CN103096720A - Bismuth-thiols as antiseptics for agricultural, industrial and other uses - Google Patents

Bismuth-thiols as antiseptics for agricultural, industrial and other uses Download PDF

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CN103096720A
CN103096720A CN201180042863XA CN201180042863A CN103096720A CN 103096720 A CN103096720 A CN 103096720A CN 201180042863X A CN201180042863X A CN 201180042863XA CN 201180042863 A CN201180042863 A CN 201180042863A CN 103096720 A CN103096720 A CN 103096720A
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mercaptan
antibiotic
compound
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sulfydryl
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CN103096720B (en
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B·H·J·贝克
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Microbion Corp
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Abstract

Compositions and methods, including novel homogeneous microparticulate suspensions, are described for treating natural and artificial surfaces that contain bacterial biofilm, including unexpected synergy or enhancing effects between bismuth-thiol (BT) compounds and certain antibiotics, to provide formulations including antiseptic formulations. Previously unpredicted antibacterial properties and anti-biofilm properties of disclosed BT compounds and BT compound-plus-antibiotic combinations are also described, including preferential efficacies of certain such compositions for treating certain gram-positive bacterial infections, and distinct preferential efficacies of certain such compositions for treating certain gram-negative bacterial infections.

Description

Bismuth-mercaptan as preservative for agricultural, industry and other purposes
The cross reference of related application
The application requires the PCT application No.PCT/US2011/023549 submitted on February 3rd, 2011 and the U.S. Provisional Application No.61/373 submitted on August 12nd, 2010,188 rights and interests, and it all is incorporated herein with way of reference separately.
Background
Technical field
Disclosure working of an invention scheme relates to composition and the method that is used for the treatment of infected by microbes.Especially, the present embodiment relates to for control (comprising the treatment of bacterial biof iotalm and other symptom) treatment of improvement that bacterium infects in agricultural, industry, manufacturing industry, clinical, individual health care and other situation.
description of related art
Promote to reply and to resist infected by microbes and/or promote to restore or maintain a series of collaborative cell of plant and animal (comprising the people) soma and the combination of interaction of molecules can be subject to the adverse effect of various external factor usually, for example opportunistic infections and hospital infection (for example, can increase the clinical protocol of infection risk); Antibiotic part or systemic application (it can affect Growth of Cells, transfer or other function and also can select the antibiotic resistance microorganism); And/or other factors.
Regrettably, system or the local antibiotic of introducing are usually invalid for the many chronic infections for the treatment of, and usually are not used, unless there is acute bacterial infection.Current method comprises uses or applies antibiotic, but this type of therapy may promote the antibiotic resistance bacteria strain appearance and/or may for the antagonism bacterial biof iotalm invalid.Therefore, when detect drug-fast bacteria (for example methicillin resistance staphylococcus aureus ((Staphylococcus aureus) or MRSA) time used the antibacterial agent particular importance that may become.Many widely used antibacterial agents are arranged, and the bacterial flora or the subgroup that still produce may not replied these reagent, or any other available treatment is not at present replied.In addition, many antibacterial agents may be toxicity can effectively resisting that produced bacterium infects under required concentration to host cell, so these antibacterial agents are unaccommodated.This problem may be in the situation that attempt infecting outstanding especially from the self-faced removing, described self-faced comprises commercially available surface characteristics thing and/or such as the agriculturally important specieses of many crops, also comprise interior epithelial surface, for example respiratory tract (for example, air flue, nasopharynx larynx passage, tracheae, lung, bronchi, bronchiole, alveolar etc.) or intestines and stomach (for example, oral cavity, oesophagus, stomach, intestines, rectum, anus etc.) or other epithelial surface.
Problematic especially is to be formed and infected by bacterial biof iotalm (the bacterium tissue of being familiar with recently), free whereby unicellular (" swimming ") bacterium is gathered into organized many cells groups (biomembrane (biofilm)) by intercellular adhesion, and described many cells group has significantly different behavior patterns, gene expression and to the susceptibility of the surrounding material that comprises antibiotic.Biomembrane can adopt the biophylaxis mechanism of not finding in planktonic bacteria, and described mechanism can protect biomembrane group to avoid antibiotic and host immune response.Established biomembrane can stop the organization healing process.
Under lasting and potential harmful infection, common microorgranic contaminant comprises staphylococcus aureus (it comprises MRSA (methicillin resistance staphylococcus aureus)), enterococcus, Escherichia coli, pseudomonas aeruginosa, streptococcus and Acinetobacter baumannii.These microorganisms show the ability of survival several months on the clinical surface of non-nutritive a bit.Shown the staphylococcus aureus surrounding of surviving on dry glass, and survival 3 to 6 months on dry blood and cotton fiber (Domenico etc., 1999Infect.Immun.67:664-669).Shown that Escherichia coli and pseudomonas aeruginosa survive the longer time (as previously mentioned) than staphylococcus aureus on dry blood and cotton fiber.
Microbial biofilm is with relevant with the obvious resistance increased of antibiotic to disinfectant.When being attached to surface, bacterium and/or fungi form the biomembrane form.This adheres to and triggers genetic transcription and change, and causes the secretion of very flexible and the polysaccharide matrix that is difficult to penetrate, the protection microorganism.Except the resistance of biomembrane to the antibiotic highly significant, their resistances to immune system.Once forming, biomembrane is very difficult to eradicate, so the prevention biofilm formation is very important clinical priority principle.Recently 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 of serious wound infection.
Complete functional skin and other epithelial tissue are (for example, the general non-blood vessel epithelial surface that forms barrier between microorganism and its external environment condition, such as in those and respiratory tract and GI lining form, the glandular tissue etc. that exist in skin, exist those) maintain for the health of people and other animal and to survive be important.
the class antibacterial agent of bismuth mercaptan-(BT)
Many have antimicrobial, particularly the natural products of antibacterial properties (for example antibiotic) and synthesis of chemicals are known in the art, and by chemical constitution and anti-microbial effect, characterized at least in part, described anti-microbial effect for example kills and wounds ability (" killing " effect of microorganism, bactericidal property for example), stop or damage ability (" inhibition " effect of growth of microorganism, antibacterial character for example), perhaps disturb microbial function, for example field planting or infection site, the bacterium of exopolysaccharide secretes and/or is converted into from swimming the ability of the expansion of biomembrane colony or biofilm formation.For example, U.S.6,582,719 have discussed (comprising bismuth-mercaptan or BT compound) such as antibiotic, disinfectant, antibacterial agents, the factor that comprises the choice and operation that affects such composition, comprise for example sterilization or antibacterial character, valid density and to the risk of toxicity of host tissue.
Bismuth, V family metal, be 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 can usually together with complexing agent, carrier and/or other medium, send to use, and modal example is Pepto
Figure BDA00002887768300031
wherein bismuth and subsalicylate combination (huge legendary turtle is closed).Research before determined, some containing mercaptan-(SH, sulfydryl) compound for example the combination of dithioglycol and bismuth exemplary bismuth mercaptan (BT) compound is provided, with current other available bismuth preparation, compare, improved the antimicrobial efficacy of bismuth.There are many mercaptan compounds that can be used for producing BT (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 referring to for example U.S.6,582,719), several in these preparations can suppress biofilm formation.
Proved the activity of the anti-following bacterium of BT compound: MRSA (methicillin resistance staphylococcus aureus), MRSE (methicillin resistance Staphylococcus epidermidis (methicillin resistant S.epidermidis)), Mycobacterium tuberculosis (Mycobacterium tuberculosis), mycobacterium avium (Mycobacterium avium), drug resistance pseudomonas aeruginosa (P.aeruginosa), enterotoxigenic E.Coli (enterotoxigenic E.coli), enterohemorrhagic Escherichia coli (enterohemorrhagic E.coli), Klebsiella Pneumoniae (Klebsiella pneumoniae), clostridium difficile (Clostridium difficile), helicobacter pylori (Heliobacter pylori), legionella pneumophila (Legionella pneumophila), enterococcus faecalis (Enterococcus faecalis), enterobacter cloacae (Enterobacter cloacae), salmonella typhimurium (Salmonella typhimurium), proteus vulgaris (Proteus vulgaris), YE (Yersinia enterocolitica), comma bacillus (Vibrio cholerae) and shigella flexneri (Shigella flexneri) (Domenico etc., 1997Antimicrob.Agents Chemother.41:1697-1703).Also has for example evidence of Candida albicans of anti-cytomegalovirus, 1 type pure hcrpesviruses (HSV-1) and HSV-2 and yeast and fungi.Proved that BT reduces Pathogenicity of Bacteria, suppresses or kills and wounds broad-spectrum antibiotic resistant microorganism (Gram-positive and Gram-negative), prevention biofilm formation, prevention septic shock, treatment septicemia and increases effect to before it being shown to the antibiotic antimicrobial susceptibility of resistance (referring to for example; Domenico etc., 2001Agents Chemother.45:1417-1421; Domenico etc., 2000Infect.Med.17:123-127; Domenico etc., 2003Res.Adv.In Antimicrob.Agents & Chemother.3:79-85; Domenico etc., 1997Antimicrob.Agents Chemother.41 (8): 1697-1703; Domenico etc., the 1999J Antimicrob.Chemother.44:601-605 such as 1999Infect.Immun.67:664-669:Huang; Veloira etc., 2003J Antimicrob.Chemother.52:915-919; Wu etc., 2002Am J Respir Cell Mot Biol.26:731-738).
Although there has been more than ten year in the BT compound, but effectively selecting the suitable BT compound for the specific indication that catches is still to be difficult to the target realized, wherein can not be predicted for the behavior of the particular B T of specified microorganisms, wherein can not be predicted for the synergistic activity of the particular B T of specified microorganisms and certain antibiotics, the wherein not always interior BT effect of predictor of external BT effect, and wherein for the BT effect of (unicellular) micropopulation that swims, may not can predict for example, BT effect for microbiologic population's (being organized into biomembranous bacterium).In addition, the restriction of the aspects 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 has solved these to be needed and other associated advantages is provided.
the protection of plant and agricultural products: description of related art
In agricultural and botany field, for the preparation that reduces biomembrane and disease in plant and to the method for these preparations of use on for example seed, plant, fruit and flower, soil and on cut-flower, trees, fruit, leaf, stem and other plant part, generally acknowledged demand is arranged.
On agricultural, due to the crop that forms the annual loss of biomembrane multi-million dollar.In plant, the problem of anthracnose and biomembrane relevant disease is well-known, although attempt multiple not satisfied method, solves it.Plant disease also affects in transportation and the industry related in preserving fruit, vegetables, cut-flower and trees and other plant product, because the normal defense mechanism that complete survival plants adopts is no longer feasible in the product of results.
Therefore, for agriculture purpose, 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.Simultaneously, need to make in cut-flower, plant and trees water flow to maintain plant tissue dilation, integrality and quality, thereby 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 (for example, at aquatic conditions or in water droplet or under the condition of other high humility), when the bacterium mating surface, produce biomembrane, and after combination, biofilm formation thing (biofilm former) starts to drain stickum, then described stickum can, in conjunction with various materials, 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 in medical environment when generation cause the infection of surrounding tissue.Medical domain especially easily is subject to the impact by problem that biofilm formation causes; The bacterium existed in biomembrane easily filters the wound of medical treatment device, conduit (urine, vein, dialysis, heart) and the indolence of implantation.On agricultural, biomembrane can cause mastitis, Pierce's disease (Pierce's disease), the ring rot in potato, various crop fusarium wilts and anthracnose in being permitted eurypalynous plant.Biomembrane also reduces quality and the life of product of cut-flower and trees.
Due to the bacteriogenic biomembrane that many plant diseases are generated by soil.In natural surroundings, most of microorganism is present in and usually is described as in biomembranous many cells aggregation.By complex matrices make cell adherence to the surface and each other, described complex matrices comprises various Extracellular Polymers (EPS), comprises exocellular polysaccharide, albumen and DNA.In morbidity during with symbiosis and bacterium and host tissue surface interaction that in symbiotic relation, plant is relevant.Day by day disclose cell cluster from childhood to the equal different biomembrane type structure of large biomembrane from the observation of plant Related Bacteria.The tendency strong effect gained biofilm structure of the surface nature of plant tissue, nutrition and water conservancy expenditure and field planting bacterium (Ramey etc., 2004Curr Opinion Microbiol.7:602-9).
Terrestrial environment possesses rich and varied micropopulation, and resources bank can be competed and change to these micropopulations.In this complexity and competitive environment, plant provides the protection oasis of nutritious tissue.Bacteria planting is on leaf, root, seed and the inner vasculature of plant.Each organization type has unique chemistry and physical property, for micropopulation provides challenge and chance.Adhering to or subsequent stage can form biomembrane, very likely causing or regulating plant-microbial interaction.When actively changing the field planting plant environment, many microorganisms can cause other time and spatial complexity.
The bacterium of surface attachment has remarkable impact to agricultural.In developed country, loss is up to 25% of crop yield due to plant disease, and this ratio is far longer than developing country.Epiphyte group is comprised of bank (reservoir) and following infection genesis, and can on host and nonhost plant, find.In the vasculature of these plants, bacterial pathogens vine wood friend bacterium viny (Xylophylus ampelinus) forms thick biomembrane (Grail and Manceau2003).Xyllela fastidiosa (Xylella fastidiosa) is the pathogenic bacteria of Pierce's disease in vine.Xyllela fastidiosa can form biomembrane in the xylem vessel of many economic important crops.Pathogenicity mechanism mainly due to by xyllela fastidiosa, assemble and biofilm formation due to the obstruction of xylem vessel.It is believed that, it is the main cause of disease progression that vascular blocks, wherein xylem sap provides the natural medium (Zaini etc., 2009FEMS Microbiol LETT.295:129-34) of the virulence that promotes Pierce's disease viny and the variegated etiolation of oranges and tangerines (citrus variegated chlorosis).
One of corresponding plants pathogene, pseudomonas syringae (Pseudomonas syringae) 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) mainly develops at the trichome near having higher nutritional utilization degree or vein place.Large aggregation is resisted desiccation stress better than autoblast.When can not be when the host plant tissue causes infecting, pseudomonas syringae be as epiphyte existence (that is, the field planting thing of the acrial part of plant) (Monier etc., PNAS2003; 100:15977-82).
Pseudomonas putida (Pseudomonas putida) but the existence of root exudates in rapid answer soil assemble in root field planting position and form the stabilate film (Microbiol2002 such as Espinosa-Urgel; 148:341-3).
The Xanthomonas campestris pv campestris mutation (Xanthomonas campestris pv.campestris) of causing a disease (Xcc) causes the black rot on crucifer, by wound site in root, arrives vasculature.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 (Xanthomonas smithii subsp.citri) is the reason of c itrus canker disease.Except Europe, this disease is all found in most of continent in the world.At many countries eradication of pathogens already.Xanthomonas axonopodis is formed on ulcer pathology on fruit, leaf and the withe of oranges and tangerines plant.Wind folder rain can be sent out bacterium origin seedbed at the most 15km so that (Sosnowski, etc., Plant Pathol2009 by pore or wound infection mandarin tree; 58:621-35).
Stewart's wilt bacterium (Pantoea stewartii subsp.Stewartii) causes Stewart's wilt (Stewart's wilt disease) and propagates by the corn flea beetle.Bacterium mainly rests in host's xylem and produces a large amount of exocellular polysaccharides (PNAS1998 such as von Bodman; 95:7687-92).
Ralstonia solanacearum (Ralstonia solanacearum) is to cause fatal withered soil-borne disease substance on many plants.Virulence depends on the EPS that controls by complicated regulating networks and cell wall degrading enzyme (the Mol Microbiol2002 such as Kang; 46:427-37).
Potato Ring Rot (Clavibacter michiganensis subsp.Sepedonicus) is the Gram-positive phytopathogen that causes bacterium ring rot in potato.Marques and colleague have showed large bacterium, are attached to the aggregation that the encases matrix (Phytopathol2003 such as Marques of xylem vessel; 93:S57).
By the quick dipping of plant tissue, produce biomembranous Erwinia chrysanthemi (Erwinia chrysanthemi) and cause soft rot.The generation of pectase can be that quorum sensing (QS) is regulated, thereby can not form the bacterium aggregation, and this can stop decompose pectin enzyme (pectinolytic enzyme) secretion.Relevant phytopathogen erwinia amylovora (Erwinia amylovora) infects approximately 75 kinds of different plant species, allly is 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, the Li that cultivate are with the Quinces Quince is to infect the most serious kind.2000 one time, state of Michigan fire blast infectious disease (fire blight epidemic) cause surpassing 220,000 trees death, reach the total losses of forty-two million.The fire blast loss of the annual U.S. and regulate expenditure assessment surpass $ 100,000,000 (Norelli etc., Plant Dis2003; 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 symptom (Phytopathol2009 such as Koczan of withering in host plant; 99:1237-44).In addition, the albumen of other gene and their codings is characterised in that the virulence factor of erwinia amylovora, and this virulence factor coding promotes enzyme (Oh and the Beer.FEMS Microbiology Lett2005 of sorbitol metabolism, proteolytic activity and results iron; 253:185-192).
No matter what part of plant is subject to the microorganism phytopathogen invasion and attack such as the biofilm formation thing, and this effect all can make plant die down or kill plants usually.By infecting leaf, pathogene reduces the ability (for example, passing through photosynthesis) of plant production food.The fluid that some phytopathogens stop up in the stem of supplying leaf is carried vascular, and, when these pathogene invasion and attack roots, the picked-up of water and nutrition reduces or interrupted fully.In soil growing plant and in vase water in cutting plants the obstruction of plant vasular structure be usually directed to produce biomembranous bacterium, it blocks water and nutriment flows.
When plant is subject to one of these microorganisms when invasion and attack, the damage caused provides the chance of other microorganism instruction plant tissue, and just with final the damage and the destruction plant of assault.Under the environmental stress such as arid or nutritional deficiency, plant especially easily is 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-and plant provides food and protection, and bacterium absorbs nitrogen and it is transformed to form the material that the host can use from air simultaneously.As another example, mycorhiza is to have the whole purpose fungi of symbiotic relation with plant roots.In view of these useful symbiosis mutually, preservation or protective plant are avoided the impact of harmful microorganism pathogene can reasonably adopt the antimicrobial that can not destroy as far as possible these symbiotic relations.
In decomposing the process that dead organism is humus, saprophytic fungus is essential, and described humus is that the good soil structure is needed.Saprophytic fungus does not have any chlorophyll, thereby can not make to use up to obtain energy (for example, passing through photosynthesis); The saprophytic fungus that replaces obtains its energy by decomposing alive or dead plant and animal body.Saprophytic fungus also can be grown with symbiotic relation with the certain plants kind, for example, the mycorhiza in the radicula of coniferale plant, it can't survive to absorb essential nutriment there is no them.Control the noxious plant pathogene chemical reagent be widely used the balance that can damage these useful fungies, and disagree with the principle of organization and administration.
Yet, other more unwelcome fungi is arranged, the plant that its invasion and attack are lived also dies down them or kills them.Another kind of microorganism phytopathogen, i.e. virus, but field planting in the cell of plant tissue, thereby usually can not treat by the chemical substance of local application, make and must destroy infected plant.The current antibiotic without the exploitation for the treatment of plant specificity (although having been found that some antibiotic of developing for other purpose are for plant), cause a large amount of economic important plant species to be subject to the pathogene bacteria attack.For example, the fire blast of verified rosaceous various plants kind infects and can't treat.By contrast, use the chemical substance of local application can kill many harmful fungoids, and can not damage plant host, because conk habitat difference,, a large amount of pathogene fungies of not expecting tend to growth rather than growth within plant tissue on plant surface, and it uses root shape structure to extract nutrients.
Because kill various plants pathogene difficulty or impossible usually, so adopt the principle of " prevention is better than treatment " for the protection of a lot of methods of plant opposing harmful microorganism pathogene.Good hygiene condition while cultivating with growing plant by observation, the chance that forms infected by microbes by prevention can be prevented many microorganism plant diseases.Usually, when these reagent of preventive use rather than while replying the infection of formation, significantly the insecticide of less amount or microbicide can be for effectively.
If they are not be grown in the best or approach under optimal conditions, for example, for example, due to self poor soil quality (, lacking nutrients) or arid or excessive rainwater or flood are arranged simultaneously, also easy infection disease more of plant.For example, utmost point wet environment can promote pathogene fungi and/or bacterial growth.For example, be illustrated in quorum sensing (Dulla and the Lindow.PNAS2008 in pseudomonas syringae by the water conservancy expenditure on blade face; 105:3-082-7).Certainly, be not that all plant diseases all can prevent by the good agriculture sanitary condition, as when some plant diseases by insect transmission and other, be in anemochoric situation.For example aphid and other suction juice insect are viral main carriers.In air and at raindrop and in dabbling with the spore of fungal disease.
Biomembrane on seed and young shoot
The bacterial adhesion seed is the process of strong effect colonization.The seed supply business deliberately uses microbial biofilm to coat seed reservation to inoculate developmental circle usually.On the contrary, the biomembrane routine source of alimentary infection normally on edible seed and young shoot for the people.Pseudomonas putida effectively adhere to seed and by field planting subsequently at the root circle.The actinomycetic plant endogenesis of the non-pathogene colony found in Wheat Tissue comes from the actinomycetic inner field planting of surperficial sterilized seed.The endophyte seed colony of useful azotobacteria can assist in ensuring that following colonization.Other research of seed field planting has been reported in the bar-shaped and spherical bacteria that in the electron scanning micrograph of alfalfa seed and young shoot, EPS is embedded in.As everyone knows, biomembrane tolerance washing and other common antibacterium processing on seed and young shoot.The discoveries such as Fett, the processing that Escherichia coli O 157 on the clover young shoot: H7 and salmonella colony need to be stricter than simple water washing to be to reduce the number of attached microbial, and can't reach all the time fully and remove.The bacterium of survival may be retained in biomembrane (the Curr Opinion Microbiol2004 such as Ramey; 7:602-9).
Cut-flower and trees
The vascular disorders substance inhabits the xylem of plant host or phloem and usually relies on the insect carrier or wound disseminates.Cutting flower or trees are wounds of the similar type that especially easily infected by vascular.The biomembrane bacterium enters at the cutting surfaces place and blocks vasculature, and disturbs water, mineral matter and nutriment to flow.Be diluted in cut-flower preservative in vase water and usually contain salicylate or aspirin to reduce biofilm formation (Domenico etc., J Antimicrob Chemo1991; 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 method Dependence Treatment, removal and the infected host plant of disposal of current eradication of pathogens.Many examples of many successful are arranged in these technology, but many not successes are wherein also arranged.Success rely on to the biology of pathogene and EPDML good understanding and with host's interaction.In the example of the host material that checks world wide internal therapy phytopathogen and catch; particularly at Australasia; various technology have been used; comprise burning, bury, pruning, compost, soil and Biofumigation, Exposure to Sunlight, steam sterilizing and bio-carrier control (Sosnowski; Deng, Plant Pathol2009; 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 that is applied to plant accounts for below 0.5% of antibiotic summation of use.Phytopathogen is rarely found to the resistance of terramycin, but the appearance of the streptomycin resistance bacterial strain of erwinia amylovora, pseudomonas putida and xanthomonas campestris has hindered the control to some important diseases.Therefore, in the antibiotic resistance risk of people's medicine antibiotic to use effect to plant be main topic of discussion (the Annu Rev Phytopathol2002 such as McManus; 40:443-65).
Streptomycin resistance (Sm r) appearance of phytopathogen makes to control complicated to the bacterial disease of plant.For example, in the U.S., on tomato and pepper, can use strepto-usually to control tomato shot hole capsicum A. mali (X.campestris pv.vesicatoria), so but because resistant strain extensively exists and seldom uses it for this purpose now.Resistance in erwinia amylovora (fire blast pathogene) has economy and political fallout widely.Wherein report Sm rother phytopathogen bacterium comprise carrot pectin bacillus (Pectobacterium carotovora), Pseudomonas cichorii (Pseudomonas chichorii), cucumber bacterium angular leaf spot fungus (Pseudomonas lachrymans), the mutation (Pseudomonas syringae pv.papulans) of causing a disease of pseudomonas syringae bleb, pseudomonas syringae cloves cause a disease mutation (Pseudomonas syringae pv.syringae) and nieffea picta Xanthomonas campestris (Xanthomonas dieffenbachiae) (the Annu Rev Phytopathol2002 such as McManus, 40:443-65).At US West and state of Michigan Sm rit is popular that the appearance of erwinia amylovora has aggravated fire blast.
