatives of 4-8 carbon atoms contained in the pharmaceutical composition provided by the present invention have no preventive and controlling effects on bacterial infection of animals, and are also produced for animals.
  • the performance has no improvement effect, and when used in combination with polymyxin, the control effect on animal diseases is remarkable, and the performance of the animal can be remarkably improved.
  • any of the embodiments of any of the aspects of the invention may be combined with other embodiments as long as they do not contradict each other.
  • any of the technical features may be applied to the technical features in other embodiments as long as they do not contradict each other.
  • the foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.
  • alkyl as used in the present invention is a hydrocarbon group which is obtained by removing one hydrogen atom from an alkane molecule;
  • C 3-17 linear or branched saturated alkyl group means that the alkyl group contains no unsaturated bond and contains 3 a straight-chain hydrocarbon group of -17 carbon atoms or a branched hydrocarbon group;
  • C 3-17 linear or branched unsaturated alkyl group means that the alkyl group is a group having 3 to 17 carbon atoms containing a double bond.
  • C 1-18 linear or branched hydroxy-substituted alkyl group means a straight-chain hydrocarbon group having 1 to 18 carbon atoms or substituted by one or more hydroxyl groups Branched hydrocarbon group.
  • Polymyxin is an antibacterial polypeptide found in polymyxal culture medium. It has five kinds of A, B, C, D, and E. The antibacterial spectrum is similar to each other and has a wide range. For most Gram-negative bacteria such as green Pseudomonas, Escherichia coli, Klebsiella pneumoniae, Haemophilus, Enterobacter, Salmonella, Shigella, Bordetella, Pasteurella and Vibrio have strong antibacterial activity. Common resistant strains are Escherichia coli, Pseudomonas aeruginosa, Salmonella, Shiga. Some strains of bacteria, Klebsiella, and the like.
  • the polymyxin synergist of the present invention is an oxygen-containing hydrocarbon derivative having 4 to 18 carbon atoms selected from a linear or branched saturated or unsaturated fatty alcohol having 4 to 18 carbon atoms. a linear or branched saturated or unsaturated fatty aldehyde having 4 to 18 carbon atoms, a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms, respectively having the structure , Equation II and Formula III:
  • R 1 , R 2 and R 3 are a C 3-17 linear or branched saturated alkyl group or a C 3-17 linear or branched unsaturated alkyl group; and may also be selected from 4 to 18 carbons.
  • the linear or branched saturated or unsaturated fatty alcohol having 4 to 18 carbon atoms is selected from the group consisting of propanol, butanol, n-pentanol, hexanol, heptanol, octanol, nonanol, and decyl alcohol. , undecyl alcohol, lauryl alcohol, myristyl alcohol, palmitol, stearyl alcohol or the corresponding isomeric alcohols of these alcohols, and the corresponding carbon atoms of these alcohols containing one chain end or a double bond in the chain Saturated fatty alcohol.
  • the linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms is selected from the group consisting of propionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, capric acid, capric acid, and eleven Carbonic acid, lauric acid, myristic acid, palmitic acid, stearic acid or an isomerized acid corresponding to these acids, and the like, and unsaturated fatty acids having a chain number or a double bond in the chain corresponding to the number of carbon atoms of these acids.
  • the linear or branched saturated or unsaturated fatty aldehyde having 4 to 18 carbon atoms is selected from the group consisting of butyraldehyde, valeraldehyde, hexanal, heptaldehyde, octanal, furfural, undecanal, and lauric aldehyde. , myristal, palmitic aldehyde, stearyl aldehyde or an isomeric aldehyde corresponding to these aldehydes, and the like, and an unsaturated fatty aldehyde having a carbon atom number of one chain terminal or a double bond in the chain.
  • the esterified derivative of a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms is selected from the group consisting of C Acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, capric acid, capric acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid or isomeric acids of these acids or these
  • the oxygen-containing hydrocarbon derivative containing 4-18 carbon atoms involved in the present invention is a petrochemical fine chemical product, and a linear or branched saturated or unsaturated fatty acid having 4-18 carbon atoms can be derived from 4- A linear or branched saturated or unsaturated fatty alcohol or fatty aldehyde of 18 carbon atoms is prepared by oxidation, and further esterified with an alcohol to form an esterified derivative.
  • the esterification reaction conditions such as the feed ratio, the reaction temperature, the selection of the catalyst, etc.
  • fatty acid and the polyol are controlled within a certain range to control the reaction between the fatty acid and the polyol in monoesterification, diesterification, etc., such as fatty acid monoglyceride, fatty acid glycerol double Preparation of esters and fatty acid triglycerides, and the like.
  • the oxygen-containing hydrocarbon derivative having 4 to 18 carbon atoms which the present invention relates to includes a linear or branched saturated or unsaturated fatty alcohol having 4 to 18 carbon atoms and a straight chain having 4 to 18 carbon atoms. a chain or branched saturated or unsaturated fatty aldehyde, a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms, and a linear or branched saturated or 4 to 18 carbon atoms In vitro biological experiments of esterified derivatives of unsaturated fatty acids, etc.
  • the minimum inhibitory concentration (MIC) of each compound against polymyxin-sensitive and resistant bacteria was determined by microdilution method and contained in the same concentration of 4- The minimum inhibitory concentration of polymyxin against polymyxin-sensitive and resistant bacteria under the culture conditions of hydrocarbon derivatives of 18 carbon atoms.
  • the experimental results show that the present invention relates to all linear or branched saturated or unsaturated fatty alcohols having 4 to 18 carbon atoms, linear or branched saturated or unsaturated groups having 4 to 18 carbon atoms.
  • An esterified derivative of a fatty aldehyde, a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms, and a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms Polymyxin-sensitive bacteria (MIC ⁇ 4.0ppm) and resistant bacteria (MIC>4.0ppm) have weak inhibitory activity, MIC ⁇ 800ppm; all linear or branched chains containing 4-18 carbon atoms involved in the present invention a saturated or unsaturated fatty alcohol and a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms are co-operating with the polymyxin at the same concentration in an in vitro biological test.
  • the effect of colistin on the sensitive bacteria showed a 10-20-fold enhancement, while the effect on the resistant strain was more significant and enhanced by about 50 times, showing a synergistic effect on the polymyxin-sensitive bacteria.
  • the esterified derivative of a linear or branched saturated or unsaturated fatty acid in the body interacts with polymyxin in a test strain in vitro, and the effect of polymyxin on sensitive or resistant bacteria is mostly The effects of the test on the application of polymyxin are consistent or similar.
  • unexpectedly, when there are free hydroxyl groups in the esterified derivatives, such as monoglycerides of fatty acids and diglycerides of fatty acids have synergistic effects on polymyxin in vitro. effect.
