CN103096720B - Bismuth-mercaptan that is agriculture, industrial and other purposes is used for as preservative - Google Patents

Bismuth-mercaptan that is agriculture, industrial and other purposes is used for as preservative Download PDF

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CN103096720B
CN103096720B CN201180042863.XA CN201180042863A CN103096720B CN 103096720 B CN103096720 B CN 103096720B CN 201180042863 A CN201180042863 A CN 201180042863A CN 103096720 B CN103096720 B CN 103096720B
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mercaptan
bis
antibiotic
compound
sulfydryl
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CN103096720A (en
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B·H·J·贝克
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Microbion Corp
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Abstract

The present invention describes and comprises the composition of novel homogeneous microparticle suspension and method and be used for the treatment of and comprise the natural of bacterial biof iotalm and artificial surfaces, it comprises concertedness beyong contemplation or humidification between bismuth-mercaptan (BT) compound and some antibiotic, to provide the preparation comprising antibiotic preparation.Invention further describes disclosed BT compound and BT compound+antibiotic combinations before the antibacterial properties do not predicted and antibiont film character, it comprises some this composition to preferential effect of some gram positive bacteria infection for the treatment of and some this composition to different preferential effect of some gram positive bacterial infection for the treatment of.

Description

Bismuth-mercaptan that is agriculture, industrial and other purposes is used for as preservative
The cross reference of related application
This application claims the U.S. Provisional Application No.61/373 that the PCT application No.PCT/US2011/023549 and 2010 that submits on February 3rd, 2011 submits to 12, on Augusts, the rights and interests of 188, it is all incorporated herein with way of reference separately.
Background
Technical field
Disclosure working of an invention scheme relates to the composition and method that are used for the treatment of infected by microbes.Especially, the present embodiment relates to for (comprising in the treatment of bacterial biof iotalm and other symptom) treatment controlling the improvement of bacteriological infection in agricultural, industry, manufacturing industry, clinical, individual health care and other situation.
description of related art
The combination of a series of collaborative cell and interaction of molecules that promote response and opposing infected by microbes and/or promotion to restore or maintain plant and animal (comprising people) soma usually can by the adverse effect of various external factor, such as opportunistic infections and hospital infection (clinical protocol of infection risk such as, can be increased); Antibiotic local or systemic application (it can affect Growth of Cells, transfer or other function and also can select antibiotic resistant microbes); And/or other factors.
Regrettably, the antibiotic that system or local are introduced is usually invalid for the many chronic infections for the treatment of, and is not usually used, unless there is acute bacterial infection.Current method comprises to be used or applies antibiotic, but this type of therapy may promote the appearance of antibiotic resistance bacteria strain and/or may for antagonism bacterial biof iotalm invalid.Therefore, when detect drug-fast bacteria (such as methicillin resistant S staphylococcus ((Staphylococcusaureus) or MRSA) time, use antibacterial agent may become particular importance.Have many widely used antibacterial agents, but the bacterial flora produced or subgroup may not replied to these reagent, or other treatment available at present any is not replied.In addition, many antibacterial agents may be toxicity can effectively to resist under the concentration needed for produced bacteriological infection host cell, and therefore these antibacterial agents are unaccommodated.This problem may be outstanding especially when attempting removing infection from self-faced, described self-faced comprises the agriculturally important species of commercial surface characteristic body and/or such as many crops, also comprise interior epithelial surface, such as respiratory tract (such as, air flue, nose throat channel, tracheae, lung, bronchi, bronchiole, alveolar etc.) or intestines and stomach (such as, oral cavity, oesophagus, stomach, intestines, rectum, anus etc.) or other epithelial surface.
Problematic is especially form infection by bacterial biof iotalm (bacterial organisms be familiar with recently), unicellular (" swimming ") bacterium free is whereby gathered into organized many cells group (biomembrane (biofilm)) by intercellular adhesion, and described many cells group has significantly different behavior patterns, gene expression and to the susceptibility of surrounding material comprising antibiotic.Biomembrane can adopt the biophylaxis mechanism do not found in planktonic bacteria, and described mechanism can protect biofilm communities from antibiotic and host immune response.Established biomembrane can stop tissue healing process.
Continuing to comprise staphylococcus aureus (it comprises MRSA (methicillin resistant S staphylococcus)), enterococcus, Escherichia coli, pseudomonas aeruginosa, streptococcus and Acinetobacter baumannii with common microorgranic contaminant under potential harmful infection.These microorganisms show the ability of several months of surviving on the clinical surface of non-nutritive a bit.Show staphylococcus aureus to survive in dry glass surrounding, and 3 to 6 months (Domenico etc., 1999Infect.Immun.67:664-669) of surviving on dry blood and cotton fiber.Escherichia coli and pseudomonas aeruginosa are shown on dry blood and cotton fiber than staphylococcus aureus survival longer time (as previously mentioned).
Microbial biofilm is relevant with the resistance obviously increased disinfectant and antibiotic.Biomembrane form is formed when bacterium and/or fungi are attached to surface.This attachment triggers genetic transcription and changes, and causes very flexible and is difficult to the secretion of the polysaccharide matrix penetrated, protection microorganism.Except biomembrane is to except the resistance of antibiotic highly significant, they are to the resistance of immune system.Biomembrane, once be formed, is very difficult to eradicate, so prevention biofilm formation is very important clinical priority principle.Nearest research shows, and open wound can be polluted fast by biomembrane.These microbial biofilms are considered to postpone wound healing, and probably relevant to the generation that serious wounds infects.
Complete functional skin and other epithelial tissue are (such as, the general non-vascular epithelial surface forming barrier between microorganism and its external environment condition, exist in those and respiratory tract and GI lining form, the glandular tissue etc. that such as, exist in skin those) maintenance be important for the health of people and other animal and survival.
bismuth mercaptan-(BT) class antibacterial agent
Many have antimicrobial, particularly the natural products (such as antibiotic) of antibacterial properties and synthesis of chemicals are known in the art, and characterized by chemical constitution and anti-microbial effect at least in part, described anti-microbial effect such as kills and wounds ability (" killing " effect of microorganism, such as bactericidal property), stop or damage ability (" suppression " effect of growth of microorganism, such as antibacterial character), or interference microbial function, such as field planting or infection site, the bacterial secretory of exopolysaccharide and/or be converted into the ability of expansion of biomembrane colony or biofilm formation from swimming.Such as, U.S.6,582,719 discuss (comprising bismuth-mercaptan or BT compound) such as antibiotic, disinfectant, antibacterial agents, comprise the factor of the choice and operation affecting such composition, comprise such as sterilization or antibacterial character, valid density and the risk of toxicity to host tissue.
Bismuth, V race metal is the element (class is silvery) with anti-microbial properties.Bismuth self may not have therapeutic action and may show some unsuitable character, therefore replaces, and usually can send together with complexing agent, carrier and/or other medium and use, modal example is Pepto wherein bismuth and subsalicylate combine (huge legendary turtle is closed).Research before is determined, some is containing mercaptan-(-SH, sulfydryl) combination of compound such as dithioglycol and bismuth provides exemplary bismuth mercaptan (BT) compound, compared with other available at present bismuth preparation, improves the antimicrobial efficacy of bismuth.Many mercaptan compounds that can be used for producing BT are had (to be disclosed in such as Domenico etc., 2001Antimicrob.Agent.Chemotherap.45 (5): 1417-1421, Domenico etc., 1997Antimicrob.Agent.Chemother.41 (8): 1697-1703, and U.S.RE37,793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248; Also see such as U.S.6,582,719) several, in these preparations can suppress biofilm formation.
Prove that BT compound resists the activity of following bacterium: MRSA (methicillin resistant S staphylococcus), MRSE (methicillin resistant Staphylococcus epidermidis (methicillinresistantS.epidermidis)), Mycobacterium tuberculosis (Mycobacteriumtuberculosis), mycobacterium avium (Mycobacteriumavium), drug resistance pseudomonas aeruginosa (P.aeruginosa), enterotoxigenic E.Coli (enterotoxigenicE.coli), enterohemorrhagic Escherichia coli (enterohemorrhagicE.coli), Klebsiella Pneumoniae (Klebsiellapneumoniae), clostridium difficile (Clostridiumdifficile), helicobacter pylori (Heliobacterpylori), legionella pneumophila (Legionellapneumophila), enterococcus faecalis (Enterococcusfaecalis), enterobacter cloacae (Enterobactercloacae), salmonella typhimurium (Salmonellatyphimurium), proteus vulgaris (Proteusvulgaris), YE (Yersiniaenterocolitica), comma bacillus (Vibriocholerae) and shigella flexneri (Shigellaflexneri) (Domenico etc., 1997Antimicrob.AgentsChemother.41:1697-1703).Also has the evidence of anti-cytomegalovirus, 1 type pure hcrpesviruses (HSV-1) and HSV-2 and yeast and fungi such as Candida albicans.Proved BT reduce Pathogenicity of Bacteria, suppress or kill and wound broad-spectrum antibiotic resistant microorganism (Gram-positive and Gram-negative), prevention biofilm formation, prevention septic shock, treatment septicemia and increase to before to it effect showing the antibiotic antimicrobial susceptibility of resistance (see such as, Domenico etc., 2001AgentsChemother.45:1417-1421; Domenico etc., 2000Infect.Med.17:123-127; Domenico etc., 2003Res.Adv.InAntimicrob.Agents & Chemother.3:79-85; Domenico etc., 1997Antimicrob.AgentsChemother.41 (8): 1697-1703; The 1999JAntimicrob.Chemother.44:601-605 such as Domenico etc., 1999Infect.Immun.67:664-669:Huang; Veloira etc., 2003JAntimicrob.Chemother.52:915-919; Wu etc., 2002AmJRespirCellMotBiol.26:731-738).
Although BT compound existed more than 10 years, but effectively select the suitable BT compound being used for the specific indication that catches to be still the target being difficult to realize, behavior wherein for the particular B T of specified microorganisms can not be predicted, wherein can not be predicted for the particular B T of specified microorganisms and the synergistic activity of certain antibiotics, wherein external BT effect may not always BT effect in predictor, and wherein for the possible BT effect can not predicted for microbiologic population's (being such as organized into biomembranous bacterium) of BT effect of (unicellular) micropopulation that swims.In addition, the restriction of the aspect such as solvability, tissue permeability, bioavilability, bio distribution may hinder safe and effective ability of sending clinical benefit in some BT compounds.Disclosure invention embodiment solves these to be needed and provides other associated advantages.
the protection of plant and agricultural products: description of related art
In agricultural and botany field, for reduce in plant biomembrane and disease preparation and on such as seed, plant, fruit and flower, soil and use the method for these preparations to have generally acknowledged demand on cut-flower, trees, fruit, leaf, stem and other plant part.
Agriculturally, lose the crop of multi-million dollar every year owing to forming biomembrane.In plant, the problem of anthracnose and biomembrane relevant disease is well-known, although attempt multiple not satisfied method to solve it.Plant disease also affects in transport and preserves the industry related in fruit, vegetables, cut-flower and trees and other plant product, because the normal protective mechanisms that complete surviving plants adopts is no longer feasible in the product of results.
Therefore, for agriculture object, need to be reduced in original position, microbial growth amount in transit or on the surface of point of sale place leaf, stem, fruit and flower, maintain the compliance to environmental legislation simultaneously.Meanwhile, need to make in cut-flower, plant and trees water flow to maintain plant tissue dilation, integrality and quality, thus strengthen the required feature of these products.
In plant, cause the organism of infectious disease to comprise fungi, bacterium, virus, protozoa, nematode and parasitic plant.By gnawing plant tissue and passing through to expose plant tissue in microorganism, insect and other insect also affect plant health.
Usually in aqueous environments (such as at aquatic conditions or in water droplet or under the condition of other high humility), when bacterium mating surface, produce biomembrane, and after the coupling, biofilm formation thing (biofilmformer) starts to drain stickum, then described stickum in conjunction with various material, can comprise metal, plastics, Medical implant and tissue.In industry and agricultural environment, these biomembranes can cause many problems, comprise the degraded of material and the obstruction of pipeline, and cause the infection of surrounding tissue when producing in medical environment.Medical domain to be especially easily subject to by biofilm formation cause the impact of problem; The bacterium existed in biomembrane easily filters the wound of the medical treatment device of implantation, conduit (urine, vein, dialysis, heart) and indolence.Agriculturally, biomembrane can cause mastitis, Pierce's disease (Pierce'sdisease), ring rot in potato, in the various crop fusarium wilt permitted in eurypalynous plant and anthracnose.Biomembrane also reduces quality and the life of product of cut-flower and trees.
Caused by the bacteriogenic biomembrane that many plant diseases are generated by soil.In natural surroundings, most of microorganism is present in and is usually described as in biomembranous many cells aggregation.By complex matrices make cell adherence to surface and each other, described complex matrices comprises various Extracellular Polymers (EPS), comprises exocellular polysaccharide, albumen and DNA.In morbidity with during symbiosis and the bacterium that plant is relevant in symbiotic relation and host tissue surface interaction.Cell cluster from childhood is day by day disclosed to all different biological film-type structure of large biomembrane from the observation of plant Related Bacteria.The tendency of the surface nature of plant tissue, nutrition and water conservancy expenditure and field planting bacterium affects gained biofilm structure (Ramey etc., 2004CurrOpinionMicrobiol.7:602-9) strongly.
Terrestrial environment possesses rich and varied micropopulation, and these micropopulations can be competed and change resources bank.In this complexity and competitive environment, plant provides the protection oasis of nutritious tissue.Bacteria planting is in the leaf of plant, root, seed and inner vasculature.Each organization type has distinct chemical and physical property, for micropopulation provides challenge and chance.Can biomembrane be formed in attachment or subsequent stage, very likely cause or regulating plant-microbial interaction.Other time and spatial complexity can be caused when many microorganisms actively change field planting plant environment.
The bacterium of surface attachment has remarkable impact to agricultural.In developed country, the caused loss of plant disease is up to 25% of crop yield, and this ratio is far longer than developing country.Epiphyte group is made up of bank (reservoir) and following infection genesis, and can find on host and non-host plants.In the vasculature of these plants, bacterial pathogens vine wood friend bacterium (Xylophylusampelinus) viny forms thick biomembrane (Grail and Manceau2003).Xyllela fastidiosa (Xylellafastidiosa) is the pathogenic bacteria of Pierce's disease in vine.Xyllela fastidiosa can form biomembrane in the xylem vessel of many economic important crops.Pathogenic mechanisms is mainly due to the obstruction by xylem vessel caused by xyllela fastidiosa gathering and biofilm formation.It is believed that, vascular obstruction is the main cause of disease progression, wherein xylem sap provides the crude media (Zaini etc., 2009FEMSMicrobiolLETT.295:129-34) of the virulence promoting Pierce's disease viny and the variegated etiolation of oranges and tangerines (citrusvariegatedchlorosis).
One of most corresponding plants pathogene, pseudomonas syringae (Pseudomonassyringae) causes the brown spot of beans.It disperses field planting on blade face with independent groupuscule (being less than ten cells), and more large group (being greater than 1000 cells) is mainly developing near the trichome or vein place with higher nutrient availability.Large aggregation resists desiccation stress better than autoblast.When causing infecting on host plant tissue, pseudomonas syringae is as epiphyte existence (that is, the field planting thing of the acrial part of plant) (Monier etc., PNAS2003; 100:15977-82).
Pseudomonas putida (Pseudomonasputida) can the existence of root exudates in rapid answer soil, assembles and form the stabilate film (Microbiol2002 such as Espinosa-Urgel in root field planting position; 148:341-3).
Xanthomonas campestris pv campestris pvs oryzae and oryzicola (Xanthomonascampestrispv.campestris) (Xcc) causes the black rot on crucifer, arrives vasculature by wound site in root.Virulence comprises degraded extracellular enzyme and exocellular polysaccharide xanthan gum, and it is the necessary (PNAS2003 such as Dow for virulence; 100:10995-1000).
Xanthomonas axonopodis Kidney bean mutation (Xanthomonassmithiisubsp.citri) is the reason of c itrus canker disease.Except Europe, this disease finds in most of continent in the world all.At many countries eradication of pathogens already.Xanthomonas axonopodis is formed in ulcer pathology on the fruit of citrus plants, leaf and withe.Wind folder rain bacterium origin seedbed can be sent out at the most 15km so that by pore or wound infection mandarin tree, (Sosnowski, etc., PlantPathol2009; 58:621-35).
P.stwartii subsp.stewartii (Pantoeastewartiisubsp.Stewartii) is caused Stewart's wilt (Stewart'swiltdisease) and is propagated by corn flea beetle.Bacterium mainly to rest in host's xylem and produces a large amount of exocellular polysaccharide (PNAS1998 such as vonBodman; 95:7687-92).
Ralstonia solanacearum (Ralstoniasolanacearum) is on many plants, cause fatal withered soil-borne disease substance.Virulence is determined by the EPS and the cell wall degrading enzyme (MolMicrobiol2002 such as Kang that complicated regulating networks control; 46:427-37).
Potato Ring Rot (Clavibactermichiganensissubsp.Sepedonicus) is the Gram-positive phytopathogen causing bacterium ring rot in potato.Marques and colleague illustrate large bacterium, are namely attached to the aggregation (Phytopathol2003 such as Marques encasing matrix of xylem vessel; 93:S57).
By the rapid impregnation of plant tissue, produce biomembranous Erwinia chrysanthemi (Erwiniachrysanthemi) and cause soft rot.The generation of pectase can be that quorum sensing (QS) regulates, and thus can not form bacteria aggregates, this can stop decompose pectin enzyme (pectinolyticenzyme) to be secreted.Relevant phytopathogen erwinia amylovora (Erwiniaamylovora) infects about 75 kinds of different plant species, is allly the rose family.The host of this bacterium comprises apple, pears, blackberry, blueberry, Xun, crabapple, fiery sour jujube (Pyracantha), hawthorn, Japanese quince or common flowering quince, quickbeam, Li, Quinces Quince, raspberry, Chinese bush cherry and meadow sweet.The apple of cultivating, Li He Quinces Quince infect the most serious kind.Cause more than 220 one time, state of Michigan fire blast infectious disease (fireblightepidemic) in 2000,000 tree death, reaches the total losses of forty-two million.The fire blast loss of the annual U.S. and regulate expenditure assessment are more than $ 100,000,000 (Norelli etc., PlantDis2003; 87:26-32).
Erwinia amylovora produces two kinds of exocellular polysaccharides, the outer sugar of born of the same parents (amylovoran) and levulan, and it causes the characteristic fire blast wilting symptoms (Phytopathol2009 such as Koczan in host plant; 99:1237-44).In addition, the feature of albumen of other gene and their codings is the virulence factor of erwinia amylovora, and this virulence factor coding promotes enzyme (Oh and Beer.FEMSMicrobiologyLett2005 of sorbitol metabolism, proteolytic activity and results iron; 253:185-192).
No matter what part of plant is subject to the antimicrobial plant pathogen invasion of such as biofilm formation thing, and this effect all can make plant die down or kill plant usually.By infecting leaf, pathogene reduces the ability (such as, passing through photosynthesis) of plant production food.Fluid conveying vascular in the stem of some phytopathogens blocking supply leaf, and when these pathogen invasion roots, the picked-up of water and nutrition reduces or is completely interrupted.In soil growing plant and in vase water in cutting plants the blocking of plant vasular structure be usually directed to produce biomembranous bacterium, its block water and nutriment flowing.
When plant be subject to one of these microorganisms invasion and attack time, the damage caused provides the chance of other microorganism instruction plant tissue, and just with assault finally damage and destroy plant.Under the environmental stress of such as arid or nutritional deficiency, plant is especially easily subject to microbiological attack.
Sometimes, microorganism " infection " is symbiosis, and wherein two organisms all obtain an advantage.A good example is well-known azotobacteria (rhizobium); in the nodules of its field planting on the root of beans (pulse family) plant-plant provides food and protection, simultaneously bacterium from air, absorb nitrogen and its is transformed with formed host can material.As another example, mycorhiza is the whole object fungi with plant roots with symbiotic relation.In view of the symbiosis that these are useful mutually, preservation or protective plant can reasonably adopt the antimicrobial that can not destroy these symbiotic relations as far as possible from the impact of harmful microorganism pathogene.
Decomposition dead organism be that in the process of humus, saprophytic fungus is required, described humus is required for good soil structure.Saprophytic fungus does not have any chlorophyll, thus can not make to use up to obtain energy (such as, passing through photosynthesis); The saprophytic fungus that replaces obtains its energy by decomposing alive or dead plant and animal body.Saprophytic fungus also can grow with symbiotic relation with certain plants kind, and such as, the mycorhiza in the radicula of coniferale plant, it cannot survive to absorb required nutriment not have them.What control the chemical reagent of harmful plant pathogens widely uses the balance can damaging these useful fungies, and disagrees with the principle of organization and administration.
But have other more unwelcome fungi, the plant that its invasion and attack are lived also makes them die down or kills them.Another kind of antimicrobial plant pathogene, i.e. virus, can field planting in the cell of plant tissue, thus usually can not use the chemical substance of local application to treat, make to destroy infected plant.The current antibiotic (although having been found that some antibiotic developed for other object are for plant) without the exploitation for the treatment of plant specificity, causes a large amount of economic important plant species to be subject to pathogene bacteria attack.Such as, the fire blast of verified rosaceous various plants kind infects and cannot treat.By contrast, use the chemical substance of local application can kill many harmful fungoids, and plant host can not be damaged, because conk habitat is different, namely, a large amount of less desirable pathogene fungi tends to grow on plant surface instead of grow within plant tissue, and it uses root shape structure to extract nutrients.
Because it is usually difficult or impossible to kill various plants pathogene, so adopt the principle of " prevention is better than treating " for the protection of a lot of methods of plant against harmful microbial pathogens.By observing good hygiene condition when cultivation and growing plant, many antimicrobial plant diseases can be prevented by stoping the chance forming infected by microbes.Usually, when the infection that these reagent of preventive use instead of response are formed, the insecticide of remarkable less amount or microbicide can be effective.
If they are not growths best or close under optimal conditions, such as, due to self difference soil quality (such as, lacking nutrients) or have arid or excessive rainwater or flood simultaneously, then plant also can more easy infection disease.Such as, pole wet environment can promote pathogene fungi and/or bacterial growth.Such as, by quorum sensing (Dulla and Lindow.PNAS2008 that the water conservancy expenditure on blade face represents in pseudomonas syringae; 105:3-082-7).Certainly, and not all plant disease all prevents by good agriculture sanitary condition, as when some plant diseases are by insect transmission and under other is anemochoric situation.Such as aphid and other suction juice insect are the main carriers of virus.In atmosphere and raindrop and in dabbling with the spore of fungal disease.
Biomembrane on seed and young shoot
Bacterial adhesion seed is the process strongly affecting colonization.Seed supply business deliberately uses the coated seed reservation of microbial biofilm to inoculate developmental circle usually.On the contrary, the usual sources of biomembrane normally alimentary infection on the seed eaten for people and young shoot.Pseudomonas putida effectively adhere to seed and by field planting subsequently at root circle.The non-pathogene actinomycetic plant endogenesis colony found in Wheat Tissue comes from the actinomycetic inner field planting of surperficial sterilized seed.The endophyte seed populations of useful azotobacteria can assist in ensuring that following colonization.Other of seed field planting studies the bar-shaped and spherical bacteria being reported in EPS in the electron scanning micrograph of alfalfa seed and young shoot and being embedded in.As everyone knows, biomembrane tolerance washing and other common antibacterium process on seed and young shoot.The discoveries such as Fett, Escherichia coli O 157 on clover young shoot: H7 and salmonella colony need the process stricter than simple water washing to reduce the number of attached microbial, and cannot reach all the time and remove completely.The bacterium of survival may be retained in the biomembrane (CurrOpinionMicrobiol2004 such as Ramey; 7:602-9).
Cut-flower and trees
Vascular disorders substance inhabits the xylem of plant host or phloem and usually relies on insect vector or wound disseminates.Cutting flower or trees are the wounds of the similar type especially easily infected by vascular.Biofilm bacteria enters at cutting surfaces place and blocks vasculature, and disturbs water, mineral matter and nutriment to flow.Be diluted in cut-flower preservative in vase water usually containing salicylate or aspirin to reduce biofilm formation (Domenico etc., JAntimicrobChemo1991; 28:801-10; Salo etc., Infection1995; 23:371-7), and provide low pH to prevent bacterial growth and disrupting biofilm.
Antimicrobial in agricultural.The elimination of phytopathogen invasion is extremely important to protective plant industry, maintenance garden and natural surroundings in the world.The endemoepidemic consequence of pathogene may be very serious, can affect national economy in some cases.The technology of the method Dependence Treatment of current eradication of pathogens, removal and the infected host plant of disposal.There are many examples of many successful in these technology, but wherein also have many unsuccessful.Success relies on the biology of pathogene and EPDML good understanding and and the interaction of host thereof.Checking that world wide internal therapy phytopathogen is with in the example of the host material caught, particularly at Australasia, use various technology, comprise burning, bury, prune, compost, soil and Biofumigation, Exposure to Sunlight, steam sterilizing and bio-carrier control (Sosnowski, Deng, PlantPathol2009; 58:621-35).
From the 1950's, also used antibiosis usually to control some bacterial disease of high price fruit, vegetables and ornamental plants.Nowadays, on plant, normally used antibiotic is terramycin and streptomycin.In the U.S., the antibiotic being applied to plant accounts for less than 0.5% of the antibiotic summation of use.The resistance of phytopathogen to terramycin is rarely found, but the appearance of the streptomycin resistance bacterial strain of erwinia amylovora, pseudomonas putida and xanthomonas campestris has hampered the control to some important diseases.Therefore, in the antibiotic resistance risk of people's medicine, the effect of antibiotic usage to plant is the main topic of discussion (AnnuRevPhytopathol2002 such as McManus; 40:443-65).
Streptomycin resistance (Sm r) appearance of phytopathogen makes to plant bacterial disease control from being complicated.Such as, in the U.S., on tomato and pepper can usage chain mould usually control tomato shot hole capsicum A. mali (X.campestrispv.vesicatoria), but due to resistant strain now extensively exist so seldom use it for this object.Resistance in erwinia amylovora (fire blast pathogene) has economy and political fallout widely.Wherein report Sm rother plant pathogenic bacterium comprise carrot pectin bacillus (Pectobacteriumcarotovora), Pseudomonas cichorii (Pseudomonaschichorii), cucumber bacterium angular leaf spot fungus (Pseudomonaslachrymans), pseudomonas syringae bleb pvs oryzae and oryzicola (Pseudomonassyringaepv.papulans), pseudomonas syringae cloves pvs oryzae and oryzicola (Pseudomonassyringaepv.syringae) and nieffea picta Xanthomonas campestris (the Xanthomonasdieffenbachiae) (AnnuRevPhytopathol2002 such as McManus, 40:443-65).At US West and state of Michigan Sm rit is popular that the appearance of erwinia amylovora exacerbates fire blast.
Streptomycin and terramycin are appointed as the minimum kind of toxicity by Environmental Protection Agency USA (U.S.EnvironmentalProtectionAgency) (EPA), and carcinogenic or Mutagenicity all do not observed by two antibiotic.
Substitutes For Antibiotic can be obtained and feasible at least to a certain extent.In fact, in most of cultivating system bacterial disease management based on host genetic resistance, assanation (avoiding or remove kind of a bacterium) and the combination of culture technique of environment producing unfavorable disease progression.The BIOLOGICAL CONTROL of various kinds to plant of bacterium and fungi is used to cause increasing concern.Root circle bacterium is considered to effective microorganism competitor in root district.Introduced representation type that many different bacterium belong to in soil, on seed, root, stem tuber or other plant block to improve plant growth.These bacteriums belong to and comprise acinetobacter (Acinetobacter), Agrobacterium (Agrobacterium), Arthrobacter (Arthrobacter), Azospirillum (Azospirillum), bacillus (Bacillus), Bradyrhizobium (Bradyrhizobium), Frankia (Frankia), pseudomonas, rhizobium (Rhizobium), Serratia (Serratia), Thiobacillus (Thiobacillus) and other Pseudomonas many.Such as, some kind of bacillus can inducible system resistance (Choudhary and Johri.MicrobiolRes2009 in many plants; 164:493-513).
Although some kind is to copper opposing (CookseyAnnuRevPhytopathol1990; 28:201-14), but the application of copper compound reduces effectively the colony of some bacterial plant pathogens, and most of fruit tree crop is responsive to copper loss wound.
A large amount of synthesis and natural therapy are existed for various plant disease.Natural therapy comprises for leaf spot, mildew and the apple vinegar that scabs; For anthracnose, early stage tomato is withered, leaf is withered, powdery mildew and the sodium bicarbonate as usual bactericide are sprayed; Neem oil; Sulphur; Garlic; Hydrogen peroxide; Compost tea etc.Multiple synthetic chemical is used for prevention or treatment plant disease, and it is water-soluble or water-insoluble preparation.Microbicide comprises Fen Evil arsenic or phenarsazine, maleimide, iso-indoles dicarboximide, halogenated aryl alkanol, 4-thiopyrimidine derivatives (United States Patent (USP) 6384040), heterocycle organo-silicon compound and isothiazolinone.Many microbicides and pyrithione derivatives are combined to prepare collaborative compound (such as, EP1468607).Some isothiazole carbamyl can be used for control (such as, the US6552056 of plant insect; WO2001/064644).
Recognize the toxicity problem of microbicide in powder or crystal form, US patent reference the 29th, microbicide is dissolved in liquid flux by No. 409 instructions, can be added to dosage formulation blends, prepare final utilization resin combination by it.Although can use liquid dispersion safely in the position of preparing final utilization resin combination, not careful use or liquid disposal also can cause environment and health hazard.Alternatively, also microbicide can be used in water insoluble thermoplastic resin.Microbicide can be added into rigid thermoplastic resin composition and give biocidal activity, thus suppressing growth of microorganism (US5,229,124) in its surface.This is the solid, the melt blended solution that are substantially made up of the microbicide be dissolved in vector resin, and this vector resin is the copolymer of vinyl alcohol and (alkylidene oxygen base) acrylate.Although microbicide can be high toxicity chemical substance, in final utilization product its low concentration and its to guarantee in final utilization product microbicide to humans and animals without harm by the retention time of resin combination.
Isothiazolinone is used as microbicide usually in agricultural, such as, and N-Alkylbenzenesulfonyl-arbamoyl base-5-chloro Isothizole derivatives (such as, US5,045,555).This microbicide is widely used in such as paper industry, textile industry, for the production of coating and adhesive, for paint, intermetallic composite coating, in Resin Industry, timber industry, building industry, agricultural, forestry, fishery, food industry and petroleum industry and in pharmaceutical sector.It shows function of killing microorganism widely, and suitable amount can be added into processing water, cycle water, raw material or product.And, sterilization or sterilization facility, factory, animal house or instrument and seed, seedling and raw material can be used it for.Other derivative of isothiazolone is also known (U.S. Patent No. 3,523,121 and J.HeterocyclicChem., 8,587 (1971)).But often kind of known derivative compound all has high toxicity to animal and fish, and this significantly limits their application.
Find that when being applied to plant sodium bicarbonate also has fungicidal property usually, but usually need frequently to apply again to realize effect.
To be set forth in the disease of soft rot and the fire blast be different from respectively caused by Erwinia chrysanthemi and erwinia amylovora iron to the effect (Expert.AnnuRevPhytopathol1999 of plant host-parasite relation; 37:307-34).Because it is unique location in biosystem, iron determines the activity of phytopathogen.Produced by the siderophore of pathogene and provide not only the effective ways obtaining iron from host tissue, also can be used as the protective agent resisting iron toxicity.When falling ill, the demand of host and corrupt split and possibility chelating is another central issue.The antimicrobial of the iron picked-up of interference bacterium and cell respiration plays an important role in plant sterilization.
It is known for having many natural productss (such as, antibiotic) synthetic chemical that is antimicrobial, anticorrosion and especially antibacterial property, and it has chemistry and biological characteristic at least partly.Example feature comprises the ability (bactericidal action) of killing microorganism; Stop or damaging the ability of growth of microorganism (bacteriostasis); Or interference microbial function ability, such as field planting or infect position, metabolite bacterial secretory (some of them foul smelling) and/or by swimming to the conversion of biomembrane colony or the expansion (antibiont membrane interaction) of biofilm structure.At U.S.6,582, discuss in 719 (comprising bismuth-mercaptan or BT compound) such as antibiotic, disinfectant, preservatives, comprise the factor of the choice and operation affecting these compositions, comprise such as sterilization, antibacterial or antibiont film is tired, valid density and the risk to host tissue toxicity.
The bacterium petite of protection in biomembrane resists preservative or disinfectant usually.Such as, the antibiotic dosage needs killing free flcating germ are increased to and reach 1,500 times to kill biofilm bacteria.Under this high concentration, some are antimicrobial may be toxicity.Such as, the compound of oxybromination and chlorination is high toxicity and corrosivity.
The suppression in blossom blight stage is the key of management fire blast.The flower occurred is infected, needs erwinia amylovora is bred in stigma surface in the epiphyte stage.Rainwater is that infection is necessary, because the sugar on hypanthodium is diluted to the osmotic potential to erwinia amylovora unrestraint by it.Rainwater is also that bacterium is distributed to the important substance of hypanthodium again by column cap.These observations show, use antibiotic spraying Best Times be in this epiphyte stage, and after abundant precipitation (Johnson and Stockwell.AnnuRevPhytopathol1998; 36:227-48).
Other bacterium epiphyte also field planting column cap, on column cap, they can interact and suppress the epiphyte of pathogene to grow.The commercially available bacterium antagonist (BlightBan, pseudomonas fluorescens A506) of erwinia amylovora can be included in antibiotic spraying scheme.The combination of bacterium antagonist and chemical method suppresses the colony of pathogene, and fills up the ecological niche provided by column cap and non-pathogene concomitantly, competition microorganism (Johnson and Stockwell.AnnuRevPhytopathol1998; 36:227-48).
PTO is the conjugate base coming from pyrithione (CAS 1121-31-9), the derivative of pyridine-N-oxides.Its antifungic action is that it is by blocking as transporting mechanism provides the proton pump of energy to destroy the ability of film transhipment.Experiment shows: the fungi of low concentration can make PTO inactivation (Chandler and Segel.Antimicrob.AgentsChemother1978; 14:60-8).ZPT is the co-ordination complex of zinc.This colorless solid is used as antimycotic and antibacterial agents.Due to its poorly soluble in water (under neutral ph 8ppm), ZPT is suitable for being used as outdoor coating, adhesive and other products, provides the protection to mildew and algae.It is effective algicide.But it is incompatible with the coating of dependence metal carboxylate curing agent.When using in the emulsion paint comprising water (iron containing a large amount of), then need the chelating agent of preferred combination iron ion.
In agricultural, special problem is the infection be made up of bacterial biof iotalm, described bacterial biof iotalm is the bacterial organisms identified relatively recently, free unicellular (" swimming ") bacterium is focused in organized many cells colony (biomembrane) through this tissue by intercellular adhesion, and described organized many cells colony has significantly different behavior patterns, gene expression and to the susceptibility comprising antibiotic environmental agent.Biomembrane can adopt undiscovered biophylaxis mechanism in planktonic bacteria, and described mechanism can protect biomembrane colony from antibiotic and host immune response impact.The biomembrane formed can stop the growth of plant, growth or wound healing process.
Microbial biofilm is relevant with the resistance obviously increased disinfectant and antibiotic.Biomembrane form is formed when bacterium and/or fungi are attached to surface.This attachment triggers genetic transcription and changes, and causes very flexible and is difficult to the secretion of the polysaccharide matrix penetrated, protection microorganism.Except biomembrane is to except the resistance of antibiotic highly significant, they are to the resistance of plant immune defense mechanism.Biomembrane, once be formed, is very difficult to eradicate, so prevention biofilm formation is very important agriculture priority principle.Nearest research shows, and open wound can be polluted fast by biomembrane.These microbial biofilms are considered to can hinder growth, grow and/or wound healing, and probably relevant to generation that is serious and the often infection of refractory.
Obviously, for treatment and prevention in plant and on infected by microbes need composition and the method for improvement, comprise the infected by microbes occurred as biomembrane.Some embodiment described herein solves this demand and provides other relevant advantage.
Brief summary of the invention
As disclosed herein and undesirably bound by theory, according to some embodiment described first herein, the preservative that bismuth-mercaptan (BT) compound uses under can being used as various agricultural, industry, manufacturing industry and other environment, and for catch and related pathologies and individual health care, also reduce the expense that this type for the treatment of of infection produces simultaneously, comprise those expenses of saving and being realized by least part of prevention of being mediated by BT or prevent.
And, in some embodiment described herein, relate to and be used for the treatment of containing bacterial biof iotalm or the bacterium relevant to biofilm formation (such as, can be formed or promote biomembranous bacterium in addition) plant or plant tissue (such as, root, bulb, stem, leaf, branch, rattan, sarment, bud, flower or its part, tender shoots (greentip), fruit, seed, kind of pod etc.) and animal tissue and/or preparation that is natural and artificial surfaces, described preparation comprises one or more BT compounds and one or more Antibiotique compositions, wherein according to non-limiting theory, antibacterial (the comprising antibiont film) do not predicted so far of said preparation is provided to act on based on present disclosure BT compound and antibiotic suitably selected composition, and/or for prevention, the effective medical needle of preventing and/or treating property is to the humidification do not predicted of the infected by microbes of the infection comprised containing bacterial biof iotalm.
What also provide herein uses the bismuth-composition of mercaptans advantageously comprising single particle suspension substantially in these and related embodiment, and the method for their synthesis and use.
According to certain embodiments of the present invention described herein, be provided for protective plant opposing bacterium at this, the method of fungi or viral pathogen, described method comprises makes plant or its position (such as, root of all or part, bulb, stem, leaf, branch, rattan, sarment, bud, flower or its part, tender shoots, fruit, seed, kind of pod etc.) with bismuth-mercaptan (BT) composition of effective dose be enough to satisfied below contact under one or more condition and time: (i) prevents plant by bacterium, fungi or viral pathogen infect, (ii) anti-bacteria, the cell viability of substantially all planktonic cells of fungi or viral pathogen or Growth of Cells, (iii) suppresses by bacterium, the biofilm formation of fungi or viral pathogen, and (iv) anti-bacteria, the biomembrane vigor of substantially all biomembrane form cells of fungi or viral pathogen or biofilm development, wherein BT composition comprises the suspended matter of single dispersing substantially of particulate, substantially the single dispersing suspended matter of described particulate comprises BT compound, and described particulate has the volume mean diameter of about 0.4 μm to about 10 μm.In further embodiment, bacterial pathogens comprises fire blight of pear bacterial cell.In another embodiment, bacterial pathogens is selected from erwinia amylovora, xanthomonas campestris nieffea picta pvs oryzae and oryzicola (Xanthomonascampestrispvdieffenbachiae), pseudomonas syringae, xyllela fastidiosa, vine wood friend bacterium, Monilinia fructicola (Moniliniafructicola), P.stwartii subsp.stewartii, Ralstonia solanacearum and Potato Ring Rot.In certain embodiments, bacterial pathogens shows antibiotic resistance.In certain embodiments, bacterial pathogens shows streptomycin resistance.In certain embodiments, plant is food crops, and in some further embodiment, described food crops is fruit tree.In some again further embodiment, fruit tree is selected from apple tree, pear tree, peach, nectarine tree, Japanese plum, apricot.In some other embodiment, food crops is the Banana tree of Musa.In some other embodiment, food crops is the plant being selected from tuberous plant, leguminous plant and graminaceous cereals plant.In some further embodiment, tuberous plant is selected from potato (Solanumtuberosum) (potato) and sweet potato (Ipomoeabatatas) (sweet potato).In some embodiment of said method, carry out one or many contact procedure.In some further embodiment, at least one contact procedure comprises spraying, flood, apply and smear one in plant.At some in other further embodiment, plant, the flowers are in blossom puts, tender shoots or growth position place carry out at least one contact procedure.In certain embodiments, on plant, the flowers are in blossom first time carries out at least one contact procedure in put 24,48 or 72 hours.
In some embodiment of said method, BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.In certain embodiments, bacterial pathogens shows antibiotic resistance.
In some further embodiment of said method, described method to comprise with plant and BT composition contact procedure simultaneously or successively and with any order, makes plant and to work in coordination with or enhancement antibiotic contacts.In certain embodiments, collaborative or strengthen antibiotic and comprise and be selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.In certain embodiments, collaborative or enhancement antibiotic is selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
According to some other embodiment, be provided for or in the plant it existing antibiotic resistance bacterium phytopathogen, overcome the method for antibiotic resistance wherein, the method comprises: (a) makes plant contact with the BT composition of effective dose under one or more condition and time below being enough to meet: (i) prevents plant by antibiotic resistance bacterium pathogenic infection, (ii) cell viability or the Growth of Cells of substantially all planktonic cells of antibiotic resistance bacterium pathogene is suppressed, (iii) suppress by the biofilm formation of described antibiotic resistance bacterium pathogene, and (iv) suppresses biomembrane vigor or the biofilm development of substantially all biomembrane form cells of antibiotic resistance bacterium pathogene, wherein BT composition comprises the suspended matter of single dispersing substantially of particulate, substantially the single dispersing suspended matter of particulate comprises BT compound, particulate has the volume mean diameter of about 0.5 μm to about 10 μm, and (b) and described plant and described BT composition contact procedure are simultaneously or successively and with any order, make plant and to work in coordination with or enhancement antibiotic contacts.
In some embodiment of said method, bismuth-composition of mercaptans comprises multiple particulate, described multiple particulate comprises bismuth-mercaptan (BT) compound, substantially all described particulates have the volume mean diameter of about 0.4 μm to about 5 μm, and produced by the process that comprises the following steps: (a) mixes under the condition being enough to obtain the solution being substantially free of solids of sedimentation and time: (i) comprise bi concns at least 50mM bismuth salt and not containing hydrophily, the acidic aqueous solution of polarity or organic solubilized agent, the ethanol of the amount of the mixture comprising about 25% ethanol is by volume enough to obtain with (ii), and (b) be enough to be formed the particulate comprised containing BT compound precipitation condition and under the time, in the mixture of (a), add the ethanolic solution that comprises containing the compound of mercaptan to obtain reaction solution, the compound wherein containing mercaptan exists with the mol ratio being about 1:3 to about 3:1 relative to bismuth in reaction solution.