Streptomycin and terramycin (EPA) are appointed as the minimum kind of toxicity by Environmental Protection Agency USA (U.S.Environmental Protection Agency), and two antibiotic are not all observed carcinogenic or Mutagenicity.
Can obtain Substitutes For Antibiotic 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 that produces the environment of unfavorable disease progression.The various kinds of use bacterium and fungi cause increasing concern to the BIOLOGICAL CONTROL of plant.Root circle bacterium is considered to effective microorganism competitor in the root district.Introduced representation type that many different bacterium belong to soil, on seed, root, stem tuber or other plant piece 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 many other Pseudomonas.For example, some kind of bacillus can be in many plants inducible system resistance (Choudhary and Johri.Microbiol Res2009; 164:493-513).
Although some kind is to copper opposing (Cooksey Annu Rev Phytopathol1990; 28:201-14), but the application of copper compound is effective to colony's reduction of some schizomycete pathogene, and most of fruit tree crop is responsive to the copper loss wound.
There are a large amount of synthetic and natural therapies for various plant diseases.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 as the sodium bicarbonate spraying of bactericide usually; Neem oil; Sulphur; Garlic; Hydrogen peroxide; Compost tea etc.Multiple synthetic chemical is for prevention or treatment plant disease, and it is water-soluble or the water-insoluble preparation.Microbicide comprises Fen Evil arsenic or phenarsazine, maleimide, iso-indoles dicarboximide, halogenated aryl alkanol, 4-sulfo-pyrimidine derivatives (United States Patent (USP) 6384040), heterocycle organo-silicon compound and isothiazolinone.Many microbicides and PTO derivative are combined to prepare the collaborative compound (for example, EP1468607).Some isothiazole carbamyl can be used for control (for example, the US6552056 of plant insect; WO2001/064644).
Recognize the toxicity problem of microbicide in powder or crystal form, United States Patent (USP) is with reference to the 29th, and No. 409 instructions are dissolved in microbicide in liquid flux, it can be added to the preparation mixture, by the final resin combination that uses of its preparation.Although can use liquid dispersion safely in the final position of resin combination of using of preparation, not careful use or liquid disposal also can cause environment and health hazard.Alternatively, also can in the water insoluble thermoplastic resin, use microbicide.Microbicide can be added into to the rigid thermoplastic resin composition and give biocidal activity, thereby be suppressed at its lip-deep growth of microorganism (US5,229,124).This is the solid that the microbicide in being dissolved in vector resin forms substantially, melt blended solution, and this vector resin is the copolymer of vinyl alcohol and (alkylidene oxygen base) acrylate.Although microbicide can be the high toxicity chemical substance, final use product in it low concentration with and by the retention time of resin combination, guarantee final use product in microbicide to humans and animals without harm.
Isothiazolinone is used as microbicide usually in agricultural, for example, and N-Alkylbenzenesulfonyl-arbamoyl base-5-chloro Isothizole derivatives (for example, US5,045,555).This microbicide is widely used in for example paper industry, textile industry, for the production of coating and adhesive, for paint, metal processing, for 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 can suitable amount be added into processing water, cycle water, raw material or product.And, can use it for sterilization or sterilizing facility, factory, animal house or instrument and seed, seedling and raw material.Other derivative of isothiazolone is also known (U.S. Patent No. 3,523,121 and J.Heterocyclic Chem., 8,587 (1971)).Yet every kind of known derivative compound all has high toxicity to animal and fish, 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.
Be set forth in and be different from effect (the Expert.Annu Rev Phytopathol1999 of iron to plant host-parasite relation in the disease of Erwinia chrysanthemi and the caused soft rot of erwinia amylovora and fire blast respectively; 37:307-34).Because it is unique location in biosystem, iron determines the activity of phytopathogen.Siderophore generation by pathogene not only provides the effective ways that obtain iron from host tissue, also can be used as resisting the protective agent of iron toxicity.In when morbidity, the host is combined with metal and the demand of possible chelating is another central issue.Disturb the antimicrobial of the picked-up of bacterium iron and cell respiration to play an important role in the plant sterilization.
It is known having many natural productss antimicrobial, anticorrosion and especially antibacterial property (for example, antibiotic) synthetic chemical, and it has chemistry and biological characteristic at least partly.Example feature comprises the ability (bactericidal action) of kill microorganisms; Stop or damaging the ability of growth of microorganism (bacteriostasis); Perhaps disturb the ability of microbial function, for example field planting or infect the bacterium secretion (some of them foul smelling) of position, metabolite and/or by swimming to the conversion of biomembrane colony or the expansion of biofilm structure (antibiont membrane interaction).At U.S.6,582, (comprising bismuth-mercaptan or BT compound) such as antibiotic, disinfectant, preservatives is discussed in 719, comprises the factor of the choice and operation that affects these compositions, comprise for example sterilization, antibacterial or the antibiont film is tired, valid density and to the risk of host tissue toxicity.
The bacterium petite of protection in biomembrane resisted preservative or disinfectant usually.For example, the antibiotic dosage that kills the free bacterium that swims need to increase to nearly 1,500 times to kill the biomembrane bacterium.Under this high concentration, some are antimicrobial may be toxicity.For example, the compound of oxybromination and chlorination is high toxicity and corrosivity.
The inhibition in blossom blight stage is the key of management fire blast.Infect for the flower occurred, need in the stage erwinia amylovora is bred on stigma surface at epiphyte.Rainwater is that infection is necessary, because it is diluted to the osmotic potential to the erwinia amylovora unrestraint by the sugar on hypanthodium.Rainwater is also that bacterium is distributed to the important substance of hypanthodium again by column cap.These observations show, the Best Times that uses the antibiotic spraying is at this epiphyte in the stage, and after abundant precipitation (Johnson and Stockwell.Annu Rev Phytopathol1998; 36:227-48).
Other bacterium epiphyte is the field planting column cap also, and on column cap, they can interact and suppress the epiphyte growth of pathogene.The commercially available bacterium antagonist of erwinia amylovora (BlightBan, pseudomonas fluorescens A506) can be included in antibiotic spraying scheme.The colony in conjunction with the inhibition pathogene of bacterium antagonist and chemical method, and fill up concomitantly the ecological niche provided by column cap and non-pathogene, competition microorganism (Johnson and Stockwell.Annu Rev Phytopathol1998; 36:227-48).
PTO is the conjugate base that comes from pyrithione (CAS 1121-31-9), the derivative of pyridine-N-oxides.Its antifungic action is that it destroys the ability of film transhipment by blocking-up for transporting mechanism provides the proton pump of energy.Experiment shows: the fungi of low concentration can make PTO inactivation (Chandler and Segel.Antimicrob.Agents Chemother1978; 14:60-8).ZPT is the co-ordination complex of zinc.This colorless solid is as antimycotic and antibacterium reagent.Due to its poorly soluble in water (8ppm under neutral pH), ZPT is suitable for, as outdoor coating, adhesive and other products, providing the protection to mildew and algae.It is effective algicide.Yet it is incompatible with the coating that relies on the metal carboxylate curing agent.While using, need the chelating agent of preferred combination iron ion in comprising the water emulsion paint of (containing a large amount of iron).
In agricultural, special problem is the infection consisted of bacterial biof iotalm, described bacterial biof iotalm is the bacterium tissue of identifying relatively recently, free unicellular (" swimming ") bacterium is focused to by intercellular adhesion through this tissue in organized many cells colonies (biomembrane), and described organized many cells colony has remarkable different behavior pattern, gene expression and to comprising the susceptibility of antibiotic environmental agent.Biomembrane can adopt undiscovered biophylaxis mechanism in planktonic bacteria, and described mechanism can protect biomembrane colony to avoid antibiotic and host immune response impact.The biomembrane formed can stop growth, growth or the wound healing process of plant.
Microbial biofilm is with relevant with the obvious resistance increased of antibiotic to disinfectant.When being attached to surface, bacterium and/or fungi form the biomembrane form.This adheres to and triggers genetic transcription and change, and causes the secretion of very flexible and the polysaccharide matrix that is difficult to penetrate, the protection microorganism.Except the resistance of biomembrane to the antibiotic highly significant, their resistances to the plant immune defense mechanism.Once forming, biomembrane is very difficult to eradicate, so the prevention biofilm formation is very important agriculture priority principle.Recently research shows, and open wound can be polluted fast by biomembrane.These microbial biofilms are considered to hinder growth, growth and/or wound healing, and probably relevant to the generation of the infection of serious and frequent refractory.
Obviously, for treatment and prevention among plant and on infected by microbes improved composition and method need to be arranged, comprise the infected by microbes occurred as biomembrane.Some embodiment described herein solves this demand and other relevant advantage is provided.
Brief summary of the invention
Expect as disclosed herein and not bound by theory, some embodiment of describing first according to this paper, bismuth-mercaptan (BT) compound can be with acting on the preservative used under 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 the prevention of saving by being mediated by BT at least partly or prevent those expenses that realize.
And, in some embodiment described herein, relate to being used for the treatment of and (for example contain bacterial biof iotalm or the bacterium relevant to biofilm formation, can form or promote in addition biomembranous bacterium) plant or plant tissue (for example, root, bulb, stem, leaf, branch, rattan, sarment, bud, flower or its part, tender shoots (greentip), fruit, seed, kind of pod etc.) and the preparation of animal tissue and/or natural and artificial surfaces, described preparation comprises one or more BT compounds and one or more Antibiotique compositions, wherein according to non-limiting theory, based on present disclosure BT compound and antibiotic suitably selected composition, provide antibiotic (the comprising the antibiont film) do not predicted so far of said preparation to act on, and/or for prevention, the not humidification of prediction of the effective medical needle of preventing and/or treating property to the infected by microbes that comprises the infection that contains bacterial biof iotalm.
This paper also provides, and what in these and related embodiment, use is advantageously to comprise the bismuth-composition of mercaptans of single particle suspension basically, and their methods synthetic and that use.
According to certain embodiments of the present invention described herein, at this, be provided for protective plant opposing bacterium, the method of fungi or viral pathogen, described method comprises makes plant or its position (for example, 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 one or more condition below being enough to meet, with under the time, contact: (i) prevent plant by bacterium, fungi or viral pathogen infect, (ii) anti-bacteria, cell viability or the Growth of Cells of all cells that swim basically of fungi or viral pathogen, (iii) suppress by bacterium, the biofilm formation of fungi or viral pathogen, and (iv) anti-bacteria, basically biomembrane vigor or the biofilm development of all biomembrane form cells of fungi or viral pathogen, single suspended matter that disperses basically that wherein the BT composition comprises particulate, basically single suspended matter that disperses of described particulate comprises the BT compound, and described particulate has approximately 0.4 μ m to the about volume mean diameter of 10 μ m.In further embodiment, bacterial pathogens comprises the fire blight of pear bacterial cell.In another embodiment, bacterial pathogens is selected from erwinia amylovora, the pathogenic mutation (Xanthomonas campestris pv dieffenbachiae) of xanthomonas campestris nieffea picta, pseudomonas syringae, xyllela fastidiosa, vine wood friend bacterium, Monilinia fructicola (Monilinia fructicola), Stewart's wilt bacterium, 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.At some, again further in 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 that is selected from tuberous plant, leguminous plant and grass family cereal.In some further embodiment, tuberous plant is selected from potato (Solanum tuberosum) (potato) and sweet potato (Ipomoea batatas) (sweet potato).In some embodiment of said method, carry out the one or many contact procedure.In some further embodiment, at least one contact procedure comprises spraying, floods, applies and smears the 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 for the first time carries out at least one contact procedure in put 24,48 or 72 hours.
In some embodiment of said method, the BT composition comprises and is selected from following one or more BT compound: 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 comprises with plant and BT composition contact procedure simultaneously or successively and with any order, makes plant and works in coordination with or the 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, penicillase resistance PCs and Aminopenicillin antibiotic.In certain embodiments, collaborative or enhancement antibiotic is to be 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 therein or on it existing the method that overcomes antibiotic resistance in the plant of antibiotic resistance bacterium phytopathogen, the method comprises: (a) be enough to meet following one or more condition with under the time, make plant contact with the BT composition of effective dose: (i) prevent plant by antibiotic resistance bacterium pathogenic infection, (ii) suppress cell viability or the Growth of Cells of all cells that swim basically of antibiotic resistance bacterium pathogene, (iii) suppress the biofilm formation by described antibiotic resistance bacterium pathogene, and biomembrane vigor or the biofilm development of all biomembrane form cells basically that (iv) suppress antibiotic resistance bacterium pathogene, single suspended matter that disperses basically that wherein the BT composition comprises particulate, basically single suspended matter that disperses of particulate comprises the BT compound, particulate has approximately 0.5 μ m to the about volume mean diameter of 10 μ m, and (b) and described plant and described BT composition contact procedure simultaneously or successively and with any order, make plant and work in coordination with or the enhancement antibiotic contacts.
In some embodiment of said method, bismuth-composition of mercaptans comprises a plurality of particulates, described a plurality of particulate comprises bismuth-mercaptan (BT) compound, basically all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m, and produce by the process that comprises the following steps: (a) obtain the condition of the solution that is substantially free of solids of sedimentation and mix under the time being enough to: (i) comprise bi concns at least 50mM bismuth salt and containing hydrophily, the acidic aqueous solution of polarity or organic solubilized agent, be enough to obtain with (ii) and comprise by volume the approximately ethanol of the amount of the mixture of 25% ethanol, and (b) be enough to form under the condition and time of the precipitation that comprises the particulate that contains the BT compound, to adding the ethanolic solution that comprises containing the compound of mercaptan in the mixture of (a) to obtain reaction solution, wherein containing the compound of mercaptan in reaction solution to exist to the mol ratio of about 3:1 with respect to the about 1:3 of bismuth.
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 and be selected from one or more following reagent containing the compound of mercaptan: 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) 3the SH[t-butanethiol]); Amyl hydrosulfide (C 5h 11the SH[amyl mercaptan]); Coacetylase; Lipoamide; Glutathione; Cysteine; Cystine; 2 mercapto ethanol; Dithiothreitol (DTT); Dithioerythritol; The 2-sulfydryl indole; TGase; (11-sulfydryl undecyl) six (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol) functionalized golden nanometer particle; 1,1', 4', 1 " terphenyl-4-mercaptan; 1,11-hendecane, two mercaptan; 1,16-hexadecane, two mercaptan; Technical grade 1, the 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; Hot two mercaptan of 1,8-; 1,9-mercaptan in the ninth of the ten Heavenly Stems two; Adamantane mercaptan; The l-butyl mercaptan; The l-decyl mercaptan; The l-dodecyl mercaptans; The l-heptanthiol; Pure l-heptanthiol; 1-hexadecane mercaptan; The l-hexyl mercaptan; L-sulfydryl-(triethylene glycol); 1-sulfydryl-functionalized golden nanometer particle of (triethylene glycol) methyl ether; 1-sulfydryl-2-propyl alcohol; L-mercaptan in the ninth of the ten Heavenly Stems; The l-octadecanethiol; The l-spicy thioalcohol; The 1-spicy thioalcohol; 1-pentadecane mercaptan; The 1-amyl hydrosulfide; The 1-propanethiol; 1-tetradecane mercaptan; Pure 1-tetradecane mercaptan; 1-hendecane mercaptan; 11-(1H-pyrroles-1-yl) hendecane-1-mercaptan; 11-amino-1-hendecane mercaptides hydrochlorate; The bromo-1-hendecane of 11-mercaptan; 11-sulfydryl-1-tip-nip; 11-sulfydryl-1-tip-nip; 11-sulfydryl hendecanoic acid; 11-sulfydryl hendecanoic acid; 11-sulfydryl undecyl trifluoroacetate; 11-sulfydryl undecyl phosphoric acid; 12-sulfydryl dodecylic acid; 12-sulfydryl dodecylic acid; 15-sulfydryl pentadecanoic acid; 16-sulfydryl hexadecanoic acid; 16-sulfydryl hexadecanoic acid; 1H, 1H, 2H, 2H-perfluor decyl mercaptan; 2,2 '-(ethylenedioxy) diethyl mercaptan; 2,3-succinimide mercaptans; The 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, the fluoro-1-hexyl mercaptan of 6-nine; 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; The 3-mercaptopropionic acid; The silica gel that 3-sulfydryl propyl group 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; The 6-mercaptohexanoic acid; 8-sulfydryl-1-octanol; The 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) list-11-(acetyl group sulfenyl) undecyl ether; Mercapto succinic acid; The 3-mercapto-propionate; Nano Tether BPA-HH; Nano Thinks tM18; Nano Thinks tM8; Nano Thinks tMaCID11; Nano Thinks tMaCID16; Nano Thinks tMaLCO11; Nano Thinks tMtHIO8; The golden nanometer particle that spicy thioalcohol is functionalized; The average M of PEG bis-mercaptan n8,000; PEG bis-mercaptan molar average molecular weight 1,500; The average molar average molecular weight 3,400 of PEG bis-mercaptan; S-(11-bromo-n-11 base) thiacetate; S-(4-cyano group butyl) thiacetate; Benzenethiol; Triethylene glycol list-11-sulfydryl undecyl ether; Trimethylolpropane tris (3-mercaptopropionic acid ester); [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol); Between carborane-9-mercaptan; Para-terpheny base-4,4 " bis-mercaptan; Tertiary lauryl mercaptan; And tertiary nonyl mercaptan.
In certain embodiments, described bacterial pathogens comprise 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) be selected from staphylococcus aureus (S.aureus), MRSA (methicillin resistance staphylococcus aureus), Staphylococcus epidermidis, MRSE (methicillin resistance Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, the drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, the methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, vancomycin resistance enterococcus (Enterococcus) (VRE), Burkholderia cepacia complex (Burkholderia cepacia complex), soil Lafranchise Salmonella (Francisella tularensis), bacillus anthracis (Bacillus anthracis), yersinia pestis (Yersinia pestis), pseudomonas aeruginosa (Pseudomonas aeruginosa), vancomycin resistance enterococcus, streptococcus pneumonia, the penicillin resistance streptococcus pneumonia, Escherichia coli, Burkholderia cepacia, bite burkholderia (Bukholderia multivorans) more, the bacterial pathogens of smegmatis mycobacterium (Mycobacterium smegmatis) and Acinetobacter baumannii (Acinetobacter baumannii).
In certain embodiments, described method comprises with plant and BT composition contact procedure simultaneously or successively and with any order, makes plant and (i) work in coordination with antibiotic and contacts 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, penicillase resistance PCs and Aminopenicillin antibiotic.In some further embodiment, collaborative antibiotic or cooperative antimicrobial efficacy enhancement antibiotic are to be 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 therein or on it existing the method that overcomes antibiotic resistance in the plant of bacterial pathogens of antibiotic resistance, described method comprises: below being enough to meet under one or more condition and time, with (2), at least one can strengthen or contact with the synergistic antibiotic of at least one BT composition simultaneously or successively and with (1) at least one bismuth-mercaptan (BT) composition of any order and effective dose to make plant: (i) prevent plant to be infected by bacterial pathogens, (ii) cell viability or the Growth of Cells of all cells that swim basically of anti-bacteria pathogene, (iii) suppress the biofilm formation by bacterial pathogens, and (iv) biomembrane vigor or the biofilm development of all biomembrane form cells basically of anti-bacteria pathogene, wherein the BT composition comprises a plurality of particulates that comprise bismuth-mercaptan (BT) compound, basically all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m, thereby and overcome at the lip-deep antibiotic resistance of epithelial tissue.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, the BT composition comprises and is selected from following one or more BT compound: 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, penicillase resistance PCs and Aminopenicillin antibiotic.In some further embodiment, collaborative or enhancement antibiotic is to be selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
According to some other embodiment, bismuth-the composition of mercaptans that comprises a plurality of particulates is provided, described a plurality of particulate comprises bismuth-mercaptan (BT) compound, basically all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m, and wherein the BT compound comprises bismuth or bismuth salt and containing the compound of mercaptan.In other embodiments, bismuth-the composition of mercaptans that comprises a plurality of particulates is provided, described a plurality of particulate comprises bismuth-mercaptan (BT) compound, basically all described particulates have about 0.4 μ m to the volume mean diameter of about 5 μ m and produce and form by the process comprised the following steps: (a) obtain the condition of the solution that is substantially free of solids of sedimentation and mix under the time being enough to, (i) comprise bi concns at least 50mM bismuth salt and containing hydrophily, the acidic aqueous solution of polarity or organic solubilized agent, be enough to obtain with (ii) and comprise 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 form under the condition and time of the precipitation that comprises the particulate that contains described BT compound, to adding the ethanolic solution that comprises containing the compound of mercaptan in the mixture of (a) to obtain reaction solution, wherein containing the compound of mercaptan in reaction solution to exist to the mol ratio of about 3:1 with respect to the about 1:3 of bismuth.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 and be selected from one or more following reagent containing the compound of mercaptan: 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, a kind of method for the preparation of bismuth-composition of mercaptans is provided, described bismuth-composition of mercaptans comprises a plurality of particulates, described a plurality of particulate comprises bismuth-mercaptan (BT) compound, basically all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m, said method comprising the steps of: (a) in the condition that is enough to obtain the solution be substantially free of solids of sedimentation with mix under the time, (i) comprise bi concns at least 50mM bismuth salt and containing hydrophily, the acidic aqueous solution of polarity or organic solubilized agent, be enough to obtain with (ii) and comprise 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 form under the condition and time of the precipitation that comprises the particulate that contains described BT compound, to adding the ethanolic solution that comprises containing the compound of mercaptan in the mixture of (a) to obtain reaction solution, the wherein said compound containing mercaptan in described reaction solution to exist to the mol ratio of about 3:1 with respect to the about 1:3 of bismuth.In certain embodiments, described method further comprises that the recovery precipitation is 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 and be selected from one or more following reagent containing the compound of mercaptan: 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) 3the SH[t-butanethiol]); Amyl hydrosulfide (C 5h 11the SH[amyl mercaptan]); Coacetylase; Lipoamide; Glutathione; Cysteine; Cystine; 2 mercapto ethanol; Dithiothreitol (DTT); Dithioerythritol; The 2-sulfydryl indole; TGase; (11-sulfydryl undecyl) six (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol) functionalized golden nanometer particle; 1,1', 4', 1 " terphenyl-4-mercaptan; 1,11-hendecane, two mercaptan; 1,16-hexadecane, two mercaptan; Technical grade 1, the 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; Hot two mercaptan of 1,8-; 1,9-mercaptan in the ninth of the ten Heavenly Stems two; Adamantane mercaptan; The l-butyl mercaptan; The l-decyl mercaptan; The l-dodecyl mercaptans; The l-heptanthiol; Pure l-heptanthiol; 1-hexadecane mercaptan; The l-hexyl mercaptan; L-sulfydryl-(triethylene glycol); 1-sulfydryl-functionalized golden nanometer particle of (triethylene glycol) methyl ether; 1-sulfydryl-2-propyl alcohol; L-mercaptan in the ninth of the ten Heavenly Stems; The l-octadecanethiol; The l-spicy thioalcohol; The 1-spicy thioalcohol; 1-pentadecane mercaptan; The 1-amyl hydrosulfide; The 1-propanethiol; 1-tetradecane mercaptan; Pure 1-tetradecane mercaptan; 1-hendecane mercaptan; 11-(1H-pyrroles-1-yl) hendecane-1-mercaptan; 11-amino-1-hendecane mercaptides hydrochlorate; The bromo-1-hendecane of 11-mercaptan; 11-sulfydryl-1-tip-nip; 11-sulfydryl-1-tip-nip; 11-sulfydryl hendecanoic acid; 11-sulfydryl hendecanoic acid; 11-sulfydryl undecyl trifluoroacetate; 11-sulfydryl undecyl phosphoric acid; 12-sulfydryl dodecylic acid; 12-sulfydryl dodecylic acid; 15-sulfydryl pentadecanoic acid; 16-sulfydryl hexadecanoic acid; 16-sulfydryl hexadecanoic acid; 1H, 1H, 2H, 2H-perfluor decyl mercaptan; 2,2 '-(ethylenedioxy) diethyl mercaptan; 2,3-succinimide mercaptans; The 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, the fluoro-1-hexyl mercaptan of 6-nine; 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; The 3-mercaptopropionic acid; The silica gel that 3-sulfydryl propyl group 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; The 6-mercaptohexanoic acid; 8-sulfydryl-1-octanol; The 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) list-11-(acetyl group sulfenyl) undecyl ether; Mercapto succinic acid; The 3-mercapto-propionate; Nano Tether BPA-HH; Nano Thinks tM18; Nano Thinks tM8; Nano Thinks tMaCID11; Nano Thinks tMaCID16; Nano Thinks tMaLCO11; Nano Thinks tMtHIO8; The golden nanometer particle that spicy thioalcohol is functionalized; The average M of PEG bis-mercaptan n8,000; PEG bis-mercaptan molar average molecular weight 1,500; The average molar average molecular weight 3,400 of PEG bis-mercaptan; S-(11-bromo-n-11 base) thiacetate; S-(4-cyano group butyl) thiacetate; Benzenethiol; Triethylene glycol list-11-sulfydryl undecyl ether; Trimethylolpropane tris (3-mercaptopropionic acid ester); [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol); Between carborane-9-mercaptan; Para-terpheny base-4,4 " bis-mercaptan; Tertiary lauryl mercaptan; And tertiary nonyl mercaptan.