  • the oxygen-containing hydrocarbon derivative having 4 to 18 carbon atoms which the present invention relates to includes a linear or branched saturated or unsaturated fatty alcohol having 4 to 18 carbon atoms and a straight chain having 4 to 18 carbon atoms. a chain or branched saturated or unsaturated fatty aldehyde, a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms, and a linear or branched saturated or 4 to 18 carbon atoms.
  • Studies on in vivo biological experiments of esterified derivatives of unsaturated fatty acids, etc. give experimental mice intramuscular test strains, and then give all oxygenated hydrocarbon derivatives and polymyxins containing 4-18 carbon atoms involved in the invention.
  • mice Combined treatment, the survival rate of mice during the statistical test.
  • the experimental results showed that the test group had no synergistic effect or resistance reversal of polymyxin in combination with polymyxin in vitro compared with the blank non-administered challenge group and the polymyxin administration positive control group.
  • Monoglycerides have shown synergistic effects in in vivo therapeutic experiments.
  • the oxygen-containing hydrocarbon derivative having 4 to 18 carbon atoms involved in the present invention includes a linear or branched saturated or unsaturated fatty alcohol having 4 to 18 carbon atoms and containing 4 to 18 carbons. a linear or branched saturated or unsaturated fatty aldehyde of an atom, a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms, and a linear or branched chain having 4 to 18 carbon atoms.
  • the esterified derivative of saturated or unsaturated fatty acid is used in combination with polymyxin in the treatment of mammals such as weaned piglets, and the intramuscular injection of the experimental culture animal piglet edema type E. coli fresh culture liquid, observation and statistics Mortality of the test group during the trial.
  • the experimental results show that all hydrocarbon derivatives containing 4-18 carbon atoms involved in the present invention have synergistic effects on polymyxin in vivo.
  • the oxygen-containing hydrocarbon derivative having 4 to 18 carbon atoms involved in the present invention includes a linear or branched saturated or unsaturated fatty alcohol having 4 to 18 carbon atoms and containing 4 to 18 carbons. a linear or branched saturated or unsaturated fatty aldehyde of an atom, a linear or branched saturated or unsaturated fatty acid having 4 to 18 carbon atoms, and a linear or branched chain having 4 to 18 carbon atoms.
  • ADFI average daily feed intake
  • ADG Weight gain
  • FCR meat to material ratio
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a polymyxin synergist with an oxygenated hydrocarbon derivative containing 4-18 carbon atoms in the preparation of a polymyxin-resistant or drug-resistant bacterial infection
  • the application of drugs for diseases is not limited to a pharmaceutical composition
  • a pharmaceutical composition comprising a polymyxin synergist with an oxygenated hydrocarbon derivative containing 4-18 carbon atoms in the preparation of a polymyxin-resistant or drug-resistant bacterial infection.
  • the medicament for treating diseases caused by polymyxin-sensitive bacteria or drug-resistant bacteria is used for treating diseases caused by infection of polymyxin-sensitive bacteria or drug-resistant bacteria in humans or animals.
  • Topical application of solution or emulsion or injection for the treatment of sensitive skin, ear, eye infection or oral disinfection can also be used for intestinal infection, sepsis, urinary tract caused by polymyxin sensitive bacteria or resistant bacteria Infection, burns or traumatic infections, meningitis, peritonitis, endocarditis, severe pertussis in children and skin and mucous membrane infections.
  • the pharmaceutical composition of the present invention may further comprise other therapeutic ingredients other than polymyxin such as antibiotics.
  • compositions disclosed herein are prepared using techniques and methods known to those skilled in the art.
  • the medicaments prepared from the compositions disclosed herein are prepared using techniques and methods known to those skilled in the art, for example, the components involved may be combined with pharmaceutically acceptable excipients, carriers, adjuvants, vehicles, or combinations thereof It is prepared by mixing at ambient temperature and atmospheric pressure.
  • the medicament for treating a disease caused by a polymyxin-sensitive bacterium or a drug-resistant bacterium infection prepared by the pharmaceutical composition of the present invention is generally a dosage form suitable for administration to a patient by a desired route, including those suitable for the following administration routes.
  • Dosage form such as oral administration: tablets, capsules, capsules, pills, tablets, powders, syrups, suspensions, solutions, emulsions, etc.; parenteral administration: sterile solutions, Suspension, reconstituted powder, etc.; transdermal administration: transdermal patch, etc.; rectal or gastrointestinal administration: suppository, lotion; inhalation type: aerosol, solution, dry powder, etc.
  • the pharmaceutical composition or medicament can be in an oral dosage form.
  • the pharmaceutical composition or medicament can be in an inhaled dosage form.
  • the pharmaceutical composition or medicament of the present invention may be in the form of a topical administration.
  • the pharmaceutical composition or medicament can be administered nasally.
  • the present invention relates to the use of a pharmaceutical composition comprising a polymyxin synergist having an oxygenated hydrocarbon derivative of 4 to 18 carbon atoms for the preparation of a feed additive.
  • the present invention provides a feed additive prepared from a pharmaceutical composition comprising a polymyxin synergist comprising an oxygenated hydrocarbon derivative having 4 to 18 carbon atoms as an animal growth promoter. It has a significant effect in improving feed utilization, improving animal performance, and stimulating animal growth. In addition, it can also be used for the prevention of diseases such as diarrhea during the breeding of animals.
  • the feed additive is prepared in accordance with existing industrial processes in the preparation process with acceptable excipients, carriers, antioxidants, diluents, anti-caking agents, vehicles, or combinations thereof.
  • the feed additive contains a substance that supplements and balances nutrients.
  • the feed additive further comprises a health care substance.
  • the feed additive further comprises a physiologically modulating metabolite.
  • the feed additive further comprises an appetite-stimulating digestive substance.
  • the feed additive further comprises a processing and preservative.
  • the feed additive can be a liquid, a solid, a semi-solid or a gel.
  • the invention also relates to a method of promoting growth of an animal, the method comprising administering to the animal an effective amount of a pharmaceutical composition of the invention or a feed additive prepared therefrom.
  • the pharmaceutical compositions of the invention or feed additives prepared therefrom are provided in separate form for use in daily rations of animals.
  • the pharmaceutical composition of the present invention or the feed additive prepared therefrom and the feed material, feed additive, carrier or diluent are prepared into an additive premixed feed, concentrated feed, compound feed, and concentrate feed supplement according to a certain ratio.
  • the feed form is for animal consumption.
  • the feed material according to the present invention refers to a feed material derived from animals, plants, microorganisms or minerals and used for processing feeds but not belonging to feed additives.
  • the feed additive according to the present invention refers to a small amount or a trace amount of substances added during the processing, production and use of feed, including nutritive feed additives and non-nutritive feed additives.