In certain embodiments, bismuth salt is Bi (NO 3) 3.In certain embodiments, acidic aqueous solution comprises at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth by weight.In certain embodiments, acidic aqueous solution comprises at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid by weight.In certain embodiments, comprise containing the compound of mercaptan and be selected from one or more following reagent: 1,2-dithioglycol; 2,3-dimercaprol dimercaptopropanol; PTO; Dithioerythritol; 3,4-dimercapto toluene; 2,3-succinimide mercaptans; 1,3-dimercaptopropane; 2-hydroxyl propanethiol; 1-sulfydryl-2-propyl alcohol; Dithioerythritol; Alpha-lipoic acid; Dithiothreitol (DTT); Methyl mercaptan (CH 3sH [m-mercaptan]); Ethyl mercaptan (C 2h 5sH [e-mercaptan]); 1-propanethiol (C 3h 7sH [n-P mercaptan]); 2-propanethiol (CH 3cH (SH) CH 3[2C 3mercaptan]); Butyl mercaptan (C 4h 9sH ([n-butanethiol]); Tert-butyl mercaptan (C (CH 3) 3sH [t-butanethiol]); Amyl hydrosulfide (C 5h 11sH [amyl mercaptan]); Coacetylase; Lipoamide; Glutathione; Cysteine; Cystine; 2 mercapto ethanol; Dithiothreitol (DTT); Dithioerythritol; 2-sulfydryl indole; TGase; (11-mercapto-undecanoic base) six (ethylene glycol); (11-mercapto-undecanoic base) four (ethylene glycol); The golden nanometer particle that (11-mercapto-undecanoic base) four (ethylene glycol) are functionalized; 1,1', 4', 1 "-terphenyl-4-mercaptan; 1,11-hendecane two mercaptan; 1,16-hexadecane dithiol; Technical grade 1,2-dithioglycol; 1,3-dimercaptopropane; Isosorbide-5-Nitrae-benzene dimethanethiol; Isosorbide-5-Nitrae-succinimide mercaptans; Isosorbide-5-Nitrae-succinimide mercaptans diacetate esters; 1,5-pentane disulfide thioalcohol; 1,6-ethanthiol; Pungent two mercaptan of 1,8-; 1,9-mercaptan in the ninth of the ten Heavenly Stems two; Adamantane mercaptan; L-butyl mercaptan; L-decyl mercaptan; L-dodecyl mercaptans; L-heptanthiol; Pure l-heptanthiol; 1-hexadecanethiol; L-hexyl mercaptan; L-sulfydryl-(triethylene glycol); The golden nanometer particle that 1-sulfydryl-(triethylene glycol) methyl ether is functionalized; 1-sulfydryl-2-propyl alcohol; L-mercaptan in the ninth of the ten Heavenly Stems; L-octadecanethiol; L-spicy thioalcohol; 1-spicy thioalcohol; 1-pentadecane mercaptan; 1-amyl hydrosulfide; 1-propanethiol; 1-tetradecane mercaptan; Pure 1-tetradecane mercaptan; 1-undecane thiol; 11-(1H-pyrroles-1-base) hendecane-1-mercaptan; 11-amino-1-undecane thiol hydrochloride; The bromo-1-undecane thiol of 11-; 11-sulfydryl-1-tip-nip; 11-sulfydryl-1-tip-nip; 11-Mercaptoundecanoic acid; 11-Mercaptoundecanoic acid; 11-mercapto-undecanoic base trifluoroacetate; 11-mercapto-undecanoic base phosphoric acid; 12-sulfydryl dodecylic acid; 12-sulfydryl dodecylic acid; 15-sulfydryl pentadecanoic acid; 16-mercaptohexadecanoic acid; 16-mercaptohexadecanoic acid; 1H, 1H, 2H, 2H-perfluor decyl mercaptan; 2,2 '-(ethylenedioxy) diethyl mercaptan; 2,3-succinimide mercaptans; 2-butyl mercaptan; 2-ethyl hexyl mercaptan; 2-methyl isophthalic acid-propanethiol; 2-methyl-2-propanethiol; 2-benzene ethyl mercaptan; Pure 3,3,4,4,5,5,6,6,6-nine fluoro-1-hexyl mercaptans; 3-(dimethoxy-methyl silicyl)-1-propanethiol; The chloro-1-propanethiol of 3-; 3-sulfydryl-1-propyl alcohol; 3-sulfydryl-2-butanols; 3-sulfydryl-N-nonyl propionamide; 3-mercaptopropionic acid; The silica gel that 3-mercaptopropyi is functionalized; 3-methyl isophthalic acid-butyl mercaptan; 4,4 '-bis-(mercapto methyl) biphenyl; 4,4 '-dimercapto stilbene; 4-(the own oxygen base of 6-sulfydryl) benzylalcohol; 4-cyano group-1-butyl mercaptan; 4-sulfydryl-n-butyl alcohol; 6-(ferrocenyl) hexyl mercaptan; 6-sulfydryl-1-hexanol; 6-mercaptohexanoic acid; 8-sulfydryl-1-octanol; 8-sulfydryl is sad; 9-sulfydryl-1 nonyl alcohol; Xenyl-4,4'-bis-mercaptan; 3-mercaptopropionic acid butyl ester; L-butyl mercaptan copper (I); Cyclohexylmercaptan; Cyclopentanethiol; The Nano silver grain that decyl mercaptan is functionalized; The golden nanometer particle that dodecyl mercaptans is functionalized; The Nano silver grain that dodecyl mercaptans is functionalized; Six (ethylene glycol) single-11-(Acetylsulfanyl) undecyl ether; Mercapto succinic acid; 3-mercapto-propionate; NanoTetherBPA-HH; NanoThinks tM18; NanoThinks tM8; NanoThinks tMaCID11; NanoThinks tMaCID16; NanoThinks tMaLCO11; NanoThinks tMtHIO8; The golden nanometer particle that spicy thioalcohol is functionalized; PEG bis-mercaptan number-average molecular weight 8,000; PEG bis-mercaptan mean molecule quantity 1,500; PEG bis-mercaptan mean molecule quantity 3,400; S-(11-bromo-n-11 base) thiacetate; S-(4-cyanobutyl) thiacetate; Benzenethiol; Triethylene glycol list-11-mercapto-undecanoic base ether; Trimethylolpropane tris (3-mercaptopropionic acid ester); [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol); Between carborane-9-mercaptan; Para-terpheny base-4,4 "-two mercaptan; Tertiary lauryl mercaptan; And tertiary nonyl mercaptan.
In certain embodiments, described bacterial pathogens comprises following at least one: (i) one or more Gram-negative bacterias, (ii) one or more gram-positive bacterias, (iii) one or more antibiotic sensitive bacterium, (iv) one or more antibiotic resistance bacterium, v () is selected from staphylococcus aureus (S.aureus), MRSA (methicillin resistant S staphylococcus), Staphylococcus epidermidis, MRSE (methicillin resistant Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, Vancomycin resistant enterococcus (Enterococcus) (VRE), Burkholderia cepacia complex (Burkholderiacepaciacomplex), soil Lafranchise Salmonella (Francisellatularensis), bacillus anthracis (Bacillusanthracis), yersinia pestis (Yersiniapestis), pseudomonas aeruginosa (Pseudomonasaeruginosa), Vancomycin resistant enterococcus, streptococcus pneumonia, Penicillin Resistant S streptococcus, Escherichia coli, Burkholderia cepacia, bite burkholderia (Bukholderiamultivorans) more, the bacterial pathogens of smegmatis mycobacterium (Mycobacteriumsmegmatis) and Acinetobacter baumannii (Acinetobacterbaumannii).
In certain embodiments, described method comprise with plant and BT composition contact procedure simultaneously or successively and with any order, make plant and (i) work in coordination with antibiotic and contact with at least one in (ii) cooperative antimicrobial efficacy enhancement antibiotic.In some further embodiment, collaborative antibiotic or cooperative antimicrobial efficacy enhancement antibiotic comprise and are selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.In some further embodiment, collaborative antibiotic or cooperative antimicrobial efficacy enhancement antibiotic are selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
In some other embodiment, be provided for the method overcoming antibiotic resistance in the plant of the bacterial pathogens that there is antibiotic resistance wherein or on it, described method comprises: be enough to meet below one or more condition and under the time, enable plant simultaneously or successively and strengthen with (2) at least one with any order with (1) at least one bismuth-mercaptan (BT) composition of effective dose or contact with the synergistic antibiotic of at least one BT composition: (i) prevents plant to be infected by bacterial pathogens, (ii) cell viability of substantially all planktonic cells of anti-bacteria pathogene or Growth of Cells, (iii) suppress by the biofilm formation of bacterial pathogens, and the biomembrane vigor of substantially all biomembrane form cells of (iv) anti-bacteria pathogene or biofilm development, wherein BT composition comprises multiple particulate comprising bismuth-mercaptan (BT) compound, substantially all described particulates have the volume mean diameter of about 0.4 μm to about 5 μm, and thus the antibiotic resistance overcome on epithelial tissue surface.In some further embodiment, bacterial pathogens shows being selected from following antibiotic resistance: methicillin, vancomycin, NAF, gentamicin, ampicillin, chloramphenicol, Doxycycline, tobramycin, clindamycin and gatifloxacin.In some other embodiment, BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.In certain embodiments, collaborative or enhancement antibiotic comprises and is selected from following antibiotic: clindamycin, gatifloxacin, aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.In some further embodiment, collaborative or enhancement antibiotic is selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
According to some other embodiment, providing package is containing the bismuth-composition of mercaptans of multiple particulate, described multiple particulate comprises bismuth-mercaptan (BT) compound, substantially all described particulates have the volume mean diameter of about 0.4 μm to about 5 μm, and wherein BT compound comprises bismuth or bismuth salt and the compound containing mercaptan.In further embodiment, providing package is containing the bismuth-composition of mercaptans of multiple particulate, described multiple particulate comprises bismuth-mercaptan (BT) compound, substantially all described particulates have the volume mean diameter of about 0.4 μm to about 5 μm and produce formation by the process comprised the following steps: (a) mixes under the condition being enough to obtain the solution being substantially free of solids of sedimentation and time, (i) comprise bi concns at least 50mM bismuth salt and not containing hydrophily, the acidic aqueous solution of polarity or organic solubilized agent, being enough to acquisition with (ii) comprises by volume at least about 5%, 10%, 15%, 20%, the ethanol of the amount of the mixture of 25% or 30% ethanol, and (b) be enough to be formed the particulate comprised containing described BT compound precipitation condition and under the time, in the mixture of (a), add the ethanolic solution that comprises containing the compound of mercaptan to obtain reaction solution, the compound wherein containing mercaptan exists with the mol ratio being about 1:3 to about 3:1 relative to bismuth in reaction solution.In certain embodiments, bismuth salt is Bi (NO 3) 3.In certain embodiments, acidic aqueous solution comprises at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth by weight.In certain embodiments, acidic aqueous solution comprises at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid by weight.In certain embodiments, compound containing mercaptan comprises and is selected from one or more following reagent: 1,2-dithioglycol, 2,3-dimercaprol dimercaptopropanol, PTO, dithioerythritol, 3,4-dimercapto toluene, 2,3-succinimide mercaptans, 1,3-dimercaptopropane, 2-hydroxyl propanethiol, 1-sulfydryl-2-propyl alcohol, dithioerythritol, alpha-lipoic acid and dithiothreitol (DTT).
In another embodiment, provide a kind of method for the preparation of bismuth-composition of mercaptans, described bismuth-composition of mercaptans comprises multiple particulate, described multiple particulate comprises bismuth-mercaptan (BT) compound, substantially all described particulates have the volume mean diameter of about 0.4 μm to about 5 μm, said method comprising the steps of: (a) mixes under the condition being enough to obtain the solution being substantially free of solids of sedimentation and time, (i) comprise bi concns at least 50mM bismuth salt and not containing hydrophily, the acidic aqueous solution of polarity or organic solubilized agent, being enough to acquisition with (ii) comprises by volume at least about 5%, 10%, 15%, 20%, the ethanol of the amount of the mixture of 25% or 30% ethanol, and (b) be enough to be formed the particulate comprised containing described BT compound precipitation condition and under the time, in the mixture of (a), add the ethanolic solution that comprises containing the compound of mercaptan to obtain reaction solution, the wherein said compound containing mercaptan exists with the mol ratio being about 1:3 to about 3:1 relative to bismuth in described reaction solution.In certain embodiments, described method comprises recovery precipitation further to remove impurity.In certain embodiments, bismuth salt is Bi (NO 3) 3.In certain embodiments, acidic aqueous solution comprises at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth by weight.In certain embodiments, acidic aqueous solution comprises at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid by weight.In certain embodiments, comprise containing the compound of mercaptan and be selected from one or more following reagent: 1,2-dithioglycol; 2,3-dimercaprol dimercaptopropanol; PTO; Dithioerythritol; 3,4-dimercapto toluene; 2,3-succinimide mercaptans; 1,3-dimercaptopropane; 2-hydroxyl propanethiol; 1-sulfydryl-2-propyl alcohol; Dithioerythritol; Alpha-lipoic acid; Dithiothreitol (DTT); Methyl mercaptan (CH 3sH [m-mercaptan]); Ethyl mercaptan (C 2h 5sH [e-mercaptan]); 1-propanethiol (C 3h 7sH [n-P mercaptan]); 2-propanethiol (CH 3cH (SH) CH 3[2C 3mercaptan]); Butyl mercaptan (C 4h 9sH ([n-butanethiol]); Tert-butyl mercaptan (C (CH 3) 3sH [t-butanethiol]); Amyl hydrosulfide (C 5h 11sH [amyl mercaptan]); Coacetylase; Lipoamide; Glutathione; Cysteine; Cystine; 2 mercapto ethanol; Dithiothreitol (DTT); Dithioerythritol; 2-sulfydryl indole; TGase; (11-mercapto-undecanoic base) six (ethylene glycol); (11-mercapto-undecanoic base) four (ethylene glycol); The golden nanometer particle that (11-mercapto-undecanoic base) four (ethylene glycol) are functionalized; 1,1', 4', 1 "-terphenyl-4-mercaptan; 1,11-hendecane two mercaptan; 1,16-hexadecane dithiol; Technical grade 1,2-dithioglycol; 1,3-dimercaptopropane; Isosorbide-5-Nitrae-benzene dimethanethiol; Isosorbide-5-Nitrae-succinimide mercaptans; Isosorbide-5-Nitrae-succinimide mercaptans diacetate esters; 1,5-pentane disulfide thioalcohol; 1,6-ethanthiol; Pungent two mercaptan of 1,8-; 1,9-mercaptan in the ninth of the ten Heavenly Stems two; Adamantane mercaptan; L-butyl mercaptan; L-decyl mercaptan; L-dodecyl mercaptans; L-heptanthiol; Pure l-heptanthiol; 1-hexadecanethiol; L-hexyl mercaptan; L-sulfydryl-(triethylene glycol); The golden nanometer particle that 1-sulfydryl-(triethylene glycol) methyl ether is functionalized; 1-sulfydryl-2-propyl alcohol; L-mercaptan in the ninth of the ten Heavenly Stems; L-octadecanethiol; L-spicy thioalcohol; 1-spicy thioalcohol; 1-pentadecane mercaptan; 1-amyl hydrosulfide; 1-propanethiol; 1-tetradecane mercaptan; Pure 1-tetradecane mercaptan; 1-undecane thiol; 11-(1H-pyrroles-1-base) hendecane-1-mercaptan; 11-amino-1-undecane thiol hydrochloride; The bromo-1-undecane thiol of 11-; 11-sulfydryl-1-tip-nip; 11-sulfydryl-1-tip-nip; 11-Mercaptoundecanoic acid; 11-Mercaptoundecanoic acid; 11-mercapto-undecanoic base trifluoroacetate; 11-mercapto-undecanoic base phosphoric acid; 12-sulfydryl dodecylic acid; 12-sulfydryl dodecylic acid; 15-sulfydryl pentadecanoic acid; 16-mercaptohexadecanoic acid; 16-mercaptohexadecanoic acid; 1H, 1H, 2H, 2H-perfluor decyl mercaptan; 2,2 '-(ethylenedioxy) diethyl mercaptan; 2,3-succinimide mercaptans; 2-butyl mercaptan; 2-ethyl hexyl mercaptan; 2-methyl isophthalic acid-propanethiol; 2-methyl-2-propanethiol; 2-benzene ethyl mercaptan; Pure 3,3,4,4,5,5,6,6,6-nine fluoro-1-hexyl mercaptans; 3-(dimethoxy-methyl silicyl)-1-propanethiol; The chloro-1-propanethiol of 3-; 3-sulfydryl-1-propyl alcohol; 3-sulfydryl-2-butanols; 3-sulfydryl-N-nonyl propionamide; 3-mercaptopropionic acid; The silica gel that 3-mercaptopropyi is functionalized; 3-methyl isophthalic acid-butyl mercaptan; 4,4 '-bis-(mercapto methyl) biphenyl; 4,4 '-dimercapto stilbene; 4-(the own oxygen base of 6-sulfydryl) benzylalcohol; 4-cyano group-1-butyl mercaptan; 4-sulfydryl-n-butyl alcohol; 6-(ferrocenyl) hexyl mercaptan; 6-sulfydryl-1-hexanol; 6-mercaptohexanoic acid; 8-sulfydryl-1-octanol; 8-sulfydryl is sad; 9-sulfydryl-1 nonyl alcohol; Xenyl-4,4'-bis-mercaptan; 3-mercaptopropionic acid butyl ester; L-butyl mercaptan copper (I); Cyclohexylmercaptan; Cyclopentanethiol; The Nano silver grain that decyl mercaptan is functionalized; The golden nanometer particle that dodecyl mercaptans is functionalized; The Nano silver grain that dodecyl mercaptans is functionalized; Six (ethylene glycol) single-11-(Acetylsulfanyl) undecyl ether; Mercapto succinic acid; 3-mercapto-propionate; NanoTetherBPA-HH; NanoThinks tM18; NanoThinks tM8; NanoThinks tMaCID11; NanoThinks tMaCID16; NanoThinks tMaLCO11; NanoThinks tMtHIO8; The golden nanometer particle that spicy thioalcohol is functionalized; PEG bis-mercaptan number-average molecular weight 8,000; PEG bis-mercaptan mean molecule quantity 1,500; PEG bis-mercaptan mean molecule quantity 3,400; S-(11-bromo-n-11 base) thiacetate; S-(4-cyanobutyl) thiacetate; Benzenethiol; Triethylene glycol list-11-mercapto-undecanoic base ether; Trimethylolpropane tris (3-mercaptopropionic acid ester); [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol); Between carborane-9-mercaptan; Para-terpheny base-4,4 "-two mercaptan; Tertiary lauryl mercaptan; And tertiary nonyl mercaptan.
In another embodiment, protection is provided to comprise such as plant surface (such as, the root of all or part, bulb, stem, leaf, branch, rattan, sarment, bud, flower or its part, tender shoots, fruit, seed, the surface of kind of pod etc.) or the natural or artificial surfaces opposing bacterial pathogens of biological tissue surface on epithelial tissue surface, one or more method of fungal pathogens and viral pathogen, comprises and epithelial tissue surface and the BT composition of effective dose one or more condition below being enough to meet is contacted with under the time: (i) prevents surperficial by bacterium, fungi or viral pathogen infect, (ii) anti-bacteria, the cell viability of substantially all planktonic cells of fungi or viral pathogen or Growth of Cells, (iii) suppresses by bacterium, the biofilm formation of fungi or viral pathogen, and (iv) anti-bacteria, the biomembrane vigor of substantially all biomembrane form cells of fungi or viral pathogen or biofilm development, wherein BT composition comprises multiple particulate comprising bismuth-mercaptan (BT) compound, and substantially all described particulates have the volume mean diameter of about 0.4 μm to about 5 μm.In certain embodiments, bacterial pathogens comprises following at least one: (i) one or more Gram-negative bacterias, (ii) one or more gram-positive bacterias, (iii) one or more antibiotic sensitive bacterium, (iv) one or more antibiotic resistance bacterium, v () is selected from staphylococcus aureus (S.aureus), MRSA (methicillin resistant S staphylococcus), Staphylococcus epidermidis, MRSE (methicillin resistant Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, Vancomycin resistant enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, pseudomonas aeruginosa, Vancomycin resistant enterococcus, streptococcus pneumonia, Penicillin Resistant S streptococcus, Escherichia coli, Burkholderia cepacia, bite burkholderia more, the bacterial pathogens of smegmatis mycobacterium and Acinetobacter baumannii.In certain embodiments, bacterial pathogens shows antibiotic resistance.In certain embodiments, bacterial pathogens shows being selected from following antibiotic resistance: methicillin, vancomycin, NAF, gentamicin, ampicillin, chloramphenicol, Doxycycline and tobramycin.
In certain embodiments, natural or artificial surfaces comprises oral cavity/surface, cheek chamber; Prosthetics; Pottery; Plastics; Polymer; Rubber; Metallic article; Painted surface; Marine structure (comprising hull, rudder, screw, anchor, cabin, ballast tank, dock, dry dock, harbour, sheet pile, bulkhead); Or other natural or artificial surfaces.
In certain embodiments, described surface comprises epithelial tissue surface, and described epithelial tissue comprises and is selected from following tissue: epidermis, corium, respiratory tract, intestines and stomach and gland serve as a contrast.
In certain embodiments, contact procedure carries out one or many.In certain embodiments, at least one contact procedure comprises spraying, floods, applies and smear one in natural or artificial surface.In certain embodiments, at least one contact procedure comprises the one in suction, picked-up and dentilave.In certain embodiments, at least one contact procedure comprises by being selected from local, in peritonaeum, oral, stomach and intestine outer, in intravenous, artery, transdermal, sublingual, subcutaneous, intramuscular, in cheek, nose, in suctions, intraocular, atrium, in ventricle, subcutaneous, fatty in, approach in joint and in sheath uses.In certain embodiments, BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.
In certain embodiments, bacterial pathogens shows antibiotic resistance.In some other embodiment, said method to comprise with described surface and described BT composition contact procedure simultaneously or successively and with any order further, and natural or artificial surfaces is contacted with collaborative antibiotic and/or enhancement antibiotic.In certain embodiments, collaborative and/or enhancement antibiotic comprises and is selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.In certain embodiments, collaborative and/or enhancement antibiotic is be selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin (rhodostreptomycin), streptomycin, tobramycin and apramycin.
In another embodiment of the present invention as herein described, provide a kind of for overcoming antibiotic resistance (such as on the self-faced that there is antibiotic resistance bacterium pathogene, the bacterium of anti-at least one to the identical bacteria culture of opposing is had to the bacterial pathogens of the known antibiotic at least one antibacterial action of antibacterial action, this pathogene to antibiotic sensitive is provided) method, its be included in be enough to meet following one or more condition and under the time, make surface simultaneously or successively and with (1) at least one bismuth-mercaptan (BT) composition of any order and effective dose and (2) at least one by and/or at least one antibiotic that can act synergistically with at least one BT composition and strengthen contact: (i) prevents surperficially to be infected by bacterial pathogens, (ii) cell viability of substantially all planktonic cells of anti-bacteria pathogene or Growth of Cells, (iii) suppress by the biofilm formation of bacterial pathogens, and the biomembrane vigor of substantially all biomembrane form cells of (iv) anti-bacteria pathogene or biofilm development, wherein BT composition comprises multiple particulate comprising bismuth-mercaptan (BT) compound, substantially all described particulates have the volume mean diameter of about 0.4 μm to about 5 μm, and overcome antibiotic resistance on the surface at epithelial tissue thus.In certain embodiments, bacterial pathogens comprises following at least one: (i) one or more Gram-negative bacterias, (ii) one or more gram-positive bacterias, (iii) one or more antibiotic sensitive bacterium, (iv) one or more antibiotic resistance bacterium, v () is selected from staphylococcus aureus (S.aureus), MRSA (methicillin resistant S staphylococcus), Staphylococcus epidermidis, MRSE (methicillin resistant Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, Vancomycin resistant enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, pseudomonas aeruginosa, Vancomycin resistant enterococcus, streptococcus pneumonia, Penicillin Resistant S streptococcus, Escherichia coli, Burkholderia cepacia, bite burkholderia more, the bacterial pathogens of smegmatis mycobacterium and Acinetobacter baumannii.
In certain embodiments, bacterial pathogens shows being selected from following antibiotic resistance: methicillin, vancomycin, NAF, gentamicin, ampicillin, chloramphenicol, Doxycycline, tobramycin, clindamycin and gatifloxacin.
In certain embodiments, natural or artificial surfaces comprises oral cavity/surface, cheek chamber; Prosthetics; Pottery; Plastics; Polymer; Rubber; Metallic article; Painted surface; Marine structure (comprising hull, rudder, screw, anchor, cabin, ballast tank, dock, dry dock, harbour, sheet pile, bulkhead); Or other natural or artificial surfaces.
In certain embodiments, surface comprises the tissue being selected from epidermis, corium, respiratory tract, intestines and stomach and gland lining.In certain embodiments, contact procedure carries out one or many.In certain embodiments, at least one contact procedure comprises spraying, rinses, floods and smear the one on surface.In some other embodiment, at least one contact procedure comprises suction, picked-up and the one of dentilave.In certain embodiments, at least one contact procedure comprises by being selected from local, in peritonaeum, oral, stomach and intestine outer, in intravenous, artery, transdermal, sublingual, subcutaneous, intramuscular, in cheek, nose, in suctions, intraocular, atrium, in ventricle, subcutaneous, fatty in, approach in joint and in sheath uses.In certain embodiments, BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.In certain embodiments, collaborative and/or strengthen antibiotic and comprise and be selected from following antibiotic: clindamycin, gatifloxacin, aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.In certain embodiments, collaborative and/or enhancement antibiotic is selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
As for another embodiment, provide antiseptic composition, it comprises: (a) at least one BT compound; B () is strengthened by BT compound and/or can synergistic at least one Antibiotique composition with BT compound; And (c) pharmaceutically acceptable excipient or carrier, comprise the carrier that local uses.In certain embodiments, BT compound is selected from: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.In certain embodiments, BT composition comprises multiple particulate comprising bismuth-mercaptan (BT) compound, and all described particulates have the volume mean diameter of about 0.4 μm to about 5 μm substantially.In certain embodiments, BT compound is selected from BisEDT and BisBAL.In certain embodiments, Antibiotique composition comprises and is selected from following antibiotic: methicillin, vancomycin, NAF, gentamicin, ampicillin, chloramphenicol, Doxycycline, tobramycin, clindamycin, gatifloxacin and aminoglycoside antibiotics.In certain embodiments, aminoglycoside antibiotics is selected from amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.In certain embodiments, aminoglycoside antibiotics is amikacin.
At some, other embodiment, provides a kind of method being used for the treatment of the natural or artificial surfaces supported or containing bacterial biof iotalm, comprise (a) bacteriological infection on the surface or in surface is accredited as comprise one of following: (i) gram-positive bacteria, (ii) Gram-negative bacteria, and (iii) comprises both (i) and (ii), (b) preparation of one or more bismuth mercaptan (BT) compositions is comprised to surface applied, if wherein (i) bacteriological infection comprises gram-positive bacteria, then preparation comprises the antibiotic that the treatment at least one BT compound of effective dose and at least one are rifamycins, (ii) if bacteriological infection comprises Gram-negative bacteria, then preparation comprises at least one BT compound and the amikacin for the treatment of effective dose, (iii) if bacteriological infection comprises gram-positive bacteria and Gram-negative bacteria, then preparation comprises one or more BT compounds for the treatment of effective dose, rifamycin and amikacin, and thus treatment surface.
In certain embodiments, biomembrane comprises one or more antibiotic resistance bacterium.In certain embodiments, treatment surface comprise following at least one: (i) eradicate bacteria biomembrane, (ii) reduces bacterial biof iotalm, and (iii) weakens the growth of bacterial biof iotalm.In certain embodiments, BT composition comprises multiple particulate comprising bismuth-mercaptan (BT) compound, and all particulates have the volume mean diameter of about 0.4 μm to about 5 μm substantially.
These aspects of embodiment of the present invention as herein described and other side are with reference to the following specifically describes and accompanying drawing and obviously.All United States Patent (USP)s, U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and the non-patent publications listed in that mention in this specification and/or request for data table, comprise U.S.RE37,793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248 this by way of reference entirety be incorporated to herein, as each is incorporated to separately herein.If desired, aspect of the present invention and embodiment can be modified to adopt the concept of various patent, patent application and patent disclosure, to provide other embodiment.
Accompanying drawing is sketched
Fig. 1 show 10% Tryptic Soy Agar (TSA) upper 37 DEG C cultivate 24 hours, with after through shown treatment 18 hours, the biomembranous viable count (logCFU of pseudomonas aeruginosa bacterium colony; Colony-forming units).Shown antibiotic therapy is TOB, tobramycin 10 × MIC; AMK, amikacin 100 × MIC; IPM, Imipenem (imipenem) 10 × MIC; CEF, Cefepime 10 × MIC; CIP, Ciprofloxacin 100 × MIC; Cpd2B, compound 2B (Bis-BAL, 1:1.5).(MIC; Minimum inhibitory concentration, such as, the least concentration of prevention bacterial growth).
Fig. 2 show on 10% Tryptic Soy Agar cultivate 24 hours, with after through shown treatment, the biomembranous viable count of S. aureus colonies (logCFU).Shown antibiotic therapeutic agent is rifampin, RIF100 × MIC; Daptomycin, DAP320 × MIC; Minocycline, MIN100 × MIC; Ampicillin, AMC10 × MIC; Vancomycin, VAN10 × MIC; Cpd2B, compound 2B (Bis-BAL, 1:1.5), Cpd8-2, compound 8-2 (Bis-Pyr/BDT (1:1/0.5).
Fig. 3 show be exposed to the scratch in time of biomembranous keratinocyte close.(*) contrast (P<0.001) is significantly different from.
Fig. 4 A and 4B shows the sub-inhibition BisEDT reversed several antibiotic antibiotic resistance.Show antibiotic effect MRSA (methicillin resistant S staphylococcus) lawn being with or without BisEDT (0.05 μ g/ml).Dull and stereotyped A only shows standard antibiotic permeate pan, the dish that dull and stereotyped B display is combined with BisEDT (BE).[GM=gentamicin, CZ=cephalosporin, FEP=Cefepime, IPM=Imipenem, SAM=ampicillin/sulbactam, LVX=lavo-ofloxacin.
Fig. 5 shows BisEDT and antibiotic to the effect of biofilm formation.Staphylococcus epidermidis is grown 48h at 37 DEG C in the XPS of TSB+2% glucose.Gatifloxacin (GF), clindamycin (CM), minocycline (MC), gentamicin (GM), vancomycin (VM), Cefazolin (CZ), NAF (NC) and rifampin (RP).Result is expressed as the mean change (n=3) of the BPC (continuous 2 times of dilution step) when 0.25 μ Μ BisEDT.
Fig. 6 shows BisEDT and antibiotic grow 48h in the TSB+2% glucose of 37 DEG C effect to Staphylococcus epidermidis.Result is expressed as the mean change (n=3) that MIC (dilution step) increases along with BisEDT.See in Fig. 5 for antibiotic definition legend.
Fig. 7 be presented at containing or not containing after three kinds of BT preparations of Cefazolin antibiotic therapy, Bis-EDT, MB-11 and MB-8-2 treatment, from the block diagram of the average staphylococcus aureus level that the bone of the open fracture in live body rat model and hardware (hardware) sample detect.The standard error of mean is shown as error line.The animal of early stage euthanasia gets rid of outside analysis, but, because severe contamination gets rid of the sample from the animal of in group 2.
Detailed Description Of The Invention
Specific embodiments disclosed herein is based on following surprising discovery: some bismuth-mercaptan (BT) compound provided herein (preferably include and have about 0.4 μm of BT particulate to about 5 μm of volume mean diameters) but not some other BT compound (even if providing as particulate) show strong anticorrosion, the antibacterial and/or antibiont film activity for specific bacteria, and described bacterium comprises the bacterium relevant to many severe infections clinically (comprise can infection) containing bacterial biof iotalm.
Surprisingly, not all BT compound as one man effectively resists this bacterioid in a predictable manner, but depends on that target bacteria bacterial classification shows different effects.Specifically, as described herein, find that some BT compound (preferably include and have about 0.4 μm of BT particulate to about 5 μm of volume mean diameters) shows higher effect to Gram-negative bacteria, and find that some other BT compound (preferably include and have about 0.4 μm of BT particulate to about 5 μm of volume mean diameters) shows higher effect to gram-positive bacteria, according to non-limiting theory, mode can be the clinical corresponding strategies of the process being provided for bacteriological infection (comprising bacterial biof iotalm to infect) first.
In addition, as hereafter be described in more detail, certain embodiments of the present invention as herein described relate to the surprising advantage provided by Novel bismuth-mercaptan (BT) composition, as described herein, described bismuth-mercaptan (BT) composition can be made into comprise the preparation of multiple BT particulate of single dispersing (such as having the volume mean diameter of about 0.4 μm to about 5 μm) substantially with regard to granularity.At some in these and related embodiment, particles B T is not provided as lipid vesicle or the liposomes component as multilayer phosphocholine-cholesterol liposome or other multilayer or unilamellar liposome vesica.
Also as herein disclosed in some embodiment, have been found that, find before to this bacterial infection do not have some of therapeutic action antibiotic antibacterial with antibiont film effect can by with these antibiotic one or more together with the BT compound selected, simultaneously or sequential therapeutic infects (such as by be directly applied in infection site such as natural or artificial surfaces or in natural or artificial surfaces) and be enhanced considerably (such as, with statistically significantly mode increase).In mode inscrutable before the disclosure, some BT compound can provide the collaborative or enhancement of the antibacterial and/or antibiont film activity for some bacteria culture or bacterial isolates to combine with some antibiotic combinations.What this type of combined as described in more detail below does not predict that character proved by following observation: although some BT/ antibiotic composition acts synergistically or demonstrates the enhancing of some bacterium of antagonism, and some other BT/ antibiotic composition fails show collaborative or strengthen antibacterial and/or antibiont film activity.
According to these and related embodiment, antibiotic and BT compound can simultaneously or successively and use with any order, and it should be noted that, disclosed hereinly be used for the treatment of specific infection (such as, the biomembrane that Gram-negative or gram-positive bacteria are formed) one or more antibiotic and the concrete composition of one or more BT compounds do not show measurable (such as, only adduction) active, but work in coordination with beyong contemplation or strengthen the effect of (super-additive) mode, as selected antibiotic, the function of the target bacteria of selected BT compound and special qualification.
Such as, such as illustrate and unrestricted, in the environment of the natural or artificial surfaces of multiple reality or potential infected by microbes, and further in the basic single particle BT formulation environment of improvement, any one or both of certain antibiotics compound disclosed herein and particular B T compound may play limited antibacterial action for specific bacteria bacterial strain or bacterial classification when being used alone, but described Antibiotique composition plays strong antibacterial action with the combination of described BT compound for identical bacterial isolates or bacterial classification, this acts in intensity the simple adduction being greater than and often planting compound effects when (having significance,statistical) is used alone, therefore think according to non-limiting theory and reflect BT to antibiotic effect and/or antibiotic to the antibiotic-BT concertedness of BT effect (such as, FICI≤0.5) or humidification is (such as, 0.5<FICI≤1.0).Therefore, not that any BT compound can be worked in coordination with any antibiotic or strengthen any antibiotic, and be not that any antibiotic can be worked in coordination with any BT compound, or strengthen any BT compound, it is generally uncertain for making antibiotic-BT concertedness and BT-antibiotic strengthen.On the contrary, according to some embodiment disclosed herein, the strong antibacterial action for specific bacteria is shockingly given in the antibiotic of working in coordination with or strengthen and the concrete combination of BT compound, described antibacterial action is included in specific environment, such as natural or artificial surfaces as herein described, and also comprise the biomembranous antibacterial action for being formed by specific bacteria in some cases.
That is, some BT described herein works in coordination with antibiotic, it comprises the antibiotic of can act synergistically with at least one BT composition comprising at least one BT compound provided herein (FICI≤0.5), wherein this concertedness is shown as detectable effect, detectable effect when there is antibiotic and there is not BT compound and/or there is BT compound and there is not antibiotic that its intensity is greater than (that is, in the mode of the statistically significant relative to suitable collating condition).Similarly, the display of some BT-antibiotic composition strengthens (0.5<FICI≤1.0), wherein this enhancing is shown as and can detects effect, detectable effect when there is antibiotic and there is not BT compound and/or there is BT compound and there is not antibiotic that its intensity is greater than (that is, in the mode relative to suitable collating condition statistically significant).
In certain embodiments, the example of this type of detectable effect can comprise the infection that (i) prevents bacterial pathogens, (ii) cell viability of substantially all planktonic cells of anti-bacteria pathogene or Growth of Cells, (iii) biofilm formation of anti-bacteria pathogene, (iv) the biomembrane vigor of substantially all biomembrane form cells of anti-bacteria pathogene or biofilm development, but the present invention is not intention to be so limited, make in the embodiment of other expection, antibiotic-BT concertedness can be shown as one or more detectable effects, described detectable effect can comprise change (increase of such as statistically significant or minimizing) one or more other significant parameter clinically, such as bacterial pathogens is to the resistance of one or more antibiotic or other medicines or chemical agent or sensitivity level, bacterial pathogens is to one or more chemistry, physics or mechanical condition are (such as, pH, ion strength, temperature, pressure) resistance or sensitivity level, and/or bacterial pathogens to one or more biological agents (such as, virus, another kind of bacterium, biologically active polynucleotides, immunocyte or Immune cell products such as antibody, cell factor, chemotactic factor (CF), comprise the enzyme of digestive enzyme, film destroy albumen, free radical such as active oxygen etc.) resistance or sensitivity level.
It will be understood by those skilled in the art that these standards and other standards many, by described standard predetermined substance to the effect of the structure of bacterial community, function and/or activity can determined (such as, Coico etc. (editor), CurrentProtocolsinMicrobiology, 2008, JohnWiley & Sons, Hoboken, NJ; Schwalbe etc., AntimicrobialSusceptibilityTestingProtocols, 2007, CRCPress, BocaRaton, FL), object determines antibiotic-BT concertedness or enhancement, exists during the simple adduction of the effect observed when the component that the effect as being provided in antibiotic-BT that is collaborative or that strengthen herein and combining of this concertedness or enhancement exceedes combination does not exist.
Such as, in certain embodiments, concertedness can by using the candidate agent of various concentration (such as, separately and the BT of combination and antibiotic) measure antibacterial action (such as herein described those) and measure, to calculate FICI (FICI) and classification bacteriocidal concentration index (FBCI), according to (Eliopoulos and Moellering such as Eliopoulos, (1996) Antimicrobialcombinations.InAntibioticsinLaboratoryMedic ine (Lorian, V. edit), 330-96 page, Williams and Wilkins, Baltimore, MD, USA).Concertedness can be defined as FICI or FBCI index≤0.5, during >4 be antagonism (such as, Odds, FC (2003) Synergy, antagonism, andwhatthechequerboardputsbetweenthem.JournalofAntimicro bialChemotherapy52:1).Concertedness can also usual definition be the minimizing of antibiotic concentration >=4 times, or alternatively, uses the FIC (FIC) that (1998Antimicrob.AgentsChemother.42:744) such as such as Hollander describes.In certain embodiments, concertedness may be defined as combination two kinds of medicines (such as, antibiotic and BT composition) effect that produces, the effect of wherein combining is greater than (such as, in the mode of statistically significant) if the effect when concentration of the second medicine is replaced by the first medicine.
Therefore, as described herein and in some preferred embodiment, BT and antibiotic combination should be understood to the collaborative (Odds, 2003) when observing the FICI value being less than or equal to 0.5.Also as described herein, in some other preferred embodiment and according to non-limiting theory, disclose some BT-antibiotic composition and can show FICI value between 0.5 and 1.0, it represents this synergitic high potential, and at least one BT of the antimicrobial efficacy of the cooperation that display can be used to strengthen separately or jointly and the antibiotic non-optimal concentration of at least one are to observe FICI value.This acts on and also can claim " enhancing " antibacterial activity or " enhancing " BT activity herein.
When exist following both time, antibiotic and/or the BT activity of enhancing can be detected: (i) at least one BT according to some embodiment, its concentration lower than (in statistically significant mode) BT to given target microorganism (such as, given bacteria culture or bacterial strain) characteristic minimum inhibitory concentration (MIC), (ii) at least one antibiotic, its concentration is lower than (in statistically significant mode) characteristic IC 50(suppress the concentration of 50% micropopulation bulk-growth; Such as, Soothill etc., 1992JAntimicrobChemother29 (2): 137) and/or lower than antibiotic concentration (BPC) is prevented to the biomembrane of given target microorganism, if cause BT-antibiotic composition to use arbitrary antimicrobial (such as relative in same concentrations, BT or antibiotic) and lack (in statistically significant mode) antimicrobial efficacy of the enhancing of anti-microbial effect that other antimicrobial (such as, antibiotic or BT) will observe.In preferred embodiments, be less than or equal to 1.0 when being measured to FICI value, and when being greater than 0.5, there is " enhancing " antibiotic and/or BT activity.
Technical staff should understand based on the disclosure, in certain embodiments, antibiotic that is collaborative or that strengthen and/or BT activity can be measured according to methods known in the art, such as use Loewe additive model (such as, FIC index, Greco model), or Bliss independent model (such as, nonparametric and semi-parameter model) or other method described herein and known in the art (such as, Meletiadis etc., 2005MedicalMycology43:133-152).Illustrative method for measuring antibiotic that is collaborative or that strengthen and/or BT activity is described in thus, such as Meletiadis etc., 2005MedicalMycology43:133-152 and quote herein bibliography (also see, Meletiadis etc., 2002RevMedMicrobiol13:101-117; White etc., 1996AntimicrobAgentsChemother40:1914-1918; Mouton etc., 1999AntimicrobAgentsChemother43:2473-2478).
The particular composition of some other embodiment expection one or more antibiotic as described herein and one or more BT compounds, it in specific infection (such as, the biomembrane formed by Gram-negative bacteria or gram-positive bacteria) interior therapeutic in can show the effect of collaborative or enhancing, even if wherein BT compound and antibiotic do not show predictable (such as, only adduction) activity in vivo, and on the contrary with collaborative or enhancing (such as, the super-additive do not predicted; Or the effect of giving when two or more these combinations of substances exist is greater than (such as, in statistically significant mode) if the effect obtained when the concentration of the second reagent is replaced by the first reagent place) mode, as selected antibiotic, selected BT compound and one or more functions comprising the target bacteria bacterial classification of infection identified especially.Therefore should understand, according to these and relevant embodiment, in some body, in situation, FICI or FBCI value (it is by external test) may not easily obtain, and contrary with BT-antibiotic concertedness or humidification, may with by can the mode that gives of quantification metrics measuring of infecting.
Such as, in one embodiment, such as in the body as described in embodiment 11 open fracture the critical defect model of rat (Rattusnorvegicus) femur in, with antibiotic therapy or independent BT Compound Phase ratio, Ureteral Calculus after BT-antibiotic combinations reduces to the count of bacteria of statistically significant, is the instruction of concertedness or humidification.Method well known to those skilled in the art can be used to measure significance,statistical.In some other embodiment, observe in this In vivo model or other In vivo model viewed count of bacteria in after for BT-antibiotic combinations injury in treating with consider antibiotic therapy or independent BT compound be concertedness or humidification index compared be reduced by least 5%, 10%, 20%, 30%, 40% or 50%.
Other exemplary sign of In vivo infection can according to the methodology of the establishment of developing for quantitative infection severity, such as, various wound scoring systems well known by persons skilled in the art measures (see, such as, the scoring systems that Europe wound management association (EWMA) is commented on, PositionDocument:Identifyingcriteriaforwoundinfection.Lo ndon:MEPLtd, 2005).The illustrative wound scoring systems that can be used for the concertedness or enhanced activity evaluating BT-antibiotic composition as herein described comprises ASEPSIS (WilsonAP, JHospInfect1995; 29 (2): 81-86; Wilson etc., Lancet1986; 1:311-13), Southampton's wound opinion rating (BMJ1992 such as BaileyIS, KarranSE, ToynK; 304:469-71).Also see, HoranTC, GaynesP, MartoneWJ etc., 1992InfectControlHospEpidemiol1992; 13:606-08.In addition, the generally acknowledged clinical signs (such as wound size, the degree of depth, granulation tissue situation, infection etc.) of the wound healing that this area clinician is known also can be measured when BT compound and/or antibiotic presence or absence.Therefore, based on present disclosure, technical staff should be easily understood that for determining whether that BT composition-antibiotic combination changes the various methods (such as, relative to suitable contrast with the enhancing of statistically significant mode or reduction) of body internal injury healing.