In another embodiment, provide protection for example to comprise, such as plant surface (, 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 on the biological tissue surface on epithelial tissue surface opposing bacterial pathogens, the method of one or more of fungal pathogens and viral pathogen, comprise that the BT composition that makes epithelial tissue surface and effective dose contacts with under the time being enough to meet following one or more condition: (i) prevent surperficial by bacterium, fungi or viral pathogen infect, (ii) anti-bacteria, cell viability or the Growth of Cells of all cells that swim basically of fungi or viral pathogen, (iii) suppress by bacterium, the biofilm formation of fungi or viral pathogen, and (iv) anti-bacteria, basically biomembrane vigor or the biofilm development of all biomembrane form cells of fungi or viral pathogen, wherein the BT composition comprises a plurality of particulates that comprise bismuth-mercaptan (BT) compound, and all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m basically.In certain embodiments, bacterial pathogens comprise 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) be selected from staphylococcus aureus (S.aureus), MRSA (methicillin resistance staphylococcus aureus), Staphylococcus epidermidis, MRSE (methicillin resistance Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, the drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, the methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, vancomycin resistance enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, pseudomonas aeruginosa, vancomycin resistance enterococcus, streptococcus pneumonia, the penicillin resistance streptococcus pneumonia, 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 surface, /Jia chamber, oral cavity; 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); Perhaps other natural or artificial surfaces.
In certain embodiments, described surface comprises the epithelial tissue surface, and described epithelial tissue comprises and is selected from following tissue: epidermis, corium, respiratory tract, intestines and stomach and gland lining.
In certain embodiments, contact procedure is carried out one or many.In certain embodiments, at least one contact procedure comprises spraying, floods, applies and smears the 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 part, peritonaeum, oral, stomach and intestine outer, in intravenous, artery, transdermal, hypogloeeis, subcutaneous, intramuscular, in cheek, nose, in suction, intraocular, atrium, in ventricle, in subcutaneous, fat, in joint and the approach in sheath use.In certain embodiments, the BT composition comprises and is selected from following one or more BT compound: 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 further comprises with described surface and described BT composition contact procedure simultaneously or successively and with any order, 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, penicillase resistance PCs and Aminopenicillin antibiotic.In certain embodiments, collaborative and/or enhancement antibiotic is to 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 example, on the self-faced there being antibiotic resistance bacterium pathogene, (overcoming antibiotic resistance, for resisting at least one the bacterium of resisting identical bacteria culture to be there is to the bacterial pathogens of 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 and (2) of any order and effective dose at least one by and/or at least one antibiotic that can strengthen with at least one BT composition synergy contact: (i) prevent surperficially by bacterial pathogens, to be infected, (ii) cell viability or the Growth of Cells of all cells that swim basically of anti-bacteria pathogene, (iii) suppress the biofilm formation by bacterial pathogens, and (iv) biomembrane vigor or the biofilm development of all biomembrane form cells basically of anti-bacteria pathogene, wherein the BT composition comprises a plurality of particulates that comprise bismuth-mercaptan (BT) compound, basically all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m, and overcome antibiotic resistance thus on the epithelial tissue surface.In certain embodiments, bacterial pathogens comprise 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) be selected from staphylococcus aureus (S.aureus), MRSA (methicillin resistance staphylococcus aureus), Staphylococcus epidermidis, MRSE (methicillin resistance Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, the drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, the methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, vancomycin resistance enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, pseudomonas aeruginosa, vancomycin resistance enterococcus, streptococcus pneumonia, the penicillin resistance streptococcus pneumonia, 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 surface, /Jia chamber, oral cavity; 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); Perhaps other natural or artificial surfaces.
In certain embodiments, surface comprises the tissue that is selected from epidermis, corium, respiratory tract, intestines and stomach and gland lining.In certain embodiments, contact procedure is carried out one or many.In certain embodiments, at least one contact procedure comprises spraying, rinses, floods and smears surperficial one.In some other embodiment, at least one contact procedure comprises the one of suction, picked-up and dentilave.In certain embodiments, at least one contact procedure comprises by being selected from part, peritonaeum, oral, stomach and intestine outer, in intravenous, artery, transdermal, hypogloeeis, subcutaneous, intramuscular, in cheek, nose, in suction, intraocular, atrium, in ventricle, in subcutaneous, fat, in joint and the approach in sheath use.In certain embodiments, the BT composition comprises and is selected from following one or more BT compound: 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, penicillase resistance PCs and Aminopenicillin antibiotic.In certain embodiments, collaborative and/or enhancement antibiotic is to be selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
As for another embodiment, antiseptic composition is provided, it comprises: (a) at least one BT compound; (b) by the BT compound, strengthen and/or with the BT compound can synergistic at least one Antibiotique composition; And (c) pharmaceutically acceptable excipient or carrier, comprise the local carrier used.In certain embodiments, the 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, the BT composition comprises a plurality of particulates that comprise bismuth-mercaptan (BT) compound, and all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m basically.In certain embodiments, the 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.
A kind of method that is used for the treatment of the natural or artificial surfaces of supporting or containing bacterial biof iotalm is provided in some other embodiment, comprise (a) by the bacterium on surface or in surface infect be accredited as comprise one of following: (i) gram-positive bacteria, (ii) Gram-negative bacteria, and (iii) comprise (i) and (ii) both, (b) preparation that comprises one or more bismuth mercaptan (BT) compositions to surface applied, wherein (i) comprises gram-positive bacteria if bacterium infects, preparation comprises at least one BT compound for the treatment of effective dose and at least one is the antibiotic of rifamycin, (ii) if infecting, bacterium comprises Gram-negative bacteria, preparation comprises at least one BT compound and the amikacin for the treatment of effective dose, (iii) if infecting, bacterium comprises gram-positive bacteria and Gram-negative bacteria, preparation comprises one or more BT compounds for the treatment of effective dose, rifamycin and amikacin, thereby and treatment surface.
In certain embodiments, biomembrane comprises one or more antibiotic resistance bacterium.In certain embodiments, treatment surface comprises with lower at least one: (i) eradicate bacterial biof iotalm, (ii) reduce bacterial biof iotalm, and (iii) weaken the growth of bacterial biof iotalm.In certain embodiments, the BT composition comprises a plurality of particulates that comprise bismuth-mercaptan (BT) compound, and all particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m basically.
These aspects of embodiment of the present invention as herein described and other side are with reference to the following specifically describes with accompanying drawing 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 in that mention in this specification and/or request for data table, listed, comprise U.S.RE37,793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248 at this, mode integral body by reference is incorporated to this paper, as each is incorporated to separately this paper.In case of necessity, aspect of the present invention and embodiment can be modified the concept that adopts various patents, patent application and patent to announce, so that other embodiment to be provided.
The accompanying drawing summary
Fig. 1 shown in upper 37 ℃ of 10% tryptic soy agar (TSA) and cultivated 24 hours, with by shown in treatment 18 hours, biomembranous survival number (the log CFU of pseudomonas aeruginosa bacterium colony; Colony-forming units).Shown in antibiotic therapy be 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, for example, the least concentration of prevention bacterial growth).
Fig. 2 shown on 10% tryptic soy agar and to have cultivated 24 hours, with by shown in treatment, the biomembranous survival number of staphylococcus aureus bacterium colony (log CFU).Shown in antibiotic therapeutic agent be 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 has shown and has been exposed to biomembranous keratinocyte scratch closure in time.(*) significantly be different from contrast (P<0.001).
Fig. 4 A and 4B have shown the inferior inhibition BisEDT of reverse to several antibiotic antibiotic resistances.Shown the antibiotic effect that is with or without BisEDT (0.05 μ g/ml) on MRSA (methicillin resistance staphylococcus aureus) lawn.Dull and stereotyped A display standard antibiotic permeate pan, dull and stereotyped B shows the dish with BisEDT (BE) combination.[GM=gentamicin, CZ=cephalosporin, FEP=Cefepime, IPM=Imipenem, SAM=ampicillin/sulbactam, LVX=lavo-ofloxacin.
Fig. 5 has shown the effect to biofilm formation of BisEDT and antibiotic.48h grows Staphylococcus epidermidis under 37 ℃ 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 BPC when 0.25 μ Μ BisEDT (continuous 2 times of dilution step).
Fig. 6 has shown Staphylococcus epidermidis is grown in the TSB+2% glucose of the 37 ℃ effect of 48h of BisEDT and antibiotic.Result is expressed as the mean change (n=3) that MIC (dilution step) increases along with BisEDT.Referring to the legend defined for antibiotic in Fig. 5.
Fig. 7 is 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 detected on the bone of the open fracture in the live body rat model and hardware (hardware) sample.The standard error of mean is shown as error line.The animal of early stage euthanasia gets rid of outside analyzing, yet, because severe contamination is got rid of the sample from an animal in group 2.
Detailed Description Of The Invention
Specific embodiments disclosed herein is based on following surprising discovery: some bismuth-mercaptan provided herein (BT) compound (preferably include and have approximately 0.4 μ m to the about BT particulate of 5 μ m volume mean diameters) but not some other BT compound (even providing as particulate) shows strong anticorrosion, the antibiotic and/or antibiont film activity for specific bacteria, described bacterium comprises the bacterium relevant to many severe infections clinically (comprising the infection that can contain bacterial biof iotalm).
Surprisingly, not all BT compound as one man effectively resists this bacterioid in measurable mode, but depends on that the target bacteria bacterial classification shows different effects.Particularly, as described herein, find that some BT compound (preferably include and have approximately 0.4 μ m to the about BT particulate of 5 μ m volume mean diameters) shows higher effect to Gram-negative bacteria, and find that some other BT compound (preferably include and have approximately 0.4 μ m to the about BT particulate of 5 μ m volume mean diameters) shows higher effect to gram-positive bacteria, according to non-limiting theory, mode can be to be provided for first the clinical corresponding strategies that bacterium infects the processing of (comprising that bacterial biof iotalm infects).
In addition, as hereinafter be described in more detail, the surprising advantage provided by novel bismuth-mercaptan (BT) composition is provided certain embodiments of the present invention as herein described, as described herein, described bismuth-mercaptan (BT) composition can be made into to comprise a plurality of with regard to granularity the preparation of the BT particulate of single dispersion the (for example have about 0.4 μ m to approximately the volume mean diameter of 5 μ m) basically.At some in these and related embodiment, particles B T not is provided as for example component of multilayer phosphocholine-cholesterol liposome or other multilayer or unilamellar liposome vesica of lipid vesicle or liposome.
Also as disclosed as some embodiment of this paper, have been found that, find before to this bacterioid infect the antibiotic antibiotic and antibiont film effect of some that there is no therapeutic action can by with these antibiotic one or more together with the BT compound of selecting, simultaneously or sequential therapeutic infect (for example, by directly being applied to infection site for example on natural or artificial surfaces or in natural or artificial surfaces) and by remarkable enhancing (for example, with statistically significantly mode increase).In inscrutable mode before the disclosure, some BT compound can provide for the collaborative of the antibiotic of some bacteria culture or bacterial isolates and/or antibiont film activity or enhancement combination with some antibiotic combinations.The not prediction character of this type of combination is proved by following observation post as described in more detail below: although some BT/ antibiotic compositions synergy or demonstrate the enhancing of some bacterium of antagonism, some other BT/ antibiotic composition is failed to show collaborative or is strengthened antibiotic and/or antibiont film activity.
According to these and related embodiment, antibiotic and BT compound can or be used successively and with any order simultaneously, and it should be noted that, disclosed hereinly (for example be used for the treatment of specific infection, the biomembrane that Gram-negative or gram-positive bacteria form) one or more antibiotic and the concrete composition of one or more BT compounds do not show measurable (for example, adduction only) activity, but work in coordination with or strengthen the effect of (super adduction) mode with beyong contemplation, as the function of selected antibiotic, selected BT compound and the special target bacteria of identifying.
For example, for example the explanation 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 preparation environment of improvement, any one of certain antibiotics compound disclosed herein and particular B T compound or both may bring into play limited antibacterial action for specific bacteria bacterial strain or bacterial classification when using separately, but the combination of described Antibiotique composition and described BT compound is brought into play strong antibacterial action for identical bacterial isolates or bacterial classification, this acts on intensity and is greater than (having significance,statistical) simple adduction of every kind of compound effects while using separately, therefore according to non-limiting theory think reflected BT to antibiotic effect and/or antibiotic to the BT effect antibiotic-the BT concertedness (for example, FICI≤0.5) or humidification (for example, 0.5<FICI≤1.0).Therefore, not that any antibiotic can be worked in coordination with or strengthen to any BT compound with any antibiotic, and be not that any antibiotic can be collaborative with any BT compound, or strengthen any BT compound, it is generally uncertain 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 strengthening and the concrete combination of BT compound, described antibacterial action is included in specific environment, natural or artificial surfaces as herein described for example, and also comprise in some cases for the biomembranous antibacterial action formed by specific bacteria.
That is to say, the collaborative antibiotic of some BT described herein, it comprise can with the antibiotic of at least one the BT composition synergy (FICI≤0.5) that comprises at least one BT compound provided herein, wherein this concertedness is shown as detectable effect, its intensity is greater than the mode of the statistically significant with respect to suitable collating condition (that is, with) and has antibiotic and do not have the BT compound and/or have the BT compound and detectable effect while not having antibiotic.Similarly, some BT-antibiotic composition shows enhancing (0.5<FICI≤1.0), wherein but this enhancing is shown as detection effect, its intensity is greater than (that is, in the mode with respect to suitable collating condition statistically significant) and has antibiotic and do not have the BT compound and/or have the BT compound and detectable effect while not having antibiotic.
In certain embodiments, the example of this type of detectable effect can comprise the infection of (i) prevention bacterial pathogens, (ii) cell viability or the Growth of Cells of all cells that swim basically of anti-bacteria pathogene, (iii) biofilm formation of anti-bacteria pathogene, (iv) biomembrane vigor or the biofilm development of all biomembrane form cells basically of anti-bacteria pathogene, but the present invention is not intention so to be 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 (for example increase of statistically significant or minimizing) one or more other significant parameter clinically, resistance or the sensitivity level of bacterial pathogens to one or more antibiotic or other medicines or chemical agent for example, bacterial pathogens is to one or more chemistry, physics or mechanical condition are (for example, pH, ion strength, temperature, pressure) resistance or sensitivity level, and/or bacterial pathogens to one or more biological agents (for example, virus, another kind of bacterium, the biologically active polynucleotides, immunocyte or immunocyte product be antibody for example, cell factor, chemotactic factor (CF), the enzyme that comprises 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 many other standards; by described standard predetermined substance to the structure of bacterial community, function and/or active effect can be determined (for example; Coico etc. (editor); Current Protocols in Microbiology; 2008, John Wiley & Sons, Hoboken, NJ; Schwalbe etc., Antimicrobial Susceptibility Testing Protocols, 2007, CRC Press, Boca Raton, FL), purpose is to determine antibiotic-BT concertedness or enhancement, during the simple adduction of the effect of observing when as collaborative in this paper is provided at or the component that effect antibiotic that strengthen-BT combination surpasses combination of this concertedness or enhancement does not exist, exists.
For example, in certain embodiments, concertedness can be by using various concentration candidate agent (for example, separately and BT and the antibiotic of combination) measure antibacterial action (for example 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) Antimicrobial combinations.In Antibiotics in Laboratory Medicine (Lorian, V. edit), the 330-96 page, Williams and Wilkins, Baltimore, MD, USA).Concertedness can be defined as FICI or FBCI index≤0.5,4 o'clock be antagonism (for example, Odds, FC (2003) Synergy, antagonism, and what the chequerboard puts between them.Journal of Antimicrobial Chemotherapy52:1).Concertedness can also usual definition be the minimizing of antibiotic concentration >=4 times, or alternatively, uses the FIC (FIC) of describing such as (1998Antimicrob.Agents Chemother.42:744) such as Hollander.In certain embodiments, concertedness (for example may be defined as two kinds of medicines of combination, antibiotic and BT composition) effect that produces, wherein the effect of combination is greater than the mode of statistically significant (for example, with) if the effect when concentration of the second medicine is replaced by the first medicine.
Therefore, as described herein reaching in some preferred embodiment, BT and antibiotic combination should be understood to the collaborative (Odds, 2003) when observing the FICI value that is 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 the FICI value between 0.5 and 1.0, it means this synergitic high potential, and can observe the FICI value by least one BT and at least one antibiotic non-optium concentration of the antimicrobial efficacy that shows independent or the common cooperation strengthened.This acts on this paper also can claim " enhancing " antibacterial activity or " enhancing " BT activity.
When exist following both the time, can detect according to some embodiment antibiotic and/or the BT activity of enhancing: (i) at least one BT, its concentration lower than (in the statistically significant mode) BT to given target microorganism (for example, given bacteria culture or bacterial strain) characteristic minimum inhibitory concentration (MIC), (ii) at least one antibiotic, its concentration is lower than (in the statistically significant mode) characteristic IC 50(the concentration that suppresses 50% micropopulation bulk-growth; For example, Soothill etc., 1992J Antimicrob Chemother29 (2): 137) and/or lower than antibiotic to the biomembrane of given target microorganism prevention concentration (BPC), if for example cause the BT-antibiotic composition, with respect in same concentrations, (using arbitrary antimicrobial, BT or antibiotic) and lack other antimicrobial (for example, antibiotic or BT) by (in the statistically significant mode) antimicrobial efficacy of the enhancing of the anti-microbial effect observed.In preferred embodiments, be less than or equal to 1.0 when being measured to the FICI value, and be greater than at 0.5 o'clock, have " enhancing " antibiotic and/or BT activity.
The technical staff should understand based on the disclosure, in certain embodiments, can measure antibiotic and/or BT activity collaborative or that strengthen according to methods known in the art, for example use Loewe additive model (for example, FIC index, Greco model), or the Bliss independent model (for example, nonparametric and semi-parameter model) or other method described herein and known in the art (for example, Meletiadis etc., 2005Medical Mycology43:133-152).For measuring the collaborative or antibiotic that strengthens and/or the illustrative method of BT activity, be described in thus, such as Meletiadis etc., the list of references that 2005Medical Mycology43:133-152 and this paper quote (also referring to, Meletiadis etc., 2002Rev Med Microbiol13:101-117; White etc., 1996Antimicrob Agents Chemother40:1914-1918; Mouton etc., 1999Antimicrob Agents Chemother43:2473-2478).
Some other embodiment expection is the particular composition of one or more antibiotic and one or more BT compounds as described herein, it in specific infection (for example, the biomembrane formed by Gram-negative bacteria or gram-positive bacteria) in interior therapeutic, can show the effect of collaborative or enhancing, even wherein BT compound and antibiotic do not show predictable (for example, adduction only) activity in vivo, and on the contrary for example, with working in coordination with or enhancing (, super adduction of not predicting; Or the effect of giving when two or more this combinations of substances exist (for example is greater than, in the statistically significant mode) if the effect obtained when the concentration of the second reagent is replaced by the first reagent place) mode, as the function of selected antibiotic, selected BT compound and one or more special target bacteria bacterial classifications that comprise infection of identifying.Therefore should understand, according to these and relevant embodiment, in some body, in situation, FICI or FBCI value (it is by external mensuration) may be difficult for obtaining, and contrary with BT-antibiotic concertedness or humidification, but the mode that may give with the quantification metrics by infecting is measured.
For example, in one embodiment, for example, in body as described as embodiment 11 in the critical defect model of the rat of open fracture (Rattus norvegicus) femur, with antibiotic therapy or independent BT Compound Phase ratio, the count of bacteria that statistically significant is observed in treatment after the BT-antibiotic combinations reduces, and is the indication of concertedness or humidification.Can use method well known to those skilled in the art to measure significance,statistical.In some other embodiment, observe after for BT-antibiotic combinations injury in treating viewed count of bacteria and consider that index that antibiotic therapy or independent BT compound are concertedness or humidification is compared and be reduced by least 5%, 10%, 20%, 30%, 40% or 50% in this body inner model or other body inner model.
The exemplary sign of other of In vivo infection can be according to developing for quantitatively infecting the methodology of the establishment of severity, for example, various wounds well known by persons skilled in the art obtain subsystem measure (referring to, for example, the Europe wound is managed the subsystem that obtains of association (EWMA) comment, Position Document:Identifying criteria for wound infection.London:MEP Ltd, 2005).The illustrative wound that can be used for estimating the concertedness of BT-antibiotic composition as herein described or enhanced activity obtains subsystem and comprises ASEPSIS (Wilson AP, J Hosp Infect1995; 29 (2): 81-86; Wilson etc., Lancet1986; 1:311-13), Southampton's wound opinion rating (Bailey IS, Karran SE, the BMJ1992 such as Toyn K; 304:469-71).Also referring to, Horan TC, Gaynes P, Martone WJ etc., 1992Infect Control Hosp Epidemiol1992; 13:606-08.In addition, the generally acknowledged clinical sign (such as wound size, the degree of depth, granulation tissue situation, infection etc.) of the known wound healing of this area clinician also can be measured when BT compound and/or antibiotic exist or do not exist.Therefore, based on present disclosure, the technical staff for example should be easily understood that, for determining whether that BT composition-antibiotic combination changes the whole bag of tricks (, enhancing or the reduction in the statistically significant mode with respect to suitable contrast) of body internal injury healing.
Consider these and related embodiment, this paper by effective dose (for example provides, treat in certain embodiments effective dose) treat the whole bag of tricks of the self-faced (surface that for example provides or comprise bacterial biof iotalm) of infected by microbes as composition provided herein or preparation, described composition or preparation comprise one or more BT compounds, and optionally comprise one or more Antibiotique compositions, for example one or more collaborative antibiotic, or one or more enhancement antibiotic.Should be understood that based on present disclosure, the expection now of some antibiotic is used for the treatment of the infection of given type, wherein before this antibiotic, by those skilled in the art, is thought invalid to the infection of same type.
Some embodiment severity thus comprises one or more compositions as the BT compound of antibacterial agent.Antibacterial agent is the material that kills and wounds microorganism or pre-micro-organism growth, usually can be applied to living tissue, this differentiates (" the The Pharmacological Basis of Therapeutics " of Goodman and Gilman by this type of material and the disinfectant that usually is applied to lifeless object, the 7th edition, the editors such as Gilman, 1985, Macmillan Publishing Co., (hereinafter, Goodman and Gilman ") 959-960 page).The common example of antibacterial agent is ethanol and the tincture of iodine.Bactericide comprises the antibacterial agent that kills and wounds microorganism (for example microbial pathogens).
The composition that some embodiments expection as herein described comprises one or more BT compounds and one or more Antibiotique compositions (for example, concertedness antibiotic and/or enhancement antibiotic) as herein provided.Antibiotic is known in the art and generally includes medicine prepared by compound that the Institute of Micro-biology by a kind of kind of the microorganism by killing and wounding another kind produces, or the synthetic product with identical or similar chemical constitution and mechanism of action, for example, the medicine of destroy microorganisms in microorganism or on microorganism, comprise this medicine when local application.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 (for example, clindamycin), penicillase resistance 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, the 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 (for example, Washington University School of Medicine, The Washington Manual of Medical Therapeutics (the 32nd edition), 2007Lippincott, Williams and Wilkins, Philadelphia, PA:Hauser, AL, Antibiotic Basics for Clinicians, 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 the RS in Edson, Terrell CL.The aminoglycosides.Mayo Clin Proc.1999 May; 74 (5): 519-28.Such antibiotic reduces Bacterioprotein biosynthesis and bacteria growing inhibiting by combination inactivation bacterial ribosome subunit.Except this type of antibacterial character, aminoglycoside also shows bactericidal action by the cell wall destroyed in Gram-negative bacteria.