  • the nutritive feed additive refers to a small amount or a trace amount of substances incorporated into the feed for supplementing the nutrients of the feed, including feed grade amino acids, vitamins, mineral trace elements, enzyme preparations, non-protein nitrogen, and the like.
  • Non-nutritive feed additives are small or trace substances that are incorporated into feeds to ensure or improve feed quality and improve feed utilization.
  • the carrier according to the present invention refers to a feedable substance capable of carrying an active ingredient, improving dispersibility, and having good chemical stability and adsorption.
  • the diluent involved in the invention refers to a substance which uniformly distributes the additive raw material in the material and dilutes the high-concentration additive raw material into a low-concentration premix or premix, which can separate the trace components from each other and reduce the active ingredients. Mutual reaction to increase the stability of the active ingredient without affecting the physicochemical properties of the substance.
  • the additive premix feed according to the present invention refers to a feed which is mainly composed of two (types) or two (types) or more nutritive feed additives, and is prepared according to a certain ratio with a carrier or a diluent, including a composite premix feed, and a trace amount. Elemental premix feed, vitamin premix feed.
  • the concentrated feed according to the present invention refers to a feed mainly prepared with a certain proportion of protein, minerals and feed additives.
  • the compound feed according to the present invention refers to a feed prepared by a plurality of feed raw materials and feed additives according to a certain proportion according to the nutritional needs of the farmed animals.
  • the concentrate supplement referred to in the present invention refers to a feed which is prepared by supplementing a plurality of feed materials and feed additives according to a certain ratio in order to supplement the nutrition of the herbivore animal.
  • the pharmaceutical composition of the present invention or a feed additive prepared therefrom is used for the raising of poultry such as chicken, guinea fowl, duck, goose, pigeon, and quails.
  • the pharmaceutical composition of the present invention or a feed additive prepared therefrom is used for livestock such as pigs, cows, sheep, horses, donkeys, rabbits, deer, cats, dogs, foxes, lynx or lynx. Feeding.
  • the pharmaceutical composition of the present invention or a feed additive prepared therefrom or the like is used for the breeding of pets.
  • oxygenated hydrocarbon derivatives containing 4-18 carbon atoms including fatty alcohols, fatty acids and fatty acid glycerides
  • polymyxin synergists especially as synergistic strains of polymyxin inhibitory strains.
  • the agent and polymyxin resistance reversal agent provide a more effective application space for the application of polymyxin, and have important application value in the pharmaceutical field and animal breeding field.
  • Example 1 In vitro biological study of the synergistic effect of oxygenated hydrocarbon derivatives on polymyxin.
  • polymyxin E (19000 IU/mg), polymyxin B (6000 IU/mg), butyric acid, caproic acid, caprylic acid, capric acid, capric acid, undecanoic acid, lauric acid, stearic acid, Undecylenic acid, neodecanoic acid, decyl alcohol, lauryl alcohol, furfural, lauric aldehyde, monoglyceride, glycerol monolauryl ester and decyl decanoate.
  • Oxygenated hydrocarbon derivatives have weak inhibition on Escherichia coli, Pseudomonas aeruginosa, Salmonella and Shigella (Table 1); Oxygenated hydrocarbon-resistant Escherichia coli sensitive to polymyxin can reduce polymyxa
  • the minimum inhibitory concentration of the corresponding strains in vitro is 2-4 times, and the different derivatives of the resistant strains can reduce the minimum inhibitory concentration of polymyxin on different strains by 64 times in vitro (Table 2).
  • mice male and female, 140, weighing 18-22g;
  • mice with similar body weight were randomly divided into 7 groups, 20 rats in each group, half male and half female.
  • the mice in each experimental group were different according to Table 4 at 1 hour before challenge and every 8 hours after challenge.
  • Drugs drugs for 3 days.
  • the P. aeruginosa B545 strain 2 ⁇ 10 7 CFU/mouse was intraperitoneally injected, and the mortality of each test group within 1 week after the challenge infection was observed.
  • mice challenge test showed that both citric acid and monoglyceride could synergistically enhance the effect of polymyxin B against Pseudomonas aeruginosa and reduce the mortality of the test mice. (Table 4).
  • 5 is the combination of polymyxin B (according to 2mg / kg body weight) and citric acid (according to the amount of 300mg / kg body weight) for intramuscular injection, 7 groups of polymyxin B (by 2mg / The amount of kg body weight) was mixed with glycerol monoterpene ester (in an amount of 300 mg/kg body weight) and then intramuscularly injected.
  • mice 180 24-day-old Du Changda ternary weaned piglets were randomly divided into 7 groups, 30 in each group.
  • the feed is a custom-made powder that does not contain any medicine.
  • Piglets in each experimental group were intramuscularly injected with different drugs 1 hour before the challenge and every 8 hours after the challenge according to Table 5. The drug was used for 3 days.
  • One hour after the first administration the mice were challenged with an intramuscular injection of Escherichia coli 3D-5 strain 5 ⁇ 10 8 CFU/mouse, and the mortality of each test group was observed within 1 week after the challenge infection.
  • 6 is an intramuscular injection of colistin sulfate (in an amount of 2 mg/kg body weight) and glycerol monoterpene ester (in an amount of 200 mg/kg body weight).
  • a total of 1,200 1 day old fast yellow broilers were randomly divided into 6 groups of 4 replicates each with 50 replicates each. Groups were grouped according to Table 6 and colistin sulfate (polymyxin E) or / and decyl citrate were added separately in the feed. During the test period, they were kept in cages, fed ad libitum and drinking water. The survival rate, weight gain and feed-to-meat ratio of each test group within 21 days of the statistical test period. The results of the test showed that the combination of decyl citrate and colistin sulfate was significantly improved in production performance compared with single use, and was dose-dependent (Table 6).