Consider these and related embodiment, there is provided herein and use effective dose (such as, treat effective dose in certain embodiments) composition as provided herein or preparation to treat the various methods of the self-faced (such as providing or comprise the surface of bacterial biof iotalm) of infected by microbes, described composition or preparation comprise one or more BT compounds, and optionally comprise one or more Antibiotique compositions, such as one or more collaborative antibiotic, or one or more enhancement antibiotic.Should be understood that based on present disclosure, the infection being used for the treatment of given type expected now by some antibiotic, wherein thought invalid to the infection of identical type by those skilled in the art before this antibiotic.
Some embodiment thus severity comprises the composition that one or more are used as the BT compound of antibacterial agent.Antibacterial agent is the material killing and wounding microorganism or pre-micro-organism growth, usually living tissue can be applied to, this type of material and the disinfectant being usually applied to lifeless object are differentiated (" ThePharmacologicalBasisofTherapeutics " of Goodman and Gilman by this, 7th edition, the editors such as Gilman, 1985, MacmillanPublishingCo., (hereafter, Goodman and Gilman ") 959-960 page).The Common examples of antibacterial agent is ethanol and the tincture of iodine.Bactericide comprises the antibacterial agent killing and wounding microorganism (such as microbial pathogens).
Some embodiment expection as herein described comprises the composition of one or more BT compounds and one or more Antibiotique compositions (such as, concertedness antibiotic as herein provided and/or enhancement antibiotic).Antibiotic is known in the art and generally includes medicine prepared by the compound produced by the Institute of Micro-biology of a kind of kind of the microorganism by killing and wounding another kind, or there is the synthetic product of identical or similar chemical constitution and the mechanism of action, such as, the medicine of destroy microorganisms in microorganism or on microorganism, comprises this medicine when applied topically.In embodiment disclosed herein is that wherein antibiotic can belong to those of one of following type: aminoglycoside, Carbapenems, cephalosporins, fluoroquinolones, glycopeptide antibiotics, Lincoln's acid amides (such as, clindamycin), penicillinase-resistant penicillin and Aminopenicillin.Therefore antibiotic can include, but not limited to penicillin, Piperacillin, cefuroxime, cefotaxime, Cefepime, Imipenem, AZT, streptomycin, tobramycin, tetracycline, minocycline, Ciprofloxacin, lavo-ofloxacin, erythromycin, Linezolid, phosphonomycin, capreomycin, isoniazid, Ansamycin (ansamycin), carbacephem, Monobactam, nitrofuran, penicillin, quinolone, sulfonamide, Clofazimine, dapsone, capreomycin, seromycin, ethambutol, 2-ethylisonicotinthionamide, isoniazid, pyrazinamide, rifampin (Rifampicin), rifampin (Rifampin), Rifabutin, Rifapentine, streptomycin, arsphenamine, chloramphenicol, phosphonomycin, Fusidic Acid, Linezolid, metronidazole, mupirocin, dull and stereotyped mycin, Quinupristin, Dalfopristin, rifaximin, Thiamphenicol, Tinidazole, aminoglycoside, beta-lactam, penicillin, cephalosporin, carbapenem, fluoquinolone, ketone lactone, Lincoln's (acyl) amine, macrolide, oxazolidone, streptogramine (stretogramin), sulfanilamide (SN), tetracycline, glycylcycline, methicillin, vancomycin, NAF, gentamicin, ampicillin, chloramphenicol, Doxycycline, tobramycin, amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin, apramycin, clindamycin, gatifloxacin, Aminopenicillin and other antibiotic known in the art.These and other useful clinically antibiotic list be those skilled in the art obtainable and known (such as, WashingtonUniversitySchoolofMedicine, TheWashingtonManualofMedicalTherapeutics (the 32nd edition), 2007Lippincott, Williams and Wilkins, Philadelphia, PA:Hauser, AL, AntibioticBasicsforClinicians, 2007Lippincott, Williams and Wilkins, Philadelphia, PA).
The exemplary class antibiotic used together with one or more BT compounds in some embodiment disclosed herein is aminoglycoside antibiotics, it is summarized EdsonRS, TerrellCL.Theaminoglycosides.MayoClinProc.1999 May; 74 (5): 519-28.Such antibiotic is by combine and inactivation bacterial ribosomal subunit reduces Bacterioprotein biosynthesis and bacteria growing inhibiting.Except this type of antibacterial character, aminoglycoside also shows bactericidal action by the cell wall destroyed in Gram-negative bacteria.
Aminoglycoside antibiotics comprise gentamicin, amikacin, streptomycin and other, and be generally considered to be used for the treatment of Gram-negative bacteria, mycobacterium and other microbial pathogens, although reported the case of resistant strain.Aminoglycoside is not absorbed by digestive tract, is therefore generally considered to be unsuitable for oral formulations.Such as amikacin, although usually effectively resist gentamicin resistance bacterial isolates, usually in intravenous or intramuscular administration, this can cause patient pain.In addition, relevant to aminoglycoside antibiotics (such as amikacin) toxicity can cause injury of kidney and/or irreversible hearing disability.
Although there is these character, some embodiment disclosed herein expection is Orally administered to be such as used for the treatment of along oral cavity, the collaborative BT/ antibiotic composition (such as, wherein antibiotic is not necessarily limited to aminoglycoside) on the epithelial tissue surface of intestines and stomach/gastral one or more position.Some other embodiment it is also contemplated that composition as herein described and the method purposes as disinfectant, and disinfectant refers to the preparation killing and wounding microorganism on xenobiotic external surface or stop it to grow.
Also as herein described by other place, BT compound can be comprise bismuth or bismuth salt and the composition containing mercaptan (such as-SH or sulfydryl) compound, it comprises those (comprising its preparation method): the Domenico etc. described in the following, 1997Antimicrob.Agent.Chemother.41 (8): 1697-1703, Domenico etc., 2001Antimicob.Agent.Chemother.45 (5): 1417-1421, and U.S.RE37,793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248; Also see such as U.S.6,582,719.But some embodiment is not so restriction, and it is expected to other BT compound comprising bismuth or bismuth salt and the compound containing mercaptan.Compound containing mercaptan can containing 1,2,3,4,5,6 or more mercaptan (such as-SH) group.In preferred embodiments, BT compound comprises by ionic bonding and/or as co-ordination complex and the bismuth associated containing the compound of mercaptan, and in some of the other embodiments, bismuth can be associated with the compound containing mercaptan by the covalent bond that such as may reside in organo-metallic compound.Such as, but it is the BT compound of organo-metallic compound that embodiment of some expection is clearly got rid of, and wherein finds the compound of bismuth and organic moiety covalent bonding.
Exemplary BT compound is shown in table 1:
table 1
exemplary BT compound *
1)CPD1B-1Bis-EDT(1∶1)BiC 2H 4S 2
2)CPD1B-2Bis-EDT(1∶1.5)BiC 3H 6S 3
3)CPD1B-3Bis-EDT(1∶1.5)BiC 3H 6S 3
4)CPD1CBis-EDT(1∶1.5)BiC 3H 6S 3
5)CPD2ABis-Bal(1∶1)BiC 3H 6S 2O
6)CPD2BBis-Bal(1∶1.5)BiC 4.5H 9O 1.5S 3
7)CPD3ABis-Pyr(1∶1.5)BiC 7.5H 6N 1.5O 1.5S 1.5
8)CPD3BBis-Pyr(1∶3)BiC 15H 12N BO 3S 3
9)CPD4Bis-Ery(1∶1.5)BiC 6H 12O 3S 3
10)CPD5Bis-Tol(1∶1.5)BiC 10.5H 9S 3
11)CPD6Bis-BDT(1∶1.5)BiC 6H 12S 3
12)CPD7Bis-PDT(1∶1.5)BiC 4.5H 9S 3
13)CPD8-1Bis-Pyr/BDT(1∶1/1)
14)CPD8-2Bis-Pyr/BDT(1∶1/0.5)
15) CPD9Bis-2 hydroxyl, propanethiol (1:3)
16)CPD10Bis-Pyr/Bal(1∶1/0.5)
17)CPD11Bis-Pyr/EDT(1∶1/0.5)
18)CPD12Bis-Pyr/Tol(1∶1/0.5)
19)CPD13Bis-Pyr/PDT(1∶1/0.5)
20)CPD14Bis-Pyr/Ery(1∶1/0.5)
21) CPD15Bis-EDT/2 hydroxyl, propanethiol (1: 1/1)
* in order to compare, show the atom ratio relative to single bismuth atom, form the known tendency of trivalent complex compound based on the stoichiometric proportion of reactant used and bismuth and sulfur-containing compound.Shown atom ratio can be to the accurate formula of all kinds in customization agent.Numeral in bracket is the ratio (such as Bi: mercaptan 1/ mercaptan 2) " CPD " of bismuth and the agent of (or multiple) mercaptan, compound.
BT compound for some disclosure embodiment can according to the preparation of fixed method (such as U.S.RE37.793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248; Domenico etc., 1997Antimicrob.Agent.Chemother.41 (8): 1697-1703, Domenico etc., 2001Antimicob.Agent.Chemother.45 (5): 1417-1421), and in some other embodiment, BT compound can also be prepared according to methodology as herein described.Therefore, some preferred embodiment expection is as herein described for the preparation of BT compound with especially for the synthetic method obtaining the BT compound of monodispersed particulate form substantially, is wherein at least 50mM containing concentration, at least 100mM, at least 150mM, at least 200mM, at least 250mM, at least 300mM, at least 350mM, at least 400mM, at least 500mM, at least 600mM, at least 700mM, at least 800mM, at least 900mM or at least 1M dissolving bismuth and not containing hydrophily, the acid bismuth aqueous solution of polarity or organic solubilized agent mixes with ethanol and obtains the first ethanolic solution, this first ethanolic solution is being enough to be formed the condition of precipitation of the particulate comprised containing BT compound and time (such as, the concentration that can understand based on present disclosure of as described herein and those skilled in the art with the second ethanolic solution comprised containing the compound of mercaptan, solvent strength, temperature, pH, mixing and/or the condition such as pressure) under reaction and obtain reaction solution, the wherein said compound containing mercaptan is present in reaction solution with the mol ratio being about 1:3 to about 3:1 relative to bismuth.
Therefore, exemplary BT comprises compound 1B-1, Bis-EDT (bismuth-1,2-dithioglycol, reactant 1:1); Compound 1B-2, Bis-EDT (1:1.5); Compound 1B-3, Bis-EDT (1:1.5); Compound 1C, Bis-EDT (solubility Bi preparation, 1:1.5); Compound 2A, Bis-Bal (the anti-lewisite agent (Britishanti-Lewisite) of bismuth-Britain (bismuth-dimercaprol dimercaptopropanol, bismuth-2,3-dimercaprol dimercaptopropanol), 1:1); Compound 2B, Bis-Bal (1:1.5); Compound 3ABis-Pyr (bismuth-PTO, 1:1.5); Compound 3BBis-Pyr (1:3); Compound 4, Bis-Ery (bismuth-dithioerythritol, 1:1.5); Compound 5, Bis-Tol (bismuth-3,4-dimercapto toluene, 1:1.5); Compound 6, Bis-BDT (bismuth-2,3-succinimide mercaptans, 1:1.5); Compound 7, Bis-PDT (bismuth-1,3-dimercaptopropane, 1:1.5); Compound 8-1Bis-Pyr/BDT (1:1/1); Compound 8-2, Bis-Pyr/BDT (1:1/0.5); Compound 9, Bis-2-hydroxyl, propanethiol (bismuth-1-sulfydryl-2-propyl alcohol, 1:3); Compound 10, Bis-Pyr/Bal (1:1/0.5); Compound 11, Bis-Pyr/EDT (1:1/0.5); Compound 12Bis-Pyr/Tol (1:1/0.5); Compound 13, Bis-Pyr/PDT (1:1/0.5); Compound 14Bis-Pyr/Ery (1:1/0.5); Compound 15, Bis-EDT/2-hydroxyl, propanethiol (1:1/1) (see such as table 1).
Undesirably bound by theory, think that the method for the BT of preparation compound of the present disclosure may be expected to produce the composition comprising BT compound, wherein this composition has one or more character expected, comprise easy large-scale production, the product purity of raising, uniformity or uniformity (comprising particle size uniformity) or for the preparation of and/or use other character of topical formulations of the present disclosure, described method can comprise preparation or obtain the acidic liquid aqueous solution (such as comprising the aqueous solution of nitric acid of bismuth nitrate) comprising bismuth in some preferred embodiment.
In a particular embodiment, have been found that the BT compound prepared first according to method as herein described shows the favourable uniformity with regard to it occurs as monodispersed microparticle suspending liquid substantially, according to some current preferred embodiment, each particulate has the volume mean diameter (VMD) of about 0.4 μm to about 5 μm.Measuring of granularity can be called as volume mean diameter (VMD), mass median diameter (MMD) or mass median aerodynamic diameter (MMAD).Such as can carry out these measurements by clashing into (MMD and MMAD) or being characterized by laser (VMD).For liquid particle, if keep environmental condition (such as standard humidity), then VMD, MMD and MMAD may be identical.But if humidity is not kept, MMD and MMAD measured value will be less than VMD, this will be the dehydration owing to clashing in measuring process.In order to the object described, VMD, MMD and MMAD measurement is considered at the standard conditions, makes the description of VMD, MMD and MMAD be suitable.Similarly, the powder size of MMD and MMAD measures and is also considered to suitable.
As described herein, preferred embodiment relates to the monodispersed suspension containing BT particulate substantially.The generation with the clear and definite BT granularity of limited geometric standard deviation (GSD) such as can optimize BT deposition, to the accessibility of the expection target site in natural or artificial surfaces or in natural or artificial surfaces, and/or experimenter is to the tolerance of the BT particulate used.Granule amount outside VMD or the MMAD size range of limited GSD restriction expection.
In one embodiment, liquid or the aerosol suspension of the particulate containing one or more BT compounds disclosed herein of the VMD with about 0.5 micron to about 5 microns is provided.In another embodiment, liquid or the aerosol suspension of VMD or MMAD with about 0.7 micron to about 4.0 microns is provided.In another embodiment, liquid or the aerosol suspension of VMD or MMAD with about 1.0 microns to about 3.0 microns is provided.In some other preferred embodiment, provide the VMD or about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8 that comprise one or more about 0.1 to about 5.0 micron or about 0.9 micron to about 1.0, the liquid suspension of the BT compound particles of about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5 or about 8.0 microns, described particulate comprises the BT compound of preparation as described herein.
Therefore in some preferred embodiment, " substantially " that describe first herein monodispersed BT preparation, such as comprise the BT composition that wherein " substantially " all particulates have the BT compound of the particulate form of the volume mean diameter (VMD) in prescribed limit (such as about 0.4 μm to about 5 μm), comprise wherein at least 80%, 85%, 90%, 91%, 92%, 93% or 94%, more preferably at least 95%, 96%, 97%, 98%, 99% or more particulate and there are those compositions of the VMD in described size range.
The advantage of the novelty of the BT that these and relevant character of the BT composition prepared according to synthetic method as herein described describe before providing and exceeding, comprise lower cost and easily produce, and can allow it to be conducive to the uniformity in the composition that characterizes according to the mode of the one or more regulation biddability in medicine, preparation and cosmetic standard.
Additionally or alternatively, substantially monodispersed BT particulate as herein described advantageously can not needed micronizing by producing, namely, without the need to expensive and the grinding of effort or supercritical fluid processing or be generally used for other device and program (such as, the Martin etc. 2008Adv.DrugDeliv.Rev.60 (3): 339 that produce particulate; Moribe etc., 2008Adv.DrugDeliv.Rev.60 (3): 328; Cape etc., 2008Pharm.Res.25 (9): 1967; The 2004Pharm.Dev.Technol.9 such as Rasenack (1): 1-13).Therefore, present embodiment provides the beneficial effect of uniform microparticle formulation substantially, that include but not limited to strengthen and uniform solubilize character substantially, be applicable to the administration form (such as oral, suck or dermatology/skin wound localized forms) of expection, the bioavilability of increase and other beneficial property.
BT compound particles suspension can as aqueous formulation, as the suspension in aqueous solvent and organic solvent (comprising Halogenated hydrocarbon propellants) or solution, use as dry powder or with other form hereafter described in detail, such as, comprise containing known wetting agent, surfactant, mineral oil or other composition of formulation scientist or additive to maintain the preparation of the single particulate in suspension.Aqueous formulation can be atomized by liquid dispenser, adopts such as waterpower or ultrasonic atomizatio.System based on propellant can utilize suitable pressurization distributor.Dry powder can utilize the dry powder dispersion device that can effectively disperse containing BT particulate.The granularity of expection and distribution can obtain by selecting appropriate device.
Also described above, additionally provide preparation herein according to some embodiment and comprise multiple method comprising bismuth-mercaptan (BT) composition of the particulate of BT compound, substantially all this particulates have about 0.1 to about 8 micron, and in some preferred embodiment the volume mean diameter (VMD) of about 0.4 micron to about 5 microns.
Generally speaking, described method comprises the steps: that (a) mixes being enough to obtain under the condition and time being substantially free of solids of sedimentation: (i) comprises bismuth salt (bismuth containing at least 50mM concentration) and containing the acidic aqueous solution of hydrophily, polarity or organic solubilized agent, is enough to obtain comprise by volume about 5%, 10%, 15%, 20%, 25% or 30% and the ethanol of the preferred amount of the mixture of about 25% ethanol with (ii); (b) be enough to be formed the particulate comprised containing described BT compound precipitation condition and under the time, in the mixture of (a), add the ethanolic solution that comprises containing the compound of mercaptan to obtain reaction solution, the wherein said compound containing mercaptan exists with the mol ratio being about 1:3 to about 3:1 relative to bismuth in described reaction solution.
In some preferred embodiment, bismuth salt can be Bi (NO 3) 3, but should be understood that according to present disclosure, bismuth can also other form provide.In certain embodiments, in acidic aqueous solution, bi concns can be at least 100mM, at least 150mM, at least 200mM, at least 250mM, at least 300mM, at least 350mM, at least 400mM, at least 500mM, at least 600mM, at least 700mM, at least 800mM, at least 900mM or at least 1M.In certain embodiments, acidic aqueous solution comprises the bismuth of by weight at least 5%, 10%, 15%, 20%, 22% or 22.5%.In some preferred embodiment, acidic aqueous solution can comprise at least 5% or more nitric acid by weight, and in some other embodiment, acidic aqueous solution can comprise at least 0.5%, at least 1%, at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5% or at least 5% nitric acid by weight.
Compound containing mercaptan can be any compound containing mercaptan as herein described, and can comprise in certain embodiments following in one or more: 1,2-dithioglycol, 2,3-dimercaprol dimercaptopropanol, PTO, dithioerythritol, 3,4-dimercapto toluene, 2,3-succinimide mercaptans, 1,3-dimercaptopropane, 2-hydroxyl propanethiol, 1-sulfydryl-2-propyl alcohol, dithioerythritol and dithiothreitol (DTT).Other exemplary compound containing mercaptan comprises alpha-lipoic acid, methyl mercaptan (CH 3sH [m-sulfydryl]), ethyl mercaptan (C 2h 5sH [e-sulfydryl]), 1-propanethiol (C 3h 7sH [n-P sulfydryl]), 2-propanethiol (CH 3cH (SH) CH 3[2C 3sulfydryl]), butyl mercaptan (C 4h 9sH ([normal-butyl sulfydryl]), tert-butyl mercaptan (C (CH 3) 3sH [tert .-butylthio]), amyl hydrosulfide (C 5h 11sH [amyl group sulfydryl]), coacetylase, lipoamide, glutathione, cysteine, cystine, 2 mercapto ethanol, dithiothreitol (DTT), dithioerythritol, 2-sulfydryl indole, TGase and can available from any one of the following mercaptan compound of Sigma-Aldhch (St.Louis, MO): (11-mercaptan undecyl) six (ethylene glycol), (11-mercapto-undecanoic base) four (ethylene glycol), (11-mercapto-undecanoic base) four (ethylene glycol) functionalized nm of gold, 1,1', 4', 1 "-terphenyl-4-mercaptan, 1,11 – hendecane two mercaptan, 1,16-hexadecane dithiol, 1,2-dithioglycol (technical grade), 1,3-dimercaptopropane, Isosorbide-5-Nitrae-benzene dimethanethiol, Isosorbide-5-Nitrae-succinimide mercaptans, Isosorbide-5-Nitrae-succinimide mercaptans diacetate esters, 1,5-pentane disulfide thioalcohol, 1,6-ethanthiol, pungent two mercaptan of 1,8-, 1,9-mercaptan in the ninth of the ten Heavenly Stems two, adamantane mercaptan, 1-butyl mercaptan, 1-decyl mercaptan, 1-dodecyl mercaptans, 1-heptanthiol, 1-heptanthiol (pure), 1-hexadecanethiol, 1-hexyl mercaptan, 1-sulfydryl-(triethylene glycol), the golden nanometer particle that 1-sulfydryl-(triethylene glycol) methyl ether is functionalized, 1-sulfydryl-2-propyl alcohol, 1-mercaptan in the ninth of the ten Heavenly Stems, 1-octadecanethiol, 1-spicy thioalcohol, 1-spicy thioalcohol, 1-pentadecane mercaptan, 1-amyl hydrosulfide, 1-propanethiol, 1-tetradecane mercaptan, 1-tetradecane mercaptan (pure), 1-undecane thiol, 11-(1H-pyrroles-1-base) hendecane-1-mercaptan, 11 – amino-1-undecane thiol hydrochlorides, the bromo-1-undecane thiol of 11-, 11-sulfydryl-1 – tip-nip, 11-sulfydryl-1 – tip-nip, 11-Mercaptoundecanoic acid, 11-Mercaptoundecanoic acid, 11-mercapto-undecanoic base trifluoroacetate, 11-mercapto-undecanoic base phosphoric acid, 12-sulfydryl dodecylic acid, 12-sulfydryl dodecylic acid, 15-sulfydryl pentadecanoic acid, 16-mercaptohexadecanoic acid, 16-mercaptohexadecanoic acid, 1H, 1H, 2H, 2H-perfluor decyl mercaptan, 2,2'-(ethylenedioxy) diethyl mercaptan, 2,3-succinimide mercaptans, 2-butyl mercaptan, 2-ethyl hexyl mercaptan, 2-methyl isophthalic acid-propanethiol, 2-methyl-2-propanethiol, 2-benzene ethyl mercaptan, 3,3,4,4,5,5,6,6,6-nine fluoro-1-hexyl mercaptan (pure), 3-(dimethoxy-methyl silicyl)-1-propane diol, the chloro-1-propanethiol of 3-, 3-sulfydryl-1-propyl alcohol, 3-sulfydryl-2-butanols, 3-sulfydryl-N-nonyl propionamide, 3-mercaptopropionic acid, the silica gel that 3-mercaptopropyi is functionalized, 3-methyl isophthalic acid-butyl mercaptan, two (mercapto methyl) biphenyl of 4,4'-, 4,4'-dimercapto stilbene, 4-(the own oxygen base of 6-sulfydryl) benzylalcohol, 4-cyano group-1-butyl mercaptan, 4-sulfydryl-1 – butanols, 6-(ferrocenyl) hexyl mercaptan, 6-sulfydryl-1-hexanol, 6-mercaptohexanoic acid, 8-sulfydryl-1-octanol, 8-sulfydryl is sad, 9-sulfydryl-1 – nonyl alcohol, xenyl-4,4'-bis-mercaptan, 3-mercaptopropionic acid butyl ester, 1-butyl mercaptan copper (I), cyclohexylmercaptan, cyclopentanethiol, the Nano silver grain that decyl mercaptan is functionalized, the golden nanometer particle that dodecyl mercaptans is functionalized, the Nano silver grain that dodecyl mercaptans is functionalized, six (ethylene glycol) single-11-(Acetylsulfanyl) undecyl ether, mercapto succinic acid, 3-mercapto-propionate, nanoTetherBPA-HH, NanoThinks tM18, NanoThinks tM8, NanoThinks tMaCID11, NanoThinks tMaCID16, NanoThinks tMaLCO11, NanoThinks tMnano particle, the average M of PEG bis-mercaptan that THIO8, spicy thioalcohol are functionalized n8,000, PEG bis-mercaptan mean molecule quantity 1,500, PEG bis-mercaptan mean molecule quantity 3,400, S-(11 – bromo-n-11 base) thiacetate, S-(4-cyanobutyl) thiacetate, benzenethiol, triethylene glycol list-11-mercapto-undecanoic base ether, trimethylolpropane tris (3-mercaptopropionic acid ester), [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol), carborane-9-mercaptan, para-terpheny base-4,4 "-two mercaptan, tertiary lauryl mercaptan and tertiary nonyl mercaptan.
Exemplary reaction condition described herein (comprise temperature, pH, reaction time, use stir or stir to dissolve solute and for controlling and the program of washing precipitation) and adopt technology well known in the art.
The method of the production BT compound described before being different from, the method of BT produced according to the present invention, BT product provides with microparticle suspending liquid, substantially fine-grained VMD is about 0.4 to about 5 micron in some preferred embodiment, and is generally about 0.1 micron to about 8 microns according to some other embodiment.Method before being also different from, according to the present embodiment, bismuth be provided in comprise concentration at least about the bismuth of 50mM to about 1M and amount at least about 0.5% to about 5% (w/w) and be preferably less than 5% (w/w) nitric acid and in acidic aqueous solution containing hydrophily, polarity or organic solubilized agent.
Technology instruction in view of generally acknowledging: bismuth is water-fast (such as U.S.RE37793) 50 μMs time, bismuth in water unstable (such as, Kuvshinova etc., 2009Russ.JInorg.Chem54 (11): 1816), and bismuth is even unstable in salpeter solution, unless there is hydrophily, polarity or organic solubilized agent, on this point, present approach provides advantage astonishing and beyong contemplation.Such as, (such as Domenico etc., 1997Antimicrob.Agents.Chemother.41:1697 in the clearly description of all BT preparation methods; U.S.6,380,248; U.S.RE37793; U.S.6,248,371), hydrophily solubilizer propane diols dissolves needed for bismuth nitrate, and prepare with the bi concns of the solution of thiol reactant far below 15mM, thus limit the available production model of BT compound.
On the contrary, according to present disclosure, dissolving bismuth does not need water-based, polarity or organic solubilized agent, and surprisingly obtains higher concentration.Hydrophily, polarity or organic solubilized agent comprise propane diols (PG) and ethylene glycol (EG), and any one of much known solubilizer can be comprised, comprise polar solvent, such as oxepane and dimethyl sulfoxide (DMSO) (DMSO), polyalcohol (comprise such as PG and EG, also comprise polyethylene glycol (PEG), polypropylene glycol (PPG), pentaerythrite etc.), polyhydroxy-alcohol such as glycerine and mannitol and other material.The miscible organic matter of water of other high polarity comprises dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF) and NMP (METHYLPYRROLIDONE).
Therefore, it will be understood by those skilled in the art that system (the such as 1995LiebigsAnn.241 that such as can use Catalan etc. according to solvent polarity/polarizability (SPP) scale value; Also see Catalan, 2001HandbookofSolvents, Wypych (editor), AndrewPubl., NY, and the bibliography wherein quoted) selective solvent, comprise provided herein be commonly used for hydrophily, polarity or organic solubilized agent those, according to the system of Catalan etc., such as, glassware for drinking water has the SPP value of 0.962, and toluene has the SPP value of 0.655, and 2-propyl alcohol has the SPP value of 0.848.Describe the method (Catalan etc., 1995) measuring solvent SPP value for the ultraviolet measurement right based on 2-N, N-dimethyl-7-nitrofluorene/2-fluoro-7-nitrofluorene probe/homomorphism.
Based on the solubility properties of particular B T composition, have expection SPP value solvent (no matter as pure one-component solvent or as 2,3, the solvent mixture of 4 kind or more kind solvent; About solvent miscibility, see such as Godfrey1972Chem.Technol.2:359) easily can be determined with reference to present disclosure by those skilled in the art, although as mentioned above, according to some preferred embodiment of synthetic method step as herein described, do not need hydrophily, polarity or organic solubilized agent to dissolve bismuth.
Solubility parameter can also comprise interaction parameter C, Hildebrand solubility parameter d or part (Hansen) solubility parameter: δ p, δ h and δ d, describes the polarity of solvent, hydrogen bonding electromotive force and dispersion force interaction electromotive force respectively.In certain embodiments, the peak describing the solubility parameter of the solvent that dissolves of bismuth salt or the co-solvent system comprising bismuth wherein can the restriction of the aqueous solution of providing package bismuth-containing salt, such as, according to the method for the preparation of particles B T composition as herein described.Such as, higher δ h value will have larger hydrogen bonding capability, and therefore have larger affinity to solvent molecule such as glassware for drinking water.Therefore higher solvent maximum observation δ h may for wherein expecting that the situation of more hydrophilic environments is preferred.
As limiting examples, have and can prepare according to following reaction scheme with the BisEDT of structure shown in following formula I:
In brief, and as nonrestrictive illustrative example, can in room temperature under agitation to the 5%HNO of excessive (11.4L) 3the aqueous solution slowly adds the acid bismuth aqueous solution of 0.331L (about 0.575 mole), such as Bi (NO 3) 3solution (such as, 43%Bi (NO 3) 3(w/w), 5% nitric acid (w/w), 52% water (w/w), can available from ShepherdChemicalCo., Cincinnati, OH), slowly add absolute ethyl alcohol (4L) subsequently.72.19mL (0.863 mole) 1 can be added to 1.5L absolute ethyl alcohol by using 60mL syringe, 2-dithioglycol, then stirring prepare separately the ethanolic solution (1.56L) of mercaptan compound such as 1,2-dithioglycol [~ 0.55M] for 5 minutes.1,2-dithioglycol (CAS540-63-6) and other mercaptan compound can available from such as Sigma-Aldrich, St.Louis, MO.Then the ethanolic solution of mercaptan compound can slowly be added into Bi (NO 3) 3/ HNO 3the aqueous solution, stirs and spends the night with forming reactions solution.According to some preferred embodiment, the compound containing mercaptan can be about 1:3 relative to bismuth and be present in reaction solution to the mol ratio of about 3:1.Make the product sedimentation of formation be the precipitation comprising particulate described herein, then also washed with the BisEDT obtaining Yellow amorphous powder solid shape with ethanol, water and acetone successively by collected by filtration.Crude product under agitation can be dissolved in absolute ethyl alcohol again, then filters and washs several times with ethanol successively, washing several times subsequently with acetone.Powder after washing can grind in 1MNaOH (500mL), filters, and washs with water, ethanol and acetone with the particles B isEDT providing purifying successively.
According to non-limiting theory, bismuth anti-bacteria produces the ability of Extracellular Polymers (EPS) (such as extracellular polysaccharide of bacteria), and this suppression causes biofilm formation to reduce.Think that bacterium adopts glue sample EPS to adhere for biomembrane.According to infection character, biofilm formation and EPS processing can promote bacteriosis originality, such as, disturb wound healing.But independent bismuth as getting involved agent without therapeutic action, but is used usually used as a part of complex compound such as BT.Therefore, bismuth-mercaptan (BT) is the based composition comprising the compound that produced by bismuth and mercaptan compound chelating and show the antimicrobial therapy effect of the bismuth significantly improved.BT shows anti-infective, antibiont film and immunoregulation effect significantly.Bismuth-mercaptan effectively resists spectrum microorganism, and does not usually affect by antibiotic resistance.BT is with the concentration prevention biofilm formation of significantly low (sub-suppression), many pathogene features of common wound pathogens are prevented with same sub-suppression level, septic shock can be prevented in animal model, and can with many antibiotic synergisms.
As described herein, one or more specify this concertedness of BT and one or more antibacterial actions when specifying Antibiotique composition to combine to be not easy to predict the function Characteristics of specific bacteria type according to independent antibiotic and BT, but surprisingly, can produce by selecting particular B T-antibiotic combinations according to concrete bacterial community, described selection comprises qualification and there is Gram-negative bacteria or gram-positive bacteria (or both).Such as, as disclosed herein, amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or other lincoln amides antibiotics), Daptomycin can be comprised with the synergistic antibiotic of some BT , Doxycycline, gatifloxacin, gentamicin, Imipenem (imipenim), lavo-ofloxacin, Linezolid , minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, one or more in tobramycin and vancomycin.In vitro study shows, such as, separately to gentamicin, Cefazolin, Cefepime, Sulfamethoxazole, Imipenem or lavo-ofloxacin susceptibility difference or at all insensitive MRSA BT compd B isEDT exist under be exposed to antibiotic time significant susceptibility is shown to any one in these antibiotic.Therefore, some embodiment of expecting herein clearly expects that wherein can comprise BT compound is selected from amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or other lincoln amides antibiotics), Daptomycin with one or more , Doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid , minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, the composition of antibiotic combination of tobramycin and vancomycin and/or method, and some other embodiment expection expected herein wherein can comprise wherein clearly get rid of one or more be selected from amikacin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or other lincoln amides antibiotics), Daptomycin , Doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid , minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and the antibiotic BT compound of vancomycin and the composition of one or more antibiotic combinations and/or method.Note, in this context, gentamicin and tobramycin belong to aminoglycoside antibiotics.That clearly gets rid of from the embodiment of some expection also has Domenico etc., 2001AgentsChemother.45:1417-1421; Domenico etc., 2000Infect.Med.17:123-127; Domenico etc., 2003Res.Adv.InAntimicrob.Agents & Chemother.3:79-85; Domenico etc., 1997Antimicrob.AgentsChemother.41 (8): 1697-1703; The 1999JAntimicrob.Chemother.44:601-605 such as Domenico etc., 1999Infect.Immun.67:664-669:Huang; Veloira etc., 2003JAntimicrob.Chemother.52:915-919; Wu etc., 2002AmJRespirCellMolBiol.26:731-738; Halwani etc., 2008Int.JPharmaceut.358:278; Some composition described in Halwani etc., 2009Int.J.Pharmaceut.373:141-146 and method, wherein it should be noted that during these openly and in no way instruct or imply monodispersity particles B T composition as disclosed herein.
Therefore as described herein, provide in some preferred embodiment and treat plant, the composition of animal or human experimenter or goods and method with comprising particles B T as herein described and optionally also comprise concertedness and/or the antibiotic composition of enhancement in some other embodiment.Various equivalent modifications will be appreciated that the suitable agricultural that wherein may need this treatment based on the disclosure, clinical, business, industry, manufacturing industry, family expenses and other circumstances and condition, its standard is determined at medical domain, especially such as surgery is comprised, battle surgery, dermatology, Wound medicine, geratology, cardiovasology, metabolic disease (such as diabetes, obesity etc.), infect and inflammation (being included in the epithelial layer of respiratory tract or intestines and stomach or other epithelial tissue surface such as glandular tissue) and other medical speciality of being correlated with and son professional.
Preferred composition according to the bacteriological infection in being used for the treatment of in natural or artificial surfaces of using of embodiment as herein described or natural or artificial surfaces can comprise the composition comprising bismuth-mercaptan (BT) compound as herein described in certain embodiments, and it is different but also comprise other compound known in the art in related embodiment, the such as composition of one or more Antibiotique compositions as herein described at some.BT compound and their method of preparation open, and are disclosed in such as Domenico etc. (1997Antimicrob.Agent.Chemother.41 (8): 1697-1703 herein; 2001Antimicrob.Agent.Chemother.45 (5) 1417-1421) and U.S.RE37,793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248.Also described above, some preferred BT compound be containing with containing those of the compound ions bonding of mercaptan or the bismuth of ligand complex or bismuth salt, such as comprise the composition with the bismuth of sulfur-containing compound chelating, and some other preferred BT compound be containing with containing those of the bismuth of compound covalent bonding of mercaptan or bismuth salt.Also preferred monodispersed particles B T composition substantially as described herein.Not according to the effort for the treatment of bacteriological infection before, also not according to the sign of any compound of describing first herein before in other environment (promoting the purposes in natural and/or artificial surfaces therapeutic combination as herein described and method as having), can predict and use the inventive method of this compounds will have beneficial effect as herein described.
According to preferred embodiment, thus provide the method being used for the treatment of natural or artificial surfaces, comprise to described surface applied at least one particles B T compound as herein described.In certain embodiments, described method also comprises simultaneously or successively and use at least one Antibiotique composition with any order, can be wherein concertedness antibiotic as herein described in some preferred embodiment, and can be enhancement antibiotic as herein described in some other preferred embodiment.Described Antibiotique composition can be aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase-resistant PCs or Aminopenicillin antibiotic.Antibiotic useful is clinically discussed in other places herein and is also described in such as WashingtonUniversitySchoolofMedicine, TheWashingtonManualofMedicalTherapeutics (the 32nd edition), 2007Lippincott, Williams and Wilkins, Philadelphia, PA; And Hauser, AL, AntibioticBasicsforClinicians, 2007Lippincott, Williams and Wilkins, Philadelphia, PA.
As described herein, some embodiment is derived from discovery beyong contemplation as follows: for the bacteriological infection comprising gram-positive bacteria, and the effective preparation of preferred treatment can comprise BT compound (such as BisEDT, bismuth: 1,2-dithioglycol; BisPyr, bismuth: PTO; BisEDT/Pyr, bismuth: 1,2-dithioglycol/PTO) and rifamycin or BT compound and Daptomycin ( , CubistPharmaceuticals, Lexington, MA) or BT compound and Linezolid ( , Pfizer, Inc., NY, NY) or BT compound (such as, BisEDT, bismuth: 1,2-dithioglycol; BisPyr, bismuth: PTO; BisEDT/Pyr, bismuth: 1,2-dithioglycol/PTO) and ampicillin, Cefazolin, Cefepime, chloramphenicol, clindamycin (or another kind of lincoln amides antibiotics), Daptomycin , Doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid , NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin one or more.
Also as described herein, some embodiment is derived from discovery beyong contemplation as follows: for the bacteriological infection comprising Gram-negative bacteria, and the effective preparation of preferred treatment can comprise BT compound and amikacin.The infection comprising Gram-negative bacteria treated by some related embodiment expection BT compound and another kind of antibiotic (such as another kind of aminoglycoside antibiotics), and described another kind of aminoglycoside antibiotics is not gentamicin or tobramycin in certain embodiments.Therefore in view of these embodiments, other relevant embodiment is expected according to the methodology that medical microbial those skilled in the art are known, by the Gram-positive known or the qualification of gram-negative standard is natural or one or more bacterial communities in artificial surfaces or on surface or subgroup, as the step selecting the suitable Antibiotique composition be included in the preparation used according to the inventive method.
Composition as herein described and method to can be applicable in various background microorganism (such as, bacterium, virus, yeast, mould and other fungi, microorganism parasite etc.) process, it is usually by applying compound as herein described (such as, separately or with one or more particles B T of one or more concertednesses disclosed herein and/or enhancement antibiotic combinations) or be applied to microorganism site (to be such as present in natural or artificial surfaces or microorganism) in natural or artificial surfaces.These self-faceds include but not limited to plant (such as, the surface of the root of all or part, bulb, stem, leaf, branch, rattan, sarment, bud, flower or its part, tender shoots, fruit, seed, kind pod etc.), mammalian tissues (such as, comprises the epithelial cell in skin, scalp, intestines and stomach gland lining, oral cavity etc., endothelial cell, biological cells and tissues film such as peritoneal membrane, pericardium, pleura, periosteum, meninx and sarcolemma etc., cornea, sclera, mucous membrane etc., and other mammalian tissues such as muscle, heart, lung, kidney, liver, spleen, gall-bladder, pancreas, bladder, neural, tooth, bone, joint, tendon, ligament etc.) the upper surface found, and also can be included in and goods find any position that microorganism exists is (such as, business, house, industry, education, health care and other institution buildings thing wall, window, floor, Stilt layer (crawlspace), loft, basement, fence, roof, ceiling, illumination and hot-water heating utensil, ventilating opening, ventilation shaft, water pipe, door handle, switch, health department, drain ditch, pond, water pipe, medical treatment and dental apparatus, implant, instrument, instrument, equipment etc., metal, glass, plastics, wood, rubber and paper products, transporting equipment, comprise cask, automobile, railway equipment, ships and light boats, boats and ships (such as, shell, rudder, anchor and/or screw surface, interior handle and ballast tank and other interior surface), barge and oceanographic equipment, comprise dock, bulkhead, harbour etc.).
Particulate antimicrobial described herein can be used for suppressing growth of microorganism; Reduce microbial infection; Treatment comprises the product of natural and/or artificial surfaces to improve the resistance of product to microbial infection; Reduce biomembrane; Prevent Bacterial Transformation to biomembrane; Prevention or suppression infected by microbes; Prevent corruption; And other purposes any as herein described.These reagent also can be used for multiple anti-viral uses, comprise prevention or stop by the virus infections of bleb coe virus (such as cytomegalovirus, herpes simplex virus type 1 and herpes simplex virus type 2) and/or the infection by other virus.In this respect, described reagent can be used for prevention or stops by various virus (such as, single strand RNA virus, single-stranded DNA viruses, Rous sarcoma virus (RSV), hepatitis A virus, hepatitis type B virus (HBV), hepatitis C (HCV), influenza virus, west nile virus (WNV), epstein-Barr virus (EBV), eastern equine encephalitis virus (EEEV), serious acute respiratory virus (SARS), human immunodeficiency virus (HIV), HPV (HPV) and HTLV (HTLV), and also comprise the known virus as phytopathogen.(such as, corium solani; Potatovirus A, M, S, X or Y; Spotted wilt of tomato poison; The virus 3 that vine leaf curl is relevant; Plum pox virus; Lactuca virus 1; Garcinia mangostana mosaic virus; Pepper light property mottle virus; Tomato mosaic virus; Tobacco mosaic virus; Mottle virus; The celestial necrotic spot virus of phoenix etc.).
Other inside of antimicrobial as herein described or outside pharmaceutical use comprise, but be not limited to treatment or prevent bacteriological infection, tuberculosis, fungal infection such as yeast and mycotic infection (such as, Mycotoruloides (such as, Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida dubliniensis) or Cryptococcus or other fungi), Helicobacter pylori infection and peptic ulcer.In one embodiment, with usually not lethal to bacterium but its dosage still enough reducing protectiveness polysaccharide layers (it will resist innate immune reaction in addition) uses described dose.Therefore this technology is believed to be helpful in the bacteriological infection eradicating immune-mediated when not damaging mankind's symbiotic microorganism (such as, normal intestinal flora etc.) and applies the degree of the possible situation of antibiotic.
for applying and process the particulate bismuth-mercaptan of water pipe.In one embodiment, be provided for herein with on the inner surface of lower device or outer surface prevention and/or control (namely, slow down, postpone, suppress) biofilm development, disrupting biofilm or reduce the method for biomembranous amount: water pipe (such as, dentist, dental hygienist and other mouth care expert and nursing staff use water pipe) or other water delivery apparatus (comprising pipe, pipeline, tap, drinking bowl, shower nozzle); Or contact or send any Other Instruments of the water drunk or apply by people or non-human animal or device (such as, comprising the dental instruments of high-speed dental drill, air-water syringe) and cleaning device or instrument (such as, ).These methods are also used in prevention in water pipe or water delivery apparatus, reduce, suppress, eliminate or stop bacterium, fungi and/or protozoic growth and differ entiation.These methods comprise application, flushing, connect or adhere to the particles B T compound surface to water pipe or water delivery apparatus.