Aminoglycoside antibiotics comprises gentamicin, amikacin, streptomycin and other, and generally is considered to be used for the treatment of Gram-negative bacteria, mycobacterium and other microbial pathogens, although reported the case of resistant strain.Aminoglycoside does not absorb by digestive tract, therefore generally is considered to be unsuitable for oral formulations.Amikacin for example, although usually effectively resist gentamicin tolerant bacteria bacterial strain, usually in intravenous or intramuscular administration, this can cause patient's pain.In addition, the toxicity for example, to aminoglycoside antibiotics (amikacin) relevant can cause injury of kidney and/or irreversible hearing disability.
Although these character is arranged, the Orally administered collaborative BT/ antibiotic composition (for example, wherein antibiotic is not necessarily limited to aminoglycoside) that for example is used for the treatment of the epithelial tissue surface of bead chamber, intestines and stomach/gastral one or more positions of some embodiment expection disclosed herein.Some other embodiment it is also contemplated that composition as herein described and the method purposes as disinfectant, and disinfectant refers to the preparation that kills and wounds microorganism on the xenobiotic external surface or stop its growth.
Also as other local description of this paper, the BT compound can be the composition that comprises bismuth or bismuth salt and contain mercaptan (for example-SH or sulfydryl) compound, it comprises those (comprising its preparation method): Domenico etc. that describe 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 referring to for example U.S.6,582,719.Yet some embodiment is not so restriction, and can expect that other comprises bismuth or bismuth salt and containing the BT compound of the compound of mercaptan.Compound containing mercaptan can contain 1,2,3,4,5,6 or more mercaptan (for example-SH) group.In preferred embodiments, the 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 associate with the compound containing mercaptan by the covalent bond for example may reside in organo-metallic compound.For example, yet it is the BT compound of organo-metallic compound that the 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)CPDlCBis-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 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)GPD6BiS-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)GPD11Bis-Pyr-EDT(1:1/0.5)
18)CPD12Bis-Pyr/Tol(1:1/0.5)
19)CPD13Bis-pyr/PDT(1:1/0.5)
30)GPD14Bis-Pyr/Ery(1:1/0.5)
21) CPD15BiS-EDT/2 hydroxyl, propanethiol (1:1/1)
*for relatively, shown the atom ratio with respect to single bismuth atom, the stoichiometric proportion of the reactant based on using and bismuth and sulfur-containing compound form the known tendency of trivalent complex compound.Shown in atom ratio can be the accurate molecular formula to all kinds in customization agent.Numeral in bracket is the ratio (Bi for example: mercaptan 1/ mercaptan 2) " CPD ", compound of bismuth and the agent of (or a plurality of) mercaptan.
Can for example, according to fixed method preparation (U.S.RE37.793, U.S.6,248,371, U.S.6,086,921 and U.S.6,380,248 for the BT compound of some disclosure embodiment; Domenico etc., 1997Antimicrob.Agent.Chemother.41 (8): 1697-1703, Domenico etc., 2001Antimicob.Agent.Chemother.45 (5): 1417-1421), and, in some other embodiment, the BT compound can also be according to methodology preparation as herein described.Therefore, some preferred embodiment expection is as herein described for the preparation of the BT compound with especially for obtaining the synthetic method of the BT compound of monodispersed particulate form basically, wherein contains concentration for 50mM 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, at least 900mM or at least 1M the dissolving bismuth and 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 with for example comprise the second ethanolic solution containing the compound of mercaptan, in the condition and the time (concentration that, as described herein and those skilled in the art will appreciate that based on present disclosure that are enough to form the precipitation that comprises the particulate that contains the BT compound, solvent strength, temperature, pH, mix and/or the condition such as pressure) lower reaction and obtain reaction solution, the wherein said compound containing mercaptan is to be present in reaction solution to the mol ratio of about 3:1 with respect to the about 1:3 of 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, and Bis-EDT (solubility Bi preparation, 1:1.5); Compound 2A, and Bis-Bal (the anti-lewisite agent of bismuth-Britain (British anti-Lewisite) (bismuth-dimercaprol dimercaptopropanol, bismuth-2,3-dimercaprol dimercaptopropanol), 1:1); Compound 2B, Bis-Bal (1:1.5); Compound 3A Bis-Pyr (bismuth-PTO, 1:1.5); Compound 3B Bis-Pyr (1:3); Compound 4, and Bis-Ery (bismuth-dithioerythritol, 1:1.5); Compound 5, and Bis-Tol (bismuth-3, the 4-dimercapto toluene, 1:1.5); Compound 6, and Bis-BDT (bismuth-2, the 3-succinimide mercaptans, 1:1.5); Compound 7, and Bis-PDT (bismuth-1, the 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, the 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) (referring to for example table 1).
Do not expect bound by theory, think that the method for the BT of preparation compound of the present disclosure may expect to produce the composition that comprises the BT compound, wherein this composition has the character of one or more expectations, comprise easy large-scale production, raising product purity, 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 (aqueous solution of nitric acid that for example comprises bismuth nitrate) that comprises bismuth in some preferred embodiment.
In specific embodiments, have been found that the BT compound for preparing first according to method as herein described shows the favourable uniformity with regard to occurring as monodispersed microparticle suspending liquid basically with regard to it, according to some current preferred embodiment, each particulate has approximately 0.4 μ m to the about volume mean diameter of 5 μ m (VMD).Measuring of granularity can be called as volume mean diameter (VMD), mass median diameter (MMD) or mass median aerodynamic diameter (MMAD).Can be for example by clashing into (MMD and MMAD) or characterizing and carry out these measurements by laser (VMD).For liquid particle, for example, if keep environmental condition (standard humidity), VMD, MMD and MMAD may be identical.Yet, if humidity is not held, MMD and MMAD measured value will be less than VMD, this is due to the dehydration of clashing in measuring process.For the purpose of describing, VMD, MMD and MMAD measurement are considered under standard conditions, and the description that makes VMD, MMD and MMAD is suitable.Similarly, the powder size of MMD and MMAD is measured and also is considered to suitable.
As described herein, preferred embodiment relates to the monodispersed suspension containing the BT particulate basically.The BT deposition can be for example optimized in generation with clear and definite BT granularity of limited geometric standard deviation (GSD), to the accessibility of the expection target site in natural or artificial surfaces or on natural or artificial surfaces, and/or the experimenter is to the tolerance of the BT particulate used.The VMD of limited GSD restriction expection or the granule amount outside the MMAD size range.
In one embodiment, provide and there is approximately 0.5 micron to about liquid or the aerosol suspension of the particulate that contains one or more BT compounds disclosed herein of VMD of 5 microns.In another embodiment, provide and there is approximately 0.7 micron to the approximately VMD of 4.0 microns or liquid or the aerosol suspension of MMAD.In another embodiment, provide and there are approximately 1.0 microns to the approximately VMD of 3.0 microns or liquid or the aerosol suspension of MMAD.In some other preferred embodiment, provide comprise one or more approximately 0.1 to approximately 5.0 microns VMD or approximately 0.1, approximately 0.2, approximately 0.3, approximately 0.4, approximately 0.5, approximately 0.6, approximately 0.7, approximately 0.8 or approximately 0.9 micron to approximately 1.0, approximately 1.5, approximately 2.0, approximately 2.5, approximately 3.0, approximately 3.5, approximately 4.0, approximately 4.5, approximately 5.0, approximately 5.5, approximately 6.0, approximately 6.5, approximately 7.0, approximately 7.5 or the about liquid suspension of BT compound particulate of 8.0 microns, the BT compound that described particulate comprises preparation as described herein.
Therefore in some preferred embodiment, the monodispersed BT preparation of " basically " that this paper describes first, for example comprise the BT composition of BT compound that " basically " all particulates wherein have the particulate form of for example, volume mean diameter (VMD) in prescribed limit (approximately 0.4 μ m to about 5 μ m), comprise wherein at least 80%, 85%, 90%, 91%, 92%, 93% or 94%, more preferably at least 95%, 96%, 97%, 98%, 99% or more multiparticulates there are those compositions of the VMD in described size range.
The advantage of the novelty of the BT that these of the BT composition prepared according to synthetic method as herein described and relevant character have been described before providing and having surpassed, comprise lower cost and easily produce, and can allow the uniformity in its composition characterized in the mode be conducive to according to the one or more rules biddability in medicine, preparation and cosmetic standard.
In addition or alternatively, basically monodispersed BT particulate as herein described can advantageously be produced and do not needed micronizing,, for example, without grinding or the supercritical fluid processing of expensive and effort or be generally used for producing other device of particulate and program (, the 2008Adv.Drug Deliv.Rev.60 (3) such as Martin: 339; Moribe etc., 2008Adv.Drug Deliv.Rev.60 (3): 328; Cape etc., 2008Pharm.Res.25 (9): 1967; The 2004Pharm.Dev.Technol.9 such as Rasenack (1): 1-13).Therefore, the present embodiment provides basically the beneficial effect of microparticle formulation uniformly, that include but not limited to strengthen and solubilize character uniformly basically, the administration form (for example oral, suction or dermatology/skin wound localized forms) that is applicable to expection, the bioavilability of increase and other beneficial property.
BT compound microparticle suspending liquid can be used as aqueous formulation, as the suspension in aqueous solvent and organic solvent (comprising the halogenated hydrocarbons propellant) or solution, use as dry powder or with other form hereinafter described in detail, for example, comprise and contain the known wetting agent of preparation technique personnel, surfactant, mineral oil or other composition or additive to maintain the preparation of the single particulate in suspension.Aqueous formulation can pass through the liquid dispenser atomization, adopts for example waterpower or ultrasonic atomizatio.System based on propellant can be utilized suitable pressurization distributor.Dry powder can utilize the dry powder dispersal device that can effectively disperse containing the BT particulate.The granularity of expection and distribution can obtain by selecting appropriate device.
Also as mentioned above, the method of bismuth-mercaptan (BT) composition of the particulate that also provides preparation to comprise a plurality of BT of comprising compounds according to some embodiment this paper, basically all this particulates have approximately 0.1 to approximately 8 microns, and in some preferred embodiment approximately 0.4 micron to the about volume mean diameter of 5 microns (VMD).
Generally speaking, described method comprises the steps: that (a) is substantially free of the condition of solids of sedimentation and mixes under the time being enough to obtain: (i) comprise bismuth salt (containing the bismuth of 50mM concentration at least) and not containing the acidic aqueous solution of hydrophily, polarity or organic solubilized agent, be enough to obtain with (ii) and comprise by volume approximately 5%, 10%, 15%, 20%, 25% or 30% and the preferred about ethanol of the amount of the mixture of 25% ethanol; (b) be enough to form under the condition and time of the precipitation that comprises the particulate that contains described BT compound, to adding the ethanolic solution that comprises containing the compound of mercaptan in the mixture of (a) to obtain reaction solution, the wherein said compound containing mercaptan in described reaction solution to exist to the mol ratio of about 3:1 with respect to the about 1:3 of bismuth.
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 1M at least.In certain embodiments, acidic aqueous solution comprises at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth by weight.In some preferred embodiment, acidic aqueous solution can comprise by weight at least 5% or more nitric acid, 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 with lower 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 3the SH[m-sulfydryl]), ethyl mercaptan (C 2h 5the SH[e-sulfydryl]), 1-propanethiol (C 3h 7the SH[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-butyl group sulfydryl]), amyl hydrosulfide (C 5h 11sH[amyl group sulfydryl]), coacetylase, lipoamide, glutathione, cysteine, cystine, 2 mercapto ethanol, dithiothreitol (DTT), dithioerythritol, the 2-sulfydryl indole, TGase and can be available from the following mercaptan compound of Sigma-Aldhch (St.Louis, MO) any: (11-mercaptan undecyl) six (ethylene glycol), (11-sulfydryl undecyl) four (ethylene glycol), (11-sulfydryl undecyl) four (ethylene glycol) functionalized nm of gold, 1,1', 4', 1 " terphenyl-4-mercaptan, 1,11 – hendecane two mercaptan, 1,16-hexadecane, two mercaptan, 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, hot two mercaptan of 1,8-, 1,9-mercaptan in the ninth of the ten Heavenly Stems two, adamantane mercaptan, the 1-butyl mercaptan, the 1-decyl mercaptan, the 1-dodecyl mercaptans, the 1-heptanthiol, 1-heptanthiol (pure), 1-hexadecane mercaptan, the 1-hexyl mercaptan, 1-sulfydryl-(triethylene glycol), 1-sulfydryl-functionalized golden nanometer particle of (triethylene glycol) methyl ether, 1-sulfydryl-2-propyl alcohol, 1-mercaptan in the ninth of the ten Heavenly Stems, the 1-octadecanethiol, the 1-spicy thioalcohol, the 1-spicy thioalcohol, 1-pentadecane mercaptan, the 1-amyl hydrosulfide, the 1-propanethiol, 1-tetradecane mercaptan, 1-tetradecane mercaptan (pure), 1-hendecane mercaptan, 11-(1H-pyrroles-1-yl) hendecane-1-mercaptan, 11 – amino-1-hendecane mercaptides hydrochlorate, the bromo-1-hendecane of 11-mercaptan, 11-sulfydryl-1 – tip-nip, 11-sulfydryl-1 – tip-nip, 11-sulfydryl hendecanoic acid, 11-sulfydryl hendecanoic acid, 11-sulfydryl undecyl trifluoroacetate, 11-sulfydryl undecyl phosphoric acid, 12-sulfydryl dodecylic acid, 12-sulfydryl dodecylic acid, 15-sulfydryl pentadecanoic acid, 16-sulfydryl hexadecanoic acid, 16-sulfydryl hexadecanoic acid, 1H, 1H, 2H, 2H-perfluor decyl mercaptan, 2,2'-(ethylenedioxy) diethyl mercaptan, 2,3-succinimide mercaptans, the 2-butyl mercaptan, 2-ethyl hexyl mercaptan, 2-methyl isophthalic acid-propanethiol, 2-methyl-2-propanethiol, 2-benzene ethyl mercaptan, the fluoro-1-hexyl mercaptan of 3,3,4,4,5,5,6,6,6-nine (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, the 3-mercaptopropionic acid, the silica gel that 3-sulfydryl propyl group 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, the 6-mercaptohexanoic acid, 8-sulfydryl-1-octanol, the 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) list-11-(acetyl group sulfenyl) undecyl ether, mercapto succinic acid, the 3-mercapto-propionate, nanoTether BPA-HH, NanoThinks tM18, NanoThinks tM8, NanoThinks tMaCID11, NanoThinks tMaCID16, NanoThinks tMaLCO11, NanoThinks tMtHIO8, functionalized nano particle, the average M of PEG bis-mercaptan of spicy thioalcohol n8,000, PEG bis-mercaptan mean molecule quantities 1,500, PEG bis-mercaptan mean molecule quantities 3,400, S-(11 – bromo-n-11 base) thiacetate, S-(4-cyano group butyl) thiacetate, benzenethiol, triethylene glycol list-11-sulfydryl undecyl ether, trimethylolpropane tris (3-mercaptopropionic acid ester), [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol), a carborane-9-mercaptan, para-terpheny base-4,4 " bis-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) also adopts technology well known in the art.
The method of the production BT compound of describing before being different from, the method of BT produced according to the present invention, the BT product provides with microparticle suspending liquid, basically fine-grained VMD is approximately 0.4 to approximately 5 microns in some preferred embodiment, and is generally approximately 0.1 micron to approximately 8 microns according to some other embodiment.Method before also being different from, according to the present embodiment, bismuth be provided in to comprise concentration at least about 50mM to the bismuth of about 1M and amount at least about 0.5% to about 5% (w/w) and preferably be less than the nitric acid of 5% (w/w) and not containing in the acidic aqueous solution of hydrophily, polarity or organic solubilized agent.
In view of generally acknowledged technology is instructed: bismuth is water-fast (for example U.S.RE37793) when 50 μ M, bismuth in water unstable (for example, Kuvshinova etc., 2009Russ.J Inorg.Chem54 (11): 1816), and bismuth is even unstable in salpeter solution, unless the hydrophily of existence, polarity or organic solubilized agent, on this point, the inventive method provides advantage astonishing and beyong contemplation.For example, in the clearly description of all BT preparation methods (such as Domenico etc., 1997Antimicrob.Agents.Chemother.41:1697; U.S.6,380,248; U.S.RE37793; U.S.6,248,371), hydrophily solubilizer propane diols is that to dissolve bismuth nitrate required, and the bi concns of the solution of preparation and thiol reactant is far below 15mM, thereby has limited 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 accident has obtained higher concentration.Hydrophily, polarity or organic solubilized agent comprise propane diols (PG) and ethylene glycol (EG), and can comprise any of many known solubilizer, comprise polar solvent, for example glycerine and mannitol and other material of epoxy hexane and dimethyl sulfoxide (DMSO) (DMSO), polyalcohol (comprise for example PG and EG, also comprise polyethylene glycol (PEG), polypropylene glycol (PPG), pentaerythrite etc.), polyhydroxy-alcohol for example.The miscible organic matter of the 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 can for example, such as the system of using Catalan etc. according to solvent polarity/polarizability (SPP) scale value (1995Liebigs Ann.241; Also referring to Catalan, 2001Handbook of Solvents, Wypych (editor), Andrew Publ., NY, and the list of references wherein quoted) selective solvent, comprise those of hydrophily, polarity or organic solubilized agent of being commonly used for provided herein, according to the system of Catalan etc., for example, glassware for drinking water has 0.962 SPP value, and toluene has 0.655 SPP value, and the 2-propyl alcohol has 0.848 SPP value.Described for based on 2-N, N-dimethyl-right ultraviolet measurement of the fluoro-7-nitrofluorene of 7-nitrofluorene/2-probe/homomorphism is measured the method (Catalan etc., 1995) of solvent SPP value.
Solubility properties based on particular B T composition, have expection SPP value solvent (no matter as pure one-component solvent still as 2,3, the solvent mixture of 4 kind or more kinds of solvents; About the solvent compatibility, referring to for example Godfrey1972Chem.Technol.2:359) can with reference to present disclosure, easily be determined 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, describe respectively polarity, hydrogen bonding electromotive force and the dispersion force interaction electromotive force of solvent.In certain embodiments, the peak of the solvent that the bismuth salt that description comprises bismuth dissolves therein or the solubility parameter of cosolvent system can provide the restriction of the aqueous solution that comprises bismuth salt, for example, according to the method for the preparation of particles B T composition as herein described.For example, higher δ h value will have larger hydrogen bonding ability, and therefore to solvent molecule for example glassware for drinking water larger affinity is arranged.Therefore the maximum observation of higher solvent δ h may be for wherein expecting that more the situation of hydrophilic environments is preferred.
As limiting examples, can prepare according to following reaction scheme by the BisEDT had with structure shown in following formula I:
Figure BDA00002887768300501
In brief, and as nonrestrictive illustrative example, can be 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 (approximately 0.575 mole), for example Bi (NO 3) 3solution (for example, 43%Bi (NO 3) 3(w/w), 5% nitric acid (w/w), 52% water (w/w), can be available from Shepherd Chemical Co., Cincinnati, OH), slowly add subsequently absolute ethyl alcohol (4L).Can add 72.19mL (0.863 mole) 1 to the 1.5L absolute ethyl alcohol by using the 60mL syringe, the 2-dithioglycol, then stir and within 5 minutes, prepare separately mercaptan compound for example 1, the ethanolic solution (1.56L) of 2-dithioglycol [～0.55M].1,2-dithioglycol (CAS540-63-6) and other mercaptan compound can be available from for example 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, stir and spend the night to form reaction solution.According to some preferred embodiment, containing the compound of mercaptan, can be present in reaction solution to the mol ratio of about 3:1 with respect to the about 1:3 of bismuth.Making the product sedimentation formed is the precipitation that comprises particulate described herein, then by filtering collecting precipitation and washing to obtain successively the BisEDT of yellow amorphous powder solid shape with ethanol, water and acetone.Crude product can under agitation be dissolved in absolute ethyl alcohol again, then filters and successively with the ethanol washing several times, washs several times with acetone subsequently.Powder after washing can grind in 1M NaOH (500mL), filter, and water, ethanol and acetone washs to provide the particles B isEDT of purifying successively.
According to non-limiting theory, the bismuth anti-bacteria produces the ability of Extracellular Polymers (EPS) (for example extracellular polysaccharide of bacteria), and this inhibition causes biofilm formation to reduce.Think that bacterium adopts glue sample EPS to adhere for biomembrane.According to infecting character, biofilm formation and EPS processing can promote bacteriosis originality, for example disturb wound healing.Yet independent bismuth is as getting involved agent without therapeutic action, but usually used as complex compound for example the part of BT use.Therefore, bismuth-mercaptan (BT) is to comprise the compound produced by bismuth and mercaptan compound chelating and a based composition that shows the antimicrobial therapy effect of the bismuth significantly improved.BT shows anti-infective, antibiont film and immunoregulation effect significantly.Bismuth-mercaptan effectively resists the spectrum microorganism, and not affected by antibiotic resistance.BT, with the concentration prevention biofilm formation of significantly low (inferior suppress), prevents many pathogene features of common wound pathogens with same inferior inhibition level, can in animal model, prevent septic shock, and can with many antibiotic synergisms.
As described herein, this concertedness of antibacterial action when one or more specify BT and one or more appointment Antibiotique composition combinations is not easy according to independent antibiotic and BT, the function Characteristics of specific bacteria type to be predicted, but surprisingly, can produce by select particular B T-antibiotic combinations according to concrete bacterial community, described selection comprises to be identified and has Gram-negative bacteria or gram-positive bacteria (or both).For example, as disclosed herein, with the synergistic antibiotic of some BT, can comprise amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or other lincoln amides antibiotics), Daptomycin
Figure BDA00002887768300511
doxycycline, gatifloxacin, gentamicin, Imipenem (imipenim), lavo-ofloxacin, Linezolid
Figure BDA00002887768300512
one or more in minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin.In vitro study shows, for example, separately poor to gentamicin, Cefazolin, Cefepime, Sulfamethoxazole, Imipenem or lavo-ofloxacin susceptibility or any one in these antibiotic shown to significant susceptibility when insensitive MRSA is exposed to antibiotic under BT compd B isEDT exists at all.Therefore, some embodiment that this paper expects is clearly expected wherein can comprise that BT compound and one or more are selected from amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or other lincoln amides antibiotics), Daptomycin
Figure BDA00002887768300513
doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid
Figure BDA00002887768300514
the composition of the antibiotic combination of minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin and/or method, and some other embodiment expection of this paper expection 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
Figure BDA00002887768300516
the antibiotic BT compound of minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin and composition and/or the method for one or more antibiotic combinations.Note, in this environment, gentamicin and tobramycin belong to aminoglycoside antibiotics.The Domenico in addition clearly got rid of from the embodiment of some expection etc., 2001Agents Chemother.45:1417-1421; Domenico etc., 2000Infect.Med.17:123-127; Domenico etc., 2003Res.Adv.In Antimicrob.Agents & Chemother.3:79-85; Domenico etc., 1997Antimicrob.Agents Chemother.41 (8): 1697-1703; Domenico etc., the 1999J Antimicrob.Chemother.44:601-605 such as 1999Infect.Immun.67:664-669:Huang; Veloira etc., 2003J Antimicrob.Chemother.52:915-919; Wu etc., 2002Am J Respir Cell Mol Biol.26:731-738; Halwani etc., 2008Int.J Pharmaceut.358:278; Halwani etc., some composition and the method in 2009Int.J.Pharmaceut.373:141-146, described, wherein it should be noted that during these openly and do not instruct absolutely or imply monodispersity particles B T composition as disclosed herein.