Abstract

一种包含多粘菌素协同增效剂的药用组合物及其用途。含有4-18个碳原子的含氧碳氢衍生物包括脂肪醇、脂肪酸和脂肪酸甘油酯作为多粘菌素增效剂，特别是作为多粘菌素抑制敏感菌株的协同增效剂和多粘菌素的耐药性逆转剂，并公开了该多粘菌素增效剂的药用组合物，进一步还将该药用组合物应用于制备治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物以及动物用饲料添加剂中，为多粘菌素的应用提供了更为有效的应用空间，在制药领域和动物养殖领域具有十分重要的应用价值。

Description

含氧碳氢衍生物作为多粘菌素的协同增效剂的应用 技术领域
本发明属于生物医药及饲料添加剂领域，具体涉及含氧碳氢衍生物作为多粘菌素的协同增效剂的应用。
背景技术
多粘菌素是从多粘杆菌发酵液中提取的一种多肽类抗生素，主要包括多粘菌素A、B、C、D和E等五种不同的组份。其中多粘菌素B则应用于人类医学临床，被认为是人类对付碳青霉烯类耐药肠杆菌科细菌的终极武器，而多粘菌素E是应用最广泛的动物抗生素类生长促进剂之一。随着抗生素的广泛应用，细菌的耐药性已经成为全球性医学难题，尤其是革兰氏阴性细菌的多药耐药性(MDR)问题尤为突出。最近有关多粘菌素新耐药基因MCR-1介导的大肠杆菌耐药性及其水平传播的可能性的报道，引起全球对细菌耐药性的恐慌性讨论，担心多粘菌素作为人类细菌性疾病化学治疗的最后一道防线被突破。过去数十年来，人们一直在试图延缓或消除细菌的耐药性，但鲜有重大进展。因此，开发能够消除多粘菌素的耐药性的组合物，对于提高多粘菌素的效果，延长其使用寿命具有重要意义。此外，由于多粘菌素的系统毒性非常大，不能高剂量使用，若有协同增效的组份开发复方药物制剂(尤其是注射剂)对于降低多粘菌素的毒副作用、提高药物安全性和疗效则具现实意义。
发明内容
本发明的目的是提供一种含有4～18个碳原子的含氧碳氢衍生物作为多粘菌素的协同增效剂在制备治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物，或动物用饲料添加剂中应用。
本发明涉及的多粘菌素协同增效剂是一种新型的非抗生素类多粘菌素协同增效剂，为含有4～18个碳原子的含氧碳氢衍生物。
本发明的含有4～18个碳原子的含氧碳氢衍生物作为多粘菌素的协同增效剂在制备治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物，或动物用饲料添加剂中应用。
在一协同增效的技术方案中，所述的含有4～18个碳原子的含氧碳氢衍生物是含有4～18个碳原子的直链或支链的饱和或不饱和脂肪醇，其结构如式Ⅰ所示：
Figure PCTCN2016077921-appb-000001
其中，R1选自C3-17直链或支链的饱和烷基、C3-17直链或支链的不饱和烷基。
在一协同增效的技术方案中，所述的R1优选自C9-11直链或支链的饱和烷基、C9-11直链或支链的不饱和烷基。
在另一协同增效的技术方案中，所述的含有4～18个碳原子的含氧碳氢衍生物为含有4～18个碳原子的直链或支链的饱和或不饱和脂肪醛，具有如式Ⅱ所示的结构：
Figure PCTCN2016077921-appb-000002
其中，R2选自C3-17直链或支链的饱和烷基、C3-17直链或支链的不饱和烷基。
在另一协同增效的技术方案中，所述的脂肪醛优选为含有10-12个碳原子的直链或支链的饱和或不饱和的脂肪醛。
在另一协同增效的技术方案中，所述的含有4～18个碳原子的含氧碳氢衍生物为含有4～18个碳原子的直链或支链的饱和或不饱和脂肪酸，具有如式Ⅲ所示的结构：
Figure PCTCN2016077921-appb-000003
其中，R3为C3-17直链或支链的饱和烷基或C3-17直链或支链的不饱和烷基。
在另一协同增效的技术方案中，所述的R3优选为C9-11直链或支链的饱和烷基或C9-11直链或支链的不饱和烷基。
在另一协同增效的技术方案中，所述的含有4～18个碳原子的含氧碳氢衍生物为结构如式Ⅳ所示的含有4～18个碳原子的直链或支链的饱和或不饱和脂肪酸的酯化衍生物：
Figure PCTCN2016077921-appb-000004
其中，R4选自C3-17直链或支链的饱和烷基、C3-17直链或支链的不饱和烷基；R5选自C1-18直链或支链的饱和烷基、C1-18直链或支链的不饱和烷基、C1-18直链或支链的羟基取代烷基。
进一步的，所述的含有4～18个碳原子的直链或支链的饱和或不饱和脂肪酸的酯化衍生物为其甘油酯。
在另一协同增效的技术方案中，所述的含有4-18个碳原子的直链或支链的饱和或不饱 和脂肪酸的甘油酯优选为该脂肪酸的甘油单酯。
在另一协同增效的技术方案中，所述的含有4-18个碳原子的直链或支链的饱和或不饱和脂肪酸的甘油酯优选为该脂肪酸的甘油双酯。
在另一协同增效的技术方案中，所述的含有4-18个碳原子的直链或支链的饱和或不饱和脂肪酸的甘油酯为该脂肪酸的甘油三酯。
在另一协同增效的技术方案中，所述的含有4-18个碳原子的直链或支链的饱和或不饱和脂肪酸的酯化衍生物的羰基端优选为含有10-12个碳原子的羰基。
本发明可以将含有4～18个碳原子的含氧碳氢衍生物和多粘菌素联合使用形成药用组合物。
本发明提供药用组合物，包含上述的含有4～18个碳原子的含氧碳氢衍生物的多粘菌素协同增效剂和多粘菌素。
在一技术方案中，所述的药用组合物还进一步包含药学上可接受的赋形剂、载体、佐剂、溶媒或它们的任意组合。
在一技术方案中，所述的药用组合物还包含有多粘菌素。
在另一技术方案中，所述的多粘菌素选自多粘菌素A、多粘菌素B、多粘菌素C、多粘菌素D、多粘菌素E等。
在另一技术方案中，所述的多粘菌素优选为多粘菌素B。
在另一技术方案中，所述的多粘菌素优选为多粘菌素E。
本发明还提供了含有4～18个碳原子的含氧碳氢衍生物作为多粘菌素的协同增效剂在制备治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物中的应用。
在一技术方案中，所述的包含多粘菌素协同增效剂的药用组合物制备的药物的成分是多粘菌素协同增效剂、药学上可接受的载体、赋形剂、溶媒和佐剂。
在另一技术方案中，所述的包含多粘菌素协同增效剂的药用组合物制备的药物的成分是多粘菌素中的一种、多粘菌素协同增效剂、药学上可接受的载体、赋形剂、溶媒和佐剂。
在另一技术方案中，所述的包含多粘菌素协同增效剂的药用组合物制备的药物在用于治疗由多粘菌素敏感菌或耐药菌感染所致疾病可通过口服、注射或局部用药的方式给药。
在一技术方案中，所述的治疗多粘菌素敏感菌或耐药菌所致的疾病的药物用于治疗人类因多粘菌素敏感菌或耐药菌感染所致的疾病包括创面、尿路、眼、耳、气管、皮肤黏膜、肠道感染、败血症、腹膜炎、脑膜炎等。