Biomembrane is the microscope colony primarily of naturally occurring bacterium and fungi composition.Microorganism forms thin layer on the surface of other water delivery apparatus comprising dental water delivery system and such as shower nozzle, tap and pipe.The water being used as cooling agent and irrigation in dental procedure can by microorganism severe contamination (such as, see, environmental protection board web epa.gov/safewater/mcl/html).The pathogene microorganism found in dental water pipe and instrument or opportunistic pathogen comprise actinomyces, Bacteroides, bacillus, Cryptosporidium, Escherichia coli, Flavobacterium, Klebsiella, Legionnella, Moraxella, mycobacterium, Peptostreptococcus, pseudomonas, staphylococcus, streptococcus and Veillonella.In addition, due to biofilm formation, Legionnella and protozoa can breed in water pipe or water delivery apparatus.When current are by pipeline or device, the biomembranous bacterium that lasting releasing exists in water pipe or water delivery apparatus and other microorganism.Patient and clinical staff are exposed to the microorganism existed in the fine droplet or water mists sprayed by pipeline or delivery apparatus.
Using and consuming for water in dental applications, Center for Disease Control's suggestion number of bacteria in the water of cooling agent/irrigation being used as No operation dental procedure should have≤aerobic the heterotrophic plate counts (HPC) of 500CFU/ml.Stricter standard is proposed by ADA (ADA), and it advises that the water used in dental treatment contains the≤bacteria levels of 200CFU/ml.The measure maintaining low-level total plate count in dental water systems comprise use antimicrobial (see, such as, McDowell etc., J.Am.Dent.Assoc.135:799-805 (2004)); Based on hydrogen peroxide disinfectant (see, such as, Linger etc., J.Am.Dent.Assoc.132:1287-91 (2001)); Before and after use to the normal developing of water pipe; The maintenance of water pipe and delivery system; The use of filtration system; The such as use of the chemical substance of disinfectant (such as, the bleaching agent 1:10 of dilution, glutaraldehyde, food-grade ethanol, product based on Chlorhexidine); Heat eradicates (thermaleradication); Copper silver ion; Chlorine dioxide; Ultraviolet; Ozone; Disinfectant combination (such as, iCX (Adex, Newburg, OR): SODIUM PERCARBONATE, silver nitrate and cationic surfactant and silver ion catalysis agent.
Can be used for preventing and/or control (that is, slow down, postpone, suppress) biofilm development, disrupting biofilm or be reduced in water pipe or water delivery apparatus inner or outer surface on the alternative antibacterial agent of biomembranous amount comprise particles B T compound as herein described (or comprising the composition of at least one particles B T compound).Particles B T compound can be introduced in water pipe, water conduit system and water delivery apparatus manually or automatically as gel, spraying, paste, liquid or powder or other form well known by persons skilled in the art.In certain embodiments, the bioactive ingredients other with comprising at least one by particles B T compound in powder or liquid form and/or at least one of inactive excipient or multiple other composition mix with formulated product, are regularly sent by described product or inject in water pipe, water delivery apparatus or water conduit system.Multiple methods known in the art can be used to prepare composition by those skilled in the art and prepare composition.Such as, the particles B T compound of the antimicrobial effective dose that can combine with DMSO can be used.In conventional use, need the level being enough to the particles B T compound preventing biofilm formation.But in other embodiments, the level of particles B T compound can be higher for reducing, remove, destroy or eliminating the biomembrane existed in water pipe, water delivery apparatus or water conduit system.
Also particles B T compound can be prepared so that from slow releasing the composition comprising the particles B T compound being applied to water pipe, water delivery apparatus or water conduit system.Also particles B T compound can be incorporated to coating, can be applied, fix, adhere to or make it contact the inner surface of water pipeline, delivery vehicle or system in some way.The composition comprising particles B T compound can be gel (such as, hydrogel, thiolates polymers (thiomer), aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.Slow releasing composition can send the particles B T compound 1,2,3,4,5,6 or 7 days (weeks) of antimicrobial effective dose or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.
Can by particles B T compound (or comprising the composition of particles B T compound) and other antimicrobial of at least one (namely, second, third, fourth class antimicrobial) combination, when combined administration, it has enhancing or Synergistic antimicrobial effect as described herein.Such as, the anti-microbial effect strengthened is can be observed when particles B T compound is used together with the antimicrobial of iron chelating.At least one in particles B T compound and oxidant, microbicide or disinfectant is combined.Can use the particles B T compound utilizing hydrophobicity mercaptan (such as, sulfo-chlorophenol) to prepare, and it goes out better to adhere to the ability of water pipe and water delivery apparatus and system than the BT compounds exhibit of hydrophobicity difference.The BT compound (such as have 1:2 mol ratio (bismuth: mercaptan) those) with net negative charge also can have good cohesive.
Particles B T compound (and comprising the composition of particles B T compound) and sodium bicarbonate or another alkali compounds or combinations of substances can be used.Due to chemistry and the physical property of sodium bicarbonate, it has a wide range of applications, and comprises clean, deodorizing and buffering.Sodium bicarbonate chemically in and stink, but not shelter or adsorb them.Can using sodium bicarbonate and particles B T compound combination as mixture or the dissolving of powder or be suspended in powder as herein described, spray, gel, paste or liquid.In other embodiments, can by particles B T compound with can contribute to maintaining required alkaline pH and also can have other alkali metal hydrogencarbonate of clean and deodorizing performance or carbonate material (such as, saleratus or calcium carbonate) combinationally uses.
As another example, particles B T compound (or comprising the composition of particles B T compound) and one or more following combinations of substances can be used. antimicrobial: such as, Chlorhexidine; Bloodroot extract; Metronidazole; Quaternary ammonium compound (such as Cetylpyridinium Chloride); Biguanides (such as, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (such as, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; Alkyl hydroxy benzoic ether; Anti-microbial cationic peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii (Coleusforskohlii) essential oil; Silver or collargol antibacterial agent; Based on the antibacterial agent of tin or copper; Mai Luka (Manuka) oil; Skin Sa grass (oregano); Thyme; Rosemary, Xue MingRosma rinus officinalis; Or other herb extracts; And grapefruit seed extract. anti-caries agent: such as, sodium fluoride and stannous fluoride, amine fluoride, sodium monofluorophosphate, sodium trimetaphosphate, zinc citrate or other zincon, and casein. plaque buffers (Plaquebuffer): such as, urea, calcium lactate, calcium glycerophosphate and polyacrylic acid strontium class. vitamin: such as, vitamin A, C and E. plant thing extract. anticalculus agent: such as alkali metal pyrophosphate salts, polymer, Organophosphonate and phosphocitrate etc. containing hypophosphites. biomolecule: such as, bacteriocin. preservative. opacifier. pH adjusting agent. sweetener. surfactant: such as, anion, nonionic, cation and amphion or amphoteric surfactant, from vegetable material saponin (see, such as, U.S. Patent No. 6,485,711). abrasive material particles: such as, the particulate abrasive, chalk, fine grinding natural whiting etc. of silica, aluminium oxide, calcium carbonate, Dicalcium Phosphate, calcium pyrophosphate, hydroxyapatite, trimetaphosphate, insoluble hexametaphosphate, cohesion. humidizer: such as, glycerine, sorbitol, propane diols, xylitol, lactitol etc. adhesive and thickening agent: such as, sodium carboxymethylcellulose, hydroxyethylcellulose , xanthan gum, gum Arabic, (such as, polyacrylate and C974P are such as synthetic polymer ).Enhanced activity composition such as antimicrobial is sent polymerizable compound.The buffering pH of oral care composition and ion strength buffer solution and salt. decolorizer: such as, per-compound (such as, peroxide diphosphonic acid potassium). effervescent system: such as, sodium bicarbonate/citric acid system.
In another embodiment, particles B T compound as herein described (or comprising the composition of particles B T compound) and at least one or multiple anti-biofilm agent can be combined for controlling biofilm development, disrupting biofilm or reducing biomembranous amount.As understood in the art, between kind, quorum sensing is relevant to biofilm formation.Strengthen LuxS-Dependent or between planting colony induction signaling Cucumber (see, such as, U.S. Patent No. 7,427,408) contribute to controlling biomembranous growth and/or propagation.Such as, exemplary agents comprise or combine or independent N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) block compound and N-butyryl-L-homoserine lactone (BHL) analog (see, such as, U.S. Patent No. 6,455,031).Comprise particles B T compound and at least one antibiont film oral hygiene composition can local delivery for destroy and stop bacterial biof iotalm and be used for the treatment of periodontosis (see, such as, U.S. Patent No. 6,726,898).
The effect of the particles B T compound as anti-biofilm agent can be strengthened by heating pipe, water delivery apparatus or water conduit system, by heating pipeline, delivery vehicle or system, particles B T compound is applied to this water pipe, water delivery apparatus or water conduit system.In certain embodiments, by pipeline, delivery vehicle or system heating between about 37 DEG C to about 60 DEG C or extremely between about 37 DEG C to about 100 DEG C.In other embodiments, by pipeline, delivery vehicle or system heating between about 45 DEG C to about 50 DEG C; Between about 50 DEG C to about 55 DEG C; Between about 55 DEG C to about 60 DEG C; Between about 60 DEG C to about 70 DEG C; Between about 70 DEG C to about 80 DEG C; Between about 80 DEG C to about 90 DEG C; Or between about 90 DEG C to about 100 DEG C.In certain embodiments, by pipeline, delivery vehicle or system heating extremely about 37 DEG C.In another specific embodiment, by pipeline, delivery vehicle or system heating to about 55 DEG C.As by those skilled in the art understand, depend on the temperature of applying, heating pipeline, delivery vehicle or system time can change.Such as, during by pipeline, delivery vehicle or system heating to lower temperature, reach required time when identical anti-microbial effect required time ratio is heated to higher temperature more of a specified duration.Those skilled in the art easily can determine the right times exposing pipeline, delivery vehicle or system at each temperature.
Particles B T compound (or comprising the composition of particles B T compound) can be used to reduce or prevent biofilm development together with other form.Such as, particles B T compound that is as described herein and that use in the art and oxidative chemicals, scale removal compound, biofilm disruption thing or rinse-system can be combinationally used.
comprise the composition of particulate bismuth-mercaptan and the purposes for teeth restoration.In further embodiment, providing package contains the composition for the particles B T compound and dental amalgam and particles B T compound and dental composite preventing and/or treating carious tooth herein.At present, be Dental Erosion by replacing as the inert substance preventing the obstruction rotted further to the treatment that only has of dental caries pathology.Dental amalgam and dental composite are most commonly used to the reparation of the tooth by caries affected.
Recurrent edge rots to be the major reason of repairing failure, particularly when being used for repairing by dental composite.Between composite and dental tissue the existence of the bacterium of interface field planting may be repairing failure key factor (see, such as, Hansel etc., J.Dent.Res.77:60-67 (1998)).In the research of Portugal (CasaPiaStudy, 1986-1989), carry out 1,748 postoperative reparations, and wherein 177 times (10.1%) failure in research process.Recurrent edge rots to be main cause failed in mercury alloy and composite repair, and mortality reaches 66% (32/48) and 88% (113/129) respectively (see .JADA2007 such as Bernardo; 138:775-83).Polymerization shrinkage is the contraction in composite material solidification process, its be regarded as postoperative edge seepage main cause (see, such as, Estefan etc., Gen.Dent.2003; 51:506-509).
Attempt Antimicrobe compound and reagent being incorporated in the reparation material of such as dentin-bonding systems (DBS), but limited success.Have the composite of anti-microbial properties and mercury alloy and other exploitation of repairing material can contribute to prevention Secondary cases carious tooth (see, such as, Imazato, Dent.Materials19:449 (2003)).The present embodiment contains the replacement of the antibacterial agent using remediation composition capable as herein described preparation, it provides advantage disclosed herein with the particles B T compound of this description described by this area, comprises a series of antimicrobial acivity, dissolubility and bioavilability, antibiont membrane interaction, avirulence, the enhancing of antibiotic effect and other character as described herein.
In certain embodiments, providing package contains the composition of particles B T compound and dental composite.Dental composite is usually containing polymerisable resin base, and this polymerisable resin base contains ceramic fillers.Particles B T compound and the method implemented by this area can be used any one of dental composite known in the art combinationally use (see, such as, O'Brien, DentalMaterialsandTheirSelection (Chicago:QuintessencePublishingCo.) (2002); Powers etc., DentalMaterials:PropertiesandManipulation (NewYork:Mosby) (2007); Roeters etc., J.Dent.32:371-77 (1998)).
In other embodiments, providing package contains the composition of particles B T compound and mercury alloy.Mercury alloy is the alloy of mercury and one or more other metals.Because silver is the main component of reacting with mercury, most of dental amalgam is called silver amalgam.Kinetics between mercury and silver is not suitable for Clinical practice, so silver is used as the alloy with other element.This alloy is commonly referred to dental amalgam, or jointly, alloy is called " dental amalgam alloy " (see, such as, International Standards Organization's standard (InternationalStandarsOrganizationStandard) ISO1559, DentalMaterials-AlloysforDentalAmalgam (1995)).Known polytype dental amalgam, and all comprise tin, and major part has some copper and a small amount of zinc.In dental amalgam self, some contain a small amount of mercury to promote that amalgamation is reacted.Conventional dental mercury alloy contains silver between 67% and 74%, 25-28% tin and 6% bronze medal, 2% zinc and 3% mercury at the most.So-called decentralized mercury alloy has about 70% silver medal, 16% tin and 13% bronze medal.The mercury alloy of different group can contain 30% bronze medal at the most, and it becomes high copper content mercury alloy.Before clinical placement, mercury alloy is mixed with 1:1 weight ratio with mercury.Therefore, the mercury content that after completing, dental amalgam is repaired is by weight about 50%.In the dental amalgam of routine, silver obtains crystal structure with the ratio of tin, and it is essentially the intermetallic compound Ag3Sn being called gamma (γ) phase.The exact percentage of this phase determines the dynamics of amalgamation reaction and many character of gained mercury alloy structure.Use higher copper dispersion alloy, the mixture of microstructure normally gamma phase and congruent melting silver-copper phase.Different manufacturer provides multi-form mercury alloy, but be generally fine grained, shape is spherical or irregularly shaped, granularity is that about 25-35 micron is (see emerging and new qualification health risk Science committee (ScientificCommitteeonEmergingandNewlyIdentifiedHealthRis ks) (SCENIHR), European commission: healthy and consumer protection Directorate-General DG (Directorate-General, Health & ConsumerProtection), on May 6th, 2008, network address: ec.europa.eu/health/ph_risk/committeesi04_seenihr/docs/s cenihr_o_016.pdf.).
By using particles B T compound to dental surface, mercury alloy or composite, particles B T compound also can be used for prevention or treatment carious tooth and/or inflammation (that is, reducing carious tooth and/or the generation of inflammation or the possibility of recurrence respectively).The composition comprising particles B T compound can mucus adhesive composite, described composition is applied to dental surface and/or gum or oral mucosa, and it can with any form of active component to required surface adhering to surface to a certain extent or send pharmaceutical effective amount.Also particles B T compound can be formulated as by the composition slow releasing being applied to oral cavity.Such as, composition can be gel (such as, hydrogel, thiolates polymers, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.This gel or liquid coating preparation can inner or applications to mercury alloy, compound or other repairing composition.Slow releasing composition can send pharmacy effective dose particles B T compound 1,2,3,4,5,6 or 7 days (weeks) or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.Said composition can use many methods known in the art to prepare by those skilled in the art.
The composition comprising particles B T compound for teeth restoration can comprise glass ion adhesive; Glass composite (giomer) (gathering acid reaction by making the fluoride containing glass and liquid to be formed); Complex (compomer) (polymerisable dimethacrylate resin and can ion leach glass-filled particle).Compomer can comprise fluoride further.
The composition comprising the particles B T compound on the surface being applied to tooth, mercury alloy or composite can comprise one or more other surfactants strengthening anti-microbial effect further.The exemplary antimicrobial used in the composition comprising particles B T compound comprises such as, Chlorhexidine, bloodroot extract, metronidazole, quaternary ammonium compound (such as Cetylpyridinium Chloride), biguanides (such as, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine), with halogenated bisphenol compound (such as, 2, 2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound, alkyl hydroxy benzoic ether, anti-microbial cationic peptide, aminoglycoside, quinolone, Lincoln's acid amides, penicillin, cephalosporin, macrolide, tetracycline, and other antibiotic known in the art, Taurolidine or tauroflex, A-decICX, Coleus forskohlii (Coleusforskohlii) essential oil, silver or collargol antibacterial agent, based on the antibacterial agent of tin or copper, chlorine or bromine oxidant, Mai Luka (Manuka) oil, skin Sa grass (oregano), thyme, rosemary, Xue MingRosma rinus officinalis or other medicinal herbal extract and grapefruit seed extract, anti-inflammatory or antioxidant, such as brufen, Flurbiprofen, aspirin, Indomethacin, aloe (aloevera), turmeric, Olive leaf P.E, cloves, panthenol, retinol, omega-fatty acid, gamma-Linolenic acid (GLA), green tea, ginger, grapestone etc.
Composition also can comprise one or more pharmaceutically acceptable carriers further, such as, and starch, sucrose, water or water/alcohol system, DMSO etc.Composition also can comprise surfactant, such as anion, nonionic, cation and amphion or amphoteric surfactant, or can comprise from vegetable material saponin (see, such as, U.S. Patent No. 6,485,711).Also the pH of the buffer compositions for orally using and the buffer of ion strength and salt can be comprised.Other optional member can be comprised: bleaching agent (such as per-compound), peroxide diphosphonic acid sylvite, effervescent system (such as sodium bicarbonate/citric acid system) etc.
comprise particulate bismuth-mercaptan composition and for oral hygiene and be used for the treatment of stomatitis the purposes of disease and infection.in another embodiment, the composition preparation comprising particles B T compound is used for oral use, and can be used for the growth of microorganism that prevents or reduce in oral cavity and for the infected by microbes that prevents and/or treats oral cavity and inflammation.Therefore, these compositions are for prevention or treatment (that is, reduce or Developing restraint, reduction occur or the possibility of recurrence) dental plaque, halitosis, periodontosis, gingivitis and other mouth infection.The oral cavity composition comprising particles B T compound also can be used for the biofilm development preventing and/or control (that is, slow down, postpone, suppress) oral surfaces, particularly tooth or gum exist, disrupting biofilm or reduce biomembranous amount.
Food particle remains, bad oral hygiene and bad oral health and improperly artificial tooth clean can impel between tooth, growth of microorganism on marginal gingiva and tongue.The growth of microorganism continued and the existence of carious tooth can cause halitosis, dental plaque (that is, the biomembrane formed by the field planting of microorganism), gingivitis and inflammation.When shortage suitable mouth care (such as, brush teeth, dental floss tooth-cleaning), can then cause more serious infection, such as periodontosis and jaw infect.
Good oral hygiene not only for oral health, but also is important for the prevention of some chronic pathology.The bacterial growth controlled in oral cavity can contribute to reducing heart disease risk, maintenance memory and the infection reduced in other position of health and inflammation risk.Diabetic occurs that the risk of serious gum problem is higher, and can contribute to controlling blood sugar by the risk keeping good oral health to reduce gingivitis.Pregnant woman perhaps more may suffer from gingivitis, and some researchs show there is relation between gum disease in pregnant woman and premature labor, low birth weight infant.
Bacterium is the main pathogens of periodontosis.Can find in dental plaque more than 500 kinds of bacterial isolateses (Kroes etc., Proc.Natl.Acad.Sci.USA96:14547-52 (1999)).Bacterium evolved in the environment in dental surface, gingival epithelium and oral cavity as biomembrane existence, which increase the difficulty for the treatment of periodontitis.Antibacterial agent and the current antibiotic being used for the treatment of this infection do not kill all attack organisms usually.The propagation of antibacterium bacterial classification can be caused to the use of the invalid material of some bacteria culture.In addition, these materials can cause the side effect making people unhappy, such as allergy, inflammation and tooth discoloration.
Bacterial plaque is the biomembrane being adhered to dental surface, restoration and prosthetic device securely.The biomembranous main method controlled in oral cavity is by mechanical cleaning (that is, brush teeth, dental floss tooth-cleaning etc.).Not carrying out in so clean initial two days, dental surface is mainly the Grain-positive facultative coccus institute field planting of streptococcus bacterial classification.Bacterial secretory contributes to bacterium to anchor to surface and provides the born of the same parents of protection outer rete malpighii to the bacterium of attachment.Once the bacterium that dental surface is attached covers, microcolony is formed.Biomembrane mainly through the cell division of the bacterium of attachment, but not is grown by the attachment of novel bacteria.Bacterium formed doubling time of patch develop in early days in fast, and slower in more ripe biomembrane.
Aggregation is there is when bacterial clump adheres to the bacterium being attached to film subsequently.The result of aggregation is the compound set forming the different bacterium be connected to each other.After original state plaque formation several days, gingival margin becomes inflammation and enlargement.Inflammation can cause the gingival sulcus of deepening to produce.Biomembrane is expanded to this gum lower area and flouring in this protection of the environment, causes the biomembranous formation of phagocytosis under ripe gum.Until become from a kind of biomembrane formed primarily of gram-positive bacteria the biomembrane comprising gram-negative anaerobic bacteria just occur gingivitis.Start between 3 and 12 weeks after gum edge plaque formation starts to form gingiva lower bacteria microcolony (primarily of gram-negative anaerobic bacteria composition) in gingival sulcus.
In biomembrane, shielded Bacterial microcolony has resistance to antibiotic (systemic administration), antibacterial agent or disinfectant (local application) and immune defense usually.Such as, the antibiotic dosage killing free flcating germ needs increase to reach 1,500 times to kill biofilm bacteria.Under this high concentration, these antibacterial agents also trend towards to patient toxic (see, such as, Coghlan1996, NewScientist2045:32-6; Elder etc., 1995, Eye9:102-9).
Making great efforts physical removal plaque bio-film is frequently the most effective means eliminating and control bacterial plaque.But, the subgingival plaque in recess not by brushing teeth, dental floss or mouth washes reach.Therefore, often by dentist or dentist carry out root surface under gum periodontal to remove be the chief component of prevention and therapy periodontitis.
In certain embodiments, particles B T compound can to join in oral hygiene composition and on device (such as coating) or in device, such as, but be not limited to toothpaste, mouthwash (i.e. oral rinse agent), buccal cavity gel, tooth powder, mouthspray (comprising the spraying disperseed by oral inhaler), edible film, chewing gum, oral cavity ointment, artificial tooth liquid cleaner, artificial tooth conserving liquid and dental floss, can be used them by any experimenter's routine.Particles B T compound can join in the oral hygiene composition used primarily of dental care industry and on device, and it comprises such as fluoride liquids therapeutic agent, Cleasing compositions, buffer compositions, oral rinse agent, dental floss and burnisher.The present embodiment expection is with particles B T compound as herein described and/or be coated to and device replace the antibacterial agent with oral hygiene composition preparation described in this area, to provide advantage disclosed herein, it comprises following scope: the enhancing of antimicrobial acivity, solvability and bioavilability, antibiont membrane interaction, non-toxic, antibiotic effect and other character as herein described.
Particles B T compound is also by coming for prevention by particles B T compound administration in dental surface or treating carious tooth and/or inflammation (that is, reducing the possibility occurring or recur carious tooth and/or inflammation respectively).The composition comprising particles B T compound can mucus adhesive composite, described composition is applied to dental surface and/or gum or oral mucosa, and it can with any form of active component to required surface adhering to surface to a certain extent or send pharmaceutical effective amount.Also particles B T compound can be formulated as by the composition slow releasing being applied to oral cavity.Such as, composition can be gel (such as, hydrogel, thiolates polymers, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.This gel or liquid coating preparation can inner or applications to mercury alloy, compound or other repairing composition.Slow releasing composition can send pharmacy effective dose particles B T compound 1,2,3,4,5,6,7 days (weeks) or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.Said composition can use many methods known in the art to prepare by those skilled in the art.
As described herein, in some other embodiment, providing package is used for oral use containing the antimicrobial compositions of particles B T compound and one or more other Antimicrobe compounds or antimicrobial.As described herein, useful especially composition when being and comprising and work as combined administration with the second antimicrobial agent of enhancing or Synergistic antimicrobial effect.Such as, the anti-microbial effect strengthened is can be observed when particles B T compound is used together with the antimicrobial of iron chelating.In other particular, particles B T compound and antiinflammatory, compound, Small molecular or large molecule (such as peptide or polypeptide) are prepared.
Any particles B T compound preparation as herein described can be used for oral use.In certain embodiments, the particles B T compound prepared with hydrophobic mercaptan (such as, sulfo-chlorophenol) can be used, and the ability adhering to tooth and oral cavity tissue that its display is larger than the BT compound of hydrophobic difference.The BT compound (such as have 1:2 mol ratio (bismuth: mercaptan) those) with net negative charge also can have good cohesive.
The oral hygiene composition comprising particles B T compound can comprise one or more active components in addition and/or one or more are applicable to excipient or the carrier in oral cavity.In one embodiment, described oral hygiene composition can comprise sodium bicarbonate or other alkali compounds or material in addition.Due to chemistry and the physical property of sodium bicarbonate, it has a wide range of applications, and comprises clean, deodorizing and buffering.Sodium bicarbonate chemically in and stink, but not shelter or adsorb them.Sodium bicarbonate can with particles B T compound combination, or as mixture of powders or dissolving or be suspended in tooth powder as herein described, gel, paste and liquid any one.In other embodiments, particles B T compound can with contribute to keeping needed for alkaline pH and also there is other alkali metal hydrogencarbonate of clean and deodorizing character or carbonate material (such as, saleratus or calcium carbonate) combines.
The oral hygiene composition comprising particles B T compound can comprise one or more following compositions in addition. antimicrobial: such as, Chlorhexidine; Bloodroot extract; Metronidazole; Quaternary ammonium compound (such as Cetylpyridinium Chloride); Biguanides (such as, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (such as, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; Alkyl hydroxy benzoic ether; Anti-microbial cationic peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii (Coleusforskohlii) essential oil; Silver or collargol antibacterial agent; Based on the antibacterial agent of tin or copper; Mai Luka (Manuka) oil; Skin Sa grass (oregano); Thyme; Rosemary, Xue MingRosma rinus officinalis; Or other herb extracts; And grapefruit seed extract. anti-inflammatory or antioxidant: such as, brufen, Flurbiprofen, aspirin, Indomethacin, aloe (aloevera), turmeric, Olive leaf P.E, cloves, panthenol, retinol, omega-fatty acid, gamma-Linolenic acid (GLA), green tea, ginger, grapestone etc. anti-caries tooth agent: such as, sodium fluoride and stannous fluoride, amine fluoride, sodium monofluorophosphate, sodium trimetaphosphate, zinc citrate or other zincon, and casein. plaque buffers: such as, urea, calcium lactate, calcium glycerophosphate and polyacrylic acid strontium class. vitamin: such as, vitamin A, C and E. plant thing extract. desensitizer: such as, potassium citrate, potassium chloride, potassium tartrate, saleratus, potassium oxalate, potassium nitrate and strontium salt. anticalculus agent: such as alkali metal pyrophosphate salts, polymer, Organophosphonate and phosphocitrate etc. containing hypophosphites. biomolecule: such as, bacteriocin, phage, antibody, enzyme etc. flavor enhancement: such as, thin He and peppermint oil, fennel, Chinese cassia tree etc. protein material: such as, collagen. preservative. opacifier. colouring agent. pH adjusts joint agent. sweetener. pharmaceutically acceptable carrier: such as, starch, sucrose, water or water/alcohol system etc. surfactant: such as, anion, nonionic, cation and amphion or amphoteric surfactant, from vegetable material saponin (see, such as, U.S. Patent No. 6,485,711). abrasive material particles: such as, the particulate abrasive, chalk, fine grinding natural whiting etc. of silica, aluminium oxide, calcium carbonate, Dicalcium Phosphate, calcium pyrophosphate, hydroxyapatite, trimetaphosphate, insoluble hexametaphosphate, cohesion. humidizer: such as, glycerine, sorbitol, propane diols, xylitol, lactitol etc. adhesive and thickener: such as, sodium carboxymethylcellulose, hydroxyethylcellulose , xanthan gum, gum Arabic, (such as, polyacrylate and C974P are such as synthetic polymer ).Enhanced activity composition such as antimicrobial is sent polymerizable compound.The buffering pH of oral care composition and ion strength buffer solution and salt. decolorizer: such as, per-compound (such as, peroxide diphosphonic acid potassium). effervescent system: such as, sodium bicarbonate/citric acid system. color change system.In specific embodiments, grinding agent is silica or fine grinding natural whiting.
Prepare and can comprise humidizer (such as, glycerine or sorbitol), surfactant, adhesive and/or flavor enhancement further with the oral hygiene composition comprising particles B T compound being used as toothpaste.Toothpaste also can comprise sweetener, brightening agent, preservative and antimicrobial.Toothpaste and for the pH of other composition of oral use usually between pH5.5 and 8.5.In certain embodiments, the oral hygiene composition comprising toothpaste has the pH between 7 and 7.5, between 7.5 and 8, between 8 and 8.5 or between 8.5 and 9, and described pH can strengthen the antimicrobial acivity of particles B T compound.Dentifrice composition as herein described can comprise in chalk, Tri-Compress, sorbitol, water, hydrated alumina, precipitated silica, lauryl sodium sulfate, sodium carboxymethylcellulose, flavor enhancement, sorbitan monooleate, saccharin sodium, tetrasodium pyrophosphate, methylparoban, nipasol one or more.If need to adopt one or more coloring agents as blue in, FD & C.Other composition be applicable to that can be contained in toothpaste preparation is described in this area, such as, and U.S. Patent No. 5,560,517.
In a specific embodiment, oral hygiene composition is oral spray, and comprises particles B T compound, alkaline buffer (such as, saleratus), alcohol, sweetener component and fragrance system.Fragrance system also can have following in more than one: essence, humidizer, surfactant, sweetener and colouring agent (see, such as, U.S. Patent No. 6,579,513).Surfactant for oral hygiene composition as herein described and as known in the art can be anion, non-ionic or both sexes.
In another embodiment, the oral hygiene composition comprising particles B T can combine with other active component such as Taurolidine and tauroflex, this be described to can be used in this area the toothpaste of the treatment comprising treatment severe infections, tooth gel and mouthwash (see, such as, UK Patent Application No.GB1557163, U.S. Patent No. 6,488,912).As described herein, the antimicrobial combination that particles B T also can be other with one or more, to such an extent as to described composition has additive effect or synergistic effect when combining with particles B T.
In yet another embodiment, oral hygiene composition as herein described can comprise at least one or the multiple antibiont film for controlling biofilm development, disrupting biofilm or minimizing biofilm biomass further.As in this area understand, between kind, quorum sensing (interspeciesquorumsensing) is relevant to biofilm formation.Can strengthen LuxS Dependent or plant between colony induction signaling (interspeciesquorumsensingsignal) (see, such as, U.S. Patent No. 7,427,408) some reagent contributes to controlling biomembranous growth and/or propagation.Such as, exemplary agents comprise or combine or independent N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) block compound and N-butyryl-L-homoserine lactone (BHL) analog (see, such as, U.S. Patent No. 6455031).Comprise particles B T compound and at least one antibiont film oral hygiene composition can local delivery for destroy and stop bacterial biof iotalm and be used for the treatment of periodontosis (see, such as, U.S. Patent No. 6,726,898).
Oral hygiene composition as herein described can comprise to be enough to normally brushing teeth, gargle or substantially play the particles B T compound of the amount of antibacterial action in time needed for dental floss tooth-cleaning.As described herein, particles B T compound can be held on oral surfaces (such as tooth, mercury alloy, compound, mucous membrane, gum).Smear, gargle wash, particles B T compound such as, can continue to be held on tooth and gum to provide antibiont film and the antiinflammatory action of prolongation after dental floss tooth-cleaning.
In other embodiments, particles B T compound is from mucus-binder polymer or contribute to the indwelling of particles B T compound in mucous membrane, tooth and other reagent slow releasing of repairing surface.Particles B T compound can be added to stable, viscosity and/or mucus adhesive water composition, described water composition also can be used for prevention and therapy mucous membrane exedens, inflammatory and/or rotten to the corn disorderly and/or send pharmaceutically active compound to mucomembranous surface with topical therapeutic or transfer to systemic circulation (see, such as, U.S. Patent No. 7,547,433).
In another embodiment, the oral hygiene composition comprising particles B T compound comprises the olive oil that can strengthen plaque removal further.Olive oil is for oral hygiene, such as, use in the product of toothpaste, mouthwash, spray, oral inhaler or chewing gum can contribute to the quantity eliminating or reduce the bacterium existed in (minimizing) bacterial plaque and/or elimination or reduction (minimizing) oral cavity, thus, reach and reduce odontopathy (such as, tooth is aging, periodontosis) and halitosis generation (see, such as, U.S. Patent No. 7,074,391).
In other embodiments, the oral hygiene composition comprising particles B T compound can comprise the mucous membrane disinfectant preparation being applied topically to oral cavity further.Oral hygiene composition can comprise further for clean tongue and the useful water-based paste (aqueousslurry) of larynx (see, such as U.S. Patent No. 6,861,049).In yet another embodiment, the oral hygiene composition comprising particles B T compound can comprise at least one further for the formation (carious tooth) of prevention (that is, reducing possibility occurrence) cavity or the peppermint agent (mint) reducing cavity number.One is called this type of peppermint agent of (OrtekTherapeutics, Inc., RoslynHeights, NY) includes and helps neutralizing acid pH and promote that calcium is adhered to arginine and the calcium of enamel surface.In the oral hygiene composition comprising particles B T compound, comprise peppermint agent therefore to improve pH and strengthen particles B T compound to the adhesion of oral surfaces.
preparation is used for the binder combination comprising particulate bismuth-mercaptan of dentistry and plastic surgery purposes thing.In another embodiment, by the composition preparation comprising particles B T compound for preventing or be reduced in bone or joint prosthesis or closing on the growth of microorganism on the tissue of described bone or joint prosthesis and skeletal structure.In specific embodiments, the method using the composition comprising particles B T compound to prevent and/or treat infected by microbes because plastic surgery formality (such as, plastic surgery operations, plastic treatment, arthroplasty (comprising two step arthroplasties), orthodontic treatment) causes and inflammation is provided.In certain embodiments, composition comprises particles B T compound and bone-cementum, and in other embodiments, described composition comprises particles B T compound and dental mesenchymal cells agent.Therefore, (namely these compositions can be used for preventing and/or treating, reduce or suppress it grow, reducing the possibility that it occurs or recurs) the infected by microbes such as osteomyelitis of skeleton and supporting construction (that is, BJM, ligament, tendon).The composition as herein described comprising particles B T compound and bone-cementum or dental mesenchymal cells agent also can be used for prevention and/or controls (namely, slow down, postpone, suppress) biofilm development, disrupting biofilm or the biomembranous amount that is reduced in joint or exists from the teeth outwards, the surface of such as joint, bone, ligament, tendon or tooth or alternative joint, bone (some or all of), ligament, tendon or tooth.
Adhesive as described herein and known in the art is by binding substances together and the binding material that can harden.This material can by tissue adhesion together or prosthese or artificial apparatus (such as, prosthetic joint, bone or tooth) can be bonded to adjacent tissue.Bone-cementum comprises such as polymethyl methacrylate (PMMA), magnesium phosphate and calcium phosphate.Calcium phosphate form is used as " substituting bone ", is used for the treatment of be full of cracks and the fracture of the bone that cannot heal enough rapidly and/or appropriately when not having embedded material.Also the composition by providing mechanical integrity will comprise bone-cementum (such as, calcium phosphate) and particles B T compound to cancellous bone is used for the treatment of cancellous bone defect.Can adhesive be absorbed at implant site place again or adhesive can be remained on implant site place.
In certain embodiments, the composition being used as bone-cementum as herein described comprises BT compound or particles B T compound and is suitable as the calcium phosphate of bone-cementum or the preparation of magnesium phosphate.Also the preparation of calcium phosphate or magnesium sulfate can be called bone-cementum containing calcium phosphate or calcium phosphate bone adhesive or the bone-cementum containing magnesium phosphate or Performances of Magnesium Phosphate Bone Cement adhesive herein.Calcium phosphate can be in the composition involved with any one in various ways that is known in this area and that use, and calcium phosphate comprises the hydroxyapatite (Ca as limiting examples 10(PO 4) 6(OH) 2); Brushite (CaHPO 4* 2H 2o); Monetite (CaHPO 4); Calcium deficiency hydroxyapatite (CDHA, Ca 9(PO 4) 5hPO 4oH); Calcium sulphate/calcium phosphate (CSPC) (see, such as, Hu etc., J.Mater.Sci.Mater.Med.2009 October 13, the electronic publication before printing) adhesive.Magnesium phosphate used in the art is also referred to as guanite (MgNH 4pO 4* 6H 2o) adhesive (see, such as, Grosshardt etc., TissueEng.A part, on July 30th, 2010, the electronic publication before printing; Also see, such as, Bohner etc., J.Pharm.Sci.86:565-72; (1997); Fulmer etc., 3:299-305 (1992); Lobenhoffer etc., J.OrthopaedicTrauma16:143-49 (2002); Lee etc., J.Carniofac.Surg.21:1084-88 (2010)).In certain embodiments, comprise particles B T compound and the composition as herein described of bone-cementum containing calcium phosphate comprise as the form of calcium phosphate calcium sulphate/calcium phosphate (CSPC) (see, such as, Hu etc., J.Mater.Sci.Mater.Med.2009 October 13, the electronic publication before printing).In some other embodiment, the composition comprising particles B T compound and calcium phosphate or magnesium phosphate adhesive can comprise shitosan (biopolymer from crustacean cell) further; At least one or Multiple Classes of Antibiotics or antimicrobial; And/or at least one or various anti-inflammatory.
Use bone-cementum for discharging medicine and reagent in the art.In certain embodiments, calcium phosphate cements can at least partly as encapsulating be used for the treatment of the hydroxyapatite microsphere of the reagent (such as, antimicrobial) of purposes form (see, such as, U.S. Patent No. 6,730,324).These adhesives comprising microsphere are included in the reagent in microsphere for slow releasing.Contain the composition comprising calcium phosphate microspheres herein, this calcium phosphate microspheres comprises particles B T compound.
Also providing package contains the composition of particles B T compound and PMMA bone-cementum herein.Use according to this area has the method for other preparation of reagents PMMA of antimicrobial acivity, and particles B T compound can be used to prepare PMMA bone-cementum (such as, see, european patent application No.EP1649874).
Also providing package contains the composition of particles B T chemical combination and dental mesenchymal cells agent (that is, dental adhesive) herein, and said composition can be used for the infected by microbes suppressing, prevent or treat tooth or gum.Dental mesenchymal cells agent can comprise any one of following compound or composition: trbasic zinc phosphate, Glass ionomer, α-calcium triphosphate (α-TCP), alkyl methacrylate (see, such as, U.S. Patent No. 6,071,528); Bismuth oxide (see, such as, Bueno etc., OralSurg.OralMed.OralPathol.OralRadiol.Endod.107:e65-69 (2009)); And capping in dog (mineraltrioxideaggregate) (MTA) (see, such as, Hwang etc., OralSurg.OralMed.OralPathol.OralRadiol.Endod.107:e96-102 (2009)).
The present embodiment contains the antimicrobial replacement using dental mesenchymal cells agent or bone-cementum preparation, it provides advantage disclosed herein with the particles B T compound of this description as described in the art, comprises a series of antimicrobial acivity, dissolubility and bioavilability, antibiont membrane interaction, avirulence, the enhancing of antibiotic effect and other character as described herein.Method according to this area can use particles B T compound and one or more other antibiosis usually prepare bone and dental mesenchymal cells agent (see, such as, U.S. Patent Application Publication No.2006/0205838; Alt etc., Antimicrob.AgentsChemother.48:4-84-88 (2004); Bohner etc., the same; Bueno etc., the same; Chuard etc., Antimicrob.AgentsChemother.37:625-32 (1993); J.Orthopaed.Res.27:1008-15 (2009); DeLalla, J.Chemother.13:48-53 (2001); Domenico etc., Peptides25:2047-53 (2004); Widmer etc., Antimicrob.AgentsChemother.35:741-46 (1991)).
Comprise bone-cementum or dental mesenchymal cells agent the amount containing the BT compound used in particles B T composition scope can for each adhesive of about 10-500 μ gBT/ gram between.The particles B T compound that the independent or antibiotic combinations other with at least one uses is provided in advantage more as described herein than the antibiotic of current use in bone and dental mesenchymal cells agent.The composition as herein described comprising particles B T compound and bone-cementum (such as, calcium phosphate) or dental mesenchymal cells agent can comprise one or more other Antimicrobe compound or reagent further.As described herein, useful especially is comprise to have the particles B T compound of enhancing or Synergistic antimicrobial effect and the composition of second antimicrobial agent when combined administration.By other embodiment, can be observed the anti-microbial effect strengthened when being used together with the antimicrobial of iron chelating by particles B T compound.In other particular, particles B T compound and antiinflammatory, compound, Small molecular or large molecule (such as peptide or polypeptide) are prepared.
Comprise the hardware (such as, screw, flat board, rivet, pin and wire etc.) that particles B T compound also can be used for the composition of bone-cementum applying for being connected, stablizing or fixing fracture, fusion, osteotomy or replace joint as described herein.Comprise the composition of particles B T compound as described herein and dental mesenchymal cells agent also for applying the remediation composition capable etc. in dental pulp, tooth cap, liner, tooth or tooth filling or tooth.Can, by the preparation of these compositions in coating, can apply, fix, adhere to or make in some way it to contact bone and/or joint related hardware this coating.In certain embodiments, coating comprises particles B T compound and calcium phosphate or Performances of Magnesium Phosphate Bone Cement adhesive.Particles B T compound and calcium phosphate or magnesium phosphate are together prepared for being applied to skeletal by the method according to this area practice.Such as, comprise particles B T compound and bone-cementum (such as, calcium phosphate or Performances of Magnesium Phosphate Bone Cement adhesive) composition can for being applied to the form of the liquid of hardware, gel, paste or spray (such as, thermal spray, it comprises plasma spraying).The composition comprising particles B T compound and bone-cementum can be gel (such as, hydrogel, thiolates polymers, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.Slow releasing composition can send the particles B T compound 1,2,3,4,5,6 or 7 days (weeks) of antimicrobial effective dose or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.According to the porosity of adhesive can at least in part Co ntrolled release speed (see, such as, Bohner etc., the same).