Therefore as described herein, in some preferred embodiment, provide with comprising particles B T as herein described and optionally also comprise composition and the method that the antibiotic composition of concertedness and/or enhancement is treated plant, animal or human experimenter or goods in some other embodiment.Various equivalent modifications will be appreciated that the suitable agricultural that wherein may need this treatment, clinical, business, industry, manufacturing industry, family expenses and other circumstances and condition based on the disclosure, its standard is definite at medical domain, especially comprises the medical speciality relevant with other such as surgery, battle surgery, dermatology, Wound medicine, geratology, cardiovasology, metabolic disease (such as diabetes, obesity etc.), infection and inflammation (being included in for example epithelial layer of glandular tissue of respiratory tract or intestines and stomach or other epithelial tissue surface) and son specialty.
According to embodiment as herein described, use be used for the treatment of on natural or artificial surfaces or preferred composition that the bacterium in natural or artificial surfaces infects can comprise the composition that comprises in certain embodiments bismuth-mercaptan as herein described (BT) compound, and for example, in some difference but also comprise other compound known in the art, the composition of one or more Antibiotique compositions as herein described in related embodiment.BT compound and their method of preparation are open at this paper, and are disclosed in such as (1997Antimicrob.Agent.Chemother.41 (8): 1697-1703 such as Domenico; 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 as mentioned above, some preferred BT compound is to contain and those of bismuth containing the compound ions bonding of mercaptan or ligand complex or bismuth salt, for example comprise the composition with the bismuth of sulfur-containing compound chelating, and some other preferred BT compound is to contain and those of the bismuth of compound covalent bonding containing mercaptan or bismuth salt.Preferred monodispersed particles B T composition basically as described herein also.The effort of not infecting according to previous treatment bacterium, also not according to before the sign of any compound of describing first of this paper in other environment (as the purposes had in promoting natural and/or artificial surfaces therapeutic combination and method as herein described), can predict and use the inventive method of this compounds will there is beneficial effect as herein described.
According to preferred embodiment, the method that is used for the treatment of natural or artificial surfaces is provided thus, comprise at least one particles B T compound as herein described of described surface applied.In certain embodiments, described method also comprises simultaneously or uses at least one Antibiotique composition successively and with any order, in some preferred embodiment, can be wherein concertedness antibiotic as herein described, 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, penicillase resistance PCs or Aminopenicillin antibiotic.Useful antibiotic is discussed in the other places of this paper and also is described in for example Washington University School of Medicine clinically, The Washington Manual of Medical Therapeutics (the 32nd edition), 2007Lippincott, Williams and Wilkins, Philadelphia, PA; And Hauser, AL, Antibiotic Basics for Clinicians, 2007Lippincott, Williams and Wilkins, Philadelphia, PA.
As described herein, some embodiment is derived from following discovery beyong contemplation: infect for the bacterium that comprises gram-positive bacteria, preferably treat effective preparation and can comprise BT compound (BisEDT for example, bismuth: 1,2-dithioglycol; BisPyr, bismuth: PTO; BisEDT/Pyr, bismuth: 1,2-dithioglycol/PTO) and rifamycin or BT compound and Daptomycin (
Figure BDA00002887768300531
cubist Pharmaceuticals, Lexington, MA) or BT compound and Linezolid (
Figure BDA00002887768300532
pfizer, Inc., NY, NY) or BT compound (for example, BisEDT, bismuth: 1,2-dithioglycol; BisPyr, bismuth: PTO; BisEDT/Pyr, 1,2-dithioglycol/PTO) and ampicillin, Cefazolin, Cefepime, chloramphenicol, clindamycin (or another kind of lincoln amides antibiotics), Daptomycin bismuth:
Figure BDA00002887768300541
doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid
Figure BDA00002887768300542
one or more of NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin.
Also as described herein, some embodiment is derived from following discovery beyong contemplation: infect for the bacterium that comprises Gram-negative bacteria, preferably treat effective preparation and can comprise BT compound and amikacin.Some related embodiment expection for example, treats with BT compound and another kind of antibiotic (another kind of aminoglycoside antibiotics) infection that comprises Gram-negative bacteria, and described another kind of aminoglycoside antibiotics is not gentamicin or tobramycin in certain embodiments.Therefore in view of these embodiments, the embodiment expection methodology known according to the medical microbial those skilled in the art that other is relevant, by Gram-positive or the gram-negative standard known, identify in natural or artificial surfaces or lip-deep one or more bacterial communities or subgroup, as a step selecting to be included in the suitable Antibiotique composition in the preparation of using according to the inventive method.
Composition as herein described and method (for example can be applicable in diversity of settings microorganism, bacterium, virus, yeast, mould and other fungi, microorganism parasite etc.) processing, it usually for example, for example, completes by compound as herein described (, separately or with one or more particles B T of one or more concertednesses disclosed herein and/or enhancement antibiotic combinations) is applied or is applied to microorganism site (being present on natural or artificial surfaces or the microorganism in natural or artificial surfaces).These self-faceds plant (for example include but not limited to, 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.), the mammalian tissues (epithelial cell that for example, comprises skin, scalp, intestines and stomach gland lining, oral cavity etc., endothelial cell, cell and tissue film such as peritoneal membrane, pericardium, pleura, periosteum, meninx and sarcolemma etc., cornea, sclera, mucous membrane etc., and other mammalian tissues muscle for example, heart, lung, kidney, liver, spleen, gall-bladder, pancreas, bladder, neural, tooth, bone, joint, tendon, ligament etc.) the upper surface of finding, and (for example also can be included in any position of discovery microorganism existence on goods, business, house, industry, education, health care and other mechanism's building walls, 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, (for example comprise cask, automobile, railway equipment, ships and light boats, boats and ships, shell, rudder, anchor and/or screw surface, interior handle and ballast tank and other inner 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 that the product of natural and/or artificial surfaces is to improve the resistance of product to microbial infection; Reduce biomembrane; Prevent that bacterium is converted into biomembrane; Prevention or inhibition infected by microbes; Prevent corruption; And any other purposes as herein described.These reagent also can be used for multiple anti-viral uses, comprise prevention or stop for example, by the virus infections of bleb coe virus (cytomegalovirus, herpes simplex virus type 1 and herpes simplex virus type 2) and/or by the infection of other virus.In this respect, described reagent can be used for prevention or by various virus (for example stops, 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.(for example, corium solani; Potatovirus A, M, S, X or Y; The spotted wilt of tomato poison; The virus 3 that the vine leaf curl is relevant; Plum pox virus; Lactuca virus 1; The garcinia mangostana mosaic virus; The light property of pepper mottle virus; Tomato mosaic virus; Tobacco mosaic virus; Mottle virus; The celestial necrotic spot virus of phoenix etc.).
Other inside or the outside pharmaceutical use of antimicrobial as herein described comprise, but for example yeast and mycotic infection be (for example to be not limited to treatment or pre-bacteriological protection infection, tuberculosis, fungal infection, Mycotoruloides (for example, Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Dublin candida albicans) or Cryptococcus or other fungi), Helicobacter pylori infection and peptic ulcer.In one embodiment, with usually not lethal to bacterium but its dosage that still enough reduces protectiveness polysaccharide layer (it will resist innate immune reaction in addition) is used described dose.Therefore this technology is believed to be helpful in the degree that the bacterium of for example, eradicating immune-mediated in the situation of not damaging mankind's symbiotic microorganism (, normal intestinal flora etc.) infects the possible situation of antibiotic of applying.
for applying and process the particulate bismuth-mercaptan of water pipe.In one embodiment, this paper is provided for preventing on the inner surface with lower device or outer surface and/or controlling (, slow down, postpone, suppress) biofilm development, disrupting biofilm or reduce the method for biomembranous amount: water pipe (water pipe that for example, dentist, dental hygienist and other mouth care expert and nursing staff use) or other water delivery apparatus (comprising pipe, pipeline, tap, drinking bowl, shower nozzle); (for example, perhaps contact or send any Other Instruments of the water of being drunk or applying by people or non-human animal or device (dental instruments that for example, comprises high-speed dental drill, air-water syringe) and cleaning device or instrument ).These methods also are used in prevention in water pipe or water delivery apparatus, reduce, suppress, eliminate or end bacterium, fungi and/or protozoic growth and differentiation.These methods comprise application, flushing, connect or adhere to the surface of particles B T compound to water pipe or water delivery apparatus.
Biomembrane is the main microscope colony by naturally occurring bacterium and Fungal community composition.Microorganism forms thin layer comprising on dental water delivery system and the surface such as other water delivery apparatus of shower nozzle, tap and pipe.The water that is used as cooling agent and irrigation in dental procedure can be by microorganism severe contamination (for example, referring to,, environmental protection board web epa.gov/safewater/mcl/html).Pathogene microorganism or the opportunistic pathogen in dental water pipe and instrument, found 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 pass through pipeline or device, continue to emit biomembranous bacterium and other microorganism of existing in water pipe or water delivery apparatus.Patient and clinical staff are exposed to the microorganism existed in the fine droplet of pipeline or delivery apparatus ejection or thin water smoke.
Using and consuming, the aerobic heterotrophic plate counts (HPC) of Center for Disease Control's suggestion should have≤500CFU/ml of number of bacteria in the water of the cooling agent/irrigation as non-operation dental procedure for water in dental applications.Stricter standard is proposed by ADA (ADA), the bacteria levels of the contain≤200CFU/ml of water that its suggestion is used in dental treatment.The measure that maintains low-level total plate count in the dental water system comprise use antimicrobial (referring to, for example, McDowell etc., J.Am.Dent.Assoc.135:799-805 (2004)); Disinfectant based on hydrogen peroxide (referring to, for example, Linger etc., J.Am.Dent.Assoc.132:1287-91 (2001)); Before using and afterwards to the normal developing of water pipe; The maintenance of water pipe and delivery system; The use of filtration system; For example, use such as the chemical substance of disinfectant (, the bleaching agent 1:10 of dilution, glutaraldehyde, food stage ethanol, product based on Chlorhexidine); Heat is eradicated (thermal eradication); Copper silver ion; Chlorine dioxide; Ultraviolet ray; Ozone; The disinfectant combination (for example, iCX (Adex, Newburg, OR): SODIUM PERCARBONATE, silver nitrate and cationic surfactant and silver ion catalyzer.
Can be used for prevention and/or control (that is, slow down, postpone, suppress) biofilm development, disrupting biofilm or be reduced in water pipe or the interior or outer surface of water delivery apparatus on the alternative antibacterial agent of biomembranous amount comprise particles B T compound as herein described (or the composition that comprises at least one particles B T compound).Can be using particles B T compound as gel, spraying, paste, liquid or powder or other form well known by persons skilled in the art be introduced into manually or automatically in water pipe, water conduit system and water delivery apparatus.In specific embodiment, particles B T compound in powder or liquid form is mixed with formulated product with at least one or the multiple other composition that may comprise the active excipient of bioactive ingredients that at least one is other and/or inanimate object, described product is regularly sent or injected in water pipe, water delivery apparatus or water conduit system.Can use multiple methods known in the art to prepare composition by those skilled in the art and prepare composition.For example, can use the particles B T compound of the antimicrobial effective dose that can combine with DMSO.In conventional the use, need to be enough to prevent the level of the particles B T compound of biofilm formation.Yet in other embodiments, the level of particles B T compound can the higher biomembrane to exist in water pipe, water delivery apparatus or water conduit system for minimizing, removal, destruction or elimination.
Also can prepare particles B T compound in order to slowly discharge from the composition that comprises the particles B T compound that is applied to water pipe, water delivery apparatus or water conduit system.Also particles B T compound can be incorporated to coating, it can be applied, fix, adhere to or make in some way the inner surface of its contact water pipeline, delivery vehicle or system.The composition that comprises particles B T compound can be gel (for example, hydrogel, mercaptides polymer (thiomer), aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.Slow releasing composition can be sent the particles B T compound 1,2,3,4,5,6 or 7 days (a week) of antimicrobial effective dose or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.
Can be by particles B T compound (or the composition that comprises particles B T compound) and at least one other antimicrobial (, second, third, fourth class antimicrobial) combination, when combined administration, it has enhancing or Synergistic antimicrobial effect as described herein.For example, can be observed the anti-microbial effect of enhancing while, using together with the antimicrobial of particles B T compound and iron chelating.By at least one combination in particles B T compound and oxidant, microbicide or disinfectant.Can use the particles B T compound that utilizes hydrophobicity mercaptan (for example, the sulfo-chlorophenol) to prepare, and its BT compound poorer than hydrophobicity shows the ability of better adhesion water pipe and water delivery apparatus and system.BT compound with net negative charge (for example has 1:2 mol ratio (bismuth: mercaptan) those) also can have good cohesive.
Can be by particles B T compound (and the composition that comprises particles B T compound) and sodium bicarbonate or another alkali compounds or combinations of substances use.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.Mixture or dissolving that can be using sodium bicarbonate and particles B T compound combination as powder or be suspended in powder as herein described, spray, gel, paste or liquid.In other embodiments, can and can contribute to maintain required alkaline pH and also can there is clean other alkali metal hydrogencarbonate or carbonate material (for example, saleratus or calcium carbonate) with deodorizing performance particles B T compound to be used in combination.
As another example, the following combinations of substances of particles B T compound (or the composition that comprises particles B T compound) and one or more can be used. antimicrobial: for example, Chlorhexidine; The bloodroot extract; Metronidazole; Quaternary ammonium compound (for example Cetylpyridinium Chloride); Biguanides (for example, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (for example, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; The alkyl hydroxy benzoic ether; The cation antimicrobial peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii (Coleus forskohlii) essential oil; Silver or collargol antibacterial agent; Antibacterial agent based on 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: for example, sodium fluoride and stannous fluoride, amine fluoride, sodium monofluorophosphate, sodium trimetaphosphate, zinc citrate or other zincon, and casein. bacterial plaque buffer (Plaque buffer): for example, urea, calcium lactate, calcium glycerophosphate and polyacrylic acid strontium class. vitamin: for example, vitamin A, C and E. plant the thing extract. anticalculus agent: such as alkali metal pyrophosphate salts, containing polymer, Organophosphonate and the phosphocitrate etc. of hypophosphites. biomolecule: for example, bacteriocin. preservative. opacifier. pH adjusting agent. sweetener. surfactant: for example, anion, nonionic, cation and amphion or amphoteric surfactant, from the saponin of vegetable material (for example, referring to,, U.S. Patent No. 6485711). abrasive material particles: for example, the particulate abrasive material of silica, aluminium oxide, calcium carbonate, Dicalcium Phosphate, calcium pyrophosphate, hydroxyapatite, trimetaphosphate, insoluble hexametaphosphate, cohesion, chalk, fine grinding natural whiting etc. humidizer: for example, glycerine, sorbitol, propane diols, xylitol, lactitol etc. adhesive and thickening agent: for example, sodium carboxymethylcellulose, hydroxyethylcellulose
Figure BDA00002887768300591
(for example, polyacrylate and C974P are for example for xanthan gum, gum Arabic, synthetic polymer
Figure BDA00002887768300592
).Enhanced activity composition for example antimicrobial is sent polymerizable compound.The pH of buffering oral care composition and ion strength buffer solution and salt. decolorizer: for example, per-compound (for example, peroxide diphosphonic acid potassium). effervescent system: for example, the sodium bicarbonate/citric acid system.
In another embodiment, particles B T compound as herein described (or the composition that comprises particles B T compound) and at least one or the combination of multiple antibiont membrane reagent can be used 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 the LuxS-Dependent or plant between colony induction signaling Cucumber (referring to, for example, U.S. Patent No. 7,427,408) contribute to control biomembranous growth and/or propagation.For example, exemplary agents comprises or N-that combine or independent (3-oxo dodecanoyl)-L-homoserine lactone (OdDHL) block compound and N-butyryl-L-homoserine lactone (BHL) analog (referring to, for example, U.S. Patent No. 6,455,031).But the oral hygiene composition local delivery that comprises particles B T compound and at least one antibiont film for destroy and stop bacterial biof iotalm and be used for the treatment of periodontosis (referring to, for example, U.S. Patent No. 6,726,898).
Can strengthen the effect as the particles B T compound of antibiont membrane reagent 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 to approximately 37 ℃ to approximately between 60 ℃ or to approximately 37 ℃ to approximately between 100 ℃.In other embodiments, by pipeline, delivery vehicle or system heating to approximately 45 ℃ to approximately between 50 ℃; To approximately 50 ℃ to approximately between 55 ℃; To approximately 55 ℃ to approximately between 60 ℃; To approximately 60 ℃ to approximately between 70 ℃; To approximately 70 ℃ to approximately between 80 ℃; To approximately 80 ℃ to approximately between 90 ℃; Perhaps to approximately 90 ℃ to approximately between 100 ℃.In specific embodiment, by extremely approximately 37 ℃ of pipeline, delivery vehicle or system heatings.In another specific embodiment, by extremely approximately 55 ℃ of pipeline, delivery vehicle or system heatings.As understood by those skilled in the art, depend on the temperature applied, the time of heating pipeline, delivery vehicle or system can change.For example, by pipeline, delivery vehicle or system heating during to lower temperature, when reaching identical anti-microbial effect required time ratio and being heated to higher temperature, required time is more of a specified duration.Those skilled in the art can easily determine in the suitable time that exposes at each temperature pipeline, delivery vehicle or system.
Particles B T compound (or the composition that comprises particles B T compound) can be used to reduce or prevent biofilm development together with other form.For example, particles B T compound and oxidative chemicals, scale removal compound, biofilm disruption thing or rinse-system as described herein and that use in the art can be used in combination.
the composition that comprises particulate bismuth-mercaptan and the purposes of repairing for the tooth body.In other embodiments, this paper provides the particles B T compound that comprises for preventing and/or treating carious tooth and the composition of dental amalgam and particles B T compound and dental composite.At present, to the treatment that only has of dental caries pathology, be to be used as the tooth reparation of the inert substance that prevents further rotten obstruction by replacement.Dental amalgam and dental composite are most commonly used to be subject to the reparation of the tooth of caries affected.
It is the major reason of repairing failure that the recurrent edge rots, particularly when dental composite is used for repairing.Between composite and dental tissue the existence of the bacterium of interface field planting may be repairing failure key factor (referring to, for example, Hansel etc., J.Dent.Res.77:60-67 (1998)).In the research of Portugal (Casa Pia Study, 1986-1989), carry out 1,748 postoperative reparation, and wherein 177 times (10.1%) failure in research process.It is main cause failed in mercury alloy and composite repair that the recurrent edge rots, and mortality reaches respectively 66% (32/48) and 88% (113/129) (referring to .JADA2007 such as Bernardo; 138:775-83).Polymerization shrinkage is the contraction in the composite material solidification process, its be regarded as postoperative edge seepage main cause (referring to, for example, Estefan etc., Gen.Dent.2003; 51:506-509).
Attempted Antimicrobe compound and reagent are incorporated in the reparation material such as dentin-bonding systems (DBS), but achievement is limited.Have the composite of anti-microbial properties and mercury alloy and other exploitation of repairing material can contribute to prevent the Secondary cases carious tooth (referring to, for example, Imazato, Dent.Materials19:449 (2003)).The present embodiment contains the replacement of the antibacterial agent that uses remediation composition capable preparation as herein described, it provides advantage disclosed herein as this area description and the particles B T compound of this description, comprises the enhancing of a series of antimicrobial acivities, dissolubility and bioavilability, antibiont membrane interaction, avirulence, antibiotic effect and other character as described herein.
In certain embodiments, provide the composition that comprises particles B T compound and dental composite.Dental composite contains polymerisable resin base usually, and this polymerisable resin base contains ceramic filler.Particles B T compound and the method for implementing by this area can be used dental composite known in the art any being used in combination (referring to, for example, O'Brien, Dental Materials and Their Selection (Chicago:Quintessence Publishing Co.) (2002); Powers etc., Dental Materials:Properties and Manipulation (New York:Mosby) (2007); Roeters etc., J.Dent.32:371-77 (1998)).
In other embodiments, provide the composition that comprises 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 use, thus by silver as with the alloy of other element.This alloy is commonly referred to dental amalgam, perhaps jointly, alloy be called " dental amalgam alloy " (referring to, for example, International Standards Organization's standard (International Standars Organization Standard) ISO1559, Dental Materials-Alloys for Dental Amalgam (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 the amalgamation reaction.The 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 approximately 70% silver medal, 16% tin and 13% bronze medal.Mercury alloy on the same group can not contain 30% bronze medal at the most, and it becomes the high copper content mercury alloy.Before clinical placement, mercury alloy is mixed with the 1:1 weight ratio with mercury.Therefore, complete after the mercury content repaired of dental amalgam be by weight approximately 50%.In conventional dental amalgam, silver obtains crystal structure with the ratio of tin, and it is essentially the intermetallic compound Ag3Sn that is called gamma (γ) phase.The accurate percentage of this phase determines the dynamics of amalgamation reaction and many character of gained mercury alloy structure.Use higher copper dispersion alloy, microstructure is the mixture of gamma phase and congruent melting silver-copper phase normally.Different manufacturers provide multi-form mercury alloy; but be generally fine grained; be shaped as spherical or irregularly shaped; granularity is that about 25-35 micron (reaches new evaluation health risk Science committee (Scientific Committee on Emerging and Newly Identified Health Risks) (SCENIHR) referring to emerging; European commission: healthy and consumer protection Directorate-General DG (Directorate-General, Health & Consumer Protection), on May 6th, 2008, network address:
ec.europa.eu/healh/ph_risk/committees/04_Scenihr/docos/scenihr_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 respectively the possibility of generation or the recurrence of carious tooth and/or inflammation).The composition that comprises particles B T compound can the mucus adhesive composite, described composition is applied to dental surface and/or gum or oral mucosa, and it can be to adhere to surface or to send any form of the active component of effective dose pharmaceutically to required surface to a certain extent.Also particles B T compound can be formulated as by the composition that is applied to oral cavity and slowly discharge.For example, composition can be gel (for example, hydrogel, mercaptides polymer, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.This gel or liquid apply preparation can inside or applications to mercury alloy, compound or other repairing composition.Slow releasing composition can be sent pharmacy effective dose particles B T compound 1,2,3,4,5,6 or 7 days (a week) or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.Can by many methods known in the art, be prepared by those skilled in the art by said composition.
The composition that comprises particles B T compound for the reparation of tooth body can comprise the glass ion adhesive; Glass composite (giomer) (forming by fluoride and the poly-acid reaction of liquid that makes to contain glass); Complex (compomer) (but glass-filled particle that polymerisable dimethyl allene acid resin and ion leach).Compomer can further comprise fluoride.
The composition of the particles B T compound that comprises the surface that is applied to tooth, mercury alloy or composite can further comprise one or more other surfactants that strengthen anti-microbial effect.The exemplary antimicrobial used in the composition that comprises particles B T compound for example comprises, Chlorhexidine, bloodroot extract, metronidazole, quaternary ammonium compound (for example Cetylpyridinium Chloride), biguanides (for example, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine), with the halogenated bisphenol compound (for example, 2, 2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound, the alkyl hydroxy benzoic ether, the cation antimicrobial peptide, aminoglycoside, quinolone, Lincoln's acid amides, penicillin, cephalosporin, macrolide, tetracycline, and other antibiotic known in the art, Taurolidine or tauroflex, A-dec ICX, Coleus forskohlii (Coleus forskohlii) essential oil, silver or collargol antibacterial agent, antibacterial agent based on tin or copper, the chlorine or bromine oxidant, Mai Luka (Manuka) oil, skin Sa grass (oregano), thyme, rosemary, Xue MingRosma rinus officinalis or other medicinal herbs extract and grapefruit seed extract, anti-inflammatory or antioxidant, such as brufen, Flurbiprofen, aspirin, Indomethacin, aloe (aloe vera), turmeric, Olive leaf P.E, cloves, panthenol, retinol, omega-fatty acid, gamma-Linolenic acid (GLA), green tea, ginger, grapestone etc.