在另一技术方案中，所述的治疗多粘菌素敏感菌或耐药菌所致的疾病的药物用于治疗 养殖动物因多粘菌素敏感菌或耐药菌感染所致的疾病。
本发明还提供含有4～18个碳原子的含氧碳氢衍生物作为多粘菌素的协同增效剂在制备动物用饲料添加剂中的应用。
在一技术方案中，所述的动物用饲料添加剂用于提高动物的生产性能促进动物生长。
在另一技术方案中，所述的动物用饲料添加剂进一步还包含有其他营养性饲料添加剂和非营养性饲料添加剂。
所述的动物用饲料添加剂适用于各个生长阶段的家畜和家禽。
所述的家畜包括各个生长阶段的猪、牛、羊、马、兔、驴、鹿、猫、狗、狐、貂或貉等食草性或非食草性动物的养殖。
所述家畜包括各个生长阶段的鸡、珍珠鸡、鸭、鹅、鸽或鹌鹑等禽类动物的养殖。
体外和体内的生物实验结果表明，本发明提供的药用组合物中含有的4-18个碳原子的含氧碳氢衍生物对多粘菌素敏感菌或耐药菌均抑制活性很弱，而与多粘菌素合用时多粘菌素对多粘菌素敏感菌或耐药菌的抑制活性具有协同增效的作用。
动物养殖实验的结果表明，本发明提供的药用组合物中含有的4-8个碳原子的含氧碳氢衍生物单独使用对动物的细菌感染不具有预防和控制的作用同时对动物的生产性能没有改善效果，当与多粘菌素联合应用于动物的养殖对动物疾病的控制效果很显著，还能显著地改善动物的生产性能。
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。前面所述的内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。
本发明涉及的术语“包含”为开放式表达方式，表示除了提及的成分外还可以含有未指出的某些成分。
本发明涉及的术语“烷基”为烷烃分子中少去一个氢原子而成为的烃基；“C3-17直链或支链的饱和烷基”表示烷基为不含不饱和键的含有3～17个碳原子的直链烃基或带有支链的烃基；“C3-17直链或支链的不饱和烷基”表示烷基为含一个双键的含有3～17个碳原子的直链烃基或带有支链的烃基；“C1-18直链或支链的羟基取代烷基”表示被一个或多个羟基取代的含有1-18个碳原子的直链烃基或带有支链的烃基。
多粘菌素是发现于多粘杆菌培养液中的抗菌性多肽，有A、B、C、D、E等五种，抗菌谱相互类似而范围宽广，对大多数革兰氏阴性菌如绿脓杆菌、大肠杆菌、肺炎克雷白杆菌、 嗜血杆菌、肠杆菌属、沙门菌、志贺菌、百日咳杆菌、巴斯德菌和弧菌等具有很强的抗菌作用，常见的耐药菌株有大肠杆菌、绿脓杆菌、沙门氏菌、志贺氏菌、克雷伯氏菌等的部分菌株。
本发明涉及的多粘菌素协同增效剂为含有4～18个碳原子的含氧碳氢衍生物选自含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醛、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸，其结构分别如式I、式II和式Ⅲ所示：
Figure PCTCN2016077921-appb-000005
其中，R1、R2和R3为C3-17直链或支链的饱和烷基或C3-17直链或支链的不饱和烷基；还可选自含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸的酯化衍生物。
所述的含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇选自丙醇、丁醇、正戊醇、己醇、庚醇、辛醇、壬醇、癸醇、十一烷醇、月桂醇、肉豆蔻醇、棕榈醇、硬脂醇或这些醇对应的同分异构醇等以及这些醇对应碳原子数的含有一个链端或链中的双键的不饱和脂肪醇。
所述的含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸选自丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一碳酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸或这些酸对应的同分异构酸等以及这些酸对应碳原子数的含有一个链端或链中的双键的不饱和脂肪酸。
所述的含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醛选自丁醛、戊醛、己醛、庚醛、辛醛、壬醛、十一醛、月桂醛、肉豆蔻醛、棕榈醛、硬脂醛或这些醛对应的同分异构醛等以及这些醛对应碳原子数含一个链端或链中双键的不饱和脂肪醛。
所述的含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸的酯化衍生物选自丙 酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一碳酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸或这些酸的同分异构酸或这些酸对应碳原子数的含有一个链端或链中的双键的不饱和脂肪酸与含有1-18个碳原子的一元醇或多元醇的酯化产物，如上述酸的甲醇酯、乙醇酯、丙醇酯、丁醇酯、戊醇酯、己醇酯、庚醇酯、辛醇酯、壬醇酯、癸醇酯、十一醇酯、月桂醇酯、肉豆蔻醇酯、棕榈醇酯、硬脂醇酯、甘油单酯、甘油双酯、甘油三酯等。
本发明涉及的含有4-18个碳原子的含氧碳氢衍生物为石油化工精细化工产品，含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸可从含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇或脂肪醛经过氧化制备得到，进一步与醇发生酯化反应生成酯化衍生物。酯化反应条件如投料比、反应温度、催化剂等的选择控制在一定范围内将所述脂肪酸与多元醇发生的反应控制在单酯化、双酯化等，如脂肪酸甘油单酯、脂肪酸甘油双酯和脂肪酸甘油三酯的制备等。
本发明涉及的含有4-18个碳原子的含氧碳氢衍生物包括含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醛、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸和含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸的酯化衍生物等在体外生物实验的研究通过微量稀释法测定各个化合物对多粘菌素敏感菌和耐药菌的最小抑菌浓度(MIC)以及在相同浓度的含有4-18个碳原子的碳氢衍生物的培养条件下多粘菌素对多粘菌素敏感菌和耐药菌的最小抑菌浓度。