Can by comprise the composition of particles B T compound and bone-cementum or dental mesenchymal cells agent and at least one have when combined administration strengthen or Synergistic antimicrobial effect (, be greater than summation action) other antimicrobial (that is, second, third, fourth class antimicrobial) combination.Such as, the anti-microbial effect strengthened is can be observed when particles B T compound is used together with the antimicrobial of iron chelating.In specific embodiments, can by the composition comprising particles B T compound and bone-cementum or dental mesenchymal cells agent be selected from other antimicrobial of following at least one and/or antiinflammatory combines: antimicrobial: such as, Chlorhexidine; Bloodroot extract; Metronidazole; Quaternary ammonium compound (such as Cetylpyridinium Chloride); Biguanides (such as, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (such as, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; Alkyl hydroxy benzoic ether; Anti-microbial cationic peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii essential oil; Silver or collargol antibacterial agent; Based on the antibacterial agent of tin or copper; Mai Luka oil; Skin Sa grass; Thyme; Rosemary, Xue MingRosma rinus officinalis; Or other herb extracts; And grapefruit seed extract. anti-inflammatory or antioxidant: such as, brufen, Flurbiprofen, aspirin, Indomethacin, aloe, turmeric, Olive leaf P.E, cloves, panthenol, retinol, omega-fatty acid, gamma-Linolenic acid (GLA), green tea, ginger, grapestone etc.In specific embodiments, the composition comprising particles B T compound and bone-cementum or dental mesenchymal cells agent can comprise further and is selected from following antibiotic: clindamycin, vancomycin, Daptomycin, cephalosporin, gentamicin, tobramycin, metronidazole, Cefaclor, Ciprofloxacin or other antibacterial agent, such as quaternary ammonium compound (such as, benzalkonium chloride, pyrisept), antimicrobial zeolite, alkali metal hydroxide or alkaline earth oxide.Described composition optionally comprises one or more pharmaceutically suitable carriers (that is, excipient) as herein described, surfactant, buffer solution, thinner and salt, and decolorizer.Antimicrobial can be prepared together with bone-cementum with the dental mesenchymal cells agent as described in this paper and this area (see, such as, Akashi etc., Biomaterials22:2713-17 (2001); U.S. Patent No. 6,071,528; Alt etc., the same).
Can by the animal model of foreign body rejection for the identification of comprise particles B T compound and dental mesenchymal cells agent or bone-cementum composition antimicrobial acivity (see, such as, the Antimicrob.AgentsChemother.1993 such as Chuard; 37:625-32).In these models in antibiotic body effect kill Stationary liquid microorganism to antimicrobial and adhere to those ability of foreign material relevant (see, such as, the J.Infect.Dis.1990 such as Widmer; 162:96-102; The AntimicrobAgentsChemother1991 such as Widmer; 35:741-6; Also see, such as, Karchmer.Clin.Infect.Dis.1998; 27:714-6).
As limiting examples and only for illustrative purpose, bone-cementum can comprise the particles B T compound in following material: 75% (2/2) styrene-methyl methacrylate copolymer, 15% polymethyl methacrylate (with aid in treatment composition) and 10% barium sulfate (for radiation thoroughly) and about 10 to about 500 μ g particles B T compounds/gram bonding powder (that is, 0.001-0.05%w/w).In other specific embodiment, the antimicrobial that at least one is other can be added.
comprise and make to paint the composition with the particulate bismuth-mercaptan of paint preparation.Some other embodiment contain particles B T compound as herein described is incorporated in paint or paint upper as paint for reducing biological incrustation and prevention and/or control (that is, slow down, postpone, suppress) biofilm development, disrupting biofilm or being reduced in the biomembranous amount that paint face exists.The composition comprising particles B T compound as herein described can make to paint or paint preparation, described paint or paint are applied to any one in various products, include but not limited to medical treatment device, orthopedic device, dental apparatus, commercial plant, electronic installation, wall, floor, ceiling, roof, pile foundation, dock, harbour, pipeline and pipeline configuration are (such as, intake screen, cooling tower), heat exchanger, dykes and dams and fabric and other surface, such as comprising automobile, train, aircraft and such as boats and ships, ships and light boats, occur on the neutralization of all types of delivery vehicles of the steamer of submarine and other steamer those.
In certain embodiments, composition as herein described and method are for preventing and/or be reduced in biological incrustation or biomembrane that the goods being exposed to water are formed.It is believed that, in marine environment from the teeth outwards biomembranous formation be promote the field planting of some set invertebrate communities at sea building and recovery key factor (see, such as, Siboni etc., FEMSMicrobiolLett2007; 274:24-9).Interact the subsequently attachment and growth that cause invertebrate and algae within a couple of days and several weeks of macrobiota and these microbial films, this be the most of hydrodynamic drag relevant to biological incrustation reason (see, such as, Schultz, Biofouling2007; 23:331-41).Old biofilm support kentrogon absorption from the teeth outwards, have nothing to do with the type of bottom (see, such as, Hunga etc., JExptlMarineBiolEcol2008; 361:36-41).Biomembrane be also significantly increased in adhesion strength in Ascidian Phallusianigra, polychaeta pipe worm magnificent coil pipe worm (Hydroideselegans) and barnacle line barnacle (Balanusamphitrite) under one or more developmental stage (see, such as, Zardus etc., BiolBull2008; 214:91-8).Biomembrane also can strengthen zebra shellfish (Zebramussel) (speckle freshwater mussel) and some artificial surfaces adhesion (see, such as, Kavouras and Maki.InvertebBiol2005; 122:138-51), it causes tax revenue to the millions of and even multi-million dollar of seafood, generating and process industry and water and wastewater treatment facility and expenses, and causes the remarkable destruction to the ecosystem introducing shellfish.
In ocean, salt water and fresh water environment, under water structure and boats and ships are collected, precipitation, attachment and growth organism.These organisms comprise algae, fungi and other microorganism and aquatic animal, such as Tunicata, hydrozoan, Bivalve, moss, polychaete worm, sponge and barnacle.The existence being called these organisms of " incrustation " of structure is harmful, and such as, it increases construction weight and/or hinders its hydrodynamics, thus reduces its operating efficiency, increases the susceptibility to corrosion and degraded or cataclastic structure.
Comprise toxic component for some paint of preventing or reduce biological incrustation and biomembrane to produce and coating up to now, this toxic component while suppressing biological incrustation and biofilm formation to required and useful plants group and fauna poisonous.Exemplary antimicrobial and chemical toxicant comprise copper and containing copper compound (such as, cuprous oxide), mercury, arsenic, tributyltin oxide (TBT), organotin (that is, have connect the tin of one or more carbon-based groups), six kinds of two parts bisphenol-A-(chloropropylene oxide epoxide, difunctionality tetraglycidel ether epoxy resin, tetraglycidel ether epoxy resin and barium metaborate epoxy resin.
Particles B T compound as herein described provides non-toxic substitute and provides advantage disclosed herein, comprises a series of antimicrobial acivity, dissolubility and bioavilability, antibiont membrane interaction, the enhancing of antibiotic effect and other character as described herein.By in conjunction with particles B T Compounds and methods for as herein described, use to become known for preparing and comprise the paint of biocide and the step of paint, paint and paint in particles B T compound can be used to substitute other antimicrobial and particles B T compound can be incorporated to these paint and paint (see, such as, U.S. Patent No. 4,596,724; 4,410,642; 4,788,302; 5,470,586; 6,162,487; 5,384,176; U.S. Patent Application Publication No.2007/125703 and 2009/0197003; Gerhart etc., J.Chem.Ecol.14:1905-17 (1988); Sears etc., J.Chem.Ecol.16:791-99 (1990); Ganguli etc., SmartMater.Struct.18:104027 (2009); Cao etc., ACSAppliedMaterialsInterfaces1:494 (2009); Kumar etc., NatureMaterials7:236-41 (2008)).The paint that particles B T compound is incorporated to can be comprised based on epoxy resin, silicone or acrylic acid paint.In more specific embodiment, can particles B T compound be incorporated in paint, by this paint formulation Yu Haiyang purposes and being exposed in seawater, and it comprise such as based on alkyd resins, based on asphalt, based on the paint of albertite, based on chlorinated rubber and the paint based on epoxy resin.
By reagent being incorporated in paint and can discharging antimicrobial in a controlled manner.The method of the drug release rate of reinforced composite is known in the art.Composite can comprise natural or synthesis, biologically absorbing polymer thing matrix and disperse herein drug particles phase (see, such as, U.S. Patent No. 7,419,681 and 5,028,664; Also such as, see, U.S. Patent application No.2009/0043388).Such as, medicament elution paint coating compositions can comprise at least one particles B T compound be dispersed in the biologically active cementing agent of modification.
Can by the preparation of particles B T compound with by the composition slow releasing comprising the particles B T compound being applied to painted surface.Also particles B T compound can be incorporated in coating (such as, epoxy coating), can be applied, fix, adhere to or make in some way the structure of coating or the surface of article of its contact preparation.Can by particles B T compound by these composition slow releasing.The slow releasing composition comprising particles B T compound can be gel (such as, hydrogel, thiolates polymers, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.Slow releasing composition can send the particles B T compound 1,2,3,4,5,6 or 7 days (weeks) of antimicrobial effective dose or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.
Use in the art and other coating that can prepare together with particles B T compound comprises polysaccharide, this polysaccharide comprises and the polysaccharide matrix of multivalent metal cation reversible crosslink (such as, see, U.S. Patent Application Publication No.2009/0202610); Titania nanotube; The surface of nanostructured; There is the nano ceric oxide of the biocompatibility glucan coating of pH dependence antioxidant properties; Polysulfones block copolymer; And other biodegradable coating (also see, such as, U.S. Patent No. 6,162,487).Particles B T compound is prepared by other coating contained herein together with the anticorrosive and anti-incrustation preservative coating used in industry, and this other coating comprises the Brazil wax fluoropolymer as limiting examples; ; PTFE; And molybdenum (moly) material.
In paint or paint, particles B T compound concentration (by weight) (such as) can be low to moderate about 0.001% to about 0.1%, and this depends on special-purpose and the desirable properties of paint or paint.Can will be incorporated to particles B T compound (or comprising the composition of particles B T compound) and other antimicrobial of at least one of paint or paint (namely, second, third, fourth class antimicrobial) combinationally use, when combined administration, it has enhancing or Synergistic antimicrobial effect as described herein.As limiting examples, the antimicrobial that can comprise in the composition comprising particles B T compound comprises: Chlorhexidine; Bloodroot extract; Metronidazole; Quaternary ammonium compound (such as Cetylpyridinium Chloride); Biguanides (such as, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (such as, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; Alkyl hydroxy benzoic ether; Anti-microbial cationic peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii essential oil; Silver or collargol antibacterial agent; Based on the antibacterial agent of tin or copper; Mai Luka oil; Skin Sa grass; Thyme; Rosemary, Xue MingRosma rinus officinalis; Or other herb extracts; And grapefruit seed extract.Composition also can optionally comprise surfactant, diluent or carrier, buffer and/or bleaching agent further, and it is as above with as described herein.
comprise the composition of the particulate bismuth-mercaptan using concrete and cement compound preparation.Some other embodiment contain particles B T compound as herein described is incorporated in industrial cement and among the concrete of the coating comprising concrete, mortar and mortar, mortar and mortar or on for prevention and/or control (that is, slow down, postpone, suppress) biofilm development, disrupting biofilm or be reduced in the biomembranous amount that concrete surface exists.On xoncrete structure or among the microorganism of growth reduce product service life and can cause health hazard to the animal and human being exposed to the microorganism existed on concrete surface (see, such as, Idachaba etc., WasteManag.Res.19:284-91 (2001); Idachaba etc., J.Hazard.Mater.90:279-95 (2002); Tazaki, CanadianMineralogist30:431-34 (1992)).
As herein and this area use, cement refers to the dried powder material (usually also can contain the lime stone of other material) for bonding concrete aggregation substance.Exemplary cement described by this area is called Portland cement (OrdinaryPortlandCement), portland blast-furnace cement, brick cement, slag lime cement and aluminous cement.Once add water and/or additive, then cement admixture is called concrete, gathers materials if particularly added.Concrete is the composite be made up of gather materials (such as, gravel and sand), cement and water.The feature of the cement used under construction is the hydraulicity or on-hydraulic.Hydraulic cement is often used in tapestry brick construction in humid climate; With the masonry structure of the harbour engineering of contact with sea water etc.; And the exploitation of reinforced concrete.
The composition as herein described comprising particles B T compound can be used for apply or said composition can be mixed with the adhesive being used for xoncrete structure, this xoncrete structure comprises such as bridge, building, pipeline, sky way, tunnel, parking garge, offshore oilfield platform, harbour, bridge wall, water system and pipeline, floor, counter top, pavement, runway, loading terminal, ice rink building (skateparkstructure) and radioactive waste support of buildings.Particles B T compound as described herein can be incorporated in adhesive as described in the art (see, such as, U.S. Patent No. 7,507,281).Adhesive or concrete alkalescence also can strengthen the anti-microbial effect of particles B T compound.
By the bacterium also degradable adhesive of acidifying such as Thiobacillus thioxidans (Thiobacillusthiooxidans).As signal and unrestriced limiting examples, display bismuth mercaptan compound BisEDT (but not being particles B T compound as herein described) delays the growth of Thiobacillus thioxidans in the concrete for refuse and core system for handling.Being presented at effective antibacterium scope of BisEDT in concrete is 10-500 μ g/g or 0.001-0.05%.Higher BisEDT horizontal disturbance concrete strength.Other compound of such as BisPYR can be used for suppressing incrustation by mould and marine alga and biofilm development.The present embodiment contains and uses particles B T compound described in this to substitute bismuth mercaptan compound and other antimicrobial material to provide advantage disclosed herein, comprises a series of antimicrobial acivity, dissolubility and bioavilability, antibiont membrane interaction, avirulence, the enhancing of antibiotic effect and other character as described herein.
Particles B T compound can be introduced manually or automatically on concrete surface as gel, spray, paste, liquid or powder or other form well known by persons skilled in the art.In certain embodiments, the at least one of bioactive ingredients other with comprising at least one for the particles B T compound of powder or liquid form and/or inactive excipient or multiple other composition are mixed with formulated product, this product is regularly sent or to inject among xoncrete structure or on (namely, be exposed on the surface of xoncrete structure, be particularly exposed to the surface of water).Multiple methods known in the art can be used to prepare composition by those skilled in the art.Such as, the particles B T compound (such as, 1mg/ml particles B T compound in DMSO) of the antimicrobial effective dose of combination DMSO can be used.For normal usage, need the level of the particles B T compound enough preventing biofilm formation.But in other embodiments, the level of particles B T compound can be higher for reducing, remove, destroy or eliminating the biomembrane be present on concrete surface existed.
Can by the preparation of particles B T compound with by the composition slow releasing of particles B T compound comprising the surface being applied to xoncrete structure.Also particles B T compound can be incorporated to coating (such as, epoxy coating), can be applied, fix, adhere to or under some modes, make it contact the surface of xoncrete structure.Can by particles B T compound by these composition slow releasing.The slow releasing composition comprising particles B T compound can be gel (such as, hydrogel, thiolates polymers, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.Slow releasing composition can send the particles B T compound 1,2,3,4,5,6 or 7 days (weeks) of antimicrobial effective dose or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.
Can by particles B T compound (or comprising the composition of particles B T compound) and other antimicrobial of at least one (namely, second, third, fourth class antimicrobial) combinationally use, when combined administration, it has enhancing or Synergistic antimicrobial effect as described herein.Such as, the anti-microbial effect strengthened is can be observed when particles B T compound is used together with the antimicrobial of iron chelating.Particles B T compound as herein described and other antimicrobial combination of at least one comprising bactericide or algicide can be used.As limiting examples, the antimicrobial that can comprise in the composition comprising particles B T compound comprises: Chlorhexidine; Bloodroot extract; Metronidazole; Quaternary ammonium compound (such as Cetylpyridinium Chloride); Biguanides (such as, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (such as, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; Alkyl hydroxy benzoic ether; Anti-microbial cationic peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii essential oil; Silver or collargol antibacterial agent; Based on the antibacterial agent of tin or copper; Mai Luka oil; Skin Sa grass; Thyme; Rosemary, Xue MingRosma rinus officinalis; Or other herb extracts; And grapefruit seed extract.Composition also can optionally comprise surfactant, diluent or carrier, buffer and/or bleaching agent further, and it is as above with as described herein.
The particles B T compound prepared through hydrophobicity mercaptan (such as, sulfo-chlorophenol) and this particles B T compound can be used can to show the performance better adhering to concrete surface (be particularly exposed to those in water) than hydrophobicity BT compound.The BT compound (such as have 1:2 mol ratio (bismuth: mercaptan) those) with net negative charge also can have good cohesive.
particles B T in rubber, silicone and plastic product.Some embodiment contain particles B T compound as herein described to be incorporated among artificial surfaces or on, this artificial surfaces comprises rubber and/or the rubber coating (comprising silicone and silicone paint) of the natural of assembling and synthesis, to reduce such as with the biomembrane of these rubber surfaces in lower device and biological incrustation: medical treatment device (such as, conduit, support, not sharp conduit (Foleycatheter) and other urological catheters, gastrostomy catheter, feeding tube etc.), orthopedic device, dental apparatus, commercial plant, electronic installation, such as among following or on the surface that occurs: all types of delivery vehicle, comprise automobile, tire, door window frame, flexible pipe, belt, mat, floor and damper (Shockproof fixing piece), railway, aircraft, boats and ships, ships and light boats, submarine, pile foundation, pipeline, pipeline, pipe and fabric, health/hydrophone tool, household products, flooring material, footwear, sports apparatus, mobile phone, the compound of computer equipment and the organic filler of use, outdoor products (comprises paving cabin plate, awning, asphalt jute, roofing film and swimming pool glued membrane, also comprise for Food & Drink anticorrosion, the sterile products of medicine production and chemical substance and water sterilization and system).
By particles B T compound as herein described being incorporated in conjunction with BT composition as herein described and method and the known preparation method for preparing this kind of article in these and other natural and artificial rubber product.As signal and unrestriced limiting examples, BT (not being particles B T as herein described) is incorporated to the excellent and dacron graft of the polyurethane of the hydrogel coating (AntimicrobAgentsChemother2001 such as Domenico; 45:1417-1421; Domenico etc., Peptides2004; 25:2047-53).WO/2002/077095 and Japanese patent application 1997-342076 describe containing the presulfurization based on the compound of silver and/or the raw rubber preparation of sulfuration to provide antimicrobial characteristics; U.S. Patent No. 6,448,306,6,555,599,6,638,993,6,848,871,6,852,782,6,943,205 and 7,060,739 are taught in the purposes based on the antimicrobial of silver in rubber mass.The silicon-ketone composition of eluted substance can comprise the antimicrobial be dispersed in the biologically active cementing agent of modification, this antimicrobial can be applied to medical treatment device or other surface (the open No.2009/0043388 of U. S. application) not using under inert polymer carrier.
Silicone oil has 2 usually, the molecular weight of 000 to 30,000 scope, and its range of viscosities is 20 to 1,000 centistoke.Silicone rubber has 40 usually, the molecular weight of 000 to 100,000 scope, and its range of viscosities is 10 to 1,000 Duo.Silicone is used for usually have in the various materials of microorganism incrustation.These comprise fluid sealant, caulking compound, grease, oil, spraying, rubber, flexible pipe and implant.Anti-incrustation based on silicone and other antimicrobial coating have been described, but it has, and effect is low, poor durability, poor biocompatibility, antimicrobial acivity are lost, service life is short, material consumption is high and the disadvantages associated of other problem (such as, SchultzJFluidsEng2004; 126:1039-47; United States Patent (USP) 4,025,693; Yan and Li.Ophthalmologica2008; 222:245-8; United States Patent (USP) 6,221,498; United States Patent (USP) 7,381,751; European patent application EP 0506113; The JPRAS1990 such as Sawada; 43:78-82; The SurfaceCoatingsInternationalPartB:CoatingsTransactions20 such as Tiller 05; 88:1-82; Juhni and NewbyProceedingsAnnualMeetingAdhesionSociety2005; 28:179-181; The Retina1999 such as Ozdamar; 19:122-6; The JMaterChem2009 such as Piccirillo; 19:6167; The U.S. discloses 2009/0215924; The Biomaterials2009 such as Bayston; 30:3167-73; The Biomaterials2002 such as Gottenbos; 23:1417-23; The AntonieVanLeeuwenhoek2001 such as Millsap; 79:337-43).Although these open describe the method be incorporated to by antimicrobial material in the rubber of preparation, in the product that their describe or method, there is no the advantage that particles B T as herein described provides.
Therefore, the present embodiment is encompassed in these and rubber like (comprising silicone) product and method and the substitute of particles B T as herein described in plastics and method for producing polymer (quote such as those).In each situation of these and other known preparation, based on openly particles B T as herein described being incorporated to substitute other antimicrobial herein, thus provide as by these particles B T the advantage disclosed herein that provides, comprise a series of antimicrobial acivity, dissolubility and bioavilability, antibiont membrane interaction, avirulence, the enhancing of antibiotic effect and other character as described herein.
Can such as do not disturb under the low concentration of method for preparing rubber, BT compound to be formulated as silicone products or on reduce biomembrane and prevent in the product of incrustation.In silicone, particles B T concentration (by weight) such as can be low to moderate about 0.0001% to about 0.1%, and this depends on special-purpose and the character of silicone rubber product.Similarly, particles B T as herein described can be incorporated on silicone or in silicone gel or oil coating with the biomembrane in prevention at the appointed time section or treatment silicone surface.Silicone rubber injects ports valve and is described in WO/2008/064173, it regularly flows out silicone oil, makes these exudates of the effective antimicrobial level of particles B T described herein give antibiont film and/or anti-incrustation ability on these valves of goods containing preparation or the silicone rubber device of similar configuration.The oil of easy erosion is by extending on any surface of valve proximity, and this provides reproducible protection to originate in special time period.Under such as this configuration can being structured in the surface of hull or be exposed in other surface of water or humidity.
For the retention time being increased in BT on rubber surface, particles B T as herein described can be selected to have larger hydrophobicity by specific thiol moiety, such as by using hydrophobicity mercaptan (such as, sulfo-chlorophenol), it can have the bond properties of increase and/or have net negative charge (such as by comprising preparation, bismuth: the 1:2 mol ratio of mercaptan) BT, it also can have the bond properties of increase.Such as silicone species can be assembled under the particles B T described herein of suitable concn exists under 100 DEG C or lower temperature.Also can prepare under the level of the obstruction biofilm formation of all 1-2ppm according to appointment and can discharge gradually to make these BT by bioerodible material.In other embodiments, expection rubber and/or plastic assembly are manufactured by material, this material slow wash-out particles B T compound and it can being replaced regularly in case biological incrustation in various industrial system or medical treatment device.
In some other embodiment, and with in above-described composition BT is incorporated under rubber (comprising silicone) item and method similar fashion, by preparing the known preparation method of goods in conjunction with BT composition described herein and method and these types, also particles B T compound described in this can be incorporated in these and other plastics and polymerization product.
These limiting examples containing the plastic product of particles B T are included in the plastics in lower device and plastic paint: medical treatment device, orthopedic device, dental apparatus, commercial plant, electronic installation, wall, floor, ceiling, roof, such as among following or on the surface that occurs: all types of delivery vehicle, comprise automobile, train, aircraft, boats and ships, ships and light boats, submarine, pile foundation, pipeline, pipeline and fabric, shower nozzle, hair products, health/hydrophone tool, household products, footwear, sports apparatus, mobile phone, use the compound of organic filler, outdoor products (comprises paving cabin plate, awning, asphalt jute, roofing film and swimming pool glued membrane) and other products (be included in Food & Drink anticorrosion and at medicine, use in chemical substance and water sterilization those).
Start to use modern plastics material since nineteen thirties.Plastics usually by polymer and usually and additive together prepare.Common polymer comprises: synthetic resin; Styrene; Polyolefin; Polyamide; Fluoropolymer; Vinyl; Acrylic compounds; Polyurethane; Cellulosic plastics; Acid imide; Acetals; Polycarbonate-based; And polysulfones.In order to improve the physical features of polymer, usually use the additive of such as plasticizer, it is used as the source of microbial nutrition.The example of these modern plasticizer comprises: phthalate, adipate ester class and other ester class.These and other plasticizer is especially easily subject to bacterium and fungi impact, particularly in high-moisture region, cause the growth of antimicrobial surface growth and spore, it can cause one or more infection in humans and animals, allergy, bad smell, dyeing, plastics embrittlement, premature product fault and other less desirable result.
Be described through and introduced anti-incrustation and other antimicrobial coating in preparation process or post-modification plastic product, but there is meritorious heterodyne, poor durability, poor biocompatibility, forfeiture antimicrobial acivity usually, serviceable bife is short, material consumption is high and the disadvantages associated of other problem (such as, U.S. Patent No. 3,624,062; 4,086,297; 4,663,077; 3,755,224; 3,890,270; 6,495,613; 4,348,308; 5,654,330; 5,281,677; 6,120,790; 5,906,825; 7,419,681; 5,028,664; 6,162,487; Markarian, Plastics, AdditivesandCompounding2009,11:18-22; EP927222B1; JP08-157641; CN1528470A; Masatoshi etc. 2006; 51:18-23; The open No.2008/0071229,2009/0202610 and 2009/0043388 of the U.S.); Existing method does not all provide the advantage provided by particles B T described herein.But, as usually known to those skilled in the art, antimicrobial to be incorporated among plastic product according to following methods or on to obtain final polymer: such as (a) on polymer surfaces to the absorption of reagent (passive or pass through surfactant); B the polymer of the antimicrobial coating be applied on the surface of shaped device is introduced by (); C the body of polymeric substrate is incorporated to by () mutually; D () covalent bond reagent is to polymer surfaces; And/or antimicrobial and formation polymer (such as, polyurethane) component mix by (e) before polymerization.
Such as, particles B T as herein described can be introduced these and similar system manually or automatically as gel, spray, liquid or powder.In one embodiment, such as, by particles B T as a powder or in liquid form be included in the active component that relates in product mixture (such as, polymeric precursors, catalyzer, reaction initiator, crosslinking agent etc.) and excipient is (such as, carrier solvent, releasing agent, dyestuff or pigment, plasticizer etc.) for plastics manufacture composition mixing, it is regularly injected manufacturing system.Such as, the particles B T solution of 1mg/ml in DMSO or suspended matter regularly can be injected formation polymer reaction liquid; Or to obtain antibiont film concentration required in the final product in the workpiece being sprayed to forming unit.
Therefore, these and the embodiment expection herein disclosed in relevant some are contained in the method for this product and disclosed particles B T composition at present, described BT composition can comprise one or more particles B T, and described BT composition also optionally comprises antibiotic such as collaborative or enhancing antibiotic as herein described further.
According to some embodiment as described herein, composition as herein described and method comprise staphylococcus aureus (S.aureus) to the limiting examples that it has the bacterium of beneficial effect, MRSA (methicillin resistant S staphylococcus), Staphylococcus epidermidis, MRSE (methicillin resistant Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, Vancomycin resistant enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, pseudomonas aeruginosa, vancomycin sensitive and Vancomycin resistant enterococcus (such as enterococcus faecalis (E.faecalis), Enterococcus faecium (E.faecium), methicillin-sensitivity and methicillin resistant staphylococcus (such as staphylococcus aureus, Staphylococcus epidermidis) and Acinetobacter baumannii, staphylococcus haemolyticus (Staphylococcushaemolyticus), staphylococcus haemolyticus (Staphylococcushominis), Enterococcus faecium (Enterococcusfaecium), micrococcus scarlatinae (Streptococcuspyogenes), Streptococcusagalactiae (Streptococcusagalactiae), bacillus anthracis, Klebsiella Pneumoniae, proteus mirabilis (Proteusmirabilis), proteus vulgaris, YE (Yersiniaenterocolytica), addicted to maltose Stenotrophomonas (Stenotrophomonasmaltophilia), streptococcus pneumonia, Penicillin Resistant S streptococcus, Burkholderia cepacia, bite burkholderia more, smegmatis mycobacterium and enterobacter cloacae.
Unless the contrary indication, the enforcement of certain embodiments of the present invention is by the conventional method of microbiology, molecular biology, biochemistry, cell biology, virology and the immunological technique within the scope of employing art technology, and in order to example illustrates, hereafter several technology is being quoted.This type of technology is fully explained in the literature.See such as Sambrook, wait MolecularCloning:ALaboratoryManual (the 2nd edition, 1989); The MolecularCloning:ALaboratoryManual such as Maniatis (1982); DNACloning:APracticalApproach, I volume and II volume (D.Glover edits); OligonucleotideSynthesis (N.Gait edits, 1984); NucleicAcidHybridization (B.Hames and S.Higgins edits, 1985); TranscriptionandTranslation (B.Hames and S.Higgins edits, 1984); AnimalCellCulture (R.Freshney edits, 1986); Perbal, APracticalGuidetoMolecularCloning (1984).
Unless the context otherwise requires, otherwise in the specification and claims word " comprise " and variant form such as " comprises " and " containing " by being interpreted as implication that is open, inclusive, be " including but not limited to ".
This specification is mentioned " embodiment " or " a kind of embodiment " or " aspect ", represents that specific features, structure or the feature described in conjunction with described embodiment is included at least one embodiment of the present invention.Therefore, term " in one embodiment " or " in one embodiment " differ to establish a capital when the different place of this specification occurs and refer to identical embodiment.And concrete feature, structure or feature can be combined in one or more embodiment in any suitable manner.
As mentioned above, some invention embodiment as herein described relates to the agricultural of described BT compound, industry, manufacturing industry and other preparation (such as, BisEDT and/or BisBAL), described preparation can also comprise one or more Antibiotique compositions as herein described in certain embodiments, such as amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or another kind of lincoln amides antibiotics), Daptomycin , Doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid , minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin; Or carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase-resistant PCs and/or Aminopenicillin antibiotic and/or aminoglycoside antibiotics, such as amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin or apramycin and/or lipopeptide antibiotics such as Daptomycin huo oxazolidinone antibiotics such as Linezolid .As disclosed herein, when using or be applied to plant or animal wherein or on it, existence can be relevant (such as biomembrane, wherein may there is the bacterium that can promote biofilm formation, but not yet biomembrane detected) bacteriological infection or comprise the such as plant of bacteriological infection that such as biomembrane or other bacterium occur, animal, goods natural or artificial surfaces time, these and related preparations can be included in the BT compound (and choosing any one kind of them or Multiple Classes of Antibiotics) of the effective dose in suitable carrier, excipient or thinner.
By can carry out using or being incorporated to of in purified form or in Suitable agricultural, manufacturing industry or other industry group compound BT compound as herein described or their salt for the agent administration of similar applications or the accepting method that is incorporated to.In preferred embodiments, the application of composition, be incorporated to or use to comprise composition is directly contacted with can be positioned at one or more or extensively be distributed in the experimenter plant at surface location place or animal or treated goods, and its can normally instigate local directly with acute or chronic infection position (such as, wound site on plant surface) contact, be complete tissue around this acute or chronic infection, but do not need to limit; Such as, some embodiment contain to injured, scratch or impaired natural or artificial surfaces topical application topical formulations described herein.
By merging described BT compound (such as, be included in U.S.RE37, 793, U.S.6, 248, 371, U.S.6, 086, 921 and/or U.S.6, 380, compound described in 248 and/or the compound prepared according to the disclosure, such as particles B T suspended matter described herein) and in some related embodiment as described herein, by merge separately or combination BT compound one or more needed for antibiotic (such as, the aminoglycoside antibiotics of such as amikacin) with as prepared according to special-purpose the suitable medium that preparation uses, dispersant, carrier, thinner or excipient can prepare preparation (such as, Pestcidal compositions), and can solid be prepared as, semi-solid, gel, emulsion, colloid, the preparation of supensoid agent or liquid or other topical application form, such as pulvis, granule, ointment, solution, lotion, gel, paste, emplastrum, paint, bioadhesive polymer, microballoon supensoid agent and aerosol spray.
By the preparation of the composition of these and related embodiment to make active component be included in wherein, and in particularly preferred embodiments, antibiotic needed for one or more (such as alone or in combination, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic or aminoglycoside antibiotics, such as amikacin or rifamycin) use BT compound as herein described, can by it simultaneously or successively and use with any order, thus can biological utilisation to desired location and the optional natural or artificial surfaces to plant or animal (comprising people) experimenter or goods once use the preparation comprising BT compound and/or antibiotic composition.Some embodiment disclosed herein contains to be used and/or is incorporated in these experimenters or BT compound and antibiotic goods, comprising can simultaneously or successively and using with any order, but the present invention is not intention to be so limited, and clearly expects the BT compound administration approach different relative to antibiotic route of administration in other embodiments.Therefore, can administration of antibiotics by any route of administration as described herein, but BT compound can be used by the approach independent of antibiotic usage approach.
The preservative (and optional antibiotic) of formulation delivered effective dose described herein to desired location, such as, infects the position of position or needs prevention infection or biofilm formation.
As mentioned above, this topical formulations can adopt any one of various ways, and comprise such as liquid, supensoid agent, emplastrum, cream, lotion, solution, spray, gel, ointment, paste etc., and/or can be prepared as containing liposome, micella and/or microballoon.See such as U.S. Patent No. 7,205,003.Such as, known by pharmaceutical preparation and cosmeceutical formulation art, cream is oil-in-water or water in oil viscous liquid or semisolid emulsions.Cream base can be washed, and containing oil phase, emulsifier and aqueous phase.Phase that oil phase is also called " interior ", is generally made up of vaseline and aliphatic alcohols such as cetanol or octadecanol.Aqueous phase usually but not must be over the volume of oil phase, and generally containing humidizer.Emulsifier in cream preparation is generally nonionic, anion, cation or amphoteric surfactant.
Solution makes the material dissolved be scattered in the homogeneous mixture of preparation in solvent by one or more chemical substances (solute) being dissolved in liquid.Solution can containing other chemical substance with buffering, stable or preservation solute.The Common examples of the solvent used when preparing solution has ethanol, water, propane diols or other medium any.
Gel is system that is semi-solid, suspension type.Single-phase gels contains the organic macromolecule be substantially uniformly distributed in carrier liquid, described carrier liquid normally water-based, but also preferably containing alcohol and optional oil.Preferably " organic macromolecule " i.e. gelling agent can be the polymer of chemical crosslinking, such as crosslinked acrylate copolymer, such as " carbomer " family polymer, such as carboxyl polyalkylene, it by be purchased with trade mark obtains.All right preferred hydrophilic polymer, such as PEO, Pluronic F68 and polyvinyl alcohol in certain embodiments; Cellulosic polymer, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropylmethyl cellulose phthalate and methylcellulose; Natural gum, such as bassora gum and xanthans; Mosanom; And gelatin.In order to prepare homogeneous gel, dispersant such as ethanol or glycerine can be added, or gelling agent can be disperseed by grinding, mechanical mixture or stirring or its combination.
As known in the art, ointment is semisolid preparation, usually based on vaseline or other petroleum derivative.It will be understood by those skilled in the art that the concrete ointment that will use is the ointment that one provides many required features (such as the property of softening etc.).The same with other carrier or medium, ointment base should be inertia, stable, nonirritating and nonsensitized.As at Remington:TheScienceandPracticeofPharmacy, the 19th edition. (Easton, Pa.:MackPublishingCo., 1995), explaining in 1399-1404 page, ointment base can be divided into four classes: oleaginous base; Emulsifiable base; Emulsion bases; And water-soluble base.Oiliness ointment base comprises such as vegetable oil, the fat available from animal and the semi-solid hydrocarbon available from oil.Emulsifying ointment agent matrix absorbability ointment base be can also be called, containing little water or not moisture, and such as Oxystearin sulphate (hydroxystearinsulfate), wool grease and hydrophilic petrolatum comprised.Emulsion ointment agent matrix is Water-In-Oil (W/O) emulsion or oil-in-water (O/W) emulsion, and comprises such as cetanol, glycerin monostearate, lanolin and stearic acid.Preferred Fend A-2 matrix by the polyethylene glycol of different molecular weight prepare (see, such as Remington, Id.).
Paste is semisolid dosage form, and wherein active substance is suspended in suitable matrix.According to medium property, the paste that paste is divided into fatty paste or is made up of single-phase aqueous gels.Matrix in fat paste is generally vaseline or hydrophilic petrolatum etc.The paste be made up of single-phase aqueous gels generally adds carboxymethyl cellulose etc. as matrix.
Preparation can also use liposome, micella and microballoon to prepare.Liposome has the microballoon folliculus that one (individual layer) or multiple (multilayer) comprise the lipid wall of double-layer of lipoid, and can encapsulate and/or adsorb one or more components of preparation as herein described to its lipid film surface in this environment, described component such as antibiotic or some carrier or excipient.Liposomal formulation herein comprises the positive (positively charged), negative (electronegative) and neutral preparations.Cationic liposome easily obtains.Such as ,-N, N, N-triethyl ammonium (DOTMA) liposome can trade name for N [1-2,3-bis-oleyl oxygen base) propyl group] (GIBCOBRL, GrandIsland, N.Y.) obtains.Similarly, anion and neutral liposome are also easy to be obtained from such as AvantiPolarLipids (Birmingham, AL), or easily can use the material preparation easily obtained.This material comprises phosphatid ylcholine, cholesterol, phosphatidyl-ethanolamine, DOPC (DOPC), DOPG (DOPG) and DOPE (DOPE) etc.These materials can also mix with proper proportion with DOTMA.The method using these materials to prepare liposome is well known in the art.
Micella known in the art be comprise be arranged make its polar head-group form outside spherical shell and hydrophobicity hydrocarbon chain towards the surfactant molecule of ball center's (formation core).Micella is making containing concentrated surfactant to be formed in the aqueous solution of the natural generation of micella.Surfactant for the formation of micella includes but not limited to potassium laurate, perfluorooctane sulfonate, decane sulfonate, dodecane sulfonic acid sodium, NaLS, docusate sodium, DTAB, DTAB, TTAB, tetradecyl trimethyl ammonium chloride, lauryl ammonium chloride, PEG-8 lauryl ether, polyethylene glycol-12 lauryl ether, nonoxinol 10 and nonoxinol 30.
Similarly, microballoon can add in topical formulations as herein described.The same with liposome and micella, microballoon encloses one or more components of invention formulation substantially.They generally but are not necessarily formed by lipid, preferably charged lipids such as phosphatide.The preparation of lipid microsphere is well known in the art.
Various additive well known by persons skilled in the art also can comprise in the formulation.Such as, solvent (comprising alcohol relatively in a small amount) can be used for some formulation components of solubilising.The example of suitable promoter includes but not limited to ether, and such as diethylene glycol monoethyl ether is (passable through commercially available) and diethylene glycol monomethyl ether; Surfactant such as sodium laurate, NaLS, softex kw, benzalkonium chloride, (231,182,184), (20,40,60,80) and lecithin (United States Patent (USP) the 4th, 783, No. 450); Alcohol, such as ethanol, propyl alcohol, octanol, benzylalcohol etc.; Polyethylene glycol and ester thereof, such as polyethylene glycol monolaurate (PEGML; See such as, U.S. Patent No. 4,568,343); Acid amides and other nitrogen-containing compound, such as urea, dimethylacetylamide (DMA), dimethyl formamide (DMF), 2-Pyrrolidone, 1-Methyl-2-Pyrrolidone, monoethanolamine, diethanol amine and triethanolamine; Terpene; Alkyl ketone; And organic acid, particularly citric acid and succinic acid.Can also use and sulfoxide, such as DMSO and C 10mSO, but more not preferred.
Some dermal osmosis accelerator can comprise those lipophilicity secondary accelerators (coenhancer) being commonly called " plasticising (plasticizing) " promoter, that is, there is the molecular weight of about 150 to 1000 dalton's scopes, be less than about 1wt%, be preferably less than about 0.5wt% and be most preferably less than the promoter of the water solubility of about 0.2wt%.The Hildebrand solubility parameter scope about 2.5 of plasticising promoter to about 10, preferable range about 5 is to about 10.Preferred lipophilic promoters is fatty ester, fatty alcohol and aliphatic ether.Concrete and example that is most preferred fatty acid ester comprises methyl laurate, ethyl oleate, PGML, propandiol dilaurate, glyceryl monolaurate, glycerin mono-fatty acid ester, n-capric acid isopropyl ester and octyl dodecyl myristate.Fatty alcohol comprises such as octadecanol and oleyl alcohol, and aliphatic ether comprises wherein glycol or triol, preferably C 2-C 4the compound that alkane glycol or triol are replaced by one or two aliphatic ether substituting group.Other dermal osmosis accelerator is that localized drug delivery those skilled in the art are known, and/or is described in pertinent literature.Edit see such as PercutaneousPenetrationEnhancers.Smith etc. (CRCPress, BocaRaton, FL, 1995).
Those except determining above, other additive various can be included in the topical formulations according to certain embodiments of the present invention.These include but not limited to antioxidant, astringent, spices, preservative, softening agent, pigment, dyestuff, humidizer, propellant and sun-screening agent and its existence can be cosmetically, medically or other side need other material classification.The representative instance being included in the optional additive of the preparation of certain embodiments of the present invention is as follows: preservative, such as sorbate; Solvent, such as isopropyl alcohol and propane diols; Astringent, such as methyl alcohol and ethanol; Softening agent, such as polyalkylene methyl glucosamine; Humidizer, such as glycerine; Emulsifier, such as tristerin, PEG-100 stearate, polyglycereol-3 hydroxylauric base ether and polysorbate 60; Sorbitol and other polyhydroxy-alcohol such as polyethylene glycol; Sun-screening agent, such as octyl methoxycinnamate (can be used as ParsolMCX through commercially available) and Uvinul BMBM (can trade name Parsol1789 obtain); Antioxidant, such as ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), betatocopherol, Gamma-Tocopherol, Delta-Tocopherol, ε-vitamin e, ζ 1-vitamin e, ζ 2-vitamin e, η-vitamin e and retinol (vitamin A); Essential oil, ceramide, essential fatty acid, mineral oil, wetting agent and other surfactant, such as can available from BASF's (Mt.Olive, NJ) serial hydrophilic polymer, vegetable oil are (such as, the liquid fraction of soybean oil, palm oil, shea butter, sunflower oil), animal oil (such as, perhydro-squalene), mineral oil, artificial oil, silicone oil or wax (such as, cyclomethicone and dimeticone), fluorinated oil (being generally PFPE), fatty alcohol (such as, cetanol) and wax (such as, beeswax, Brazil wax and paraffin); Dermal sensation conditioning agent; And thickener and structural agent (structurants), such as expansive clay and crosslinked carboxy polyalkylene (carboxypolyalkylene), passable trade mark is through commercially available.
Other additive comprises such as pyrrolidine carboxylic acid and amino acid; Organic anti-microbial agents, such as 2,4,4'-tri-chloro-2-dihydroxy diphenyl ether (triclosan) and benzoic acid; Antiinflammatory, such as acetylsalicylic acid and glycyrrhetinic acid; Antiseborrheic, such as retinoic acid; Vasodilator, such as nicotinic acid; Melanogenesis inhibitor, such as kojic acid; And composition thereof.The activating agent that other advantageously comprises can be there is, such as alpha-hydroxy acid, 2-ketoacid, poly hydroxy acid, humidizer, collagen, marine extracts and antioxidant, such as ascorbic acid (vitamin C), alpha-tocopherol (vitamin E) or other vitamin e, such as above-mentioned those, and retinol (vitamin A) and/or its suitable salt, ester, acid amides or other derivative.Other reagent comprises those that can improve oxygen supply in living tissue, such as, described in WO94/00098 and WO94/00109.Sun-screening agent can also be comprised.