Composition also can further comprise one or more pharmaceutically acceptable carriers, for example, and starch, sucrose, water or water/pure system, DMSO etc.Composition also can comprise surfactant, for example anion, nonionic, cation and amphion or amphoteric surfactant, or can comprise saponin from vegetable material (referring to, for example, U.S. Patent No. 6,485,711).Also can comprise the pH of the buffer compositions for orally using and buffer and the salt of ion strength.Can comprise other optional member: bleaching agent (such as per-compound), peroxide diphosphonic acid sylvite, effervescent system (such as the sodium bicarbonate/citric acid system) etc.
the composition that comprises particulate bismuth-mercaptan and for oral hygiene be used for the treatment of stomatitis the purposes of disease and infection.in another embodiment, will comprise the composition preparation of particles B T compound for oral use, and can be used for prevention or reduce growth of microorganism and infected by microbes and the inflammation for preventing and/or treating oral cavity in oral cavity.Therefore, these compositions are for prevention or treatment (that is, the possibility that occurs or recur is grown, reduced in reduction or inhibition) dental plaque, halitosis, periodontosis, gingivitis and other mouth infection.The oral cavity composition that comprises particles B T compound also can be used for prevention and/or control (that is, slow down, postpone, suppress) oral surfaces, particularly tooth or gum on the biofilm development that exists, disrupting biofilm or reduce biomembranous amount.
Residual, the bad oral hygiene of food particle and bad oral health and improperly artificial tooth clean can impel between tooth, around gum and the growth of microorganism on tongue.Lasting growth of microorganism 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.For example, when lacking suitable mouth care (, brush teeth, dental floss tooth-cleaning), can then cause more serious infection, for example periodontosis and jaw infect.
Good oral hygiene is not only for oral health, but also is important for the prevention of some chronic symptom.The bacterial growth of controlling in oral cavity can contribute to reduce the cardiopathy risk, keeps memory and reduce infection and the inflammation risk in other position of health.The diabetic occurs that the risk of serious gum problem is higher, and can contribute to control blood sugar by the risk that keeps good oral health to reduce gingivitis.The pregnant woman perhaps more may suffer from gingivitis, and some researchs show, between gum disease in the pregnant woman and premature labor, low birth weight infant, relation is arranged.
Bacterium is the main pathogens of periodontosis.Can find to surpass 500 kinds of bacterial isolateses (Kroes etc., Proc.Natl.Acad.Sci.USA96:14547-52 (1999)) in dental plaque.Bacterium has been evolved as surviving as biomembrane in the environment in dental surface, gingival epithelium and oral cavity, and this has increased the difficulty for the treatment of periodontitis.Antibacterial agent and the current antibiotic that is used for the treatment of this infection do not kill all attack organisms usually.To some bacteria culture, the use of invalid material can cause the propagation of antibacterium bacterial classification.In addition, these materials can cause the side effect that makes the people unhappy, for example allergy, inflammation and tooth discoloration.
Bacterial plaque is the biomembrane that is adhered to securely dental surface, restoration and prosthetic device.Control biomembranous main method in oral cavity and be by mechanical cleaning (that is, brush teeth, dental floss tooth-cleaning etc.).Do not carrying out in such clean initial two days, dental surface is mainly the facultative coccus of the Grain-positive institute field planting of streptococcus bacterial classification.The bacterium secretion contributes to the outer rete malpighii of born of the same parents that bacterium is anchored to surface and the bacterium adhered to is provided to protection.Once the bacterium that dental surface is attached covers, microcolony forms.Biomembrane is mainly by the cell division of the bacterium that adheres to, but not by novel bacteria adhere to grow.The doubling time that bacterium forms patch is fast in developing in early days, and slower in more ripe biomembrane.
The copolymerization collection appears when bacterial clump adheres to the bacterium that has been attached to film subsequently.The result of copolymerization collection is the compound set that forms different bacterium connected to one another.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 is flouring in this protection of the environment, causes the biomembranous formation of phagocytosis under ripe gum.Until become by a kind of biomembrane mainly be comprised of gram-positive bacteria the biomembrane that comprises gram-negative anaerobic bacteria, gingivitis just appears.Start to form gingiva lower bacteria microcolony (mainly being formed by gram-negative anaerobic bacteria) between 3 and 12 weeks after gum edge plaque formation starts in gingival sulcus.
In biomembrane, shielded Bacterial microcolony has resistance to antibiotic (systemic administration), antibacterial agent or disinfectant (local application) and immune defense usually.For example, the antibiotic dosage that kills the free bacterium that swims need to increase nearly 1,500 times to kill the biomembrane bacterium.Under this high concentration, these antibacterial agents also trend towards to the patient toxic (referring to, for example, Coghlan1996, New Scientist2045:32-6; Elder etc., 1995, Eye9:102-9).
Making great efforts physical removal bacterial plaque biomembrane frequently is the most effective means of eliminating and control bacterial plaque.Yet the subgingival plaque in recess can not be by brushing teeth, dental floss or oral cavity are cleaned to reach.Therefore, often by dentist or dentist carry out root surface under gum periodontal to remove be the chief component of prevention and treatment periodontitis.
In certain embodiments, particles B T compound can join in oral hygiene composition and device upper (for example coating) or in device, for example, but be not limited to toothpaste, mouthwash (being the 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 preservation liquid and dental floss, can use them by any experimenter is conventional.Particles B T compound can join in the oral hygiene composition mainly used by the dental care industry and, on device, it comprises for example 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 on device and replace the described antibacterial agent of preparing with oral hygiene composition in this area, so that advantage disclosed herein to be provided, it comprises following scope: the enhancing of antimicrobial acivity, solvability and bioavilability, antibiont membrane interaction, non-toxicity, antibiotic effect and other character as herein described.
Particles B T compound also can be by coming particles B T compound administration for prevention or treatment carious tooth and/or inflammation (that is, reducing respectively the possibility that occurs or recur carious tooth and/or inflammation) in dental surface.The composition that comprises particles B T compound can the mucus adhesive composite, described composition is applied to dental surface and/or gum or oral mucosa, and it can be to adhere to surface or to send any form of the active component of effective dose pharmaceutically to required surface to a certain extent.Also particles B T compound can be formulated as by the composition that is applied to oral cavity and slowly discharge.For example, composition can be gel (for example, hydrogel, mercaptides polymer, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.This gel or liquid apply preparation can inside or applications to mercury alloy, compound or other repairing composition.Slow releasing composition can be sent pharmacy effective dose particles B T compound 1,2,3,4,5,6,7 days (a week) or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.Can by many methods known in the art, be prepared by those skilled in the art by said composition.
As described herein, in some other embodiment, provide the antimicrobial compositions that comprises particles B T compound and one or more other Antimicrobe compounds or antimicrobial for oral use.As described herein, useful especially is the composition that comprises and have while working as combined administration second antimicrobial agent enhancing or the Synergistic antimicrobial effect.For example, can be observed the anti-microbial effect of enhancing while, using together with the antimicrobial of particles B T compound and iron chelating.In other particular, for example, by particles B T compound and antiinflammatory, compound, little molecule or large molecule (peptide or polypeptide) preparation.
Can be by any particles B T compound preparation as herein described for oral use.In certain embodiments, can use the particles B T compound for example, prepared with hydrophobic mercaptan (, the sulfo-chlorophenol), and it shows the ability that adhere to tooth and oral cavity tissue larger than the BT compound of hydrophobic difference.BT compound with net negative charge (for example has 1:2 mol ratio (bismuth: mercaptan) those) also can have good cohesive.
The oral hygiene composition that comprises particles B T compound can comprise in addition one or more active components 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 any in tooth powder as herein described, gel, paste and liquid.In other embodiments, particles B T compound can with other alkali metal hydrogencarbonate or carbonate material (for example, saleratus or the calcium carbonate) combination that contribute to keep required alkaline pH and also there is clean and deodorizing character.
The oral hygiene composition that comprises particles B T compound can comprise one or more following compositions in addition. antimicrobial: for example, Chlorhexidine; The bloodroot extract; Metronidazole; Quaternary ammonium compound (for example Cetylpyridinium Chloride); Biguanides (for example, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (for example, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; The alkyl hydroxy benzoic ether; The cation antimicrobial peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; Coleus forskohlii (Coleus forskohlii) essential oil; Silver or collargol antibacterial agent; Antibacterial agent based on 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: for example, brufen, Flurbiprofen, aspirin, Indomethacin, aloe (aloe vera), turmeric, Olive leaf P.E, cloves, panthenol, retinol, omega-fatty acid, gamma-Linolenic acid (GLA), green tea, ginger, grapestone etc. anti-carious tooth agent: for example, sodium fluoride and stannous fluoride, amine fluoride, sodium monofluorophosphate, sodium trimetaphosphate, zinc citrate or other zincon, and casein. the bacterial plaque buffer: for example, urea, calcium lactate, calcium glycerophosphate and polyacrylic acid strontium class. vitamin: for example, vitamin A, C and E. plant the thing extract. desensitizer: for example, potassium citrate, potassium chloride, potassium tartrate, saleratus, potassium oxalate, potassium nitrate and strontium salt. anticalculus agent: such as alkali metal pyrophosphate salts, containing polymer, Organophosphonate and the phosphocitrate etc. of hypophosphites. biomolecule: for example, bacteriocin, phage, antibody, enzyme etc. flavor enhancement: for example, thin He and peppermint oil, fennel, Chinese cassia tree etc. protein material: for example, collagen. preservative. opacifier. colouring agent. pH adjusts the joint agent. sweetener. pharmaceutically acceptable carrier: for example, starch, sucrose, water or water/pure system etc. surfactant: for example, anion, nonionic, cation and amphion or amphoteric surfactant, from the saponin of vegetable material (for example, referring to,, U.S. Patent No. 6485711). abrasive material particles: for example, the particulate abrasive material of silica, aluminium oxide, calcium carbonate, Dicalcium Phosphate, calcium pyrophosphate, hydroxyapatite, trimetaphosphate, insoluble hexametaphosphate, cohesion, chalk, fine grinding natural whiting etc. humidizer: for example, glycerine, sorbitol, propane diols, xylitol, lactitol etc. adhesive and thickener: for example, sodium carboxymethylcellulose, hydroxyethylcellulose
Figure BDA00002887768300681
(for example, polyacrylate and C974P are for example for xanthan gum, gum Arabic, synthetic polymer
Figure BDA00002887768300682
enhanced activity composition for example antimicrobial is sent polymerizable compound.The pH of buffering oral care composition and ion strength buffer solution and salt. decolorizer: for example, per-compound (for example, peroxide diphosphonic acid potassium). effervescent system: for example, the sodium bicarbonate/citric acid system. color change system.In specific embodiments, grinding agent is silica or fine grinding natural whiting.
Preparation can further comprise humidizer (for example, glycerine or sorbitol), surfactant, adhesive and/or flavor enhancement with the oral hygiene composition that comprises particles B T compound 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 that comprises toothpaste has between 7 and 7.5, between 7.5 and 8, between 8 and 8.5 or the pH 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 one or more 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.For example can adopt one or more colouring agents, FD&amp if need; C indigo plant.Other applicable composition that can be contained in toothpaste preparation is described in this area, for example, 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 (for example, saleratus), alcohol, sweetener component and fragrance system.The fragrance system also can have with lower more than one: essence, humidizer, surfactant, sweetener and colouring agent (referring to, for example, 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 that comprises particles B T can with for example Taurolidine and the tauroflex combination of other active component, this in this area, be described to can be used for comprising the treatment for the treatment of severe infections toothpaste, tooth gel and mouthwash (referring to, for example, British Patent Application No.GB1557163, U.S. Patent No. 6,488,912).Antimicrobial combination as described herein, 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 further comprise at least one or the multiple antibiont film for controlling biofilm development, disrupting biofilm or reducing biofilm biomass.As understood in this area, (interspecies quorum sensing) is relevant to biofilm formation for quorum sensing between kind.Can strengthen the LuxS Dependent or plant between colony induction signaling (interspecies quorum sensing signal) (referring to, for example, U.S. Patent No. 7,427,408) some reagent contribute to control biomembranous growth and/or propagation.For example, exemplary agents comprises or N-that combine or independent (3-oxo dodecanoyl)-L-homoserine lactone (OdDHL) block compound and N-butyryl-L-homoserine lactone (BHL) analog (referring to, for example, U.S. Patent No. 6455031).But the oral hygiene composition local delivery that comprises particles B T compound and at least one antibiont film for destroy and stop bacterial biof iotalm and be used for the treatment of periodontosis (referring to, for example, U.S. Patent No. 6,726,898).
Oral hygiene composition as herein described can comprise to be enough to normally brushing teeth, gargling or basically playing the particles B T compound of the amount of antibacterial action in time that dental floss tooth-cleaning is required.As described herein, particles B T compound for example can be held in, on oral surfaces (tooth, mercury alloy, compound, mucous membrane, gum).Smear, gargle wash, particles B T compound for example, can continue to be held on tooth and gum so that antibiont film and the antiinflammatory action of prolongation to be provided after dental floss tooth-cleaning.
In other embodiments, particles B T compound is from mucus-binder polymer or contribute to particles B T compound to keep somewhere in mucous membrane, tooth and repair lip-deep other reagent slowly to discharge.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 treatment mucous membrane ulcer, 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 (referring to, for example, U.S. Patent No. 7,547,433).
In another embodiment, the oral hygiene composition that comprises particles B T compound further comprises the olive oil that can strengthen plaque removal.Olive oil is for oral hygiene, for example the use in the product of toothpaste, mouthwash, spray, oral inhaler or chewing gum can contribute to eliminate or reduce the quantity of the bacterium existed in (minimizing) bacterial plaque and/or elimination or reduction (minimizing) oral cavity, thus, reach and (for example reduce odontopathy, tooth is aging, periodontosis) and the generation of halitosis (referring to, for example, U.S. Patent No. 7,074,391).
In other embodiments, the oral hygiene composition that comprises particles B T compound can further comprise the mucous membrane disinfectant preparation that is applied topically to oral cavity.Oral hygiene composition can further comprise for clean tongue and the useful water-based paste (aqueous slurry) of larynx (referring to, for example U.S. Patent No. 6,861,049).In yet another embodiment, the oral hygiene composition that comprises particles B T compound can further comprise at least one formation (carious tooth) for prevention (that is, reducing possibility occurrence) cavity or the peppermint agent (mint) of reduction cavity number.A kind of being called this type of peppermint agent of (Ortek Therapeutics, Inc., Roslyn Heights, NY) includes and helps neutralizing acid pH and promote calcium to be adhered to arginine and the calcium on enamel surface.Comprising the peppermint agent in the oral hygiene composition that comprises particles B T compound therefore can improve pH and strengthen the adhesion of particles B T compound to oral surfaces.
preparation is for the binder combination that comprises particulate bismuth-mercaptan of dentistry and plastic surgery purposes thing.In another embodiment, will comprise the composition preparation of particles B T compound for preventing or being reduced in bone or joint prosthesis or closing on the tissue of described bone or joint prosthesis and the growth of microorganism on skeletal structure.In specific embodiments, provide with the composition that comprises particles B T compound and for example prevent and/or treat, due to plastic surgery formality (, plastic surgery operations, plastic treatment, arthroplasty (comprising two step arthroplasties), orthodontic treatment) infected by microbes caused and the method for inflammation.In certain embodiments, composition comprises particles B T compound and bone-cementum, and in other embodiments, described composition comprises particles B T compound and tooth adhesive.Therefore, the infected by microbes that these compositions can be used for preventing and/or treating (that is, reduce or suppress its growth, reducing the possibility of its generation or recurrence) skeleton and supporting construction (that is, BJM, ligament, tendon) is osteomyelitis for example.The composition as herein described that comprises particles B T compound and bone-cementum or tooth adhesive also can be used for prevention and/or controls (, slow down, postpone, suppress) biofilm development, disrupting biofilm or the biomembranous amount that is reduced in joint or exists from the teeth outwards, for example surface of 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 the binding material that material is bonded together and can hardens.This material can be by tissue adhesion together or prosthese or artificial apparatus (for example, prosthetic joint, bone or tooth) can be bonded to adjacent tissue.Bone-cementum comprises for example polymethyl methacrylate (PMMA), magnesium phosphate and calcium phosphate.The calcium phosphate form, as " substituting bone ", is used for the treatment of enough be full of cracks and fractures rapid and/or the appropriately bone of healing when there is no embedded material.Also can for example, by the composition that provides mechanical integrity will comprise bone-cementum (, calcium phosphate) and particles B T compound to cancellous bone, be used for the treatment of the cancellous bone defect.Can absorb again at the implant site place adhesive or adhesive can be remained on to the implant site place.
In specific embodiment, the composition 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 to bone-cementum or calcium phosphate bone adhesive or the bone-cementum that contains magnesium phosphate or the Performances of Magnesium Phosphate Bone Cement adhesive that contains calcium phosphate herein.Calcium phosphate can be with any being comprised in composition in known in this area and the various ways used, 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) (referring to, for example, 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 (referring to, for example, Grosshardt etc., Tissue Eng.A part, on July 30th, 2010, the printing before electronic publication; Also referring to, for example, Bohner etc., J.Pharm.Sci.86:565-72; (1997); Fulmer etc., 3:299-305 (1992); Lobenhoffer etc., J.Orthopaedic Trauma16:143-49 (2002); Lee etc., J.Carniofac.Surg.21:1084-88 (2010)).In specific embodiment, the composition as herein described that comprises particles B T compound and the bone-cementum that contains calcium phosphate comprise calcium sulphate/calcium phosphate (CSPC) as the form of calcium phosphate (referring to, for example, Hu etc., J.Mater.Sci.Mater.Med.2009 October 13, the electronic publication before printing).In some other embodiment, the composition that comprises particles B T compound and calcium phosphate or magnesium phosphate adhesive can further comprise shitosan (from the biopolymer of crustacean cell); At least one or Multiple Classes of Antibiotics or antimicrobial; And/or at least one or various anti-inflammatory.
Use in the art bone-cementum to be used for discharging medicine and reagent.In certain embodiments, the calcium phosphate adhesive can at least partly as the form of sealing the hydroxyapatite microsphere of the reagent (for example, antimicrobial) that is used for the treatment of purposes (referring to, for example, U.S. Patent No. 6,730,324).Comprise that these adhesives of microsphere are for slowly discharging and be included in the reagent in microsphere.The composition that comprises the calcium phosphate microsphere body contained in this paper, and this calcium phosphate microsphere body comprises particles B T compound.
This paper also provides the composition that comprises particles B T compound and PMMA bone-cementum.The method that has other reagent preparation PMMA of antimicrobial acivity according to the described use in this area, can be used particles B T compound preparation PMMA bone-cementum (for example, referring to,, european patent application No.EP1649874).
This paper also provides the composition that comprises particles B T chemical combination and tooth adhesive (that is, dental adhesive), and said composition can be used for suppressing, preventing or treat the infected by microbes of tooth or gum.The tooth adhesive can comprise any of following compound or composition: trbasic zinc phosphate, Glass ionomer, α-calcium triphosphate (α-TCP), alkyl methacrylate (referring to, for example, U.S. Patent No. 6,071,528); Bismuth oxide (referring to, for example, Bueno etc., Oral Surg.Oral Med.Oral Pathol.Oral Radiol.Endod.107:e65-69 (2009)); And capping in dog (mineral trioxide aggregate) (MTA) (referring to, for example, Hwang etc., Oral Surg.Oral Med.Oral Pathol.Oral Radiol.Endod.107:e96-102 (2009)).
The present embodiment contains antimicrobial replacement of using tooth adhesive or bone-cementum preparation, it is as provided advantage disclosed herein with the particles B T compound of this description as described in this area, comprises the enhancing of a series of antimicrobial acivities, dissolubility and bioavilability, antibiont membrane interaction, avirulence, antibiotic effect and other character as described herein.According to the described method in this area can use particles B T compound and one or more other antibiosis usually prepare bone and tooth adhesive (referring to, for example, U.S. Patent Application Publication No.2006/0205838; Alt etc., Antimicrob.Agents Chemother.48:4-84-88 (2004); Bohner etc., the same; Bueno etc., the same; Chuard etc., Antimicrob.Agents Chemother.37:625-32 (1993); J.Orthopaed.Res.27:1008-15 (2009); De Lalla, J.Chemother.13:48-53 (2001); Domenico etc., Peptides25:2047-53 (2004); Widmer etc., Antimicrob.Agents Chemother.35:741-46 (1991)).
Comprise bone-cementum or tooth adhesive contain particles B T composition in the scope of amount of the BT compound that uses can each adhesive for about 10-500 μ g BT/ gram between.Be provided in bone and tooth adhesive than the antibiotic of current use advantage as described herein separately or with particles B T compound that at least one other antibiotic combinations is used.The composition as herein described that comprises particles B T compound and bone-cementum (for example, calcium phosphate) or tooth adhesive can further comprise one or more other Antimicrobe compound or reagent.As described herein, useful especially is to comprise to have particles B T compound enhancing or the Synergistic antimicrobial effect and the composition of second antimicrobial agent when combined administration.By other embodiment, can be observed the anti-microbial effect of enhancing while using together with the antimicrobial by particles B T compound and iron chelating.In other particular, for example, by particles B T compound and antiinflammatory, compound, little molecule or large molecule (peptide or polypeptide) preparation.
The composition that comprises as described herein particles B T compound and bone-cementum also can be used for applying for being connected, the stable or fixing hardware (for example, screw, flat board, rivet, pin and wire etc.) in fracture, fusion, osteotomy or replacement joint.The composition that comprises particles B T compound and tooth adhesive as described herein is also for applying remediation composition capable in dental pulp, tooth cap, liner, tooth or tooth filling or tooth etc.These compositions can be prepared to coating, this coating can be applied, fixes, adheres to or make in some way its contact bone and/or joint related hardware.In specific embodiment, coating comprises particles B T compound and calcium phosphate or Performances of Magnesium Phosphate Bone Cement adhesive.According to the method for this area practice, particles B T compound and calcium phosphate or magnesium phosphate are together prepared with for being applied to skeletal.For example, the composition that comprises particles B T compound and bone-cementum (for example, calcium phosphate or Performances of Magnesium Phosphate Bone Cement adhesive) can be the form of the liquid, gel, paste or the spray that are applied to hardware (for example, thermal spray, it comprises plasma spraying).The composition that comprises particles B T compound and bone-cementum can be gel (for example, hydrogel, mercaptides polymer, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.Slow releasing composition can be sent the particles B T compound 1,2,3,4,5,6 or 7 days (a week) 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 control at least in part rate of release (referring to, for example, Bohner etc., the same).
The composition that comprises particles B T compound and bone-cementum or tooth adhesive and at least one can be had when the combined administration strengthen or the Synergistic antimicrobial effect (, be greater than summation action) other antimicrobial (that is, second, third, fourth class antimicrobial) combination.For example, can be observed the anti-microbial effect of enhancing while, using together with the antimicrobial of particles B T compound and iron chelating.In specific embodiments, can by the composition that comprises particles B T compound and bone-cementum or tooth adhesive be selected from least one following other antimicrobial and/or antiinflammatory combination: antimicrobial: for example, Chlorhexidine; The bloodroot extract; Metronidazole; Quaternary ammonium compound (for example Cetylpyridinium Chloride); Biguanides (for example, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (for example, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; The alkyl hydroxy benzoic ether; The cation antimicrobial peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; The Coleus forskohlii essential oil; Silver or collargol antibacterial agent; Antibacterial agent based on 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: for example, 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 that comprises particles B T compound and bone-cementum or tooth adhesive can further comprise and is selected from following antibiotic: clindamycin, vancomycin, Daptomycin, cephalosporin, gentamicin, tobramycin, metronidazole, Cefaclor, Ciprofloxacin or other antibacterial agent, for example quaternary ammonium compound (for example, benzalkonium chloride, pyrisept), antimicrobial zeolite, alkali metal hydroxide or alkaline earth oxide.Described composition optionally comprises one or more pharmaceutically suitable carrier (that is, excipient), surfactant, buffer solution, thinner and salt as herein described, and decolorizer.Can by antimicrobial with as the described tooth adhesive of this paper and this area, together with bone-cementum, prepare (referring to, for example, 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 the antimicrobial acivity of the composition that comprises particles B T compound and tooth adhesive or bone-cementum (referring to, for example, the Antimicrob.Agents Chemother.1993 such as Chuard; 37:625-32).In these models in antibiotic body effect to antimicrobial kill fixing phase microorganism and adhere to those ability of exogenous material relevant (referring to, for example, the J.Infect.Dis.1990 such as Widmer; 162:96-102; The Antimicrob Agents Chemother1991 such as Widmer; 35:741-6; Also referring to, for example, 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 the aid in treatment composition) and 10% barium sulfate (for thoroughly radiation) and approximately the 10 bonding powder to about 500 μ g particles B T compound/grams are (that is, 0.001-0.05%w/w).In other specific embodiment, can add at least one other antimicrobial.
comprise the composition that makes to paint particulate bismuth-mercaptan of preparing with paint.Some other embodiment contain in particles B T compound as herein described is incorporated to paint or paint upper as paint with for reducing biological incrustation and prevention and/or control (that is, slow down, postpone, suppress) biofilm development, disrupting biofilm or be reduced on the paint face the biomembranous amount existed.The composition that comprises particles B T compound as herein described can make to paint or the paint preparation, described paint or paint are applied in various products any, 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 (for example, intake screen, cooling tower), heat exchanger, dykes and dams and fabric and other surface, for example comprising automobile, train, aircraft and such as boats and ships, ships and light boats, among all types of delivery vehicles of the steamer of submarine and other steamer and on occur those.