实验结果表明，本发明涉及的所有含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醛、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸和含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸的酯化衍生物对多粘菌素敏感菌(MIC<4.0ppm)和耐药菌(MIC>4.0ppm)的抑制活性很弱，MIC≥800ppm；本发明涉及的所有含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇和含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸在体外生物实验研究时在相同浓度下与多粘菌素共同作用于试验菌株，多粘菌素对敏感菌的作用效果呈现了10-20倍的增强，而对耐药菌株的作用效果更为显著、增强约50倍，呈现出明显对多粘菌素敏感菌的协同增效作用和对多粘菌素耐药菌的耐药逆转的效果；但是含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸的酯化衍生物在体外与多粘菌素共同作用于试验菌株，多粘菌素对敏感菌或是耐药菌的作用效果大部分和多粘菌素的单独应用试验的效果一致或相似，意外的是当酯化衍生物中有游离羟基时如脂肪酸的甘油单酯和脂肪酸的甘油双酯对多粘菌素具有体外的协同增效作用。
本发明涉及的含有4-18个碳原子的含氧碳氢衍生物包括含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醛、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸和含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸的酯化衍生物等在体内生物实验的研究给试验小鼠肌注试验菌株后给与发明涉及的所有含有4-18个碳原子的含氧碳氢衍生物和多粘菌素联合治疗，统计试验过程小鼠的存活率。实验结果表明，试验组相比空白不给药攻毒组和多粘菌素给药阳性对照组在体外与多粘菌素联用对多粘菌素无协同增效或耐药逆转作用的脂肪酸甘油单酯、在体内治疗实验中表现出了协同增效的效果。
进一步的，本发明涉及的含有4-18个碳原子的含氧碳氢衍生物包括含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醛、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸和含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸的酯化衍生物等在哺乳动物如断奶仔猪的治疗实验中与多粘菌素联合应用，肌注给与实验动物仔猪水肿型大肠杆菌新鲜培养菌液，观察并统计试验期间试验组的死亡率。实验结果中体现出本发明涉及的所有含有4-18个碳原子的碳氢衍生物在体内对多粘菌素具有协同增效的作用。
进一步的，本发明涉及的含有4-18个碳原子的含氧碳氢衍生物包括含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醇、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪醛、含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸和含有4-18个碳原子的直链或支链的饱和或不饱和的脂肪酸的酯化衍生物等与多粘菌素应用于畜禽等动物在养殖中的生产性能研究，考察在养殖过程中动物的平均日采食量(ADFI)、平均日增重(ADG)和饲料报酬率如肉料比(FCR)。在畜禽的养殖过程中，发明涉及的含有4-18个碳原子碳氢衍生物与多粘菌素的联合应用相比碳氢衍生物或多粘菌素阳性对照组及不给药空白组动物的动物的生产性能显著得到改善。
本发明涉及的包含有含有4-18个碳原子的含氧碳氢衍生物的多粘菌素协同增效剂的药用组合物在制备治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物中的应用。
所述的治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物用于治疗人类或动物由多粘菌素敏感菌或耐药菌感染所致的疾病。局部用药以溶液剂或乳剂或注射剂应用于治疗敏感菌引起的皮肤、耳、眼的感染或口腔消毒，还可用于多粘菌素敏感菌或耐药菌引起的肠道感染、败血症、尿路感染、烧伤或外创面感染、脑膜炎、腹膜炎、心内膜炎、幼儿重症百日咳及皮肤黏膜感染。另外，本发明所述的药用组合物还可以包含除多粘菌素外的其他治疗成分如抗 生素、抗结核药、抗真菌药、抗病毒药、抗寄生虫药、抗肿瘤药、心脑血管系统药物、神经系统药物、呼吸系统药物、消化系统药物、免疫系统药物等用于其他复杂疾病的治疗。
本发明公开的药用组合物使用本领域技术人员已知的技术和方法制备。由本发明公开的组合物制备的药物使用本领域技术人员已知的技术和方法制备，例如可将涉及的各组分与药学上可接受的赋形剂、载体、辅剂、溶媒或它们的组合在环境温度和大气压下混合来制备。
由本发明所述的药用组合物制备的治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物通常是适合于通过所需途径对患者给药的剂型，包括那些适合以下给药途径的剂型，如口服给药：片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、混悬剂、溶液剂、乳剂等；胃肠道外给药：无菌溶液剂、混悬剂、复溶粉剂等；透皮给药：透皮贴片剂等；直肠或腔道给药：栓剂、洗剂；吸入剂型：气雾剂、溶液剂、干粉剂等和局部给药：乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂、凝胶剂等。在一技术方案中，所述的药用组合物或药物可以是口服剂型。在另一技术方案中，所述的药用组合物或药物可以是吸入剂型。在另一技术方案中，本发明所述的药用组合物或药物可以是局部给药剂型。在另一技术方案中，所述的药用组合物或药物可以经鼻给药。
本发明涉及的包含有含有4-18个碳原子的含氧碳氢衍生物的多粘菌素协同增效剂的药用组合物在制备饲料添加剂中的应用。
在一些实施方案中，本发明提供的由包含有含有4-18个碳原子的含氧碳氢衍生物的多粘菌素协同增效剂的药用组合物制备的饲料添加剂作为动物生长促进剂使用改善饲料利用率、提高动物的生产性能、刺激动物生长方面具有显著的效果。另外，还可以用于动物在养殖过程中的疾病如腹泻等的预防。
所述的饲料添加剂在制备过程与可接受的赋形剂、载体、抗氧化剂、稀释剂、抗结块剂、溶媒或它们的组合按照现有工业工艺方法制备。在一实施方案中，所述的饲料添加剂含有补充和平衡营养的物质。在另一实施方案中，所述的饲料添加剂还含有保健类物质。在另一实施方案中，所述的饲料添加剂还含有生理调节代谢类物质。在另一实施方案中，所述的饲料添加剂还含有增食欲助消化类物质。在另一实施方案中，所述的饲料添加剂还含有加工和保存剂类物质。