The preparation of certain embodiments of the present invention can also comprise conventional additives, such as opacifier, aromatic, colouring agent, gelling agent, thickener, stabilizing agent, surfactant etc.Other material can also be added, such as antimicrobial, to prevent to go bad during storage, that is, suppress the growth of microorganism such as yeast and mould.The antimicrobial be applicable to is selected from methyl esters and propyl ester (such as, methylparoban and propyl ester), Sodium Benzoate, sorbic acid, miaow urea (imidurea) and the combination thereof of P-hydroxybenzoic acid usually.
Except BT compound (such as, be preferably uniform particulate substantially provided herein, optional with one or more collaborative antibiotic combinations as herein described) outside, topical formulations also can containing applicable specific application or one or more the other activating agents of effective dose being incorporated to mode.
Pharmacologically acceptable carrier also can add in the topical formulations of some embodiment of the present invention, and can be any carrier that this area routine uses.Example comprises water, lower alcohol, higher alcohol, honey, polyhydroxy-alcohol, monose, disaccharides, polysaccharide, sugar alcohol, such as glycol (2-carbon), triol (3-carbon), antierythrite and threitol (4-carbon), arabitol, xylitol and ribitol (5-carbon), mannitol, sorbitol, dulcitol and iditol (6-carbon), isomaltol, maltitol, lactitol and polysaccharide polyol, hydrocarbon ils, fatty and oily, wax, fatty acid, silicone oil, nonionic surface active agent, ionic surfactant, silicone surfactant and examples of such carriers based on the mixture of water and the mixture of emulsion-based.
Topical formulations embodiment routine of the present invention can be applied to any natural (such as, plant or animal, comprise people) or artificial (such as, goods) surface, these surfaces need the frequency reaching expected result necessity to treat with amount.In certain embodiments, therapeutic frequency depends on the intensity of the character of application, active component (such as, BT compound and choosing any one kind of them or multiple other active component, such as antibiotic, such as, amikacin or other antibiotic), for delivering active ingredients vectorial effect and removed the easy degree of preparation by environmental factor physical contact, precipitation, wind, the temperature of other material or object (such as, with).
Such as, in composition as herein described, the typical concentration range of the such as active substance of BT compound can be that the about 0.001-30% weight of such as composition total weight is to about 0.01-5.0% and more preferably to about 0.1-2.0%.As a representative example, the composition of these embodiments of the present invention can equal about 1.0mg/cm 2to about 20.0mg/cm 2speed be applied to natural or artificial surfaces.The representative example of topical formulations includes but not limited to aerosol, alcohol, anhydrous substrate (such as lipstick and powder), the aqueous solution, cream, emulsion (comprising Water-In-Oil or oil in water emulsion), fat, foaming agent, gel, water-alcohol solution, liposome, lotion, microemulsion, ointment, oil, organic solvent, polyalcohol, polymer, powder, salt, silicone derivative and wax.Preparation can comprise such as chelating agent, conditioner, softening agent, excipient, humidizer, protectant, thickener or UV absorbent.It will be understood by those skilled in the art that and be different from those preparation embodiment used in the present invention listed.
Chelating agent can optionally be included in some preparation, and can be selected from and be applicable to have the ability in conjunction with divalent cation metal such as Ca 2+, Mn 2+or Mg 2+any natural or synthesis of chemicals.The example of chelating agent includes but not limited to EDTA, EDETATE SODIUM, EGTA, citric acid and dicarboxylic acids.
Conditioner also can optionally be included in some preparation.The example of skin conditioning agent includes but not limited to acetylcysteine, N-acetyl dihydrosphingosine, acrylate/acrylic acid Shan Yu ester/dimethyl silicone polymer acrylate copolymer, adenosine, ring adenylic acid, adenylic acid, adenosine triphosphate, alanine, albumin, marine algae extract, allantoin and derivative, aloe vera extract, PCA aluminium (aluminumPCA), amyloglucosidase, ursin, arginine, azulenes, bromelain, buttermilk powder, butanediol, caffeine, calcium gluconae, capsaicine, Loviscol, carnosine, beta carotene, casein, catalase, cephalin, ceramide, chamomile (chamomillarecutita) flower extract, cholecalciferol, cholesterol ester, cocoyl-betain, coacetylase, modified corn starch, crystalline protein, ring ethyoxyl polymethyl siloxane, cysteine DNA, cromoci, darutoside (darutoside), dextran sulfate, dimethicone copolyol, dimethyl-silicon alkanol hyaluronic acid ester, DNA, elastin laminin, elastin laminin amino acid, epidermal growth factor, ergocalciferol, ergosterol, PCA Octyl Nitrite, fibronectin, folic acid, gelatin, gliadin, beta glucan, glucose, glycine, glycogen, glycolipid, glycoprotein, glycosaminoglycan, glycosphingolipid, horseradish peroxidase, hydrogenation albumen, protein hydrolysate, jojoba oil, keratin, Keratin amino acids and kinetin, lactoferrin, lanosterol, PCA lauryl, lecithin, linoleic acid, linolenic acid, lipase, lysine, lysozyme, malt extract, maltodextrin, melanocyte, methionine, rock salt, nicotinic acid, vitamin PP, oat amino acid, oryzanol, palmityl protein hydrolysate, pancreatin, papain, PEG, pepsin, phosphatide, phytosterol, placenta enzyme, Placental Lipids, pyridoxal 5-phosphate, quercetin, resorcinol acetic acid esters (resorcinolacetate), vitamin b3, RNA, saccharomycete lysate extract, silk amino acid, sphingolipid, stearamidopropyl betain, stearoyl palmitate, vitamin e, tocopherol acetate, Vitamin E linoleate, ubiquinone, grape (vitisvinifera) seed oil, wheat amino acid, xanthan gum and zinc gluconate.As those skilled in the art can easily understand, be different from above-listed those conditioner can with disclosed composition or the formulation compositions provided by it.
In certain embodiments, preparation described herein can also optionally comprise one or more softening agents, and the example includes but not limited to: acetylated lanolin, acetyl lanolin alcohol, acrylate/C 10-30alkyl acrylate cross-linked polymer, acrylate copolymer, alanine, marine algae extract, aloe vera extract or gel, medicine hollyhock extract, starch octenyl succinate anhydride, aluminum stearate, apricot (prunusarmeniaca) benevolence oil, arginine, arginine aspartate, Arnica extract, ascorbic acid, ascorbyl palmitate, aspartic acid, junket pears (perseagratissima) oil, barium sulfate, barrier sphingolipid (barriersphingolipid), butanols, beeswax, behenyl alcohol, cupreol, BHT, birch (white birch) bark extract, borage (boragoofficinalis) extract, 2-bromo-2-nitropropane-1,3-glycol, butcher's broom (ruscusaculeatus) extract, butanediol, Calendula officinalis extract, calendula oil, the wax root of Beijing euphorbia (euphorbiacerifera) wax, Tower rape oil, caprylic/capric glyceryl ester, cardamom (elettariacardamomum) oil, babassu (coperniciacerifera) wax, carrageenan (chondruscrispus), carrot (daucuscarotasativa) oil, castor-oil plant (ricinuscommunis) oil, ceramide, ceresine, ceteareth-5, ceteareth-12, ceteareth-20, cetearyl octanoate, ceteth-20, ceteth-24, cetyl acetate, cetanol caprylate, cetanol palmitate, Roman chamomile (anthemisnobilis) oil, cholesterol, cholesterol ester, Cholesteryl hydroxystearate, citric acid, Salvia sclarea (salviasclarea) oil, cocoa (theobromacacao) fat, cocoyl-caprylate/decylate, coconut (cocosnucifera) oil, collagen, collagen amino acid, corn (zeamays) oil, fatty acid, decyl oleate, dextrin, diazolidinyl urea (diazolidinylurea), dimethicone copolyol, dimethiconol, dioctyl adipate, dioctyl succinate, dipentaerythritol six caprylate/six decylate, DMDMH, DNA, antierythrite, ethoxydiglycol, ethyl linoleate, Eucalyptus Globulus oil, oenothera erythrosepala (Oenotherabiennis) oil, fatty acid, tructose, gelatin, shametace oil, aminoglucose, glucose glutamate, glutamic acid, glycerin polyether-26, glycerine, glycerine, distearin, hydroxystearin, glyceryl laurate ester, glyceryl linoleate, myristic acid glyceride, olein, tristerin, tristerin SE, glycine, glycol stearate, glycol stearate SE, glycosaminoglycan, grape (vitisvinifera) seed oil, fibert (corylusamericana) oil, fibert (corylusavellana) macadamia nut oil, hexylene glycol, honey, hyaluronic acid, safflower (carthamustinctohus) oil, rilanit special, hydrogenated coco acid glyceride, hydrogenated coconut oil, hydrogenated lanolin, hydrolecithin, Hydrogenated glyceryl palmiate, hydrogenated palm kernel oil, hydrogenated soybean oil, hydrogenated tallow acid glyceride, hydrogenated vegetable oil, hydrolytic collagen, elastin hydrolysis, hydrolysis glycosaminoglycan, hydrolysis of keratin, hydrolytic soya bean protein, hydroxylated lanolin, hydroxy-proline, imidazolidinyl urea, iodine propilolic alcohol butyl mephenesin Carbamate, iso-spermaceti ester alcohol stearic acid, different cetanol stearyl stearate, Isodecyl oleate, IPIS, isopropyl lanolate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isostearoyl amine DEA, isostearic acid, isostearyl lactate, neopentanoic acid isostearate, jasmine (jasminumofficinale) oil, Jojoba (buxuschinensis) oil, sea grass, candlenut tree (aleuritesmoluccana) oil, lactamide MEA, lanolin alcohol polyethers-16, lanolin alcohol polyethers-10 acetic acid esters, lanolin, lanoceric acid, lanolin alcohol, lanolin oil, lanolin wax, lavender (lavandulaangustifolia) oil, lecithin, lemon (citrusmedicalimonum) oil, linoleic acid, linolenic acid, macadimia nut oil, dolomol, magnesium sulfate, maltitol, chamomile (chamomillarecutita) oil, Glucate SS, methyl-monosilane alcohol PCA ester, microwax, mineral oil, ermine oil, Mortierella oil, Tetradecyl lactate, myristyl myristate, myristyl propionate, neopentyl glycol dicaprylate/dicaprate, octyldodecanol, myristic acid octyl group ten diester, stearoyl octyldodecyl ten diester, hydroxy stearic acid ester monooctyl ester, octyl palmitate, octyl salicylate, octyl stearate, oleic acid, olive (oleaeuropaea) oil, oranges and tangerines (citrusaurantiumdulcis) oil, palm (oleaeuropaea) oil, palmitic acid, pantethine, panthenol, DL-Pantyl Ethyl Ether, paraffin, PCA, peach (prunuspersica) benevolence oil, peanut (arachishypogaea) oil, PEG-8C1218 ester, PEG-15 coco amine, PEG-150 distearate, PEG-60 glyceryl isostearate, PEG-5 tristerin, PEG-30 tristerin, PEG-7 rilanit special, Cremophor RH40, PEG-60 rilanit special, PEG-20 Glucate SS, the full oleate of PEG-40 anhydrosorbitol, PEG-5 sojasterol, PEG-10 sojasterol, PEG-2 stearate, PEG-8 stearate, PEG-20 stearate, PEG-32 stearate, PEG-40 stearate, PEG-50 stearate, PEG-100 stearate, PEG-150 stearate, pentadecalactone, peppermint (menthapiperita) oil, vaseline, phosphatide, polyamino sugar condensation product, polyglycereol-3 diisopstearate, polyquaternium-24, polysorbate 20, polysorbate 40, polysorbate 60, polyoxyethylene sorbitan monoleate, polysorbate 85, myristic acid potassium, potassium palmitate, potassium sorbate, potassium stearate, propane diols, propylene/dicaprate, propylene, propylene glycol dipelargonate, glycol laurate, propylene glycol stearate, propylene glycol stearate SE, PVP, pyridoxine dipalmitate, quaternary ammonium salt-15, quaternary ammonium salt-18 hectorite, quaternary ammonium salt-22, retinol, retinol palmitate, rice (oryzasativa) rice bran oil, RNA, rosemary, Xue MingRosma rinus officinalis (rosmarinusofficinalis) oil, attar of rose, safflower (carthamustinctorius) oil, Salvia japonica (salviaofficinalis) oil, salicylic acid, santal (santalumalbum) oil, serine, haemocyanin, sesame (sesamumindicum) oil, shea butter (Butyrospermum), silk powder, sodium chondroitin sulfate, DNA sodium, Sodium Hyaluronate, sodium lactate, sodium palmitate, Anjidew NL50, polyglutamic acid sodium, odium stearate, soluble collagen, sorbic acid, sorbitan laurate, sorbitan oleate, sorbitan palmitate, anhydrosorbitol sesquistearate, sorbitan stearate, sorbitol, soybean (glycinesoja) oil, sphingolipid, saualane, squalene, stearmide MEA-stearate, stearic acid, stearoxy dimethicone, stearoxyl trimethyl silane, octadecanol, stearyl glycyrrhetinate, stearoyl heptanoate, stearyl stearate, sunflower (helianthusannuus) seed oil, sweet almond (prunusamygdalusdulcis) oil, synthetic bees wax, vitamin e, tocopherol acetate, Vitamin E linoleate, San Shan Yu essence, neopentanoic acid tridecyl ester, tridecyl base ester, triethanolamine, tristearin, urea, vegetable oil, water, wax, wheat (triticumvulgare) embryo oil and Yilan (canangaodorata) oil.
Surfactant is also expected to be included in some preparation of expecting herein, and the surfactant being applicable to any natural of cosmetic composition or synthesis can be selected from, such as cation, anion, amphion, non-ionic surface active agent or its mixture.(see Rosen, M., " SurfactantsandlnterfacialPhenomena " second edition, JohnWiley & Sons, NewYork, the 1988,1st chapter, the 431st page).The example of cationic surface active agent includes but not limited to DMDAO or other amine oxide, long chain primary amines, diamines and polyamines and salt, quaternary ammonium salt, polyoxyethylated long-chain amine and quaternized polyoxyethylated long-chain amine.The example of anionic surfactant includes but not limited to SDS; Carboxylate (such as, soap); Sulfonate, sulphate, phosphate and polyphosphate; Alkyl phosphate; Monoalkyl phosphoric acid esters (MAP); With perfluorocarboxylic acid salt.The example of zwitterionic surfactant includes but not limited to cocamidopropyl propyl amide hydroxy sulfo lycine (CAPHS) and is pH sensitivity and needs other material of SC (namely in the suitable pH of design preparation, alkyl aminopropionic acid, imidazoline carboxylate and betain) or be not those materials (such as, sulfobetaines (sultaine)) of pH sensitivity.The example of nonionic detergent includes but not limited to alkylphenol ethoxylate, alcohol ethoxylate, polyoxyethylenated polyoxypropylene glycol, polyoxyethylenated mercaptan, higher fatty ester, alkanolamide, tertiary acetytenic glycol (tertiaryacetylenicglycol), polyoxyethylated silicone, N-alkyl pyrrolidone and APG.Such as and according to non-limiting theory, wetting agent, mineral oil or other surfactant can also be comprised, such as nonionic detergent or such as the material of one or more members of series (BASF, Mt.Olive, NJ), to reduce the gathering of BT particulate in microparticle suspending liquid.Any surfactant composition is acceptable.Some embodiment can comprise at least one anionic surfactant and a kind of cationic surface active agent, or at least one cationic surface active agent and a kind of amphoteric surfactant, they are compatible, namely do not form the compound of obvious sediment when combined.
The example that can also be present in the thickener in some topical formulations includes but not limited to acrylamide copolymer, agarose, amylopectin, bentonite, calcium alginate, calcium carboxymethylcellulose, carbomer, carboxymethyl chitin, carboxymethyl cellulose (cellulosegum), dextrin, gelatin, hydrogenated tallow, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropul starch, alginic acid magnesium, methylcellulose, microcrystalline cellulose, pectin, various PEG ' s, polyacrylic acid, polymethylacrylic acid, polyvinyl alcohol, various PPG ' s, sodium acrylate copolymer, carrageenan sodium, xanthan gum and yeast beta-dextran.Be different from those thickener above-listed also in embodiment used in the present invention.
According to some embodiment of expecting herein, BT preparation can comprise one or more sun-screening agents or UV absorbent.When needs ultraviolet-(UVA and UVB) absorbent properties, such material can comprise such as benzophenone, BP-1, BP-2, BP-3, UVINUL MS 40, benzophenone-5, benzophenone-6, benzophenone-7, benzophenone-8, Benzophenone 9, BP-1 0, BP-1 1, BP-1 2, benzyl salicylate, PABA butyl ester, cinnamate, Cinoxate, DEA-Methoxycinnamate, diisopropyl methyl cinnamate, dihydroxypropyl PABA ethyl ester, diisopropyl ethyl cinnamate, methoxycinnamate acetoacetic ester, ethyl PABA, urocanic acid ethyl ester, sad dimethoxy-cinnamic acid glyceride (glyceryloctanoatedimethoxycinnamate), PABA glyceride, ethylene glycol salicylate, Homosalate, isopropyl benzylalcohol salicylate, titanium, zinc, zirconium, silicon, the oxide of manganese and cerium, PABA, PABA ester, Parsol1789 and isopropyl benzyl salicylate, and composition thereof.It will be understood by those skilled in the art that be different from above-listed those sun-screening agent and UV absorbent or protective agent some embodiment used in the present invention in.
BT preparation disclosed herein is usually effective between the pH value of about 2.5 to about 10.0.Preferably, composition pH following pH scope or near: about pH5.5 is to about pH8.5, about pH5 to about pH10, about pH5 to about pH9, about pH5 to about pH8, about pH3 to about pH10, about pH3 to about pH9, about pH3 to about pH8 and about pH3 to about pH8.5.Most preferably, pH is about pH7 to about pH8.Those of ordinary skill in the art can add suitable pH modifying ingredients to the present composition to regulate pH to acceptable scope." about " it is that the pH comprising wherein actual measurement at any given time may be less than or greater than the preparation that designated value is no more than 0.7,0.6,0.5,0.4,0.3,0.2 or 0.1pH unit that the pH specified is readily appreciated by one skilled in the art, and wherein thinks that preparation composition and holding conditions can cause departing from of pH and original value.
Cream, lotion, gel, ointment, paste etc. can spread upon affected surface and rub in lightly.Solution can be applied in the same manner, but more generally uses the application such as dropper, swab, and is carefully applied to affected region.Application scheme depends on the many factors that can easily determine, such as, infect severity and the responsiveness to initial treatment thereof.Those of ordinary skill easily can determine optimised quantity, application process and the repetition rate of preparation to be administered.Generally speaking, consider the preparation of these and related embodiment of the present invention by with weekly or twice or more time to once a day, twice, range applications three times, four times or more.
Therefore, as discussed above, BT preparation used herein also can comprise acceptable carrier, comprise any applicable thinner or excipient, it comprises itself to accepting the experimenter of composition (such as, plant or animal, comprise people) or the harmless and any medicament can used without excessive toxicity of goods.Acceptable carrier can include but not limited to liquid, such as water, salt solution, glycerine and ethanol etc., and can comprise tackifier (such as balsam fir resin) or coalescing agents as colloid or cellulose nitrate cellulose solution.Discussing in detail see REMINGTON'SPHARMACEUTICALSCIENCES (MackPub.Co., N.J. current edition) of pharmaceutically acceptable carrier, thinner and other excipient.
BT preparation can comprise in conjunction with BT compound reagent and thus auxiliary its be delivered to or be retained on experimenter or goods and expect position.The reagent be applicable to that can play this effect comprises inclusion agents, such as cyclodextrin; Other material can comprise albumen or liposome.
BT preparation is used with effective dose, applies or merged, and this effective dose depends on various factors, comprises the character at delivery location (wherein relevant place); The activity of the specific b T compound (comprise in preparation and comprise or do not contain antibiotic, such as aminoglycoside antibiotics, such as amikacin) adopted; The metabolic stability of compound and action length; The condition of (plant or animal, comprise people) experimenter or goods; The mode used and time; BT compound wear rate in the common procedure of the activity that experimenter or goods carry out; And other factors.Generally speaking, treating effective daily dose is that (for 70kg mammal) is from about 0.001mg/kg (i.e. 0.07mg) to about 100mg/kg (i.e. 7.0g); Preferably, treating effective dose is that (for 70kg mammal) is from about 0.01mg/kg (i.e. 7mg) to about 50mg/kg (i.e. 3.5g); More preferably, treating effective dose is that (for 70kg mammal) is from about 1mg/kg (i.e. 70mg) to about 25mg/kg (i.e. 1.75g).Expection plant effective dose low by about 10,20,50 or 75% or lower.
Effective dosage ranges provided herein is not intended to restrictive and represents preferred dosage range.But most preferred dosage will be formulated according to individual subjects, this be various equivalent modifications understanding with confirmable (see, such as, the editors such as Berkow, TheMerckManual, the 16th edition, MerckandCo., Rahway, N.J., 1992; The editors such as Goodman, GoodmanandGilman'sThePharmacologicalBasisofTherapeutics, the 10th edition, PergamonPress, Inc., Elmsford, N.Y. (2001); Avery ' sDrugTreatment:PrinciplesandPracticeofClinicalPharmacolo gyandTherapeutics, the 3rd edition, ADISPress, Ltd., Williams and Wilkins, Baltimore, MD. (1987); Ebadi, Pharmacology, Little, BrownandCo., Boston (1985); Osolcia1. edit, Remington'sPharmaceuticalSciences, the 18th edition, MackPublishingCo., Easton, PA (1990); Katzung, BasicandClinicalPharmacology, AppletonandLange, Norwalk, CT (1992)).
If needed, treating required accumulated dose for often kind can by using through the multiple dose of a time or single dose.Some preferred embodiment expections every day, weekly, every 10 days, every 14 days or per longer time section single application BT preparations.Generally speaking, in various embodiments, treatment can by the smaller dose lower than compound optimal dose.After this, dosage is increased by a small margin, until reach optimum efficiency under the circumstances as described.
for the protection of the bismuth-mercaptan of plant and agricultural products
Some embodiment disclosed herein relates to and comprises biomembranous infected by microbes and the composition infected and method for the protection of plant and flower opposing, thus reduces withered and increase life of product.
According to some embodiment as herein described, comprise above summarized those, be provided for protective plant opposing bacterium, the method of fungi or viral pathogen, the method be included in be enough to meet following one or more condition and under the time, plant is contacted: (i) prevents plant by bacterium with the BT composition of effective dose, fungi or viral pathogen infect, (ii) anti-bacteria, the cell viability of substantially all planktonic cells of fungi or viral pathogen or Growth of Cells, (iii) suppress by bacterium, the biofilm formation of fungi or viral pathogen, and (iv) anti-bacteria, the biomembrane vigor of substantially all biomembrane form cells of fungi or viral pathogen or biofilm development, wherein BT composition comprises the suspended matter of single dispersing substantially of the particulate containing BT compound, described particulate has the volume mean diameter of about 0.5 μm to about 10 μm.
In certain embodiments, bacterial pathogens comprises fire blight of pear bacterial cell and in certain embodiments, and bacterial pathogens is selected from: erwinia amylovora, xanthomonas campestris nieffea picta pvs oryzae and oryzicola, pseudomonas syringae, xyllela fastidiosa, vine wood friend bacterium, Monilinia fructicola, P.stwartii subsp.stewartii, Ralstonia solanacearum and Potato Ring Rot.In certain embodiments, bacterial pathogens shows antibiotic resistance and in some other embodiment, bacterial pathogens shows streptomycin resistance.In certain embodiments, plant is food crops, and in some further embodiment, food crops is fruit tree, and in some again further embodiment, fruit tree is selected from: apple tree, pear tree, peach, nectarine tree, Japanese plum and apricot.In certain embodiments, food crops is the Banana tree of Musa.In some other embodiment, food crops is the plant being selected from tuberous plant, leguminous plant and graminaceous cereals plant.In some further embodiment, tuberous plant is selected from potato (potato) and sweet potato (sweet potato).
In certain embodiments, contact procedure carries out one or many.In certain embodiments, at least one contact procedure comprises spraying, floods, applies and smear one in plant.In certain embodiments, plant the flowers are in blossom puts, tender shoots or growth position place or in other plant parts of such as root, bulb, stem, leaf, branch, rattan, sarment, bud, flower or its part, tender shoots, fruit, seed, kind pod etc., place or in carry out at least one contact procedure.In certain embodiments, on plant, the flowers are in blossom first time carries out at least one contact procedure in put 24,48 or 72 hours.In certain embodiments, BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.In certain embodiments, bacterial pathogens shows antibiotic resistance.
In some embodiment of said method, described method comprises further: with plant and BT composition contact procedure simultaneously or successively and with any order, makes plant and to work in coordination with or enhancement antibiotic contacts.In some further embodiment, collaborative or strengthen antibiotic and comprise and be selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.In certain embodiments, collaborative or enhancement antibiotic is selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
In further embodiment, be provided for or in the plant it existing antibiotic resistance bacterium phytopathogen, overcome the method for antibiotic resistance wherein, comprise: (a) be enough to meet below one or more condition and under the time, plant is contacted: (i) prevents plant by antibiotic resistance bacterium pathogenic infection with the BT composition of effective dose, (ii) cell viability or the Growth of Cells of substantially all planktonic cells of antibiotic resistance bacterium pathogene is suppressed, (iii) suppress by the biofilm formation of antibiotic resistance bacterium pathogene, and (iv) suppresses biomembrane vigor or the biofilm development of substantially all biomembrane form cells of antibiotic resistance bacterium pathogene, wherein BT composition comprises the suspended matter of single dispersing substantially of particulate, substantially the single dispersing suspended matter of particulate comprises BT compound, particulate has the volume mean diameter of about 0.5 μm to about 10 μm, and (b) and plant and BT composition contact procedure are simultaneously or successively and with any order, make plant and to work in coordination with or enhancement antibiotic contacts.
bismuth mercaptan-(BT) base preservative
Also described above, many have antimicrobial (such as, antibacterium, antiviral, antimycotic), particularly the natural products (such as antibiotic) of antibacterial properties and synthesis of chemicals are known in the art, and characterized by chemical constitution and anti-microbial effect at least in part, described anti-microbial effect such as kills and wounds ability (" killing " effect of microorganism, such as bactericidal property), stop or damage ability (" suppression " effect of growth of microorganism, such as antibacterial character), or interference microbial function, such as field planting or infection site, the bacterial secretory of exopolysaccharide and/or be converted into the ability of expansion of biomembrane colony or biofilm formation from swimming.Hereinbefore, such as, U.S.6,582,719 discuss (comprising bismuth-mercaptan or BT compound) such as antibiotic, disinfectant, antibacterial agents, comprise the factor of the choice and operation affecting such composition, such as sterilization or antibacterial character, valid density and the risk of toxicity to host tissue.
The mercaptan compound of the different V race metal (such as, arsenic, antimony) of bismuth mercaptan (BT) and alternative bismuth is more than discussed.The composition and the method that relate to the favourable particles B T composition particulate of the volume mean diameter with about 0.5 μm to about 10 μm are also discussed herein.Therefore, some exemplary belongs to antimicrobial purposes described herein, be included in treatment or prevention in plant to infect and biomembranous anti-biofilm agent, described reagent is present in composition usually, said composition contains the one of the concentration of by weight 0.0001% to 0.001% or multiple particulate bismuth mercaptan, is preferably alkaline form.Composition can comprise BT and one or more carriers or excipient and/or can comprise other composition of such as other compatibility bactericide further, and in certain preferred aspects, it comprises collaborative or enhancement antibiotic as described herein.
To contain but target crop to be protected in non-limiting embodiments comprises such as following plant variety: cereal (such as, wheat, barley, rye, oat, rice, Chinese sorghum and respective crop) at some; Beet (such as, sugar beet and fodder beet); The operatic circle; Drupe and fruitlet (such as, apple, pears, plum, peach, almond, cherry, strawberry, raspberry and blackberry, blueberry); Leguminous plant (such as, soya bean, French beans, pea, soybean); Oils plant (such as, rape seed, leaf mustard, opium poppy, olive, sunflower, coconut, castor oil plant, cocoa bean, peanut); Mellon plant (such as, cucumber, custard squash, muskmelon); Fibre plant (such as, cotton, flax, hemp, jute); Citrus fruit (such as, orange, lemon, grapefruit, oranges and tangerines); Vegetables (such as, spinach, romaine lettuce, asparagus, cabbage, carrot, onion, tomato, potato, hot red pepper); Lauraceae (such as, avocado, Chinese cassia tree, camphor); And other plant, such as corn, tobacco, nut, coffee, sugarcane, tea, grape vine, lupulus, banana and natural rubber plant and ornamental plants (complex form), comprise flowering plant and the cut-flower by its results.Therefore, the composition comprising a kind of or multiple particles B T compound is as herein provided contacted by making crop, some embodiment contains prolongation and such as comes from food (such as, fruit, vegetables, cereal, seed etc.) cut-flower or target crop results target crop life of product (such as, relative to the control group not contacting particles B T described in this statistically commercially available, the nutrition of significant prolongation things and/or can time of use attractive in appearance).
The valid density of the particles B T as described herein used in these and related embodiment depends on many factors, comprises BT, pH, temperature, the selection of mol ratio of BT component and the microorganism of intrusion.Validity also depends on the target of the prevention of infection or the existing treatment infecting (such as, biomembrane) whether application-specific.Under most of condition, preventive dose meets the demands.Effective maintenance concentration of BT may near the MIC of maximum resistant organisms.This concentration in the scope of 1-2 μ g/ml, but may can reach 8 μ g/ml or larger at the most, and this depends on concrete particles B T compound.In an exemplary embodiment, the particles B is PTO (BisPyr) being applied to plant is provided with 5:1 mol ratio (bismuth: PTO).In another embodiment, bismuth mercaptan BisPyr/Ery (Bis-PTO/dithioerythritol) two in particulate form can be provided as broad spectrum antimicrobicide.In yet another embodiment, the target to the infected by microbes of plant and cut-flower/tree and potent protection particles B T and specific antibiotic as herein provided (preferably collaborative or enhancement antibiotic) can be provided to provide.Based on the concertedness observed between BisEDT and gentamicin, in certain embodiments, preferably this BT-antibiotic antibiotic combinations is applied for agricultural.
In other embodiments, the interpolation of the particles B T preparation of sodium bicarbonate (sodium bicarbonate) or other alkaline matter (such as, saleratus, calcium carbonate) can increase or strengthen the anti-microbial effect of BT.Other composition of agricultural particles B T preparation comprises surfactant and other antimicrobial, such as, and Chlorhexidine, sanguinarine extract, metronidazole, quaternary ammonium compound (such as Cetylpyridinium Chloride), biguanides (such as CHG, Hexetidine, Octenidine, Alexidine), and halogenated bisphenol compound, such as 2, 2' di-2-ethylhexylphosphine oxide-(the chloro-6-bromophenol of 4-) or other phenol antibacterium compound, alkyl hydroxy benzoic ether, anti-microbial cationic peptide, aminoglycoside, quinolone, Lincoln's acid amides, penicillin, cynnematin, macrolide, tetracycline and other antibiotic, Taurolidine or tauroflex, A-decICX, Coleus forskohlii essential oil, silver or collargol antibacterial agent, based on the antibacterial agent of tin or copper, chlorine or bromine oxide, Mai Luka oil, skin Sa grass, thyme, rosemary, Xue MingRosma rinus officinalis or other medicinal herbal extract, grapefruit seed extract, anti-inflammatory or antioxidant be brufen, Flurbiprofen, aspirin, Indomethacin, aloe, turmeric, Olive leaf P.E, cloves, panthenol, retinol, omega-fatty acid, gamma-Linolenic acid (GLA), green tea, ginger, grapestone etc. such as, pharmaceutically acceptable carrier, such as, starch, sucrose, water or water/alcohol system, DMSO etc., surfactant, such as anion, nonionic, cation and amphion or amphoteric surfactant or the saponin (such as, United States Patent (USP) 6,485,711) from vegetable material, buffer and salt, and other optional member that may comprise, such as, bleaching agent (such as per-compound), peroxide diphosphonic acid sylvite, effervescent system (such as sodium bicarbonate/citric acid system) etc.
In certain embodiments, also can by agricultural use and the particles B T used on plant composition with produce as described herein additional, strengthen or synergistic these and optionally other agent combination use or in liposome or form of nanoparticles with enhanced activity with send.Some embodiment clearly gets rid of particles B T preparation, this particles B T preparation comprises such as that phosphatide is (such as, phosphocholine) and/or the liposome of liposome containing cholesterol, and some other embodiment does not limit and can comprise these and other liposome.Also prepare the concrete preparation of particles B T, said preparation contains carrier, excipient or promotes that adhesion preparation is to other additive (such as, glucose, starch, citric acid, carrier oil, emulsion, dispersant, surfactant etc.) on surface.
In the embodiment that other is contained, can will on plant or agricultural crops, be used as the particles B T preparation of anti-biofilm agent and be used for other agent combination controlling biofilm development.Known, such as, between kind, quorum sensing is relevant to biofilm formation.Increase some reagent of colony induction signaling between LuxS dependent pathway or kind (such as, U.S. Patent No. 7,427,408 and 6,455,031) contribute to controlling biomembrane, such as, block compound and/or N-butyryl-L-homoserine lactone (BHL) analog of N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL).These anti-biofilm agent combinationally used with particles B T described herein can be sent for anti-bacteria biofilm development with blade face spraying form or are used for the treatment of preformed biomembrane.In another embodiment, these anti-biofilm agent be included in biodegradable particulate for Co ntrolled release and/or with other antimicrobial in liposomal form.
Therefore, particles B T as herein described can be used to improve antibiont membrane interaction together with other technology existed according to some embodiment.This particles B T can work in coordination with or strengthen the activity of the certain plants pathogene of opposing antibiotics streptomycin and/or gentamicin.Streptomycin can not kill bacterium, but the propagation that can suppress them of replacing and thus reduce the speed of field planting at chapiter place, thus eliminate bacterium in nectary (nectarthode) propagation subsequently (see, such as, Domenico etc., JAntimicrobChemo1991; 28:801-10; The ResearchAdvancesinAntimicrobAgentsChemother2003 such as Domenico; 3:79-85).By using spraying adjuvant (such as, the Regulaid of activator type tM) further benefit can be obtained, this spraying adjuvant enough improves covering and the infiltration of streptomycin, makes this antibiotic amount reducing safe handling.
This particles B T and any active ingredient combinations of current use in opposing agricultural and phytomicroorganism pathogene can be used, this active component comprises those with antibiont film activity, such as oxidant, chelating agent (such as, iron chelating agent), bactericide and disinfectant.According to the disclosure, preferred combination can increase and maybe can strengthen or this antibiont membrane interaction collaborative.Such as by using the hydrophobicity mercaptan (such as, sulfo-chlorophenol) of adhesion property given and strengthening, some embodiment contains and is formulated as hydrophobicity to strengthen the particles B T composition of the time of staying of BT from the teeth outwards.The BT with net negative charge (such as, bismuth: the 1:2 mol ratio of mercaptan) also can have the adhesion property of enhancing.
Can using BT compound particles suspended matter as aqueous formulation, as suspended matter or in the organic solvent comprising Halogenated hydrocarbon propellants solution, dispersed oil or use as dry powder.Aqueous formulation can by adopting the liquid dispenser atomization of waterpower or ultrasonic atomizatio.System based on propellant can utilize suitable pressurization distributor.Dry powder can utilize the dry powder dispersion device that can effectively disperse containing BT particulate.The granularity of expection and distribution can obtain by selecting appropriate device.
In this specification, unless the context requires otherwise, otherwise word " comprises ", " comprising " and " containing " will be understood to imply the group comprising described step or component or step or component, but do not get rid of the group of other step any or component or step or component." by ... composition " represent comprise and be limited to phrase " by ... composition " after any content.Therefore, phrase " by ... composition " the listed component of instruction is required or compulsory, and cannot there is other component." substantially by ... composition " represents any component listed after comprising this phrase, and is limited to other component of activity or the effect not disturbing or promote that listed component is specified in the disclosure.Therefore, phrase " substantially by ... composition " the listed component of instruction is required or compulsory, but other component is optional and can exist or can not exist, and this depends on whether they affect activity or the effect of listed component.
In this specification and in the appended claims, indicate in addition unless context is clear, singulative " ", " one " and " being somebody's turn to do " comprise and multiplely refer to thing.As used herein, in specific embodiments, indicate when term " about " or " approximately " are before numerical value this value add deduct 5%, 6%, 7%, 8% or 9% scope.In other embodiments, indicate when term " about " or " approximately " are before numerical value this value add deduct 10%, 11%, 12%, 13% or 14% scope.And in other embodiments, indicate when term " about " or " approximately " are before numerical value this value add deduct 15%, 16%, 17%, 18%, 19% or 20% scope.
Bibliography: Badireddy etc., BiotechnolBioengineering2008; 99:634-43; Badireddy etc., Biomacromolecules, 2008; 9:3079-89; Bayston etc., Biomaterials2009; 30:3167-73.Codony etc., JAppliedMicrobiol2003; 95:288-93.Domenico etc., JAntimicrobChemo1991; 28:801-810.Domenico etc., AntimicrobAgentsChemother1997; 41:1697-703.Domenico etc., 1999InfectImmun67:664-669.Domenico etc., AntimicrobAgentsChemother2001; 45:1417-21.Domenico etc., ResearchAdvancesinAntimicrobAgentsChemother2003; 3:79-85.Domenico etc., Peptides2004.; 25:2047-53.Domenico etc., 2005AntibioticsforClinicians9:291-297.Dufrene, JBacteriol2004; 186:3283-5.Eboigbodin etc., Biomacromolecules2008; 9:686-95.FeazelLM, BaumgartnerLK, PetersonKL etc., Opportunisticpathogensenrichedinshowerheadbiofilms.PNAS2 009 (before printing electronic edition).GeeseyGG, LewandowskiZ, FlemmingH-C (editor).Biofoulingandbiocorrosioninindustrialwatersystems.CRCPre ss, BocaRaton, FL, 1994.Huang etc., JAntimicrobChemother1999; 44:601-5; Juhni etc., ProceedingsAnnualMeetingAdhesionSociety2005; 28:179-181.Omoike etc., Biomacromolecules2004; 5:1219-30.OuazzaniK, BentamaJ.Bio-foulinginmembraneprocesses:micro-organism/s urfaceinteractions, hydrodynamicdetachmentmethod.Congres2008; 220:290-4.Ozdamar etc., Retina1999; 19:122-6.Piccirillo etc., JMaterChem2009; 19:6167.Reunala etc., CurrOpinAllergyClinImmunol2004; 4:397-401.Romo etc., EnvironProgress1999; 18:107-12.SahaDC, ShahinS, RackowEC, AstizME, DomenicoP.2000.Cytokinemodulationbybismuth-ethanedithiol inexperimentalsepsis. the 10th international conference .Inflamm.Res.Assoc., HotSprings, VA.Sawada etc., JPRAS1990; 43:78-82.Schultz, JFluidsEng2004; 126:1039-47.TillerJC, HartmannL, ScherbleJ.Reloadableantimicrobialcoatingsbasedonamphiphi licsiliconenetworks.SurfaceCoatingsInternationalPartB:Coaf/'ngsTransactions2005；88:1-82。Tsuneda etc., FEMSMicrobiolLett2003; 223:287-92.Vu etc., Molecules2009; 14:2535-54.Yan etc., Ophthalmologies2008; 222:245-8.Yeo etc., WaterSciTechnol2007; 55:35-42.
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Following embodiment exemplarily mode and non-limiting way is provided.
Embodiment
Embodiment 1
The preparation of BT compound
Following BT compound is according to the method preparation of Domenico etc. (U.S.RE37,793, U.S.6,248,371, U.S.6,086,921, U.S.6,380,248) or as according to hereafter for the particulate of the synthetic schemes of BisEDT description.In order to compare, form the known tendency of trivalent complex compound based on the stoichiometric ratio of reactant used and bismuth and sulfur-containing compound, showing the atom ratio relative to single bismuth atom.Numeral in bracket is ratio (the such as Bi: mercaptan 1/ mercaptan 2 of bismuth and one (or more) thiol reagent; Also see table 1).
1)CPD1B-1Bis-EDT(1∶1)BiC2H4S2
2)CPD1B-2Bis-EDT(1∶1.5)BiC 3H 6S 3
3)CPD1B-3Bis-EDT(1∶1.5)BiC 3H 6S 3
4) CPD1CBis-EDT (solubility Bi preparation) (1: 1.5) BiC 3h 6s 3
5)CPD2ABis-Bal(1∶1)BiC 3H 6S 2O
6)CPD2BBis-Bal(1∶1.5)BiC 4.5H 9O 1.5S 3
7)CPD3ABis-Pyr(1∶1.5)BiC 7.5H 6N 1.5O 1.5S 1.5
8)CPD3BBis-Pyr(1∶3)BiC 15H 12N 3O 3S 3
9)CPD4Bis-Ery(1∶1.5)BiC 6H 12O 3S 3
10)CPD5Bis-Tol(1∶1.5)BiC 10.5H 9S 3
11)CPD6Bis-BDT(1∶1.5)BiC 6H 12S 3
12)CPD7Bis-PDT(1∶1.5)BiC 4.5H 9S 3
13)CPD8-1Bis-Pyr/BDT(1∶1/1)
14)CPD8-2Bis-Pyr/BDT(1∶1/0.5)
15) CPD9Bis-2 hydroxyl, propanethiol (1:3)
16)CPD10Bis-Pyr/Bal(1∶1/0.5)
17)CPD11Bis-Pyr/EDT(1∶1/0.5)
18)CPD12Bis-Pyr/Tol(1∶1/0.5)
19)CPD13Bis-Pyr/PDT(1∶1/0.5)
20)CPD14Bis-Pyr/Ery(1∶1/0.5)
21) CPD15Bis-EDT/2 hydroxyl, propanethiol (1:1/1)
Particulate bismuth-1,2-dithioglycol (Bis-EDT, soluble bismuth preparation) is prepared as follows:
Under stirring at room temperature to the 5%HNO of excessive (11.4L) in 15L polypropylene carboy 3the aqueous solution slowly drips the Bi (NO of 0.331L (~ 0.575 mole) 3) 3the aqueous solution (43%Bi (NO 3) 3(w/w), 5% nitric acid (w/w), 52% water (w/w), ShepherdChemicalCo., Cincinnati, OH, production code member 2362; δ ~ 1.6g/mL), slowly add absolute ethyl alcohol (4L) subsequently.Some white precipitates produce, but are dissolved by Keep agitation.72.19mL (0.863 mole) 1 is added to 1.5L absolute ethyl alcohol by using 60mL syringe, 2-dithioglycol, then stirring prepare 1 in five minutes individually, the ethanolic solution (~ 1.56L, ~ 0.55M) of 2-dithioglycol (CAS540-63-6).Then in 5 hours, 1,2-dithioglycol/EtOH is slowly dropped to Bi (NO 3) 3/ HNO 3the aqueous solution, continues stirring and spends the night.Make the product sedimentation of generation for precipitation, continue about 15 minutes, use peristaltic pump to remove filtrate with 300mL/min afterwards.Then by collecting product in meticulous filter filtration on paper in the Buchner funnel of 15-cm diameter, and wash three times, to obtain the BisEDT (694.51gm/ mole) for Yellow amorphous powder solid shape with the ethanol of 500-mL volume, USP water and acetone successively subsequently.Product is put into 500mL amber glass bottle also under vacuo through CaCl 2dry 48 hours.Recycled materials (output ~ 200g) give out mercaptan characteristic odor.Crude product is dissolved in 750mL absolute ethyl alcohol again, stirs 30 minutes, then filter and use 3 × 50mL ethanol, 2 × 50mL acetone to wash successively, and again with the washing of 500mL acetone.By powder grinding in 1MNaOH (500mL) of again washing, filter, and with the washing of 3 × 220mL water, 2 × 50mL ethanol and 1 × 400mL acetone, to obtain the pure BisEDT of 156.74gm.The productive rate batch obtaining about 78-91% subsequently prepared in essentially the same way.