In specific embodiment, composition as herein described and method are for prevention and/or be reduced in biological incrustation or the biomembrane formed on the goods that are exposed to water.It is believed that, in marine environment from the teeth outwards biomembranous formation be the key factor that promotes field planting and the recovery of some set invertebrate groups on building at sea (referring to, for example, Siboni etc., FEMS Microbiol Lett2007; 274:24-9).The interacting subsequently of macrobiota and these microbial films causes adhering to and growing of within a couple of days and several weeks invertebrate and algae; this be the most of hydrodynamic drag relevant to biological incrustation reason (referring to; for example, Schultz, Biofouling2007; 23:331-41).Old biomembrane supports kentrogon absorption from the teeth outwards, with the type of bottom, have nothing to do (referring to, for example, Hunga etc., J Exptl Marine Biol Ecol2008; 361:36-41).Biomembrane also significantly be increased in the adhesion strength under one or more developmental stage in Ascidian Phallusia nigra, the magnificent coil pipe worm of polychaeta pipe worm (Hydroides elegans) and barnacle line barnacle (Balanus amphitrite) (referring to; for example; Zardus etc., Biol Bull2008; 214:91-8).Biomembrane also can strengthen zebra shellfish (Zebra mussel) (speckle freshwater mussel) and some artificial surfaces adhesion (referring to, for example, Kavouras and Maki.Inverteb Biol2005; 122:138-51), it causes tax revenue and expenses to the millions of and even multi-million dollar of seafood, generating and process industry and water and waste water disposal facility, and causes the remarkable destruction of the ecosystem to introducing shellfish.
In ocean, salt water and fresh water environment, the organism of collecting, precipitate, adhere to and grow on structure and boats and ships under water.These organisms comprise algae, fungi and other microorganism and aquatic animal, for example Tunicata, hydrozoan, Bivalve, moss, polychaete worm, sponge and barnacle.The existence of these organisms that is called " incrustation " of structure is harmful to, and for example, it increases construction weight and/or hinders its hydrodynamics, thereby reduces its operating efficiency, increases the susceptibility to corrosion and degraded or cataclastic structure.
Up to now for prevention or reduce some paint and the coating that biological incrustation and biomembrane produce and comprise toxic component, this toxic component when suppressing biological incrustation and biofilm formation to required poisonous with useful plants group and fauna.The compound that exemplary antimicrobial and chemical toxicant comprise copper and contain copper (for example, cuprous oxide), mercury, arsenic, tributyltin oxide (TBT), organotin (that is, thering is the tin that connects 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-toxicity substitute and advantage disclosed herein is provided, and comprises the enhancing of a series of antimicrobial acivities, dissolubility and bioavilability, antibiont membrane interaction, antibiotic effect and other character as described herein.By in conjunction with particles B T Compounds and methods for as herein described, use becomes known for the step that preparation comprises paint and the paint of biocide, in paint and paint, can use particles B T compound to substitute other antimicrobial and particles B T compound can be incorporated to these paint and paint (referring to, for example, 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., Smart Mater.Struct.18:104027 (2009); Cao etc., ACS Applied Materials Interfaces1:494 (2009); Kumar etc., Nature Materials7:236-41 (2008)).The paint that particles B T compound can be incorporated to comprises based on epoxy resin, silicone or acrylic acid paint.In more specific embodiment, particles B T compound can be incorporated in paint, by Yu Haiyang purposes and being exposed in seawater for this paint formulation, and it for example comprises based on alkyd resins, based on asphalt, paint based on albertite, based on chlorinated rubber and the paint based on epoxy resin.
Can discharge in a controlled manner antimicrobial by reagent being incorporated in paint.The method of the drug release rate of reinforced composite is known in the art.The drug particles phase that composite can comprise is natural or synthetic, biologically absorbing polymer thing matrix and this paper disperse (referring to, for example, U.S. Patent No. 7,419,681 and 5,028,664; Also for example, referring to,, U.S. Patent application No.2009/0043388).For example, medicament elution paint composition can comprise at least one the particles B T compound in the biologically active cementing agent that is dispersed in modification.
The preparation of particles B T compound slowly can be discharged with the composition by comprising the particles B T compound that is applied to painted surface.Also particles B T compound can be incorporated to for example, in coating (, epoxy coating), it can be applied, fix, adhere to or make in some way the structure of coating of its contact preparation or the surface of article.Particles B T compound slowly can be discharged by these compositions.The slow releasing composition that comprises particles B T compound can be gel (for example, hydrogel, mercaptides polymer, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.Slow releasing composition can be sent the particles B T compound 1,2,3,4,5,6 or 7 days (a week) of antimicrobial effective dose or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.
Other coating that uses in the art and can prepare together with particles B T compound comprises polysaccharide, and this polysaccharide comprises and the polysaccharide matrix of multivalent metal cation reversible crosslink (for example, referring to,, U.S. Patent Application Publication No.2009/0202610); Titania nanotube; The surface of nanostructured; Nano ceric oxide with biocompatibility glucan coating of pH dependence antioxidant properties; The polysulfones block copolymer; And other biodegradable coating (also referring to, for example, U.S. Patent No. 6,162,487).Other coating that this paper is contained is prepared particles B T compound together with the anticorrosive and anti-incrustation preservative coating used in industry, and this other coating comprises the Brazil wax fluoropolymer as limiting examples;
Figure BDA00002887768300791
pTFE; And molybdenum (moly) material.
In paint or paint, particles B T compound concentration (by weight) can (for example) be low to moderate approximately 0.001% to approximately 0.1%, and this depends on special-purpose and the desirable properties of paint or paint.Can will be incorporated to paint or the particles B T compound (or the composition that comprises particles B T compound) of paint and at least one other antimicrobial (, second, third, fourth class antimicrobial) be used in combination, when combined administration, it has enhancing or Synergistic antimicrobial effect as described herein.As limiting examples, the antimicrobial that can comprise in the composition that comprises particles B T compound comprises: Chlorhexidine; The bloodroot extract; Metronidazole; Quaternary ammonium compound (for example Cetylpyridinium Chloride); Biguanides (for example, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (for example, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; The alkyl hydroxy benzoic ether; The cation antimicrobial peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; The Coleus forskohlii essential oil; Silver or collargol antibacterial agent; Antibacterial agent based on 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 further optionally comprise surfactant, diluent or carrier, buffer and/or bleaching agent, and it is as above with as described herein.
the composition that comprises the particulate bismuth-mercaptan that uses concrete and cement compound preparation.Some other embodiment contain by particles B T compound as herein described, be incorporated in industrial cement and among concrete, mortar and the mortar of the coating that comprises concrete, 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 existed on concrete surface.On xoncrete structure or among the microorganism of growth reduce the service life of product and can cause the animal and human to be exposed to the microorganism existed on concrete surface health hazard (referring to, for example, Idachaba etc., Waste Manag.Res.19:284-91 (2001); Idachaba etc., J.Hazard.Mater.90:279-95 (2002); Tazaki, Canadian Mineralogist30:431-34 (1992)).
As this paper and this area, used, cement refers to the dried powder material (usually also can contain the lime stone of other material) for bonding concrete aggregation substance.The described exemplary cement in this area is called Portland cement (Ordinary Portland Cement), portland blast-furnace cement, brick cement, slag lime cement and aluminous cement.Once add water and/or additive, cement admixture is called concrete, if particularly add and gather materials.Concrete is the composite for example, be comprised of gather materials (, gravel and sand), cement and water.The cement used under construction is characterised in that the hydraulicity or on-hydraulic.Hydraulic cement is often used in tapestry brick construction in humid climate; Masonry structure with harbour engineering of contact with sea water etc.; And the exploitation of reinforced concrete.
Can be by the composition as herein described that comprises particles B T compound for applying or said composition can being mixed with the adhesive for xoncrete structure, this xoncrete structure comprises for example 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 (skate park structure) and radioactive waste support of buildings.Particles B T compound as described herein can be incorporated in adhesive as described as this area (referring to, for example, U.S. Patent No. 7,507,281).Adhesive or concrete alkalescence also can strengthen the anti-microbial effect of particles B T compound.
Bacterium by acidifying such as Thiobacillus thioxidans (Thiobacillus thiooxidans) is degradable adhesive also.As signal and unrestriced limiting examples, demonstration bismuth mercaptan compound BisEDT(but be not particles B T compound as herein described) delay the growth the concrete Thiobacillus thioxidans 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 such as BisPYR can be used for suppressing by incrustation and the biofilm development of mould and marine alga.The present embodiment contains uses this described particles B T compound to substitute bismuth mercaptan compound and other antimicrobial material so that advantage disclosed herein to be provided, and comprises the enhancing of a series of antimicrobial acivities, dissolubility and bioavilability, antibiont membrane interaction, avirulence, 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 specific embodiment, the particles B T compound of powder or liquid form is mixed with formulated product with at least one or the multiple other composition that comprise the active excipient of bioactive ingredients that at least one is other and/or inanimate object, this product is regularly sent or inject among xoncrete structure or on (, be exposed on the surface of xoncrete structure, particularly be exposed to the surface of water).Can use multiple methods known in the art to prepare composition by those skilled in the art.For example, can use the particles B T compound (for example, 1mg/ml particles B T compound in DMSO) of the antimicrobial effective dose of combination DMSO.For conventional purposes, need enough levels of the particles B T compound of prevention biofilm formation.Yet, in other embodiments, the level of particles B T compound can be higher with for reducing, remove, destroy or eliminate the biomembrane on concrete surface that is present in existed.
The preparation of particles B T compound slowly can be discharged by the composition with the particles B T compound by comprising the surface that is applied to xoncrete structure.Also particles B T compound can be incorporated to coating (for example, epoxy coating), it can be applied, fix, adhere to or make the surface of its contact xoncrete structure under some modes.Particles B T compound slowly can be discharged by these compositions.The slow releasing composition that comprises particles B T compound can be gel (for example, hydrogel, mercaptides polymer, aeroge or organogel) or liquid.Organogel can comprise organic solvent, lipoic acid, vegetable oil or mineral oil.Slow releasing composition can be sent the particles B T compound 1,2,3,4,5,6 or 7 days (a week) of antimicrobial effective dose or 2,3,4,5,6,7 weeks or 1,2,3,4,5 or 6 months.
Can be by particles B T compound (or the composition that comprises particles B T compound) and at least one other antimicrobial (, second, third, fourth class antimicrobial) be used in combination, when combined administration, it has enhancing or Synergistic antimicrobial effect as described herein.For example, can be observed the anti-microbial effect of enhancing while, using together with the antimicrobial of particles B T compound and iron chelating.Particles B T compound as herein described and at least one other antimicrobial combination that comprises bactericide or algicide can be used.As limiting examples, the antimicrobial that can comprise in the composition that comprises particles B T compound comprises: Chlorhexidine; The bloodroot extract; Metronidazole; Quaternary ammonium compound (for example Cetylpyridinium Chloride); Biguanides (for example, chlorhexidine gluconate, Hexetidine, Octenidine, Alexidine); Halogenated bisphenol compound (for example, 2,2' di-2-ethylhexylphosphine oxide (the chloro-6-bromophenol of 4-) or other phenol antimicrobial compound; The alkyl hydroxy benzoic ether; The cation antimicrobial peptide; Aminoglycoside; Quinolone; Lincoln's acid amides; Penicillin; Cephalosporin; Macrolide; Tetracycline; Other antibiotic known in the art; The Coleus forskohlii essential oil; Silver or collargol antibacterial agent; Antibacterial agent based on 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 further optionally comprise surfactant, diluent or carrier, buffer and/or bleaching agent, and it is as above with as described herein.
Can use the particles B T compound that for example, prepares through hydrophobicity mercaptan (, sulfo-chlorophenol) and this particles B T compound can show the performance that better adheres to concrete surface (particularly be exposed to those in water) than hydrophobicity BT compound.BT compound with net negative charge (for example has 1:2 mol ratio (bismuth: mercaptan) those) also can have good cohesive.
particles B T in rubber, silicone and plastic product.some embodiment contain particles B T compound as herein described is incorporated among artificial surfaces or on, this artificial surfaces comprises natural and synthetic rubber and/or the rubber coating (comprising silicone and silicone paint) of assembling, for example, for example to reduce biomembrane and the biological incrustation at these rubber surfaces with in lower device: medical treatment device (, conduit, support, not sharp conduit (Foley catheter) 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 vehicles, 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 these class article in these and other natural and artificial rubber product.As signal and unrestriced limiting examples, by BT(, be not particles B T as herein described) be incorporated to the excellent and dacron graft of polyurethane that hydrogel applies (the Antimicrob Agents Chemother2001 such as Domenico; 45:1417-1421; Domenico etc., Peptides2004; 25:2047-53).Presulfurization and/or raw rubber preparation sulfuration that WO/2002/077095 and Japanese patent application 1997-342076 description contain the compound based on silver-colored is 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 of the antimicrobial based on silver-colored in rubber mass.The silicon-ketone composition of eluted substance can comprise the antimicrobial in the biologically active cementing agent that is dispersed in 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 the inert polymer carrier.
Silicone oil has the molecular weight of 2,000 to 30,000 scopes usually, and its range of viscosities is 20 to 1,000 centistokes.Silicone rubber has the molecular weight of 40,000 to 100,000 scopes usually, and its range of viscosities is 10 to 1,000 Duo.Silicone is used for to the various materials of microorganism incrustation are arranged usually.These comprise fluid sealant, caulking compound, grease, oil, spraying, rubber, flexible pipe and implant.Anti-incrustation and other antimicrobial coating based on silicone have been described; but it has, and effect is low, poor durability, biocompatibility are poor, antimicrobial acivity is lost, service life is short, material consumption is high and the disadvantages associated of other problem (for example, Schultz J Fluids Eng2004; 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 Surface Coatings International Part B:Coatings Transactions2005 such as Tiller; 88:1-82; Juhni and Newby Proceedings Annual Meeting Adhesion Society2005; 28:179-181; The Retina1999 such as Ozdamar; 19:122-6; The J Mater Chem2009 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 Antonie Van Leeuwenhoek2001 such as Millsap; 79:337-43).Although these are open describes antimicrobial material is incorporated to the method in the rubber of preparation, in the product that their are described 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 (those that for example, quote below).In these and other each situation of known preparation, openly particles B T as herein described can be incorporated to substitute other antimicrobial based on this paper, thereby the advantage disclosed herein as provided by these particles B T is provided, comprises the enhancing of a series of antimicrobial acivities, dissolubility and bioavilability, antibiont membrane interaction, avirulence, antibiotic effect and other character as described herein.
Can under the low concentration that does not for example disturb method for preparing rubber, the BT compound be formulated as the silicone products or on reduce biomembrane and prevent in the product of incrustation.In silicone, particles B T concentration (by weight) can for example be low to moderate approximately 0.0001% to approximately 0.1%, and this depends on special-purpose and the character of silicone rubber product.Similarly, can be incorporated on silicone by particles B T as herein described or in silicone gel or oil coating with prevention in section at the appointed time or treat the biomembrane on silicone surface.Silicone rubber injects ports valve and is described in WO/2008/064173, it regularly flows out silicone oil, makes these exudates of effective antimicrobial level of particles B T described herein give antibiont film and/or anti-incrustation ability on the silicone rubber device of these valves of the goods that contain preparation or similar configuration.Easily the oil of erosion is by extending on any surface of valve proximity, and this provides reproducible protection source in special time period.Can for example this configuration be structured under the surface of hull or be exposed in other surface of water or humidity.
For the retention time that is increased in BT on rubber surface, by specific thiol moiety, can select particles B T as herein described to there is larger hydrophobicity, for example, for example, by (using hydrophobicity mercaptan, the sulfo-chlorophenol), it can have the bond properties of increase and/or (for example have net negative charge by comprising preparing, bismuth: the BT 1:2 mol ratio of mercaptan), it also can have the bond properties of increase.At 100 ℃ or lower temperature, under existing, for example the silicone material can be assembled the particles B T described herein of suitable concn.Under the level of the obstruction biofilm formation of all 1-2ppm according to appointment, also can prepare can bioerodible material so that these BT can discharge gradually.In other embodiments, expection rubber and/or plastic assembly be by the material manufacture, the slow wash-out particles B of this material T compound and it can being replaced regularly in case the biological incrustation in various industrial systems or medical treatment device.
In some other embodiment, and with above-described composition and method similar fashion BT being incorporated under rubber (comprising silicone) item, by the preparation method that goods are known for preparing in conjunction with BT composition described herein and method and these types, also this described particles B T compound can be incorporated in these and other plastics and polymerization product.
The limiting examples of the plastic product that these contain particles B T is 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 vehicles, 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, those that use in chemical substance and water sterilization).
Start to use the 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 such as plasticizer, it is 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 especially easily is subject to bacterium and fungi impact, particularly in the high-moisture zone, cause the growth of microorganism superficial growth and spore, it can cause one or more infection in humans and animals, allergy, bad smell, dyeing, plastics embrittlement, too early product bug and other result of not expecting.
Described by introducing anti-incrustation and other antimicrobial coating in preparation process or the post-modification plastic product, but usually have meritorious heterodyne, poor durability, biocompatibility poor, lose antimicrobial acivity, serviceable bife is short, material consumption is high and the disadvantages associated of other problem (for example, 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, Additives and Compounding2009,11:18-22; EP927222B1; JP08-157641; CN1528470A; Masatoshi etc. 2006; 51:18-23; The open No.2008/0071229,2009/0202610 and 2009/0043388 of the U.S.); The advantage provided by particles B T described herein all is not provided existing method.Yet, as usually known to those skilled in the art, according to following methods, antimicrobial is incorporated among plastic product or on to obtain final polymer: for example (a) on polymer surfaces to the absorption of reagent (passive or pass through surfactant); (b) polymer that will be applied to the lip-deep antimicrobial coating of shaped device is introduced; (c) body of polymeric substrate is incorporated to mutually; (d) covalent bond reagent is to polymer surfaces; And/or (e) before polymerisation by antimicrobial with form polymer (for example, polyurethane) component and mix.
For example, can be using particles B T as herein described as gel, spray, liquid or powder introduce these and similar system manually or automatically.In one embodiment, for example, by particles B T for example, with powder or liquid form and (be included in the active component that relates in product mixture, polymerization precursor, catalyzer, reaction initiator, crosslinking agent etc.) and excipient is (for example, carrier solvent, releasing agent, dyestuff or pigment, plasticizer etc.) the composition of manufacturing for plastics mix, it is regularly injected to manufacturing system.For example, the particles B T solution of 1mg/ml in DMSO or suspended matter regularly can be injected to formation polymer reaction liquid; Perhaps it is sprayed in the workpiece of forming unit to obtain antibiont film concentration required in final products.
Therefore, these some disclosed embodiment expections relevant with this paper are contained in the method for this product and current disclosed particles B T composition, described BT composition can comprise one or more particles B T, and described BT composition also optionally further comprises for example collaborative or enhancing antibiotic as herein described of antibiotic.
According to some embodiment as described herein, the limiting examples that composition as herein described and method have the bacterium of beneficial effect to it comprises staphylococcus aureus (S.aureus), MRSA (methicillin resistance staphylococcus aureus), Staphylococcus epidermidis, MRSE (methicillin resistance Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, the drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, the methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, vancomycin resistance enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, pseudomonas aeruginosa, responsive and the vancomycin resistance enterococcus of vancomycin (enterococcus faecalis (E.faecalis) for example, Enterococcus faecium (E.faecium), methicillin-sensitivity and methicillin resistance staphylococcus (staphylococcus aureus for example, Staphylococcus epidermidis) and Acinetobacter baumannii, staphylococcus haemolyticus (Staphylococcus haemolyticus), staphylococcus haemolyticus (Staphylococcus hominis), Enterococcus faecium (Enterococcus faecium), micrococcus scarlatinae (Streptococcus pyogenes), Streptococcusagalactiae (Streptococcus agalactiae), bacillus anthracis, Klebsiella Pneumoniae, proteus mirabilis (Proteus mirabilis), proteus vulgaris, YE (Yersinia enterocolytica), have a liking for maltose Stenotrophomonas (Stenotrophomonas maltophilia), streptococcus pneumonia, the penicillin resistance streptococcus pneumonia, Burkholderia cepacia, bite burkholderia more, smegmatis mycobacterium and enterobacter cloacae.
Unless the contrary indication, the enforcement of certain embodiments of the present invention will adopt the conventional method of microbiology, molecular biology, biochemistry, cell biology, virology and immunological technique in the art technology scope, and, for the example explanation, hereinafter several technology are quoted.This type of technology is fully explaination in the literature.Referring to for example Sambrook, wait Molecular Cloning:A Laboratory Manual (the 2nd edition, 1989); The Molecular Cloning:A Laboratory Manual (1982) such as Maniatis; DNA Cloning:A Practical Approach, I volume and II volume (D.Glover edits); Oligonucleotide Synthesis (N.Gait edits, 1984); Nucleic Acid Hybridization (B.Hames and S.Higgins edit, 1985); Transcription and Translation (B.Hames and S.Higgins edit, 1984); Animal Cell Culture (R.Freshney edits, 1986); Perbal, A Practical Guide to Molecular Cloning (1984).
Unless context separately has requirement, otherwise word " comprises " and variant form for example " comprises " and " containing " will be interpreted as implication open, inclusive in the specification and claims, is " including but not limited to ".
This specification is mentioned " embodiment " or " a kind of embodiment " or " aspect ", means that specific features, structure or the characteristics described in conjunction with described embodiment are included at least one embodiment of the present invention.Differ to establish a capital when therefore, term " in one embodiment " or " in one embodiment " occur in the different places of this specification and refer to identical embodiment.And concrete feature, structure or characteristics can be combined in one or more embodiments in any suitable manner.
As mentioned above, agricultural, industry, manufacturing industry and other preparation that some invention embodiment as herein described relates to described BT compound are (for example, BisEDT and/or BisBAL), described preparation can also comprise one or more Antibiotique compositions as herein described in certain embodiments, for example amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or another kind of lincoln amides antibiotics), Daptomycin doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid
Figure BDA00002887768300882
minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin; Or carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillase resistance PCs and/or Aminopenicillin antibiotic and/or aminoglycoside antibiotics, for example amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin or apramycin and/or lipopeptide antibiotics Daptomycin for example
Figure BDA00002887768300883
the Huo oxazolidinone antibiotics is Linezolid for example
Figure BDA00002887768300884
as disclosed herein, when for example, to plant or animal uses or is applied to therein or on it, existence can be relevant (for biomembrane, wherein may there is the bacterium that can promote biofilm formation, but biomembrane not yet detected) bacterium while infecting or comprising the natural or artificial surfaces such as plant, animal, goods that the bacterium that occurs such as biomembrane or other bacterium infects, 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 the agent administration for similar applications or the accepting method that is incorporated to, can carry out in purified form or the using or being incorporated to of BT compound as herein described or their salt in suitable agricultural, manufacturing industry or other industry group compound.In preferred embodiments, the application of composition, be incorporated to or use and comprise and make composition and can be positioned at or extensively be distributed in the experimenter plant at surface location place or animal or treated goods directly contact at one or more, with and can normally instigate local directly with acute or chronic infection position (for example, wound site on plant surface) contact, be complete tissue around this acute or chronic infection, but do not need to be limited; For example, some embodiment contains to injured, scratch or impaired natural or artificial surfaces topical application topical formulations described herein.