所述的饲料添加剂可以是液体、固体、半固体或凝胶。
一方面，本发明还涉及促进动物生长的方法，所述的方法包括给与动物有效量的本发明所述药用组合物或由其制备的饲料添加剂。在一实施方案中，本发明提供的本发明所述药用组合物或由其制备的饲料添加剂以单独形式添加到动物的每日口粮中使用。在另一实施方 案中，本发明所述药用组合物或由其制备的饲料添加剂与饲料原料、饲料添加剂、载体或稀释剂等按照一定比例制备成添加剂预混合饲料、浓缩饲料、配合饲料、精料补充饲料等饲料形式供动物食用。
本发明涉及的饲料原料是指来源于动物、植物、微生物或矿物质，用于加工制作饲料但不属于饲料添加剂的饲用物质。
本发明涉及的饲料添加剂是指在饲料加工、制作、使用过程添加的少量或者微量物质，包括营养性饲料添加剂和非营养性饲料添加剂。营养性饲料添加剂是指为补充饲料营养成分而掺入饲料中的少量或者微量物质，包括饲料级氨基酸、维生素、矿物质微量元素、酶制剂、非蛋白氮等。非营养性饲料添加剂是指为保证或改善饲料品质、提高饲料利用率等作用而掺入饲料中的少量或者微量物质。
本发明涉及的载体是指能够承载活性成分，改善其分散性，并有良好的化学稳定性和吸附性的可饲用物质。
本发明涉及的稀释剂是指将添加剂原料均匀分布于物料中，将高浓度的添加剂原料稀释为低浓度的预混剂或预混料的物质，可将微量成分彼此分开，减少活性成分之间的相互反应，以增加活性成分的稳定性但不影响有关物质的物化性质。
本发明涉及的添加剂预混合饲料是指由两种(类)或两种(类)以上的营养性饲料添加剂为主，与载体或者稀释剂按照一定比例配制的饲料，包括复合预混合饲料、微量元素预混合饲料、维生素预混合饲料。
本发明涉及的浓缩饲料是指主要有蛋白质、矿物质和饲料添加剂按照一定比例配制的饲料。
本发明涉及的配合饲料是指根据养殖动物营养需要，将多种饲料原料和饲料添加剂按照一定比例配制的饲料。
本发明涉及的精料补充料是指为补充草食动物的营养，将多种饲料原料和饲料添加剂按照一定比例配制的饲料。
在另一实施方案中，本发明所述药用组合物或由其制备的饲料添加剂等用于鸡、珍珠鸡、鸭、鹅、鸽子和鹌鹑等家禽的饲养。
在另一实施方案中，本发明所述药用组合物或由其制备的饲料添加剂等用于猪、牛、羊、马、驴、兔、鹿、猫、狗、狐、貂或貉等家畜的饲养。
在另一实施方案中，本发明所述药用组合物或由其制备的饲料添加剂等用于宠物的饲养。
本发明首次发现含有4-18个碳原子的含氧碳氢衍生物包括脂肪醇、脂肪酸和脂肪酸甘油酯能作为多粘菌素增效剂，特别是作为多粘菌素抑制敏感菌株的协同增效剂和多粘菌素的耐药性逆转剂，为多粘菌素的应用提供了更为有效的应用空间，在制药领域和动物养殖领域具有十分重要的应用价值。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1：含氧碳氢衍生物对多粘菌素协同增效作用的体外生物学研究。
实验样品：多粘菌素E(19000IU/mg)、多粘菌素B(6000IU/mg)、丁酸、己酸、辛酸、壬酸、癸酸、十一酸、月桂酸、硬脂酸、十一烯酸、新癸酸、癸醇、月桂醇、癸醛、月桂醛、甘油单癸酯、甘油单月桂酯和癸酸癸酯。
实验菌株：大肠杆菌3Y-9(对多粘菌素E敏感)、大肠杆菌3D-5和沙门氏菌CU0208(对多粘菌素E耐药)、绿脓杆菌B545和志贺氏菌4082(对多粘菌素B耐药)。
实验方法：用微量稀释法测试各实验样品对实验菌株的体外最小抑制浓度(MIC)，如表1所示。同时测试在培养中分别添加100ppm含氧碳氢碳氢衍生物时多粘菌素E或多粘菌素B对不同菌株的最小抑菌浓度，与无相关含氧碳氢衍生物时多粘菌素的MIC值相比较，判断其增效程度。试验结果见表1和2。
实验结果：含氧碳氢衍生物对大肠杆菌、绿脓杆菌、沙门氏菌和志贺氏菌抑制作用弱(表1)；含氧碳氢衍生物对多粘菌素敏感的大肠杆菌可以降低多粘菌素对相应菌株的体外最小抑菌浓度2-4倍，对耐药菌株不同的衍生物可以降低多粘菌素的对不同菌株的体外最小抑菌浓度最高64倍(表2)。
表1 多粘菌素和含氧碳氢衍生物对大肠杆菌等革兰氏阴性菌的体外最小抑菌浓度(MIC,ug/ml)
Figure PCTCN2016077921-appb-000006
Figure PCTCN2016077921-appb-000007
表2 含氧碳氢衍生物100ppm条件下多粘菌素对不同菌株的体外最小抑菌浓度(MIC,ug/ml)
Figure PCTCN2016077921-appb-000008
Figure PCTCN2016077921-appb-000009
注：在100ppm不同含氧碳氢衍生物条件下，测试多粘菌素E对大肠杆菌和沙门氏菌的最小抑菌浓度，测试多粘菌素B对绿脓杆菌和志贺氏菌的体外最小抑菌浓度。
实施例2癸酸对多粘菌素协同抑菌作用的剂量研究
实验样品：多粘菌素E、多粘菌素B、癸酸；
实验菌株：大肠杆菌3Y-9(对多粘菌素E敏感)、大肠杆菌3D-5和沙门氏菌CU0208(对多粘菌素E耐药)、绿脓杆菌B545和志贺氏菌4082(对多粘菌素B耐药)。
实验方法：用微量棋盘稀释法测试在培养中分别含有不同浓度癸酸时多粘菌素E或多粘菌素B对相应菌株的体外最小抑制浓度。
实验结果：癸酸对相关试验菌株抑制活性弱(表1)；而在不同浓度的癸酸联合应用下，随着癸酸浓度的提高多粘菌素对相应菌株的最小抑菌浓度降低，呈明显的现剂量效应关系(表3)。
表3 不同浓度癸酸条件下多粘菌素对不同细菌的体外最小抑制浓度(MIC，ug/ml)
Figure PCTCN2016077921-appb-000010
Figure PCTCN2016077921-appb-000011
注：在不同癸酸浓度条件下，测试多粘菌素E对大肠杆菌和沙门氏菌的最小抑菌浓度，测试多粘菌素B对绿脓杆菌和志贺氏菌的体外最小抑菌浓度。
实施例3 动物试验：癸酸和甘油单癸酯在小鼠体内对多粘菌素B协同增效作用的研究
实验样品：癸酸、甘油单癸酯；
实验动物：小鼠，雌雄各半，140只，体重18-22g；
实验方法：140只体重相近的小鼠，随机分成7组，每组20只，雌雄各半，各试验组小鼠按表4在攻毒前1小时和攻毒后每8小时肌注不同的药物，药物连用3天。在首次给药1小时后腹腔注射攻击感染绿脓杆菌B545株2×107CFU/鼠，观察攻击感染后1周内各试验组的死亡率。
实验结果：小鼠攻毒试验结果显示，癸酸和甘油单癸酯均能协同增强多粘菌素B抗绿脓杆菌的效果，降低试验小鼠的死亡率。(表4)。
表4 癸酸和甘油单癸酯在小鼠体内对多粘菌素B协同增效作用的试验结果
Figure PCTCN2016077921-appb-000012
注：5是将多粘菌素B(按2mg/kg体重的量)和癸酸(按300mg/kg体重的量)混合后进行肌肉注射、7组是将多粘菌素B(按2mg/kg体重的量)和甘油单癸酯(按300mg/kg体重的量)混合后进行肌肉注射。