Pass through 1h and 13the data analysis of C nuclear magnetic resonnance (NMR), infrared spectrum (IR), ultraviolet spectra (UV), mass spectrum (MS) and elementary analysis, product is accredited as has the structure shown in above formula I.Develop a kind of HPLC method to measure the chemical purity of BisEDT, in DMSO, prepare sample (0.5mg/mL) thus.λ is measured by the DMSO solution scanning BisEDT at 190 to 600nm max.At room temperature carry out equal strength HPLC wash-out with 1mL/min, mobile phase is acetonitrile: 0.1% formic acid in water (9:1), has at 265nm (λ max) the UV detector that detects, 2 μ L volume injected, is furnished with YMCPackPVCSilNP, 5 μm, Waters (MilliporeCorp., Milford, MA) model 2695 chromatograph of 250 × 4.6mm internal diameter analytical column (Waters), detect unimodal, reflection chemical purity is 100 ± 0.1%.Elementary analysis is consistent with the structure of formula (I).
Qualification dry particulate matter is to evaluate particle size properties.In brief, by particulate Eddy diffusion in 2% f-68 (BASF, Mt.Olive, NJ), suspension under standard configuration in water bath sonicator instrument ultrasonic 10 minutes, then Nanosizer/ZetasizerNano-S Particle Size Analyzer (model ZEN1600 (without ζ-potential measurement ability) is used, MalvernInstruments, Worcestershire, UK) recommend to analyze according to manufacturer.According to the combined data of twice measurement, particulate shows Unimodal Distribution, and all detectable events at the volume mean diameter (VMD) of about 0.6 micron to 4 microns, and have peak VMD at about 1.3 microns.By contrast, when BisEDT is by existing method (Domenico etc., when preparing, majority of particles Heterodisperse and have significantly larger size, eliminate their qualification based on VMD 1997Antimicrob.AgentsChemother.41 (8): 1697-1703).
Embodiment 2
The bacterium colony biological film model that chronic wounds infects:
Suppressed by BT compound
Because the bacterium existed in chronic wounds adopts biomembrane life style, use substantially according to described method (Anderl etc., 2003AntimicrobAgentsChemother47:1251-56; Walters etc., 2003AntimicrobAgentsChemother47:317; Wentland etc., 1996Biotchnol.Prog.12:316; Zheng etc., 2002AntimicrobAgentsChemother46:900) the biomembrane test b T for preparing is for the effect of biomembranous antibacterium cell survival.
In brief, bacterium colony biomembrane is grown 24 hours on 10% Tryptic Soy Agar, then transfer to the MuellerHinton plate containing therapeutic agent.After treatment, biofilm dispersion is entered in the peptone water containing 2%w/v glutathione (in and BT), and before coated plate counting serial dilution to peptone water.The two kinds of bacteriums be separated from chronic wounds are utilized separately for the bacterium colony biomembrane produced for testing.These are Gram negative bacterial strain pseudomonas aeruginosa and gram-positive methicillin resistant S staphylococcus (MRSA).
Substantially (Anderl etc., 2003AntimicrobAgentsChemother47:1251-56 as described below; Walters etc., 2003AntimicrobAgentsChemother47:317; Wentland etc., 1996Biotchnol.Prog.12:316; Zheng etc., 2002AntimicrobAgentsChemother46:900), the microporous barrier upper grown that bacterial biof iotalm bacterium colony is left standstill on a lbmc agar plate.This bacterium colony biomembrane shows many common attribute of other biological film model, and such as, they are made up of the cell assembled in the matrix of high degree of hydration.Also as other people report (Brown etc., JSurgRes56:562; Millward etc., 1989Microbios58:155; Sutch etc., 1995JPharmPharmacol47:1094; Thrower etc., 1997JMedMicrobiol46:425), find that the bacterium in bacterium colony biomembrane shows same significantly reduced antimicrobial susceptibility, this quantizes in more ripe external biological membrane reactor.Bacterium colony biomembrane easily and can repeatedly produce in a large number.According to non-limiting theory, this bacterium colony biological film model has some common traits of infected wound: bacterium has the Air Interface place growth of nutrients and the minimum flow velocity supplied under biomembrane.Many nutrient sources, for cultivating bacterium colony biomembrane, comprise blood agar, and it is considered to can nutritional condition in analogue body.
The planktonic bacteria liquid culture dripped by inoculating 5 μ l on the polycarbonate leaching film of 25mm diameter prepares bacterium colony biomembrane.This film was exposed to ultraviolet 10 minutes by every side and by sterilizing before inoculation.Bacterium 37 DEG C of grow overnight in bacteria culture media will be planted, and in fresh culture, be diluted to the optical density of under 600nm 0.1 before precipitation on film.Then film is placed on the agar plate containing growth medium.Then this plate is capped and is inverted in 37 DEG C of incubators.Every 24 hours, use aseptic nipper that film and bacterium colony biomembrane are transferred to new plate.Bacterium colony biomembrane usually after growth 48 hours for experiment, now each film has about 10 9individual bacterium.Bacterium colony Biofilm Environment is employed successfully in cultivates many single bacterial classifications and mixed bacteria biomembrane.
In order to measure combating microorganisms agent, (such as, BT compound, comprises the composition of BT compound; Antibiotic and BT compound-antibiotic composition) susceptibility, bacterium colony biomembrane is transferred to the agar plate supplementing the agent of candidate's antimicrobial therapy.Wherein be exposed to the duration of antimicrobial therapy more than 24 hours, bacterium colony biomembrane is transferred to and newly treats plate by every day.In the treatment end of term, bacterium colony biomembrane is put into pipe containing 10ml buffer solution and vortex 1-2 minute with disperse biofilm.In some cases, be necessary with the simple processed sample of Potter-Elvehjem Tissue Grinders with break up cell aggregation.Then by the cell suspending liquid serial dilution obtained and coated plate with count survival bacterium, be reported as the colony-forming units (CFU) of per unit area.Use log 10transformation assay survival data.
For bacterial biof iotalm bacterium colony culture (pseudomonas aeruginosa, the PA of every type; Methicillin resistant S staphylococcus, MRSA or SA), test five kinds of antibiotic and 13 kinds of BT compounds.Antimicrobial for PA test comprise be referred to herein as BisEDT and compound 2B, 4,5,6,8-2,9,10, the BT of 11 and 15 (see table 1) and antibiotic tobramycin, amikacin, Imipenem, Cefazolin and Ciprofloxacin.Antimicrobial for SA test comprise be referred to herein as BisEDT and compound 2B, 4,5,6,8-2,9, the BT of 10 and 11 (see table 1) and rifamycin antibiotic is flat, Daptomycin, minocycline, ampicillin and vancomycin.As above described in " accompanying drawing summary ", according to fixed micro-biological process, with about 10-400 doubly to the concentration determination antibiotic of minimal inhibitory concentration (MIC).
At the concentration tested, seven kinds of BT compounds exhibit go out the remarkable effect to PA bacteria living, and two kinds of BT compounds prove at the concentration tested to the remarkable effect of MRSA survival; Representational result display, Fig. 1 all shows the BT effect (in both cases, relative to shown antibiotic effect) to bacteria living for BisEDT and BT compound 2B (for PA test) and Fig. 2 for BT compound 2B and 8-2 (testing for SA).Also as illustrated in fig. 1 and 2, cause acting synergistically with adding of BT compound shown in shown antibiotic combinations, the effect reducing bacteria living is thus enhanced relative to the antibacterial action of independent antibiotic or independent BT compound.In PA survival measures, concentration is that the compound 15 (Bis-EDT/2 hydroxyl, propanethiol (1:1/1)) of 80 μ g/mL demonstrates the effect (not shown) suitable with use 1600 μ g/mLAMK to add effect (Fig. 1) that 80 μ g/mLBisEDT obtain.
Embodiment 3
The drip biological film model that chronic wounds infects:
Suppressed by BT compound
Drip biomembrane represents art-recognized for the formation of the authoritative model with the biomembranous effect of test candidate antimicrobial compound antibacterium.The print (substrate) that goes that drip biomembrane is being placed in drip-flow reactor passage above produces.Many dissimilar materials can be used as the substrate that bacterial biof iotalm is formed, and comprise ground glass microslide.Nutrient broth enters drip bio-reactor Cytology Lab, then along downward 10 gradient flowings of coupongs major axis by the indoor near instillation top.
Biomembrane is grown in drip bio-reactor, and be exposed to separately or the BT compound combined with other antibacterial agent (comprising BT compound) and/or be exposed to separately or with the Antibiotique composition of other antibacterial agent combination, or be exposed to other the conventional or candidate therapeutic for chronic wounds.Therefore, the effect of BT compound to bacterial biof iotalm in drip-flow reactor is identified.In drip-flow reactor, biomembrane prepares (such as, Stewart etc., 2001JApplMicrobiol.91:525 according to fixed method; Xu etc., 1998Appl.Environ.Microbiol.64:4035).This design is included on the polystyrene coupongs that have a down dip in covering chamber and cultivates biomembrane.Exemplary medium contains 1g/l glucose, 0.5g/lNH 4nO 3, 0.25g/lKCl, 0.25g/lKH 2pO 4, 0.25g/lMgSO 4-7H 2o, supplement adult donor's cow's serum (ph6.8) that 5%v/v simulates rich proteinaceous serum, iron restrictive condition is similar to the biofilm development condition in body in such as chronic wounds.This medium dropwise (50ml/h) flows through four coupongs contained in four independent parallel chambers, each measurement 10cm × 1.9cm, degree of depth 1.9cm.Indoor reactor is made up of polysulfone plastic.Each room is furnished with independent removable plastic lid, and this vinyl cover can tight seal.Biofilm reactor is put into 37 DEG C of incubators, bacterial cell culture media is by making it to be heated through the aluminium radiator kept in incubator.The method creates the antibiotic-resistant phenotype observed in some biomembrane, simulate low fluid shearing environment and close to the interface feature of chronic wounds, continuous print nutritional supplementation is provided simultaneously, and with many for the identification of compatible with the analytical method of monitoring the effect of the candidate introduced antibacterial scheme.Drip-flow reactor be used successfully to cultivate many pure with hybrid biomembrane.Biomembrane grew 2 to 5 days usually before application of antimicrobial reagents.
In order to measure antibiont film to the biomembranous effect grown in drip-flow reactor, be corrected through biomembranous fluid stream or supplement treatment preparation in need (such as, one or more BT compounds and/or one or more antibiotic, or contrast, and/or other candidate agent).Flowing continues the treatment phase of regulation.Then the biomembrane coupongs through treatment are taken out fast from reactor, biomembrane is scraped into the beaker containing 10ml buffer solution.This sample Potter-Elvehjem Tissue Grinders rapid processing (usual 30 seconds to 1 minute) is with disperse bacterial aggregation.Suspension by serial dilution and coated plate with according to standard microbiology method counting survival microorganism.
Embodiment 4
The wound biomembrane that keratinocyte scratch is repaired suppresses:
Biomembrane is suppressed by BT compound
The external keratinocyte that present embodiment describes the wound healing determined scrapes the amendment of wound model, with reach have with biomembrane relevant wounds pathology and wound healing and particularly with acute or chronic wounds or the model containing biomembranous wound correlation described herein.Keratinocyte according to the effect of chronic wounds biomembrane scrapes wound model, the independent indoor that mammal (such as people) keratinocyte is communicated with at mutual fluid with the cultivation of bacterial biof iotalm colony are carried out, to allow the effect of the condition assessing the effect affecting the soluble component Human Keratinocytes wound healing event that biomembrane produces.
Newborn people's foreskin cells in the vinyl disc of process as monolayer culture, wherein individual layer control " wound " or scratch by mechanical system (such as, by the physical damage of individual layer, such as, by with the instrument be applicable to the such as acellular district of substantial linear between aseptic operation cutter, razor, cell scraper, tweezers or other instrument scraping individual layer district) formed.Known external keratinocyte single-layer model system stands cell structure and function course to stimulate the mode of body internal injury healing to respond injuries.According to embodiment disclosed herein, observe the existence of bacterial biof iotalm to the impact of this process, such as on the impact of scratch healing time, and in these and related embodiment, also have evaluated the effect of the existence that selected candidate antimicrobial (such as antibacterial and antibiont film) treats.
According to the injured keratinocyte individual layer that morphology, biochemistry, molecular genetics, stechiology and other parametric test are cultivated under biomembrane exists, (such as, increase or reduce) biomembranous detrimental effect in the mode relative to suitable contrast statistically significant determining whether the introducing of BT compound changes.First wound is exposed to each independent BT compound, and is exposed to the combination of the BT compound of consideration, so that in assessment, this type of tests the toxicity of often kind of BT compounds for treating before treating the effect affected model wound healing process biomembrane.
In representative embodiment, three days biological Membrance cuiture are in remaining on the film in above-mentioned tissue-culture well (such as, TransWell film insert etc.) and be communicated with keratinocyte individual layer fluid, keratinocyte individual layer is scratched to start wound healing process.The biomembrane cultivated outward at real acute or chronic wounds is considered for these and related embodiment.
Therefore, it has been developed to for assessment of the vitro system of effect of solubility biofilm components to Human keratinocytes migration and propagation.This system uses dialysis membrane separating bio film and keratinocyte.Keratinocyte cultivates (Fleckman etc., 1997JInvest.Dermatol.109:36 from neonatal foreskin as previously mentioned; Piepkorn etc., 1987JInvest.Dermatol.88:215-219) and confluent monolayer is grown on glass cover-slip.Then, keratinocyte can be scratched to produce " wound " with homogeneous width, monitors cell repair process (such as, Tao etc., 2007PLoSONE2:e697 subsequently; The 2007Eur.JCellBiol.86:747 such as Buth; The 2000Ann.Acad.Med.Singapore29:27 such as Phan).Then artificial wound is placed in the bottom of aseptic bilateral room, and uses asptic technique to assemble described room.The both sides of room are filled with Keratinocyte Growth Media (EpiLife), contain or do not contain antibiotic and/or bismuth-mercaptan.Nonvaccinated system is with comparing.
The microbionation of system wound separation is cultivated 2 hours in a static condition, is attached to surface in upper room to enable bacterium.After the setting stage, the liquid nutrient medium room of being flowing in starts to remove the cell do not adhered to.Then media flow continues, by washing the cell do not adhered to off with the speed minimizing upper indoor planktonic cells growth.After the culture period of 6 to 48 hours, system (keratinocyte on cover glass and the suprabasil bacterial biof iotalm of film) is decomposed, and takes out cover glass and analyzes.In the relevant embodiments, biofilm grew before assembly chamber in upper room.In other related embodiment, the independent Dual culture of biomembrane and scratch keratinocyte individual layer one or more BT compounds do not exist and in the presence of carry out, optionally comprise or get rid of one or more antibiotic, to measure candidate agent such as BT compound or potential collaborative BT compound+antibiotic combinations (such as, BT compound provided herein, the BT such as provided in particulate form and following one or more: amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or another kind of Lincoln's acid amides antibiotic), Daptomycin , Doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid , minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin) effect that the keratinocyte of scratch is repaired, such as, to identify change (such as, to increase relative to the statistically significant mode of suitably contrast or to reduce) combination of the agent of time that at least one index such as wound reparation of scratch healing is carried out or other wound reparation index or agent is (such as, Tao etc., 2007PLoSONE2:e697, the 2007Eur.JCellBiol.86:747 such as Buth, the 2000Ann.Acad.Med.Singapore29:27 such as Phan).
Embodiment 5
The wound biomembrane that keratinocyte scratch is repaired suppresses
According to the method described in above-described embodiment 4, the Human keratinocytes be separated is cultivated on the cover slip and scratch.Injured culture is remained on the film support be communicated with keratinocyte cultures fluid under biomembranous condition of culture that is independent or that there is Dual culture.Then between test period, keratinocyte growth and/or migration redefine the scratch closing time interval of keratinocyte individual layer in scraping district.Fig. 3 describes biomembrane fluid and is communicated with the existence of (but not being direct contact) to the effect of the healing time of scraping keratinocyte individual layer.
Therefore, contemplate qualification in certain embodiments and be used for the treatment of the method for the material of chronic wounds, under being included in and thering is no candidate's antibiont film, under bacterial biof iotalm existence, cultivate scratch cell (such as keratinocyte or fibroblast) individual layer; And assessment candidate's antibiont film do not exist and in the presence of the healing index of scratch cell monolayer, wherein promote the material of at least one healing index (such as, BT compound, such as monodispersed BT microparticle suspending liquid substantially as herein described, separately or with antibiotic synergistic combination, described antibiotic such as following one or more: amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin, Daptomycin , Doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid , minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin) be accredited as and be suitable for treating acute or chronic wounds or the material containing biomembranous wound.
Embodiment 6
Concertedness bismuth-mercaptan (BT)-antibiotic combinations
Present embodiment shows that the synergistic situation of the proof of the antibiotic combination of one or more bismuth-mercaptan compounds and one or more anti-various bacteria kinds and bacterial strain (comprising several antibiotic resistance bacterium).
Materials and methods.Study of Sensitivity is passed through according to NCCLS scheme at 96 hole tissue culturing plate (NalgeNuncInternational, Denmark) in, broth dilution carries out (NationalCommitteeforClinicalLaboratoryStandards. (1997) .MethodsforDilutionAntimicrobialSusceptibilityTestsforBa cteriathatGrowAerobically:ApprovedStandardM7-A2andInform ationalSupplementM100-S10.NCCLS, Wayne, PA, USA).
In brief, use overnight bacterial culture to prepare 0.5McFarland standard suspension, it dilutes 1:50 (~ 2 × 10 further in the Mueller-Hinton broth bouillon (BBL, Cockeysville, MD, USA) of cation adjustment 6cfu/mL).Add BT (as above preparing) and antibiotic with progressive concentration, keep final volume constant in 0.2mL.Culture being hatched 24 hours at 37 DEG C, recommending the absorption being used in 630nm to assess turbidity by using ELISA plate reader (BiotekInstruments, Winooski, VT, USA) according to manufacturer.Minimal inhibitory concentration (MIC) is represented as the Developing restraint lowest concentration of drug of 24 hours.Live bacteria count (cfu/mL) is measured by the standard coated plate on nutrient agar.Smallest bacteria concentration (MBC) is expressed as the drug concentration reducing initial viability 99.9% when hatching for 24 hours.
Chessboard method is used to assess the activity of antimicrobial combination.According to (Eliopoulos and Moellering such as Eliopoulos, (1996) Antimicrobialcombinations. is shown in AntibioticsinLaboratoryMedicine (Lorian, V. edit), 330-96 page, Williams and Wilkins, Baltimore, MD, USA), FICI (FICI) and classification bacteriocidal concentration index (FBCI) is calculated.Concertedness is defined as FICI or FBCI index≤0.5, without interaction during >0.5-4, antagonism (Odds during >4, FC (2003) Synergy, antagonism, andwhatthechequerboardputsbetweenthem.JournalofAntimicro bialChemotherapy52:1).Concertedness is also the minimizing of antibiotic concentration >=4 times by usual definition.
Result is shown in table 2-17.
Table 2
staphylococcus aureus-NAF resistance
BE=0.2 μ g/mlBisEDT; Bacterial isolates available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.NAF is available from Sigma (St.Louis, MO).
Table 3
staphylococcus aureus-NAF resistance
BE=0.2 μ g/mlBisEDT; Bacterial isolates available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.NAF is available from Sigma.
Table 4
staphylococcus aureus
rifampin/neomycin/paromomycin
BE=0.2 μ g/mlBisEDT; Bacterial strain S2446-3 available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Antibiotic is available from Sigma.
Table 5
staphylococcus epidermidis-GM resistance
GM=gentamicin; Bacterial strain S2400-1 available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Gentamicin is available from Winthrop Pharmacy; Concertedness is overstriking
Table 6
staphylococcus epidermidis-S2400-1
biomembrane prevents
Data represent with μ g/ml; Bacterial strain S2400-1 available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Antibiotic is available from Winthrop Pharmacy.
Table 7
staphylococcus epidermidis-S2400-1
MIC
Data represent with μ g/ml; Bacterial strain S2400-1 available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Antibiotic is available from the Pharmacy of Winthrop.
Table 8
staphylococcus epidermidis-S2400-1
MBC
Data represent with μ g/ml; Bacterial strain S2400-1 available from the Clinical microorganism laboratory of Winthrop university hospital, Mineola, NY.Antibiotic is available from the Pharmacy of Winthrop.
Table 9
staphylococcus epidermidis
ATCC35984
MIC
Data represent with μ g/ml; Antibiotic available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 10
escherichia coli-ampicillin/chlorampenicol resistant
AB=antibiotic; CM=chloramphenicol; AM=ampicillin; BE=BisEDT, 0.3 μ g/ml; Bacterial strain available from the laboratory of doctor MJCasadaban, DepartmentofMolecularGeneticsandCellBiology, TheUniversityofChicago, Chicago, IL.Antibiotic available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 11
escherichia coli-tetracycline-resistance:
doxycycline+BisEDT
DOX=Doxycycline; BE=BisEDT, 0.3 μ g/ml; Bacterial strain available from the laboratory of doctor IChopra, DepartmentofBacteriology, TheUniversityofBristol, Bristol, UK.Antibiotic available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 12
pseudomonas aeruginosa-tobramycin-resistance:
bisEDT concertedness
Agr=glucosaminide resistance; NN=tobramycin; PA=pseudomonas aeruginosa; BE=BisEDT, 0.3 μ g/ml; Bacterial strain available from the laboratory of doctor K.Poole, DepartmentofMicrobiologyandImmunology, QueensUniversity, Ontario, CN.Tobramycin available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 13
burkholderia cepacia
tobramycin+BE concertedness
MIC
NN=tobramycin; BE=BisEDT, 0.4 μ g/ml; Bacterial strain available from the laboratory of doctor J.J.LiPuma, DepartmentofPediatricsandCommunicableDiseases, UniversityofMichigan, AnnArbor, MI; Veloira etc. 2003 in addition.Tobramycin available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 14
burkholderia cepacia
tobramycin+BE concertedness
MBC
NN=tobramycin; BE=BisEDT, 0.4 μ g/ml; Bacterial strain available from the laboratory of doctor J.J.LiPuma, DepartmentofPediatricsandCommunicableDiseases, UniversityofMichigan, AnnArbor, MI; Veloira etc. 2003 in addition.Tobramycin available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 15
tobramycin resistant strain
MIC
NN=tobramycin; BE=BisEDT, 0.8 μ g/ml; Lipo-BE-NN=liposome BE-NN; Bacterial strain available from the laboratory of doctor A.Omri, DepartmentofChemistryandBiochemistry, LaurentianUniversity, Ontario, CN; (M bacterial strain is mucinoid Burkholderia cepacia; PA=pseudomonas aeruginosa; SA=staphylococcus aureus).Tobramycin available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 16
tobramycin resistant strain
MBC
NN=tobramycin; BE=BisEDT, 0.8 μ g/ml; Lipo-BE-NN=liposome BE-NN; Bacterial strain available from doctor A.Omri laboratory, DepartmentofChemistryandBiochemistry, LaurentianUniversity, Ontario, CN; (M bacterial strain is mucinoid Burkholderia cepacia; PA=pseudomonas aeruginosa; SA=staphylococcus aureus).Tobramycin available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 17
bisEDT-PTO concertedness
BE=BisEDT; NaPYR=pyrithione zinc; Chemicals is available from Sigma-Aldrich; Concertedness overstriking.Shown bacterial isolates is from American type culture collection (ATCC, Manassas, VA).
Embodiment 7
Comparative bismuth-mercaptan (BT) and antibiotic antagonism comprise the gram-positive bacteria of antibiotic resistance bacteria strain and the effect of Gram-negative bacteria
In the present embodiment, have evaluated BisEDT and compare the external activity of agent for the gram-positive bacteria of responsible Skin and soft tissue infection and multiple clinical separation strains of Gram-negative bacteria.
Materials and methods.Test compounds and test concentrations scope as follows: BisEDT (Domenico etc., 1997; Domenico etc., Antimicrob.AgentsChemother.45 (5): 1417-1421. and embodiment 1), 16-0.015 μ g/mL; Linezolid (ChemPacificaInc., #35710), 64-0.06 μ g/mL; Daptomycin (CubistPharmaceuticals#MCB2007), 32-0.03 μ g/mL and 16-0.015 μ g/mL; Vancomycin (Sigma-Aldrich, St.Louis, MO, #V2002), 64-0.06 μ g/mL; Cefotaxime (Sigma#C3809), 64-0.06 μ g/mL and 32-0.03 μ g/mL; Imipenem (UnitedStatesPharmacopeia, NJ, #1337809) 16-0.015 μ g/mL and 8-0.008 μ g/mL; Ciprofloxacin (UnitedStatesPharmacopeia, #IOC265), 32-0.03 μ g/mL and 4-0.004 μ g/mL; Gentamicin (Sigma#G3632) 32-0.03 μ g/mL and 16-0.015 μ g/mL.Except gentamicin, all test samples are dissolved in DMSO; Gentamicin is dissolved in water.Stoste is prepared to maximum concentration with 40 times in test board.DMSO final concentration is in a test system 2.5%.
Microorganism.Test microbes is available from following clinical labororatory: CHP, ClarianHealthPartners, Indianapolis, IN; UCLA, UniversityofCaliforniaLosAngelesMedicalCenter, LosAngeles, CA; GRMicro, London, UK; PHRITBCenter, PublicHealthResearchInstituteTuberculosisCenter, NewYork, NY; ATCC, American type culture collection, Manassas, VA; MtSinaiHosp., MountSinaiHospital, NewYork, NY; UCSF, UniversityofCaliforniaSanFranciscoGeneralHospital, SanFrancisco, CA; BronsonHospital, BronsonMethodistHospital, Kalamazoo, MI; Quality control separated strain is available from American type culture collection (ATCC, Manassas, VA).Microorganism line on the agar medium being applicable to respective microorganism is separated.By swab from picking colony separating plate and the suitable meat soup put into containing cryoprotector suspend.Suspension is divided into equal portions and enters low temperature phial and remain on-80 DEG C.Abbreviation: BisEDT, bismuth-1,2-dithioglycol; LZD, Linezolid; DAP, Daptomycin; VA, vancomycin; CAZ, cefotaxime; IPM, Imipenem; CIP, Ciprofloxacin; GM, gentamicin; MSSA, methicillin sensitive S staphylococcus; CLSIQC, ClinicalandLaboratoryStandardsInstitute quality control bacterial strain; MRSA, methicillin resistant S staphylococcus; CA-MRSA, the acquired methicillin resistant S staphylococcus of group; MSSE, methicillin-susceptible Staphylococcus epidermidis; MRSE, methicillin resistant Staphylococcus epidermidis; VSE, vancomycin sensitive enterococcus.
Separated strain is rule from cryovial in appropriate culture medium: trypticase soy agar (Becton-Dickinson, Sparks, MD) for most of microorganism, or trypticase soy agar adds 5% Blood In Sheep (ClevelandScientific, Bath, OH) for streptococcus.By plate 35 DEG C of overnight incubation.Comprise quality control microorganism.The medium measured for MIC is MuellerHintonII meat soup (MHBII-BectonDickinson, #212322), for most of microorganism.The horse blood (ClevelandScientific lot number H13913) that MHBII supplements 2% dissolving is with the growth of adaptation Streptococcus pyogenes and Streptococcusagalactiae.Medium adds to each micro-dilution plate hole the dilution that 5 μ L drug solutions produce to offset with 102.5% normal weight preparation.In addition, in order to test Daptomycin, the extra 25mg/LCa of culture media supplemented 2+.
MIC assay method follows program (the ClinicalandLaboratoryStandardsInstitute.MethodsforDiluti onAntimicrobialSusceptibilityTestsforBacteriaThatGrowAer obically that ClinicalandLaboratoryStandardsInstitute describes; ApprovedStandard-seven edition.ClinicalandLaboratoryStandardsInstitute file M7-A7 [ISBN1-56238-587-9] .ClinicalandLaboratoryStandardsInstitute, 940WestValleyRoad, Suite1400, Wayne, Pennsylvania19087-1898USA, 2006) and adopt automatic fluid operator to carry out serial dilution and liquid transfer.Automatic fluid operator comprises Multidrop384 (Labsystems, Helsinki, Finland), Biomek2000 and Multimek96 (BeckmanCoulter, FullertonCA).The hole of the 2-12 row of the micro-dilution plate (Falcon3918) in standard 96 hole is filled 150 μ lDMSO or water, the gentamicin on Multidrop384.Medicine (300 μ l) is dispensed into the 1st row of appropriate row in these plates.These will become motherboard, therefrom prepare test board (daughter board).Biomek2000 completes the transfer through the 11st row in mother matrix.The hole not drug containing and be growth of microorganism control wells of the 12nd row in daughter board.Multidrop384 is used to load the suitable test media (above-mentioned) of 185 μ l for daughter board.Daughter board is prepared on Multimek96 instrument, and Multimek96 instrument is from each hole transferase 45 μ l drug solution of motherboard to the respective respective aperture of each daughter board in a single step.
The standardization kind mycorhiza of each microorganism is according to the preparation of CLSI method (ISBN1-56238-587-9, the same quote).Suspension is prepared in MHB, to equal the turbidity of 0.5McFarland standard.Suspension is diluted 1:9 in the meat soup of applicable microorganism.The kind bacterium of each microorganism is dispersed to the aseptic reservoir (BeckmanCoulter) of longitudinal subdivision, and uses Biomek2000 to inoculate plate.Daughter board is inverted and is placed on Biomek2000 working surface, and the drug concentration inoculated from low to high is carried out.10 μ l standardization kind bacterium are sent into each hole by Biomek2000.This causes final cell concentration position about 5 × 105 colony-forming units/mL in daughter board.Therefore, the Kongzui of daughter board is eventually containing 185 μ l meat soups, 5 μ l drug solutions and 10 μ l bacterium kind bacterium.Plate is superposed three floor heights, uppermost plate lid covers, and puts into plastic sack, and hatches about 18 hours for most of separated strain at 35 DEG C.Streptococcus plate is being hatched 20 hours readings afterwards.Plate visualizer is used to watch microplate from bottom.For often kind of test media, observe nonvaccinated solvability control board Chinese traditional medicine precipitation sign.Read MIC and be recorded as the lowest concentration of drug suppressing visible growth of microorganism.
Result.All marketed drug are solvable under all test concentrations in broth bouillon.BisEDT shows traces of precipitated when 32 μ g/mL, but MIC reading is unaffected, because the inhibition concentration of all test microbes is far below this concentration.In each mensuration day, suitable quality control bacterial strain is included in MIC mensuration.Optionally, the MIC value obtained from these bacterial strains with for quality control clearance (ClinicalandLaboratoryStandardsInstitute.PerformanceStand ardsforAntimicrobialSusceptibilityTesting disclosed in each dose; EighteenthInformationalSupplement.CLSI file M100-S18 [ISBN1-56238-653-0] .ClinicalandLaboratoryStandardsInstitute, 940WestValleyRoad, Suite1400, Wayne, Pennsylvania19087-1898USA, 2008) compare.
In each mensuration day, suitable quality control bacterial strain is included in MIC mensuration.Optionally, the MIC value obtained from three bacterial strains with for quality control clearance (ClinicalandLaboratoryStandardsInstitute.PerformanceStand ardsforAntimicrobialSusceptibilityTesting disclosed in each dose; EighteenthInformationalSupplement.CLSI file M100-S18 [ISBN1-56238-653-0]) compare.It is disclosed that in 141 values of the quality control bacterial strain of quality control clearance, 140 (99.3%) in specified scope.An exception is Imipenem and staphylococcus aureus 29213, takes turns generation value (≤0.008 μ g/mL) one, and this is a dilution lower than disclosed QC scope.This takes turns other Quality Control results all in the quality control clearance of specifying.
BisEDT proves to have powerful activity for methicillin sensitive S staphylococcus (MSSA), methicillin resistant S staphylococcus (MRSA) and group acquired MRSA (CA-MRSA), suppress all test strain when 1 μ g/mL or lower concentration, the MIC90 value wherein for all three microorganism groups is 0.5 μ g/mL.BisEDT shows the activity being greater than Linezolid and vancomycin, and is equal to the activity of Daptomycin.Imipenem in anti-MSSA than BisEDT more effectively (MIC90=0.03 μ g/mL).But, MRSA and CAMRSA to Imipenem resistance, and BisEDT demonstrate with to the activity be equal to shown in MSSA.BisEDT is to methicillin-susceptible and methicillin resistant Staphylococcus epidermidis (MSSE and MRSE) high activity, and MIC90 value is respectively 0.12 μ g/mL and 0.25 μ g/mL.BisEDT other test agent any in anti-MSSE than except Imipenem more has activity.BisEDT is the most activated anti-MRSE agent of test.
BisEDT is presented at the activity that anti-vancocin sensitive Enterococcus faecalis (VSEfc) aspect is equal to Daptomycin, vancomycin and Imipenem, and MIC90 value is 2 μ g/ml.Obviously, BisEDT is the most activated vancomycin resistant enterococcus faecalis (VREfc) agent of test, and MIC90 value is 1 μ g/mL.
BisEDT resists vancomycin sensitive Enterococcus faecium (VSEfm) pole activity, and MIC90 value is 2 μ g/mL; Its activity is equal to or is similar to Daptomycin and a dilution factor higher than the activity of vancomycin.BisEDT and Linezolid are the most activated anti-Enterococcus faecium (VREfm) agent of test, show the MIC90 value of 2 μ g/mL separately.The activity (MIC90 value is 0.5 μ g/mL) of the anti-micrococcus scarlatinae of BisEDT is equal to vancomycin, is greater than Linezolid and is slightly less than Daptomycin and cefotaxime.This compound inhibits all test strain when 0.5 μ g/mL or lower concentration.In these researchs, to BisEDT the most insensitive kind be Streptococcusagalactiae, the MIC90 value wherein observed is 16 μ g/mL.The all test substances of specific activity except gentamicin of BisEDT are all low.
BisEDT shows with the activity of the Gram-negative bacteria compared included by agent antagonism the BisEDT effect (MIC90 value is 2 μ g/mL) resisting Acinetobacter baumannii, makes BisEDT become the most activated test compounds.Relatively agent causes these agent not conform to the MIC90 value of scale for the MICs of the raising of a large amount of test separated strain.BisEDT is the most effective Escherichia coli inhibitor, suppresses all bacterial strains when 2 μ g/mL or lower concentration (MIC90=2 μ g/mL).The specific activity Imipenem of this compound is low, but higher than cefotaxime, Ciprofloxacin and gentamicin.BisEDT also demonstrates the activity of antagonism pneumobacillus, and MIC90 value is 8 μ g/mL, this equates Imipenem.The relative high MIC90 value instruction that Imipenem, cefotaxime, Ciprofloxacin and gentamicin show this be the microorganism group of height antibiotic resistance.BisEDT is the most effective resisting pseudomonas aeruginosa agent in test compounds, and MIC90 value is 4 μ g/mL.For this test separated strain group, there is the high-level resistance to comparing agent.
In a word, BisEDT show needle to the broad ranges of efficacy of multiple clinical separation strains representing multiple kinds, comprise usually to the kind relevant with skin structure infection with chronic skin acute in people.BisEDT and the crucial activity comparing agent are assessed for 723 clinical separation strains of gram-positive bacteria and Gram-negative bacteria.BT compound demonstrates broad spectrum of activity, and for the many test microbes in this research, BisEDT is the most effective in test compounds in antibacterial activity.BisEDT resists MSSA, MRSA, CA-MRSA, MSSE, MRSE and micrococcus scarlatinae is the most effective, and wherein MIC90 value is 0.5 μ g/mL or lower.Also demonstrate the powerful activity to VSEfc, VREfc, VSEfm, VREfm, Acinetobacter baumannii, Escherichia coli and pseudomonas aeruginosa, wherein MIC90 value is within the scope of 1-4 μ g/mL.Observe the MIC value for Klebsiella Pneumoniae (MIC90=8 μ g/mL) and Streptococcusagalactiae (MIC90=16 μ g/mL).
Embodiment 8
Particles B T-antibiotic strengthens and synergistic activity
The present embodiment display particulate bismuth-mercaptan (BT) promotes antibacterial activity by enhancing and/or cooperative interaction.
When treatment is infected, main exacerbation factor is that resistance appears in bacterial antibiotic.Methicillin resistant in Staphylococcus epidermidis (MRSE) and staphylococcus aureus (MRSA) in fact reflects Multidrug resistance, makes these pathogene be difficult to eradicate.But, from the bacterial strain of hundreds of test, there is no the resistance of staphylococcus display to BT.In addition, sub-(subMIC) concentration that suppresses reduces some important antibiotic resistances.
staphylococcus aureus.SubMIC bismuth dithioglycol (BisEDT) illustrating (Fig. 4) the sensibilization of the antibiotic of MRSA-is again provided, show some antibiotics, comprise the antibiotic effect of the enhancing of gentamicin, Cefazolin, Cefepime, Imipenem, Sulfamethoxazole and lavo-ofloxacin.Therefore, the most of antibiotic activity of the non-specific enhancing of BisEDT.
Use the antimicrobial Study of Sensitivity (table 18) of broth dilution that some antibiotic combined with the BisEDT of subMIC level carry out for 12 kinds of MRSA bacterial strains.Both biomembrane prevention concentration (BPC) and minimal inhibitory concentration (MIC) is measured in particular organisms Membrance cuiture base (BHIG/X).MIC and BPC of gentamicin and Cefazolin is reduced by subMICBisEDT (BisEDTMIC, 0.2-0.4 μ g/ml), but not below susceptibility flex point.SubMICBisEDT Enhanced MR SA is to close to the gatifloxacin of susceptibility flex point and the MRSA susceptibility of Cefepime.These bacterial strains are to vancomycin sensitive, but all the more so when there is subMICBisEDT.Usually, MIC and BPC2 to 5 times is reduced with subMICBisEDT.
Table 18.
bT-antibiotic composition is to the antimicrobial acivity of MRSA
12 kinds of MRSA clinical isolates are grown on BHIG/X and are exposed in the antibiotic of the serial dilution that there is 0-0.1 μ g/mlBisEDT.MIC and BPC calculated with μ g/ml is the mean value ± standard deviation from least three tests.Right-hand column lists the standard MIC of antibiotics sensitivity (S) and resistance (R)
The broth dilution research of Cefepime resistance MRSA separated strain is shown in table 19.The BisEDT of 0.1 μ g/ml strengthens the Cefepime inhibit activities of 11 in 12 separated strains significantly.In this particular studies, data show the concertedness of many separated strains between BisEDT and Cefepime (FIC<0.5) at susceptibility flex point place.
Table 19
cefepime resistance MRSA is by BisEDT sensitization
In the BHIG/X medium of XPS, the susceptibility 48h of the Cefepime that 12 Cefepime resistance MRSA couple and subMICBisEDT combine is tested at 37 DEG C.
Table 20 is shown in the result of celbenin or gentamicin combination research.The BisEDT (0.2 μ g/ml) combined with celbenin reduces the MIC90 of celbenin to MRSA and reaches (FIC, 0.74) more than 4 times.The BisEDT combined with gentamicin reduces gentamicin to the MIC90 of MRSA more than 10 times (FIC, 0.6).BT has reversed the gentamicin resistance separated strain of whole four kinds of tests to the resistance [Domenico etc., 2002] of clinical respective concentration.Substantially the MIC of these antimicrobials, particularly gentamicin is reduced.Meat soups for these researchs are the trypticase soy broth (TSB) containing 2% glucose, result of its display in the Mueller-HintonII meat soup that with the addition of 1% sheep blood see the similar of result.
Table 20
mRSA: celbenin or gentamicin+BisEDT concertedness
NAF or GM, μ g/ml; The BE of 0.2 μ g/ml
staphylococcus epidermidis.the existence of BisEDT promotes most of antibiotic activity.About BPC, when combining with BisEDT, clindamycin and gatifloxacin show antibiont film activity (Fig. 5) stronger to Staphylococcus epidermidis significantly.With the statement of different terms, when there is subMICBisEDT, the BPC for clindamycin, gatifloxacin and gentamicin reduces by 50 times, 10 times and 4 times respectively.
Notice and to prevent in concentration (BPC) only moderate to reduce for minocycline, vancomycin and Cefazolin at biomembrane, and remain unaffected at 0.05 μ g/mlBisEDT rifampin and celbenin.Do not detect biomembrane at 0.1 μ g/mlBisEDT, no matter whether adopt antibiotic, show do not have antagonism to occur.This BisEDT concentration for Staphylococcus epidermidis close to MIC [Domenico etc., 2003] (see Fig. 5).
About growth inhibition, exist in the antibiotic of 8 tests during 0.1 μ g/ml (0.5 μ Μ) BisEDT and have 7 to strengthen antagonism Staphylococcus epidermidis (Fig. 6) significantly.Change the most obvious for clindamycin and gentamicin MIC, be secondly vancomycin, Cefazolin, minocycline, gatifloxacin and celbenin, rifampin is unaffected.This bacterial strain is in the antibiotic (NC, CZ, GM, CM) of resistance to it, and only the resistance of Cefazolin is reversed to clinical respective horizontal by BisEDT.
The antibiotic tested for great majority and subMICBisEDT reduce slightly to the staphylococcic minimum bactericidal concentration of epidermis (MBC).Gentamicin shows large MBC and reduces (4 to 16 times), secondly be Cefazolin (4 to 5 times), vancomycin and celbenin (3 to 4 times), minocycline and gatifloxacin (2 to 3 times), and the MBC of clindamycin and rifampin keep substantially constant.Clindamycin is bacteriostatic agent, and this illustrates that it lacks bactericidal activity.Cefazolin resistance is reversed for MBC [Domenico etc., 2003].These effects are accumulations.
In the synergistic effect (table 21) in vivo also demonstrating antimicrobial of graft infection rat model.The BisEDT level being low to moderate 0.1 μ g/ml can promote to prevent anti-Staphylococcus epidermidis biomembrane 7 days.
As table 21 summarize, with 0.1 μ g/mlBisEDT, 10 μ g/mlRIP and 10 μ g/ml rifampins dipping implant, the rat of implanted s.c. alone or in combination.Use tuberculin syringe will with 2 × 10 7the physiological solution (1ml) that cfu/ml contains MS and MR bacterial strain is inoculated into graft surface.All grafts after the transfer 7 days time be moved out of and in sterile saline solution ultrasonic 5 minutes with remove adhere to bacterium.The quantitative of bacterium alive is obtained by cultivating dilution on blood agar plate.Detectable limit is approximately 10cfu/cm 2.
Table 21
staphylococcus epidermidis in RIP, BT and the anti-graft infection model of rifampin
aeach group has 15 animals; MS, methicillin-susceptible Staphylococcus epidermidis; MR, methicillin resistant Staphylococcus epidermidis
bby the impregnated Dacron graft segment of 0.1mg/lBT, 10mg/lRIP, 10mg/l rifampin
cthe statistically significant when comparing with control group MS with MR
dstatistically significant when compared with MS3 group
ethe statistically significant when comparing with MR3 group with MR1, MR2
gram-negative bacteria.The activity subMICBisEDT of tobramycin antagonism pseudomonas aeruginosa strengthens several times (table 22).In these trials, more properly MIC is defined as IC 24.