实施例4 动物试验：甘油单癸酯与多粘菌素E协同控制仔猪水肿病的研究
实验样品：多粘菌素E(硫酸粘杆菌素)、甘油单癸酯、大肠杆菌3D-5株(仔猪水肿 型大肠杆菌)；
实验动物：杜长大三元杂断奶仔猪，180头，24日龄，体重相近；
实验方法：180头24日龄杜长大三元断奶仔猪随机分成7组，每组30头。饲料为定制不添加任何药物的保育粉料。各试验组仔猪按表5在攻毒前1小时和攻毒后每8小时肌注不同的药物，药物连用3天。在首次给药1小时后肌肉注射攻击感染大肠杆菌3D-5株5×108CFU/鼠，观察攻击感染后1周内各试验组仔的死亡率。
实验结果：甘油单癸酯与硫酸粘杆菌素联合应用时比单独使用甘油单癸酯或硫酸粘杆菌素时对仔猪水肿病的治疗效果更显著，二者表现出明显的协同作用。(表5)
表5 甘油单癸酯与多粘菌素E协同控制仔猪水肿病的试验结果
Figure PCTCN2016077921-appb-000013
注：6是将硫酸粘杆菌素(按2mg/kg体重的量)和甘油单癸酯(按200mg/kg体重的量)混合后进行肌肉注射。
实施例5 动物试验：癸酸癸酯与多粘菌素E在肉鸡饲料中联合应用的效果研究
将1200羽1日龄快大黄羽肉鸡随机分成6组，每组4个重复，每个重复50羽。按表6分组并在饲料中分别添加硫酸粘杆菌素(多粘菌素E)或/和癸酸癸酯。试验期笼养，自由采食和饮水，统计试验期21天内各试验组的存活率、增重和料肉比。试验结果显示，癸酸癸酯与硫酸粘杆菌素合用组比单用时的生产性能显著提高，且呈剂量相关性(表6)。
表6 癸酸与多粘菌素E在肉鸡料中的联合应用效果
Figure PCTCN2016077921-appb-000014

Claims (19)

  1. 含有4～18个碳原子的含氧碳氢衍生物作为多粘菌素的协同增效剂在制备治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物，或动物用饲料添加剂中应用。
  2. 根据权利要求1所述的应用，其特征在于，所述的含氧碳氢衍生物是结构如式Ⅰ所示的含有4～18个碳原子的脂肪醇：
    Figure PCTCN2016077921-appb-100001
    其中，R1选自C3-17直链或支链的饱和烷基、C3-17直链或支链的不饱和烷基。
  3. 根据权利要求2所述的应用，其特征在于，所述的脂肪醇为含有10-12个碳原子的脂肪醇，R1选自C9-11直链或支链的饱和烷基、C9-11直链或支链的不饱和烷基。
  4. 根据权利要求2所述的应用，其特征在于，所述的含有4～18个碳原子的脂肪醇选自丙醇、丁醇、正戊醇、己醇、庚醇、辛醇、壬醇、癸醇、十一烷醇、月桂醇、肉豆蔻醇、棕榈醇、硬脂醇或这些醇对应的同分异构醇，或这些醇对应碳原子数的含有一个链端或链中的双键的不饱和脂肪醇。
  5. 根据权利要求1所述的应用，其特征在于，所述的含氧碳氢衍生物是结构如式Ⅱ所示的含有4-18个碳原子的脂肪醛：
    Figure PCTCN2016077921-appb-100002
    其中，R2选自C3-17直链或支链的饱和烷基、C3-17直链或支链的不饱和烷基。
  6. 根据权利要求5所述的应用，其特征在于，所述的R2选自C9-11直链或支链的饱和烷基、C9-11直链或支链的不饱和烷基。
  7. 根据权利要求5所述的应用，其特征在于，所述的含有4-18个碳原子的脂肪醛选自丁醛、戊醛、己醛、庚醛、辛醛、壬醛、十一醛、月桂醛、肉豆蔻醛、棕榈醛、硬脂醛或这些醛对应的同分异构醛，或这些醛对应碳原子数含一个链端或链中双键的不饱和脂肪醛。
  8. 根据权利要求1所述的应用，其特征在于，所述的含氧碳氢衍生物是结构如式Ⅲ所示的含有4～18个碳原子的脂肪酸：
    Figure PCTCN2016077921-appb-100003
    其中，R3选自C3-17直链或支链的饱和烷基、C3-17直链或支链的不饱和烷基。
  9. 根据权利要求8所述的应用，其特征在于，所述的脂肪酸为含有10-11个碳原子的脂肪酸，R3选自C9-11直链或支链的饱和烷基、C9-11直链或支链的不饱和烷基。
  10. 根据权利要求8所述的应用，其特征在于，所述的含有4～18个碳原子的脂肪酸选自丙酸、丁酸、戊酸、己酸、庚酸、辛酸、壬酸、癸酸、十一碳酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸或这些酸对应的同分异构酸，或这些酸对应碳原子数的含有一个链端或链中的双键的不饱和脂肪酸。
  11. 根据权利要求1所述的应用，其特征在于，所述的含氧碳氢衍生物是结构如式Ⅳ所示的含有4～18个碳原子的脂肪酸的酯化衍生物：
    Figure PCTCN2016077921-appb-100004
    其中，R4选自C3-17直链或支链的饱和烷基、C3-17直链或支链的不饱和烷基；R5选自C1-18直链或支链的饱和烷基、C1-18直链或支链的不饱和烷基、C1-18直链或支链的羟基取代烷基。
  12. 根据权利要求11所述的应用，其特征在于，所述的酯化产物为含有10-12个碳原子的脂肪酸与含有1-18个碳原子的脂肪醇反应的产物，R4选自C9-11直链或支链的饱和烷基、C9-11直链或支链的不饱和烷基；R5选自C1-18直链或支链的饱和烷基、C1-18直链或支链的不饱和烷基、C1-18直链或支链的羟基取代烷基。
  13. 根据权利要求11所述的应用，其特征在于，所述的含有4～18个碳原子的脂肪酸的酯化衍生物为甘油单癸酯或甘油单月桂酯。
  14. 根据权利要求1所述的应用，其特征在于，所述的多粘菌素选自多粘菌素A、多粘菌素B、多粘菌素C、多粘菌素D或多粘菌素E。
  15. 根据权利要求1所述的应用，其特征在于，所述的治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物为人用或动物用治疗多粘菌素敏感菌或耐药菌感染所致疾病的药物。
  16. 根据权利要求15所述的应用，其特征在于，所述的多粘菌素敏感菌或耐药菌感染所致疾病包括创面、尿路、眼、耳、气管、皮肤黏膜、肠道的感染和败血症、腹膜炎及脑膜 炎。
  17. 根据权利要求1所述的应用，其特征在于，所述的动物用饲料添加剂为动物生长促进剂。
  18. 根据权利要求17所述的应用，其特征在于，所述的动物包括各个生长阶段的畜禽。
  19. 根据权利要求18所述的应用，其特征在于，所述的畜禽为鸡、珍珠鸡、鸭、鹅、鸽、鹌鹑、猪、牛、羊、马、兔、驴、鹿、猫、狗、狐、貂或貉。
PCT/CN2016/077921 2016-03-04 2016-03-30 含氧碳氢衍生物作为多粘菌素的协同增效剂的应用 WO2017147958A1 (zh)

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