Table 22
tobramycin resistance pseudomonas aeruginosa: BisEDT effect
When there is tobramycin (NN) and BisEDT (BE:0.33 μ g/ml), the resistant strain of pseudomonas aeruginosa is incubated at Mueller-HintonII meat soup at 37 DEG C.MIC is determined as the antibiotic concentration that prevention 24 ± 1h grows.
0.4 μ g/mlBisEDT makes in 10 separated strains 7 to tobramycin resistance Burkholderia cepacia tobramycin sensitivity (mean F IC:0.48), and reduces MIC 90reach 10 times (table 23).MIC and MBC is reduced significantly to reach the level [Veloira etc., 2003] of the clinical Burkholderia cepacia separated strain of opposing 50 with subMICBisEDT.BisEDT and the tobramycin high Collaboration opposing pseudomonas aeruginosa of liposomal form are proved.(Halwani etc., 2008; Halwani etc., 2009).
Table 23
tobramycin and BisEDT resist Burkholderia cepacia
athree bacterial strains suppressed by the BisEDT of 0.4 μ g/ml are got rid of from study further.FIC index≤0.5 represents concertedness: FICI>0.5 and <1.0 represents enhancing.
Make chloramphenicol and ampicillin resistant Escherichia coli to these medicaments insensitives (table 24) by adding subMICBisEDT.
Table 24
chloramphenicol/ampicillin resistant Escherichia coli: BisEDT effect
Colibacillary resistant strain is incubated in Mueller-HintonII meat soup at 37 DEG C existing alone or in combination under chloramphenicol (CM) or ampicillin (AMP) and BisEDT (BE:0.33 μ g/ml).MIC is determined as the antibiotic concentration suppressing long-living 24 ± 1h.
Make tetracyclin resistance Escherichia coli responsive to Doxycycline by adding subMICBisEDT (table 25).Described combination show needle, to the concertedness of TETM and TETD bacterial strain (FIC≤0.5), has the summation action for TETA and TETB bacterial strain.
Table 25
tetracyclin resistance Escherichia coli: BisEDT effect
E. coli resistance bacterial strain 37 DEG C is incubated in Mueller-HintonII meat soup existing alone or in combination under Doxycycline (DOX) and BisEDT (BE:0.33 μ g/ml).MIC is determined as the antibiotic concentration of Developing restraint 24 ± 1h.
bibliography:
DomenicoP,RO'Leary,BACunha.1992.DifferentialeffectofbismuthandsalicylatecompoundsonantibioticsensitivityofPseudomonasaeruginosa.EurJClinMicrobiolInfecDis11:170-175；DomenicoP,DParikh,BACunha.1994.Bismuthmodulationofantibioticactivityagainstgastrointestinalbacterialpathogens.MedMicrobiolLett3:114-119；DomenicoP,KazzazJA,DavisJM,NiedermanMS.2002.Subinhibitorybismuthethanedithiol(BisEDT)sensitizesresistantStaphylococcusaureustonafcillinorgentamicin.AnnualMeeting,ASM,SaltLakeCity,UT；DomenicoP,KazzazJA,DavisJM.2003.Combatingantibioticresistancewithbismuth-thiols.ResearchAdvancesinAntimicrobAgentsChemother3:79-85；DomenicoP,EGurzenda,AGiacometti,OCirioni,RGhiselli,FOrlando,MKorem,VSaba,GScalise,NBalaban.2004.BisEDTandRIPactinsynergytopreventgraftinfectionsbyresistantstaphylococci.Peptides25:2047-2053；HalwaniM,BlommeS,SuntresZE,AlipourM,AzghaniAO,KumarA,OmriA.2008.Liposomalbismuth-ethanedithiolformulationenhancesantimicrobialactivityoftobramycin.IntlJPharmaceut358:278-84；HalwaniM,HebertS,SuntresZE,LafrenieRM,AzghaniAO,OmriA.2009.Bismuth-thiolincorporationenhancesbiologicalactivitiesofliposomaltobramycinagainstbacterialbiofilmandquorumsensingmoleculesproductionbyPseudomonasaeruginosa.IntJPharmaceut373:141-6；VeloiraWG,GurzendaEM,DomenicoP,DavisJM,KazzazJA.2003.SynergyoftobramycinandbismuththiolsagainstBurkholderiacepacia.JAntimicrobChemother52:915-919.
Embodiment 9
Particles B T-antibiotic strengthens and synergistic activity
The present embodiment display particulate bismuth mercaptan BisEDT is by promoting antibacterial activity with for the organic concrete antibiotic enhancing of concrete microorganism target and/or cooperative interaction.Respective one point data is shown according to the combination in the method used in embodiment 8 substantially generation table 26.
Table 26
for the FICI value of single-point BisEDT-antibiotic composition
SA, staphylococcus aureus; MRSA, methicillin resistant S staphylococcus; EFc, enterococcus faecalis; SP, streptococcus pneumonia; PRSP, Penicillin Resistant S streptococcus; EC, Escherichia coli; KP, Klebsiella Pneumoniae; PA, pseudomonas aeruginosa; Bcep, Burkholderia cepacia; Bmult, bites burkholderia more; Abau, Acinetobacter baumannii; Msmeg, smegmatis mycobacterium.
Embodiment 10
Particles B T-antibiotic strengthens and synergistic activity
The compound action of other reagent of the representative strains of particles B is-EDT and the four kind of Bis-EDT analog that test is prepared as mentioned above and anti-some gram negative pathogenic bacterium.The General Purpose Laboratory method improved is used to measure the concertedness (FICI≤0.5) utilizing FIC (FIC) and FIC index (FICI), strengthen (0.5<FICI≤1.0), Antagonism (FICI>4.0) and indifference (1.0<FICI≤4.0) (EliopoulosGandRMoellering.1991.Antimicrobialcombinations .InAntibioticsinLaboratoryMedicine, 3rd edition, VLorian. Williams and Wilkins is edited, Baltimore, MD, 432-492 page, Odds, 2003J.Antimicrob.Chemother.52 (1): 1).Checkerboard is used to measure FIC index and adopt in this study.
Table 27
fractions tested
The stoste of all test article is prepared as the 40 × final goal concentration in appropriate solvent.In all test article solution under these conditions.Final drug concentration in FIC analysis plates is set as that each reagent comprised is to the MIC value of each test microbes, unless bacterial strain is to test agent complete resistance.The concentration range of test is shown in table 27.Organism is original is accepted in clinical source in test, or from the biological product collecting center of Unite States Standard.During reception, separator is scoring on Tryptic Soy Agar II (TSA).Clone from these plates results and prepare cell suspending liquid in the suitable broth growth medium comprising cryoprotector.Then the serving such as freezing at-80 DEG C.The freezing seed of microorganism to be tested in given analysis is thawed, separator is scoring on TSA plate, and hatches at 35 DEG C.The all microorganisms of test in MuellerHintonII meat soup (BectonDickinson, lot number 9044411).Prepare meat soup with 1.05 × normal weight/volume, thus compensate the medicine of 5% volume in final test plate.
The broth microdilution of aerobic bacteria is used to measure minimal inhibitory concentration (MIC) value (ClinicalandLaboratoryStandardsInstitute (CLSI) .MethodsforDilutionAntimicrobialSusceptibilityTestsforBa cteriaThatGrowAerobically in advance; ApprovedStandard-the 8th edition.CLSI file M07-A8 [ISBN1-56238-689-1] .ClinicalandLaboratoryStandardsInstitute, 940WestValleyRoad, Suite1400, Wayne, Pennsylvania19087-1898USA, 2009).
The broth microdilution (Sweeney etc., 2003Antimicrob.AgentsChemother.47 (6): 1902-1906) described before use measures FIC value.For preparing test board, use automated fluid processor (Multidrop384, Labsystems, Helsinki, Finland; Biomek2000andMultimek96, BeckmanCoulter, FullertonCA) carry out serial dilution and liquid transfer.
Use Multidrop384 in 2-12 row, solvent suitable for 150 μ L is inserted in the appropriate well of the micro-dilution plate (Falcon3918) in standard 96-hole.Each for 300 microlitres the second testing drug is added in each hole of plate the 1st row.For drug regimen plate, use these plates to prepare the medicine " motherboard " that continuous drug dilution is provided.Use Biomek2000 to shift each second drug solution (40 ×) of 150 μ L from the hole of the 1st row of motherboard, and carry out 11 2 times of serial dilutions.Use multichannel pipette, manually by the motherboard serial dilution from the top to bottom of Bis-EDT (and analog).Two pieces of motherboards (one piece for each second medicine and one piece for Bis-EDT (or analog)) are combined to form " checkerboard " pattern to drug regimen plate by transfer equal-volume (use multichannel pipette).Capable and each self-contained serial dilution of independent a kind of reagent measured for MIC of 12 row of H.
Use Multidrop384 to load 180 μ L test media at " daughter board ", then, use Multimek96 to shift 10 μ L drug solutions from each hole of drug regimen motherboard to daughter board separately corresponding hole in a separate step.Finally, daughter board is inoculated by test microbes.The standardized kind of bacterium of each microorganism is prepared according to disclosed guide (CLSI, 2009).For all separators, the kind bacterium of each microorganism is distributed to the aseptic storage center split by length (BeckmanCoulter), and uses Biomek2000 to inoculate plate.Instrument delivery 10 μ L standardized kind of bacterium to each hole to produce about 5 × 10 in daughter board 5the final cell concentration of colony-forming units/mL.
In establishment 8 × 12 checkerboard, produce test lattice, wherein with the drug concentration of change than coming independent (the 12nd row capable of H) and each compound of combined test.All microorganism sheetpiles fold three height, top board covers with lid, puts into plastic sack, and hatch about 20 hours at 35 DEG C.After hatching, from incubator, remove microplate and use ScienceWare plate reader to observe from bottom.The hole of the MIC (H is capable) of the medicine 1 of the reading card of mark preparation, the MIC (12 row) of medicine 2 and growth-non-growth interface.
Excel program is used to measure the MIC of the independent compound 1 of the MIC/ of the compound 1 of FIC:(combination according to following formula)+(MIC of the compound 2 that the MIC/ of the compound 2 of combination is independent).FIC passing type by independent: (FIC 1+ FIC 2+ ... FIC n)/n calculates the FICI of checkerboard, and wherein n=calculates the quantity in the single hole of every block plate of FICs.When single reagent produces underproof MIC result, the height concentration of next is used as the MIC value in FIC calculating.
Particles B isEDT, four kinds of particles B T analogs and all other reagent (with the combination of reagent) be solvable in all final test concentration.MIC and the FICI value measured is shown in following table.
Table 28
for minimal inhibitory concentration and the FIC result of MB-1B-3 and Piperacillin gather
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 29
for the minimal inhibitory concentration of MB-1B-3 and AZT and FIC result gather
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 30
the minimal inhibitory concentration of MB-15 and Piperacillin and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 31
the minimal inhibitory concentration of MB-15 and AZT and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 32
the minimal inhibitory concentration of MB-8-2 and Piperacillin and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 33
the minimal inhibitory concentration of MB-8-2 and AZT and gathering of FIC result
1mIC, minimal inhibitory concentration
2flCI, FICI
Table 34
the minimal inhibitory concentration of MB-11 and Piperacillin and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 35
the minimal inhibitory concentration of MB-11 and AZT and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 36
the minimal inhibitory concentration of MB-2B and Piperacillin and gathering of FIC result
11mIC, minimal inhibitory concentration
2fICI, FICI
Table 37
the minimal inhibitory concentration of MB-2B and AZT and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 38
the minimal inhibitory concentration of MB-1B-3 and cefotaxime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 39
the minimal inhibitory concentration of MB-1B-3 and Cefepime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 40
the minimal inhibitory concentration of MB-15 and cefotaxime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 41
the minimal inhibitory concentration of MB-15 and Cefepime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 42
the minimal inhibitory concentration of MB-8-2 and cefotaxime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 43
the minimal inhibitory concentration of MB-8-2 and Cefepime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 44
the minimal inhibitory concentration of MB-11 and cefotaxime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 45
the minimal inhibitory concentration of MB-11 and Cefepime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 46
the minimal inhibitory concentration of MB-2B and cefotaxime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 47
the minimal inhibitory concentration of MB-2B and Cefepime and gathering of FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Embodiment 11
Bismuth mercaptan is to the effect of the infection in the critical defect of rat femur
The current standard of open fracture nursing is flushing, debridement and antibiotic; Its objective is that the degree infected extremely does not occur the bacterial loads reduced in wound.Although there are these to treat, open tibial fracture is infected to the severity still worsening and reach 75%.What is interesting is, even if usually cause early infection by Gram-negative bacteria, also can relate to the later infections Gram-positive infection due to of healing problem and excision, usual staphylococcus kind (Johnson2007).
One of reason of the anti-standard care of staphylococcus aureus is that they can form biomembrane.Bacterium in biomembrane can be resisted the Antimicrobe compound (Costerton1987) of the similar microorganism killed in medium.
The object of this research measures BT or independently or the infection of whether will fall in oligosaprobic open fracture model with antibiotic.The rat femur critical defective model polluted is good Acceptance Model and for the experiment described in the present embodiment.This model is provided for more various potential treatment and infects reduction and/or improve the standardized model of the effect of curing.
Compound (CPD) CPD-8-2 (bismuth pyrithione/succinimide mercaptans: table 1) and CPD-11 (bismuth pyrithione/dithioglycol: table 1) has shown the two kinds of BIS-BiS analogs resisting the bacterium potential that in vitro biomembrane is concealed, although activity profile is different from Bis-EDT.
When with when not using with the tobramycin in polymethyl methacrylate (PMMA) adhesive pearl medium and vancomycin, three kinds of BT preparations, the inhibitory action of Bis-EDT, CPD-11 and CPD-8-2 (see table 1) display to sv staphylococcus aureus.Three kinds of particles B T preparations are produced as hydrogel gel form useful clinically as herein described.By these BT with 5mg/ml -1concentration be suspended in gel and test, found that this concentration is the debita spissitudo that gel is sent.Gel preparation is laminating in wound profile, does not need to remove after application.
Use two treatment groups (treatmentarm): in the first set, be used alone BT; In the second set, BT and systemic antibiotics (ABx) is used.
A () BT is independent.
Cultivate latter six hours with staphylococcus aureus, remove wound, with normal saline washing and by 1mlBT gel insertion breach.
(b) BT and systemic antibiotics (ABx).
Cultivate latter six hours with staphylococcus aureus, remove wound, the BT gel added with normal saline washing and by 1ml inserts in breach.The antibiotic used is for being equivalent to 5mgKg -1the Cefazolin of dosage, through by hypodermic injection twice daily totally 3 days after damage.The first dosage is used immediately before removing.Data in the past show this dosage and bacteria levels will be caused by ≈ 10 6be reduced to ≈ 10 4, therefore still allow the dependent interaction of different B T to be measured.
C () contrasts
Cultivate latter six hours with staphylococcus aureus, remove with salt solution and irrigate.Also treat control-animal in the manner described above with Cefazolin.
Program:
The program of in vivo Damage of Rats model is carried out as described in Chen etc.(2002J.Orthop.Res.20:142；2005J.Orthop.Res.23:816；2006J.BoneJointSurg.Am.88:1510；2007J.Orthop.Trauma21:693)。Rat anesthesia is made arrangements for surgery.By Outboard Sections before 3cm cut channel exposure femur backbone.Periosteum and appended muscle are peeled off from bone.Acetyl substrate (27 × 4 × 4mm) will be gathered be put on the anterolateral surface of femur.Preboring orifice plate is to accept the wire kirschner wire of 0.9mm diameter.Form the matrix of these plates with the profile of applicable femur backbone.Use plate as template, pilot hole to be drilled through two shells of femur, and wire kirschner wire is inserted through plate and femur.Otch from plate 6mm is used as bone removing guide.Use little reciprocating saw to produce defect, to make great efforts prevention fire damage, tissue is cooled by continuous flushing simultaneously.
With 1 × 10 5the staphylococcus aureus of CFU inoculates each 10 animals of some groups, and after cultivating as mentioned above with BT separately or treat 6 hours with antibiotic combination.Organize as follows: Bis-EDT gel; MB-11 gel; MB-8-2 gel; Bis-EDT gel & Abx; MB-11 gel & Abx; MB-8-2 gel & Abx; Contrast (Abx is independent).
Post operation 14 days anesthetized animals, send to microbiological analysis by bone and hardware, the results are shown in Fig. 7.
Based on efficiency analysis, often organize 10 animals and will provide effect of 80% with the difference detecting between treatment and control group 25%.This supports the expection standard deviation of 35% and the α of 0.05.
As shown in Figure 7, the Cefazolin combined with Bis-EDT, MB-11 and MB-8-2 enhances antibacterial activity to reduce the infection of staphylococcus aureus of the bone damaged relative to Cefazolin or independent Bis compound.Compared with independent Cefazolin, the Cefazolin combined with MB-11 and MB-8-2 shows the antibacterial activity that strengthens to reduce the infection of staphylococcus aureus that hardware detects.Bis-EDT seems not affect the activity of Cefazolin in this.
Embodiment 12
Bismuth-containing compound resists halobiontic activity
This embodiment describes the antimicrobial acivity of bismuth-containing compound.The conventional method implemented by those skilled in the art measures the MIC value that three kinds of bismuth-containing compounds such as bismuth dimercaprol dimercaptopropanol (BisBAL), bismuth dimercapto toluene (BisTOL) and bismuth dithioglycol (BisEDT) resist three kinds of different marine bacterias.Data are shown in following table:
BT compound (μ g/ml) BisBAL BisTOL BisEDT
Vibrio alginolyticus (V.alginolyticus) 3.1 1 0.1
Seawater Halomonas (H.marina) 17.5 7.2 2.6
Except hydrocarbon sea bacillus (M.hydrocarbonoclasicus) 2 0.4 .28
Embodiment 13
Bismuth-containing compound is to the effect of barnacle attachment behavior
Compound, BisBAL and BisTOL is included in determination method to measure the inhibit activities of each compound to kentrogon attachment behavior.The technology that method is put into practice according to this area is carried out.BisBAL has the EC of 1.6ppm 50(producing the concentration that 50% attachment suppresses), and BisTOL has the EC of 15.4ppm 50.In another experiment, BisEDT be directly dissolved in natural sea-water or be first dissolved in DMSO, being then diluted in natural sea-water.EC 50measured value has significant difference.When being directly dissolved in seawater, BisEDT has the EC of 1.5ppm 50, and when being first dissolved in DMSO, it has the EC of 2.1ppm 50.Commercial insecticide, the EC of SEANINE211 50for 0.5ppm.
Embodiment 14
The impact that bismuth-containing compound adheres to marine alga
Measure the impact that three kinds of bismuth-containing compounds such as bismuth dimercaprol dimercaptopropanol (BisBAL), bismuth dimercapto toluene (BisTOL) and bismuth dithioglycol (BisEDT) adhere to marine alga, particularly each compound suppresses the ability that Enteromorpha spore (Enteromorphaspore) germinates.Each compound is tested under 0.001,0.01,0.1,1.0 and 10.0 μ g/ml.BisEDT is most compounds effective, under 1 μ g/mlBisEDT, suppresses the marine alga spore population of about 50% to be germinateed, and under 10 μ g/ml, suppresses about 75% marine alga spore-germination.The spore-germination of BisBAL and BisTOL to this specific seaweed species of 10 milligrams/ml does not have inhibitory action at the most.
Embodiment 15
The impact that bismuth-containing compound adheres to marine alga
Three kinds of bismuth-containing compounds such as bismuth dimercaprol dimercaptopropanol (BisBAL), bismuth dimercapto toluene (BisTOL) and bismuth dithioglycol (BisEDT) are measured to the growth of marine diatom according to the technology that this area is implemented.The attachment (diatom/visual field) of marine diatom is suppressed by the concentration (0.001,0.01,0.1,1.0 and 10.0 μ g/ml) increasing by three kinds of compounds respectively.Under 0.1 μ g/ml, each compounds exhibit goes out inhibit activities; BisEDT is the most active, and its display about 100% suppresses.Under 0.1 μ g/ml, BisTOL and BisBAL shows the marine diatom attachment of about 30% separately.
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Above-mentioned various embodiment capable of being combined is to provide other embodiments.By reference to its entirety by relate in this specification and/or all United States Patent (USP)s, U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and the non-patent listed in application data page be openly incorporated to herein.If need to adopt various patent, application and disclosed design to carry out each side of revision for execution scheme to provide other other embodiments.
Can be carried out these and other to embodiment according to above-mentioned detailed description to change.Usually, in following claims, the term used should not be construed as claim is limited to specific embodiments disclosed in specification and claim, and should be interpreted as all possible embodiment that comprises together with whole equivalency range of this claim defined.Therefore, claim not limited by disclosure.

Claims (45)

1., for a method for directed toward bacteria, fungi or viral pathogen protective plant, it comprises:
Bismuth-mercaptan (BT) composition of described plant and effective dose one or more condition below being enough to meet is contacted with under the time:
I () prevents described plant to be infected by described bacterium, fungi or viral pathogen,
(ii) described bacterium, the cell viability of planktonic cells of fungi or viral pathogen or Growth of Cells is suppressed,
(iii) suppress by the biofilm formation of described bacterium, fungi or viral pathogen, and
(iv) described bacterium, the biomembrane vigor of biomembrane form cell of fungi or viral pathogen or biofilm development is suppressed,
Wherein said BT composition comprises the single dispersing suspended matter of solia particle, the single dispersing suspended matter of described solia particle comprises BT compound, described BT compound is not micronized, grinds or does not experience supercritical fluid processing, and described particulate has the volume mean diameter of 0.4 μm to 10 μm
Wherein said BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.
2. method according to claim 1, wherein said bacterial pathogens comprises fire blight of pear bacterial cell.
3. method according to claim 1, wherein said bacterial pathogens is selected from erwinia amylovora, xanthomonas campestris nieffea picta pvs oryzae and oryzicola, pseudomonas syringae, xyllela fastidiosa, vine wood friend bacterium, Monilinia fructicola, P.stwartii subsp.stewartii, Ralstonia solanacearum and Potato Ring Rot.
4. method according to claim 1, wherein said bacterial pathogens shows antibiotic resistance.
5. method according to claim 1, wherein said bacterial pathogens shows streptomycin resistance.
6. method according to claim 1, wherein said plant is food crops.
7. method according to claim 6, wherein said food crops is fruit tree.
8. method according to claim 7, wherein said fruit tree is selected from apple tree, pear tree, peach, Japanese plum, apricot.
9. method according to claim 7, wherein said fruit tree is selected from nectarine tree.
10. method according to claim 6, wherein said food crops is the Banana tree of Musa.
11. methods according to claim 6, wherein said food crops is the plant being selected from tuberous plant, leguminous plant and graminaceous cereals plant.
12. methods according to claim 11, wherein said tuberous plant is selected from potato and sweet potato.
13. methods according to claim 1, wherein said contact procedure carries out one or many.
14. methods according to claim 13, wherein at least one contact procedure comprises spraying, floods, applies and smear one in described plant.
15. methods according to claim 13, wherein described plant, the flowers are in blossom puts, tender shoots or growth position place carry out at least one contact procedure.
16. methods according to claim 13, wherein on described plant, the flowers are in blossom first time carries out at least one contact procedure in put 72 hours.
17. methods according to claim 13, wherein on described plant, the flowers are in blossom first time carries out at least one contact procedure in put 48 hours.
18. methods according to claim 13, wherein on described plant, the flowers are in blossom first time carries out at least one contact procedure in put 24 hours.
19. methods according to any one of claim 1-18, it to comprise with described plant and described BT composition contact procedure simultaneously or successively and with any order further, makes described plant and to work in coordination with or enhancement antibiotic contacts.
20. methods according to claim 19, wherein said collaborative or enhancement antibiotic comprises and is selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.
21. methods according to claim 20, wherein said collaborative or enhancement antibiotic is selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
22. 1 kinds for wherein or overcome the method for antibiotic resistance in the plant it existing antibiotic resistance bacterium phytopathogen, it comprises:
(a) below being enough to meet one or more condition and make the BT composition of described plant contact effective dose under the time:
I () prevents described plant by described antibiotic resistance bacterium pathogenic infection,
(ii) cell viability or the Growth of Cells of the planktonic cells of antibiotic resistance bacterium pathogene is suppressed,
(iii) suppress by the biofilm formation of described antibiotic resistance bacterium pathogene, and
(iv) biomembrane vigor or the biofilm development of the biomembrane form cell of described antibiotic resistance bacterium pathogene is suppressed,
Wherein said BT composition comprises the single dispersing suspended matter of solia particle, the single dispersing suspended matter of described solia particle comprises BT compound, described BT compound is not micronized, grinds or does not experience supercritical fluid processing, and described particulate has the volume mean diameter of 0.5 μm to 10 μm; And
B () and described plant and described BT composition contact procedure simultaneously or successively and with any order, make described plant and to work in coordination with or enhancement antibiotic contacts,
Wherein said BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.
23. methods according to any one of claim 1-18 or 20-22, wherein said bismuth-composition of mercaptans comprises multiple solia particle, described multiple solia particle comprises bismuth-mercaptan (BT) compound, described particulate has the volume mean diameter of 0.4 μm to 5 μm, and is produced by the process comprised the following steps:
(a) be enough to obtain not containing the solution of solids of sedimentation condition and mix under the time: (i) comprise bi concns at least 50mM bismuth salt and containing the acidic aqueous solution of hydrophily, polarity or organic solubilized agent, be enough to obtain the ethanol of the amount of the mixture comprising 25% ethanol by volume with (ii); With
(b) be enough to be formed the particulate comprised containing described BT compound precipitation condition and under the time, in the mixture of (a), add the ethanolic solution that comprises containing the compound of mercaptan to obtain reaction solution, the wherein said compound containing mercaptan exists with the mol ratio relative to bismuth 1:3 to 3:1 in described reaction solution.
24. methods according to claim 19, wherein said bismuth-composition of mercaptans comprises multiple solia particle, described multiple solia particle comprises bismuth-mercaptan (BT) compound, described particulate has the volume mean diameter of 0.4 μm to 5 μm, and is produced by the process comprised the following steps:
(a) be enough to obtain not containing the solution of solids of sedimentation condition and mix under the time: (i) comprise bi concns at least 50mM bismuth salt and containing the acidic aqueous solution of hydrophily, polarity or organic solubilized agent, be enough to obtain the ethanol of the amount of the mixture comprising 25% ethanol by volume with (ii); With
(b) be enough to be formed the particulate comprised containing described BT compound precipitation condition and under the time, in the mixture of (a), add the ethanolic solution that comprises containing the compound of mercaptan to obtain reaction solution, the wherein said compound containing mercaptan exists with the mol ratio relative to bismuth 1:3 to 3:1 in described reaction solution.
25. methods according to claim 23, wherein said bismuth salt is Bi (NO 3) 3.
26. methods according to claim 24, wherein said bismuth salt is Bi (NO 3) 3.
27. methods according to claim 23, wherein said acidic aqueous solution comprises 5%, 10%, 15%, 20%, 22% or 22.5% bismuth by weight.
28. methods according to claim 24, wherein said acidic aqueous solution comprises 5%, 10%, 15%, 20%, 22% or 22.5% bismuth by weight.
29. methods according to claim 23, wherein said acidic aqueous solution comprises 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid by weight.
30. methods according to claim 24, wherein said acidic aqueous solution comprises 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid by weight.
31. methods according to claim 23, the wherein said compound containing mercaptan comprises and is selected from one or more following reagent: 1,2-dithioglycol; 2,3-dimercaprol dimercaptopropanol; PTO; Dithioerythritol; 3,4-dimercapto toluene; 2,3-succinimide mercaptans; 1,3-dimercaptopropane; 2-hydroxyl propanethiol; 1-sulfydryl-2-propyl alcohol; Alpha-lipoic acid; Dithiothreitol (DTT); Methyl mercaptan (CH 3sH [m-mercaptan]); Ethyl mercaptan (C 2h 5sH [e-mercaptan]); 1-propanethiol (C 3h 7sH [n-P mercaptan]); 2-propanethiol (CH 3cH (SH) CH 3[2C 3mercaptan]); Butyl mercaptan (C 4h 9sH ([n-butanethiol]); Tert-butyl mercaptan (C (CH 3) 3sH [t-butanethiol]); Amyl hydrosulfide (C 5h 11sH [amyl mercaptan]); Coacetylase; Lipoamide; Glutathione; Cysteine; Cystine; 2 mercapto ethanol; 2-sulfydryl indole; TGase; (11-mercapto-undecanoic base) six (ethylene glycol); (11-mercapto-undecanoic base) four (ethylene glycol); The golden nanometer particle that (11-mercapto-undecanoic base) four (ethylene glycol) are functionalized; 1,1', 4', 1 "-terphenyl-4-mercaptan; 1,11-hendecane two mercaptan; 1,16-hexadecane dithiol; Technical grade 1,2-dithioglycol; Isosorbide-5-Nitrae-benzene dimethanethiol; Isosorbide-5-Nitrae-succinimide mercaptans; Isosorbide-5-Nitrae-succinimide mercaptans diacetate esters; 1,5-pentane disulfide thioalcohol; 1,6-ethanthiol; Pungent two mercaptan of 1,8-; 1,9-mercaptan in the ninth of the ten Heavenly Stems two; Adamantane mercaptan; L-butyl mercaptan; L-decyl mercaptan; L-dodecyl mercaptans; L-heptanthiol; Pure l-heptanthiol; 1-hexadecanethiol; L-hexyl mercaptan; L-sulfydryl-(triethylene glycol); The golden nanometer particle that 1-sulfydryl-(triethylene glycol) methyl ether is functionalized; L-mercaptan in the ninth of the ten Heavenly Stems; L-octadecanethiol; 1-spicy thioalcohol; 1-pentadecane mercaptan; 1-amyl hydrosulfide; 1-propanethiol; 1-tetradecane mercaptan; Pure 1-tetradecane mercaptan; 1-undecane thiol; 11-(1H-pyrroles-1-base) hendecane-1-mercaptan; 11-amino-1-undecane thiol hydrochloride; The bromo-1-undecane thiol of 11-; 11-sulfydryl-1-tip-nip; 11-Mercaptoundecanoic acid; 11-mercapto-undecanoic base trifluoroacetate; 11-mercapto-undecanoic base phosphoric acid; 12-sulfydryl dodecylic acid; 15-sulfydryl pentadecanoic acid; 16-mercaptohexadecanoic acid; 1H, 1H, 2H, 2H-perfluor decyl mercaptan; 2,2 '-(ethylenedioxy) diethyl mercaptan; 2-butyl mercaptan; 2-ethyl hexyl mercaptan; 2-methyl isophthalic acid-propanethiol; 2-methyl-2-propanethiol; 2-benzene ethyl mercaptan; Pure 3,3,4,4,5,5,6,6,6-nine fluoro-1-hexyl mercaptans; 3-(dimethoxy-methyl silicyl)-1-propanethiol; The chloro-1-propanethiol of 3-; 3-sulfydryl-1-propyl alcohol; 3-sulfydryl-2-butanols; 3-sulfydryl-N-nonyl propionamide; 3-mercaptopropionic acid; The silica gel that 3-mercaptopropyi is functionalized; 3-methyl isophthalic acid-butyl mercaptan; 4,4 '-bis-(mercapto methyl) biphenyl; 4,4 '-dimercapto stilbene; 4-(the own oxygen base of 6-sulfydryl) benzylalcohol; 4-cyano group-1-butyl mercaptan; 4-sulfydryl-n-butyl alcohol; 6-(ferrocenyl) hexyl mercaptan; 6-sulfydryl-1-hexanol; 6-mercaptohexanoic acid; 8-sulfydryl-1-octanol; 8-sulfydryl is sad; 9-sulfydryl-1 nonyl alcohol; Xenyl-4,4'-bis-mercaptan; 3-mercaptopropionic acid butyl ester; L-butyl mercaptan copper (I); Cyclohexylmercaptan; Cyclopentanethiol; The Nano silver grain that decyl mercaptan is functionalized; The golden nanometer particle that dodecyl mercaptans is functionalized; The Nano silver grain that dodecyl mercaptans is functionalized; Six (ethylene glycol) single-11-(Acetylsulfanyl) undecyl ether; Mercapto succinic acid; 3-mercapto-propionate; NanoTetherBPA-HH; NanoThinks tM18; NanoThinks tM8; NanoThinks tMaCID11; NanoThinks tMaCID16; NanoThinks tMaLCO11; NanoThinks tMtHIO8; The golden nanometer particle that spicy thioalcohol is functionalized; PEG bis-mercaptan number-average molecular weight 8,000; PEG bis-mercaptan mean molecule quantity 1,500; PEG bis-mercaptan mean molecule quantity 3,400; S-(11-bromo-n-11 base) thiacetate; S-(4-cyanobutyl) thiacetate; Benzenethiol; Triethylene glycol list-11-mercapto-undecanoic base ether; Trimethylolpropane tris (3-mercaptopropionic acid ester); [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol); Between carborane-9-mercaptan; Para-terpheny base-4,4 "-two mercaptan; Tertiary lauryl mercaptan; And tertiary nonyl mercaptan.
32. methods according to claim 24, the wherein said compound containing mercaptan comprises and is selected from one or more following reagent: 1,2-dithioglycol; 2,3-dimercaprol dimercaptopropanol; PTO; Dithioerythritol; 3,4-dimercapto toluene; 2,3-succinimide mercaptans; 1,3-dimercaptopropane; 2-hydroxyl propanethiol; 1-sulfydryl-2-propyl alcohol; Alpha-lipoic acid; Dithiothreitol (DTT); Methyl mercaptan (CH 3sH [m-mercaptan]); Ethyl mercaptan (C 2h 5sH [e-mercaptan]); 1-propanethiol (C 3h 7sH [n-P mercaptan]); 2-propanethiol (CH 3cH (SH) CH 3[2C 3mercaptan]); Butyl mercaptan (C 4h 9sH ([n-butanethiol]); Tert-butyl mercaptan (C (CH 3) 3sH [t-butanethiol]); Amyl hydrosulfide (C 5h 11sH [amyl mercaptan]); Coacetylase; Lipoamide; Glutathione; Cysteine; Cystine; 2 mercapto ethanol; 2-sulfydryl indole; TGase; (11-mercapto-undecanoic base) six (ethylene glycol); (11-mercapto-undecanoic base) four (ethylene glycol); The golden nanometer particle that (11-mercapto-undecanoic base) four (ethylene glycol) are functionalized; 1,1', 4', 1 "-terphenyl-4-mercaptan; 1,11-hendecane two mercaptan; 1,16-hexadecane dithiol; Technical grade 1,2-dithioglycol; Isosorbide-5-Nitrae-benzene dimethanethiol; Isosorbide-5-Nitrae-succinimide mercaptans; Isosorbide-5-Nitrae-succinimide mercaptans diacetate esters; 1,5-pentane disulfide thioalcohol; 1,6-ethanthiol; Pungent two mercaptan of 1,8-; 1,9-mercaptan in the ninth of the ten Heavenly Stems two; Adamantane mercaptan; L-butyl mercaptan; L-decyl mercaptan; L-dodecyl mercaptans; L-heptanthiol; Pure l-heptanthiol; 1-hexadecanethiol; L-hexyl mercaptan; L-sulfydryl-(triethylene glycol); The golden nanometer particle that 1-sulfydryl-(triethylene glycol) methyl ether is functionalized; L-mercaptan in the ninth of the ten Heavenly Stems; L-octadecanethiol; 1-spicy thioalcohol; 1-pentadecane mercaptan; 1-amyl hydrosulfide; 1-propanethiol; 1-tetradecane mercaptan; Pure 1-tetradecane mercaptan; 1-undecane thiol; 11-(1H-pyrroles-1-base) hendecane-1-mercaptan; 11-amino-1-undecane thiol hydrochloride; The bromo-1-undecane thiol of 11-; 11-sulfydryl-1-tip-nip; 11-Mercaptoundecanoic acid; 11-mercapto-undecanoic base trifluoroacetate; 11-mercapto-undecanoic base phosphoric acid; 12-sulfydryl dodecylic acid; 15-sulfydryl pentadecanoic acid; 16-mercaptohexadecanoic acid; 1H, 1H, 2H, 2H-perfluor decyl mercaptan; 2,2 '-(ethylenedioxy) diethyl mercaptan; 2-butyl mercaptan; 2-ethyl hexyl mercaptan; 2-methyl isophthalic acid-propanethiol; 2-methyl-2-propanethiol; 2-benzene ethyl mercaptan; Pure 3,3,4,4,5,5,6,6,6-nine fluoro-1-hexyl mercaptans; 3-(dimethoxy-methyl silicyl)-1-propanethiol; The chloro-1-propanethiol of 3-; 3-sulfydryl-1-propyl alcohol; 3-sulfydryl-2-butanols; 3-sulfydryl-N-nonyl propionamide; 3-mercaptopropionic acid; The silica gel that 3-mercaptopropyi is functionalized; 3-methyl isophthalic acid-butyl mercaptan; 4,4 '-bis-(mercapto methyl) biphenyl; 4,4 '-dimercapto stilbene; 4-(the own oxygen base of 6-sulfydryl) benzylalcohol; 4-cyano group-1-butyl mercaptan; 4-sulfydryl-n-butyl alcohol; 6-(ferrocenyl) hexyl mercaptan; 6-sulfydryl-1-hexanol; 6-mercaptohexanoic acid; 8-sulfydryl-1-octanol; 8-sulfydryl is sad; 9-sulfydryl-1 nonyl alcohol; Xenyl-4,4'-bis-mercaptan; 3-mercaptopropionic acid butyl ester; L-butyl mercaptan copper (I); Cyclohexylmercaptan; Cyclopentanethiol; The Nano silver grain that decyl mercaptan is functionalized; The golden nanometer particle that dodecyl mercaptans is functionalized; The Nano silver grain that dodecyl mercaptans is functionalized; Six (ethylene glycol) single-11-(Acetylsulfanyl) undecyl ether; Mercapto succinic acid; 3-mercapto-propionate; NanoTetherBPA-HH; NanoThinks tM18; NanoThinks tM8; NanoThinks tMaCID11; NanoThinks tMaCID16; NanoThinks tMaLCO11; NanoThinks tMtHIO8; The golden nanometer particle that spicy thioalcohol is functionalized; PEG bis-mercaptan number-average molecular weight 8,000; PEG bis-mercaptan mean molecule quantity 1,500; PEG bis-mercaptan mean molecule quantity 3,400; S-(11-bromo-n-11 base) thiacetate; S-(4-cyanobutyl) thiacetate; Benzenethiol; Triethylene glycol list-11-mercapto-undecanoic base ether; Trimethylolpropane tris (3-mercaptopropionic acid ester); [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol); Between carborane-9-mercaptan; Para-terpheny base-4,4 "-two mercaptan; Tertiary lauryl mercaptan; And tertiary nonyl mercaptan.
33. methods according to any one of claim 1-18 or 20-22, wherein said bacterial pathogens comprises following at least one:
(i) one or more Gram-negative bacterias;
(ii) one or more gram-positive bacterias;
(iii) one or more antibiotic sensitive bacterium;
(iv) one or more antibiotic resistance bacterium;
V () is selected from following bacterial pathogens: staphylococcus aureus (S.aureus), methicillin resistant S staphylococcus (MRSA), Staphylococcus epidermidis, methicillin resistant Staphylococcus epidermidis (MRSE), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, Vancomycin resistant enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, streptococcus pneumonia, Penicillin Resistant S streptococcus, Burkholderia cepacia, bite burkholderia more, smegmatis mycobacterium and Acinetobacter baumannii.
34. methods according to claim 19, wherein said bacterial pathogens comprises following at least one:
(i) one or more Gram-negative bacterias;
(ii) one or more gram-positive bacterias;
(iii) one or more antibiotic sensitive bacterium;
(iv) one or more antibiotic resistance bacterium;
V () is selected from following bacterial pathogens: staphylococcus aureus (S.aureus), methicillin resistant S staphylococcus (MRSA), Staphylococcus epidermidis, methicillin resistant Staphylococcus epidermidis (MRSE), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, Vancomycin resistant enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, streptococcus pneumonia, Penicillin Resistant S streptococcus, Burkholderia cepacia, bite burkholderia more, smegmatis mycobacterium and Acinetobacter baumannii.
35. methods according to any one of claim 1-18 or 20-22, it comprise with described plant and described BT composition contact procedure simultaneously or successively and with any order, make described plant and (i) work in coordination with antibiotic and contact with at least one in (ii) cooperative antimicrobial efficacy enhancement antibiotic.
36. methods according to claim 19, it comprise with described plant and described BT composition contact procedure simultaneously or successively and with any order, make described plant and (i) work in coordination with antibiotic and contact with at least one in (ii) cooperative antimicrobial efficacy enhancement antibiotic.
37. methods according to claim 35, wherein said collaborative antibiotic or described cooperative antimicrobial efficacy enhancement antibiotic comprise and are selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.
38. methods according to claim 36, wherein said collaborative antibiotic or described cooperative antimicrobial efficacy enhancement antibiotic comprise and are selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.
39. according to method according to claim 37, and wherein said collaborative antibiotic or described cooperative antimicrobial efficacy enhancement antibiotic are selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
40. according to method according to claim 38, and wherein said collaborative antibiotic or described cooperative antimicrobial efficacy enhancement antibiotic are selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
41. 1 kinds for wherein or it exists antibiotic resistance bacterial pathogens plant in overcome the method for antibiotic resistance, it comprises:
Be enough to meet following one or more condition and under the time, the while of enabling described plant or successively and strengthen with (2) at least one with any order with (1) at least one bismuth-mercaptan (BT) composition of effective dose or contact with the synergistic antibiotic of described at least one BT composition:
I () prevents described plant to be infected by described bacterial pathogens,
(ii) cell viability or the Growth of Cells of the planktonic cells of described bacterial pathogens is suppressed,
(iii) suppress by the biofilm formation of described bacterial pathogens, and
(iv) biomembrane vigor or the biofilm development of the biomembrane form cell of described bacterial pathogens is suppressed,
Wherein said BT composition comprises multiple solia particle comprising bismuth-mercaptan (BT) compound, and described BT compound is not micronized, grinds or does not experience supercritical fluid processing, and described particulate has the volume mean diameter of 0.4 μm to 5 μm; And thus the antibiotic resistance overcome on described epithelial tissue surface,
Wherein said BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.
42. methods according to claim 41, wherein said bacterial pathogens shows being selected from following antibiotic resistance: methicillin, vancomycin, NAF, gentamicin, ampicillin, chloramphenicol, Doxycycline, tobramycin, clindamycin and gatifloxacin.
43. methods according to claim 41, wherein said BT composition comprises and is selected from one or more following BT compounds: BisBAL, BisEDT, Bis-dimercaprol dimercaptopropanol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-sulfydryl-2-propyl alcohol and Bis-EDT/2-hydroxyl-1-propanethiol.
44. methods according to claim 43, wherein said collaborative or enhancement antibiotic comprises and is selected from following antibiotic: clindamycin, gatifloxacin, aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, penicillinase-resistant PCs and Aminopenicillin antibiotic.
45. methods according to claim 44, wherein said collaborative or enhancement antibiotic is selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
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