For example, by (merging described BT compound, 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, for example, particles B T suspended matter described herein) and in some related embodiment as described herein, by merge separately or one or more required antibiotic of combination BT compound (for example, aminoglycoside antibiotics such as amikacin) with as can prepare the suitable medium that preparation is used according to special-purpose, dispersant, carrier, thinner or excipient (for example can prepare preparation, Pestcidal compositions), and can be prepared as solid, semi-solid, gel, emulsion, colloid, the preparation of supensoid agent or liquid or other topical application form, pulvis for example, 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 so that active component is included in wherein, and in particularly preferred embodiments, one or more required antibiotic (for example alone or in combination, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, glycopeptide antibiotics, lincoln amides antibiotics, penicillase resistance PCs and Aminopenicillin antibiotic or aminoglycoside antibiotics, for example amikacin or rifamycin) use BT compound as herein described, can or use successively and with any order its while, thereby once use the preparation that comprises BT compound and/or antibiotic composition to desired location and optionally to plant or animal (comprising the people) but the natural or artificial surfaces biological utilisation of experimenter or goods.Some embodiment disclosed herein contains to be used and/or is incorporated in these experimenters or BT compound and antibiotic goods, comprising can be simultaneously or successively and using with any order, but the present invention is not intention so to be limited, and clearly expect in other embodiments the different BT compound administration approach with respect to antibiotic route of administration.Therefore, but by any route of administration administration of antibiotics as described herein, but use the approach of approach can use the BT compound by being independent of antibiotic.
The preservative of formulation delivered effective dose described herein (and optional antibiotic), to desired location, for example infects the position of position or needs prevention infection or biofilm formation.
As mentioned above, this local preparation can adopt any 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 and contain liposome, micella and/or microballoon.Referring to for example U.S. Patent No. 7,205,003.For example, as pharmaceutical preparation and cosmeceutical formulation art, known, cream is oil-in-water or water in oil viscous liquid or semi-solid emulsion.Cream matrix can be washed, and contains oil phase, emulsifier and water.Oil phase also is called " interior " phase, and generally by vaseline and fatty alcohol, for example cetanol or octadecanol form.Water usually but must surpass the volume of oil phase, and generally contains humidizer.Emulsifier in the cream preparation is generally nonionic, anion, cation or amphoteric surfactant.
Solution is to be scattered in by one or more chemical substances (solute) being dissolved in to the material that liquid makes dissolving the homogeneous mixture prepared in solvent.Solution can contain other chemical substance with buffering, stable or preservation solute.The common example of the solvent used while preparing solution has ethanol, water, propane diols or any other medium.
Gel is system semi-solid, the suspension type.Single-phase gels contains the organic macromolecule basically be uniformly distributed in carrier liquid, and described carrier liquid is water-based normally, but also preferably contains alcohol and optional oil.Preferably " organic macromolecule " is gelling agent, can be the polymer of chemical crosslinking, crosslinked acrylate copolymer for example, " carbomer " family polymer for example, carboxyl polyalkylene for example, it can by be purchased with
Figure BDA00002887768300901
trade mark obtains.In certain embodiments can also preferred hydrophilic polymer, for example PEO, Pluronic F68 and polyvinyl alcohol; Cellulosic polymer, for example hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropylmethyl cellulose phthalate and methylcellulose; Natural gum, for example bassora gum and xanthans; Mosanom; And gelatin.In order to prepare even gel, can add dispersant for example ethanol or glycerine, or gelling agent can combine to disperse by grinding, mechanical mixture or stirring or its.
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 a kind of ointment that many required features (such as property of softening etc.) is provided.The same with other carrier or medium, ointment base should be inertia, stable, nonirritating and nonsensitized.As Remington:The Science and Practice of Pharmacy, the 19th edition. (Easton, Pa.:Mack Publishing Co., 1995), in the 1399-1404 page, to explain, ointment base can be divided into four classes: oleaginous base; Emulsifiable base; Emulsion bases; And water-soluble base.The oiliness ointment base comprises vegetable oil for example, available from the fat of animal with available from the semi-solid hydrocarbon of oil.But the emulsification ointment base also is called the absorbability ointment base, contains seldom water or not moisture, and comprise for example Oxystearin sulphate (hydroxystearin sulfate), wool grease and hydrophilic petrolatum.The emulsion ointment base is Water-In-Oil (W/O) emulsion or oil-in-water (O/W) emulsion, and comprises for example cetanol, glycerin monostearate, lanolin and stearic acid.Preferred Fend A-2 matrix by the polyethylene glycol preparation of different molecular weight (referring to, for example 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 by the single-phase water gel.Matrix in the fat paste is generally vaseline or hydrophilic petrolatum etc.The paste of being made by the single-phase water gel generally adds carboxymethyl cellulose etc. as matrix.
Preparation can also be used liposome, micella and microballoon preparation.Liposome is to have the microballoon folliculus that one (individual layer) or a plurality of (multilayers) comprises the lipid wall of double-layer of lipoid, and can seal and/or adsorb one or more components of preparation as herein described to its lipid film surface in this environment, described component is antibiotic or some carrier or excipient for example.The Liposomal formulation of this paper comprises the positive (positively charged), negative (electronegative) and neutral preparation.Positive liposome is easily to obtain.For example, N[1-2,3-bis-oleyl oxygen bases) propyl group]-N, N, N-triethyl ammonium (DOTMA) liposome can trade name
Figure BDA00002887768300911
(GIBCO BRL, Grand Island, N.Y.) obtains.Similarly, anion and neutral fats plastid also easily obtain from for example Avanti Polar Lipids (Birmingham, AL), or can easily use the material preparation of easy acquisition.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 of 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 the hydrophobicity hydrocarbon chain towards the surfactant molecule of ball center's (formation core).Micella forms in containing concentrated surfactant and make the aqueous solution of the natural generation of micella.The surfactant that is used to form micella includes but not limited to potassium laurate, perfluorooctane sulfonate, decane sodium 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 has been sealed one or more components of preparation of the present invention basically.They generally but not necessarily by lipid, preferably charged lipids for example phosphatide form.The preparation of lipid microsphere is well known in the art.
Various additive well known by persons skilled in the art also can be included in preparation.For example, solvent (alcohol that comprises relative a small amount of) can be used for some formulation components of solubilising.The example of suitable promoter includes but not limited to ether, and for example diethylene glycol monoethyl ether (can
Figure BDA00002887768300921
through being purchased acquisition) and diethylene glycol monomethyl ether; Surfactant for example sodium laurate, NaLS, softex kw, benzalkonium chloride,
Figure BDA00002887768300922
(231,182,184),
Figure BDA00002887768300923
(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, for example polyethylene glycol monolaurate (PEGML; Referring to for example, U.S. Patent No. 4,568,343); Acid amides and other nitrogen-containing compound, for example 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, for example DMSO and C 10mSO, but more not preferred.
Some dermal osmosis accelerator can comprise those lipophilicity secondary accelerators (coenhancer) that are commonly called " plasticising (plasticizing) " promoter, that is, have about 150 to 1000 dalton's scopes molecular weight, be less than about 1wt%, preferably be less than about 0.5wt% and most preferably be less than the promoter of the water solubility of about 0.2wt%.The Hildebrand solubility parameter scope of plasticising promoter approximately 2.5 to approximately 10, preferable range approximately 5 to approximately 10.Preferred lipophilicity promoter is fatty ester, fatty alcohol and aliphatic ether.Example concrete and most preferred fatty acid ester comprises methyl laurate, ethyl oleate, PGML, propane diols dilaurate, glyceryl monolaurate, glycerin mono-fatty acid ester, n-capric acid isopropyl ester and octyl dodecyl myristate.Fatty alcohol comprises for example octadecanol and oleyl alcohol, and aliphatic ether comprises wherein glycol or triol, preferred 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 the localized drug delivery those skilled in the art are known, and/or is described in pertinent literature.Referring to for example Percutaneous Penetration Enhancers, edit.Smith etc. (CRC Press, Boca Raton, FL, 1995).
Except top definite those, various other additives 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 with and to exist can be that beauty treatment is upper, medically or other material classification of needing of other side.The representative instance of optional additive of preparation that is included in certain embodiments of the present invention is as follows: preservative, for example sorbate; Solvent, for example isopropyl alcohol and propane diols; Astringent, for example methyl alcohol and ethanol; Softening agent, for example polyalkylene methyl glucosamine; Humidizer, for example glycerine; Emulsifier, for example tristerin, PEG-100 stearate, polyglycereol-3 hydroxyl lauryl ether and polysorbate 60; Sorbitol and other polyhydroxy-alcohol be polyethylene glycol for example; Sun-screening agent, for example octyl methoxycinnamate (can be used as Parsol MCX through being purchased acquisition) and Uvinul BMBM (can trade name Parsol1789 obtain); Antioxidant, for example 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, for example can be available from BASF's (Mt.Olive, NJ)
Figure BDA00002887768300931
the hydrophilic polymer of series, vegetable oil are (for example, the liquid fraction of soybean oil, palm oil, shea butter, sunflower oil), animal oil (for example, perhydro-squalene), mineral oil, artificial oil, silicone oil or wax are (for example, cyclomethicone and dimeticone), fluorinated oil (being generally PFPE), fatty alcohol (for example, cetanol) and wax (for example, beeswax, Brazil wax and paraffin); The dermal sensation conditioning agent; And thickener and structural agent (structurants), for example expansive clay and crosslinked carboxyl polyalkylene (carboxypolyalkylene), can
Figure BDA00002887768300941
trade mark is through being purchased acquisition.
Other additive comprises for example pyrrolidine carboxylic acid and amino acid; Organic antimicrobial, for example 2,4, the chloro-2-dihydroxy diphenyl ether of 4'-tri-(triclosan) and benzoic acid; Antiinflammatory, for example acetylsalicylic acid and glycyrrhetinic acid; Antiseborrheic, for example retinoic acid; Vasodilator, for example nicotinic acid; Melanogenesis inhibitor, for example kojic acid; And composition thereof.The activating agent that can exist other to advantageously comprise, for example alpha-hydroxy acid, 2-ketoacid, poly hydroxy acid, humidizer, collagen, marine extracts and antioxidant, for example ascorbic acid (vitamin C), alpha-tocopherol (vitamin E) or other vitamin e, for example 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, for example, described in WO94/00098 and WO94/00109.Can also comprise sun-screening agent.
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.Can also add other material, antimicrobial for example, rotten during with the prevention storage, that is, suppress for example growth of yeast and mould of microorganism.Applicable antimicrobial is selected from methyl esters and propyl ester (for example, methylparoban and propyl ester), Sodium Benzoate, sorbic acid, miaow urea (imidurea) and the combination thereof of P-hydroxybenzoic acid usually.
Except the BT compound (for example, be preferably uniform particulate basically provided herein, optional and one or more collaborative antibiotic combinations as herein described) outside, topical formulations also can contain applicable specific application or be incorporated to one or more other activating agents of the effective dose of mode.
On pharmacology, acceptable carrier also can add in the topical formulations of some embodiment of the present invention, and can be the conventional any carrier used in this area.Example comprises water, lower alcohol, higher alcohol, honey, polyhydroxy-alcohol, monose, disaccharides, polysaccharide, sugar alcohol, glycol (2-carbon) for example, 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, the mixture based on water of silicone surfactant and examples of such carriers and the mixture of emulsion-based.
Topical formulations embodiment routine of the present invention can be applied to any natural (for example, plant or animal, comprise the people) or artificial (for example, goods) surface, these surfaces need to reach frequency and the amount of expected result necessity and treat.In specific embodiment, therapeutic frequency depend on application character, active component intensity (for example, BT compound and choosing any one kind of them or multiple other active component, antibiotic for example, for example, amikacin or other antibiotic), for vectorial effect of delivering active ingredients and the easy degree of for example, removing preparation by environmental factor physical contact, precipitation, wind, the temperature of other material or object (, with).
In composition as herein described, such as the typical concentration scope of the active substance of BT compound, can be for example that the approximately 0.001-30% weight of for example 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 (for example 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 for example chelating agent, conditioner, softening agent, excipient, humidizer, protectant, thickener or UV absorbent.It will be understood by those skilled in the art that being different from listed those preparation can be used in embodiment of the present invention.
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 Ca for example 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 gland glycosides phosphoric acid, adenylic acid, adenosine triphosphate, alanine, albumin, marine algae extract, allantoin and derivative, aloe vera extract, PCA aluminium (aluminum PCA), amyloglucosidase, ursin, arginine, azulenes, bromelain, buttermilk powder, butanediol, caffeine, calcium gluconae, capsaicine, Loviscol, carnosine, beta carotene, casein, catalase, cephalin, ceramide, chamomile (chamomilla recutita) flower extract, cholecalciferol, cholesterol ester, cocoyl-betain, coacetylase, modified corn starch, crystalline protein, the 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, the 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 acid and kinetin, lactoferrin, lanosterol, the 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, the placenta enzyme, Placental Lipids, pyridoxal 5-phosphate, quercetin, resorcinol acetic acid esters (resorcinol acetate), vitamin b3, RNA, saccharomycete lysate extract, silk amino acid, sphingolipid, the amino CAB of stearoyl, the stearoyl palmitate, vitamin e, tocopherol acetate, Vitamin E linoleate, ubiquinone, grape (vitis vinifera) 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 the combination of disclosed composition or the preparation 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 (prunus armeniaca) benevolence oil, arginine, arginine aspartate, the Arnica extract, ascorbic acid, ascorbyl palmitate, aspartic acid, junket pears (persea gratissima) oil, barium sulfate, barrier sphingolipid (barrier sphingolipid), butanols, beeswax, behenyl alcohol, cupreol, BHT, birch (white birch) bark extract, borage (borago officinalis) extract, the bromo-2-nitropropane-1 of 2-, the 3-glycol, butcher's broom (ruscus aculeatus) extract, butanediol, Calendula officinalis extract, calendula oil, the wax root of Beijing euphorbia (euphorbia cerifera) wax, Tower rape oil, the caprylic/capric glyceryl ester, cardamom (elettaria cardamomum) oil, babassu (copernicia cerifera) wax, carrageenan (chondrus crispus), carrot (daucus carota sativa) oil, castor-oil plant (ricinus communis) oil, ceramide, ceresine, ceteareth-5, ceteareth-12, ceteareth-20, the cetostearyl alcohol caprylate, cetanol polyethers-20, cetanol polyethers-24, cetyl acetate, the cetanol caprylate, the cetanol palmitate, Roman chamomile (anthemis nobilis) oil, cholesterol, cholesterol ester, Cholesteryl hydroxystearate, citric acid, Salvia sclarea (salvia sclarea) oil, cocoa (theobroma cacao) fat, cocoyl-caprylate/decylate, coconut (cocos nucifera) oil, collagen, collagen amino acid, corn (zea mays) oil, fatty acid, decyl oleate, dextrin, diazolidinyl urea (diazolidinyl urea), dimethicone copolyol, dimethiconol, dioctyl adipate, dioctyl succinate, dipentaerythritol six caprylates/six decylates, DMDMH, DNA, antierythrite, the ethyoxyl diethylene glycol, ethyl linoleate, Eucalyptus Globulus oil, oenothera erythrosepala (Oenothera biennis) oil, fatty acid, tructose, gelatin, shametace oil, aminoglucose, the glucose glutamate, glutamic acid, glycerin polyether-26, glycerine, glycerine, distearin, hydroxy stearic acid glyceride, glyceryl laurate ester, glyceryl linoleate, myristic acid glyceride, olein, tristerin, tristerin SE, glycine, glycol stearate, glycol stearate SE, glycosaminoglycan, grape (vitis vinifera) seed oil, fibert (corylus americana) oil, fibert (corylus avellana) macadamia nut oil, hexylene glycol, honey, hyaluronic acid, safflower (carthamus tinctohus) oil, rilanit special, hydrogenation coconut oil glyceride, hydrogenated coconut oil, hydrogenated lanolin, hydrolecithin, the hydrogenated palm acid glyceride, hydrogenated palm kernel oil, hydrogenated soybean oil, the hydrogenated tallow acid glyceride, hydrogenated vegetable oil, hydrolytic collagen, elastin hydrolysis, the 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 stearoyl stearate, Isodecyl oleate, IPIS, isopropyl lanolate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isostearoyl amine DEA, isostearic acid, isostearyl lactate, the neopentanoic acid isostearate, jasmine (jasminum officinale) oil, Jojoba (buxus chinensis) oil, sea grass, candlenut tree (aleurites moluccana) oil, lactamide MEA, lanolin alcohol polyethers-16, lanolin alcohol polyethers-10 acetic acid esters, lanolin, lanoceric acid, lanolin alcohol, lanolin oil, lanolin wax, lavender (lavandula angustifolia) oil, lecithin, lemon (citrus medica limonum) oil, linoleic acid, linolenic acid, macadamia nut oil, dolomol, magnesium sulfate, maltitol, chamomile (chamomilla recutita) oil, Glucate SS, methyl-monosilane alcohol PCA ester, microwax, mineral oil, ermine oil, Mortierella oil, Tetradecyl lactate, myristyl myristate, the propionic acid myristin, neopentyl glycol dicaprylate/dicaprate, octyldodecanol, myristic acid octyl group ten diester, stearoyl stearic acid octyl group ten diester, the hydroxy stearic acid ester monooctyl ester, octyl palmitate, octyl salicylate, octyl stearate, oleic acid, olive (olea europaea) oil, oranges and tangerines (citrus aurantium dulcis) oil, palm (olea europaea) oil, palmitic acid, pantethine, panthenol, DL-Pantyl Ethyl Ether, paraffin, PCA, peach (prunus persica) benevolence oil, peanut (arachis hypogaea) oil, the PEG-8C1218 ester, the PEG-15 coco amine, the PEG-150 distearate, the PEG-60 glyceryl isostearate, the PEG-5 tristerin, the PEG-30 tristerin, the PEG-7 rilanit special, Cremophor RH40, the PEG-60 rilanit special, the PEG-20 Glucate SS, the full oleate of PEG-40 anhydrosorbitol, the PEG-5 sojasterol, the PEG-10 sojasterol, the PEG-2 stearate, the PEG-8 stearate, the PEG-20 stearate, the PEG-32 stearate, the PEG-40 stearate, the PEG-50 stearate, the PEG-100 stearate, the PEG-150 stearate, pentadecalactone, peppermint (mentha piperita) 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, propane diols dicaprylate/dicaprate, the propane diols dicaprylate, propylene glycol dipelargonate, the propane diols laurate, propylene glycol stearate, propylene glycol stearate SE, PVP, the pyridoxine dipalmitate, quaternary ammonium salt-15, quaternary ammonium salt-18 hectorite, quaternary ammonium salt-22, retinol, retinol palmitate, rice (oryza sativa) rice bran oil, RNA, rosemary, Xue MingRosma rinus officinalis (rosmarinus officinalis) oil, attar of rose, safflower (carthamus tinctorius) oil, Salvia japonica (salvia officinalis) oil, salicylic acid, santal (santalum album) oil, serine, haemocyanin, sesame (sesamum indicum) oil, shea butter (Butyrospermum), the 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, the anhydrosorbitol sesquistearate, sorbitan stearate, sorbitol, soybean (glycine soja) oil, sphingolipid, saualane, squalene, stearmide MEA-stearate, stearic acid, stearoxy dimethicone, stearoxyl trimethyl silane, octadecanol, stearyl glycyrrhetinate, the stearoyl heptanoate, the stearoyl stearate, sunflower (helianthus annuus) seed oil, sweet almond (prunus amygdalus dulcis) oil, synthetic bees wax, vitamin e, tocopherol acetate, Vitamin E linoleate, San Shan Yu essence, neopentanoic acid tridecyl ester, stearic acid tridecyl ester, triethanolamine, tristearin, urea, vegetable oil, water, wax, wheat (triticum vulgare) embryo oil and Yilan (cananga odorata) oil.
Surfactant is also expected to be included in some preparation of this paper expection, and can be selected from any natural or synthetic surfactant that is applicable to cosmetic composition, for example cation, anion, amphion, non-ionic surface active agent or its mixture.(referring to Rosen, M., " Surfactants and lnterfacial Phenomena " second edition, John Wiley & Sons, New York, 1988, the 1 chapters, the 431st page).The example of cationic surface active agent includes but not limited to DMDAO or other amine oxide, long-chain primary amine, diamines and polyamines and salt, quaternary ammonium salt, polyoxyethylene long-chain amine and quaternized polyoxyethylene long-chain amine.The example of anionic surfactant includes but not limited to SDS; Carboxylate (for example, soap); Sulfonate, sulphate, phosphate and polyphosphate; Alkyl phosphate; Monoalkyl phosphoric acid esters (MAP); With perfluorocarboxylic acid salt.The example of zwitterionic surfactant include but not limited to cocamidopropyl propyl amide hydroxy sulfo lycine (CAPHS) and be the pH sensitivity and other material need SC in the suitable pH of design preparation (, alkyl aminopropionic acid, imidazoline carboxylate and betain) or be not those materials (for example, 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 (tertiary acetylenic glycol), polyoxyethylene SiClx ketone, N-alkyl pyrrolidone and APG.For example, and according to non-limiting theory, can also comprise wetting agent, mineral oil or other surfactant, for example nonionic detergent or for example
Figure BDA00002887768301001
one or more members' of series (BASF, Mt.Olive, NJ) material, to reduce the gathering of BT particulate in microparticle suspending liquid.Any surface-active combination is acceptable.Some embodiment can comprise at least one anionic surfactant and a kind of cationic surface active agent, perhaps at least one cationic surface active agent and a kind of amphoteric surfactant, they are compatible, when mixing, do not form the compound of obvious sediment.
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 (cellulose gum), 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.Being different from above-listed those thickener also can be used in embodiment of the present invention.
According to some embodiment of this paper expection, the BT preparation can comprise one or more sun-screening agents or UV absorbent.When needs ultraviolet ray-(UVA and UVB) absorbent properties, such material can comprise for example 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, the PABA butyl ester, cinnamate, Cinoxate, the DEA-Methoxycinnamate, the diisopropyl methyl cinnamate, dihydroxypropyl PABA ethyl ester, the diisopropyl ethyl cinnamate, the methoxy cinnamic acid ethyl ester, ethyl PABA, the urocanic acid ethyl ester, sad dimethoxy-cinnamic acid glyceride (glyceryl octanoate dimethoxycinnamate), PABA glyceride, the ethylene glycol salicylate, Homosalate, isopropyl benzylalcohol salicylate, titanium, zinc, zirconium, silicon, the oxide of manganese and cerium, PABA, the PABA ester, Parsol1789 and isopropyl benzyl salicylate, and composition thereof.It will be understood by those skilled in the art that being different from above-listed those sun-screening agent and UV absorbent or protective agent can be used in certain embodiments of the present invention.
BT preparation disclosed herein usually approximately 2.5 to approximately between 10.0 pH value effectively.Preferably, the pH of composition 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 that about pH7 is to about pH8.Those of ordinary skills can add suitable pH regulate composition to the present composition to regulate pH to acceptable scope." approximately " pH of appointment is interpreted as that by those skilled in the art the pH that comprises wherein actual measurement at any given time may be less than or greater than designated value and be no more than 0.7,0.6,0.5,0.4,0.3,0.2 or the preparation of 0.1pH unit, wherein thinks that preparation forms 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 use dropper, the application such as swab, and carefully be applied to affected zone.Application scheme depends on the many factors that can easily determine, for example infects severity and to the responsiveness of initial treatment.Those of ordinary skill can easily be determined the optimised quantity of preparation to be administered, application process and repetition rate.Generally speaking, consider the preparation of these and related embodiment of the present invention will be with weekly or twice or more times to once a day, twice, three times, four times or range applications more frequently.
Therefore, as discussed above, BT preparation used herein also can comprise acceptable carrier, comprise any applicable thinner or excipient, it comprises that itself to the experimenter that accepts composition (for example, plant or animal, comprise the people) or goods are harmless and any medicament that can use without excessive toxicity.Acceptable carrier can include but not limited to liquid, such as water, salt solution, glycerine and ethanol etc., and can comprise tackifier (for example balsam fir resin) or film forming agent for example colloid or cellulose nitrate cellulose solution.Discussing in detail referring to REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub.Co., N.J. current edition) of pharmaceutically acceptable carrier, thinner and other excipient.
Thereby can comprising being delivered to or being retained on experimenter or goods in conjunction with the reagent of BT compound and auxiliary its, the BT preparation expects position.The applicable reagent that can play this effect comprises inclusion agents, for example cyclodextrin; Other material can comprise albumen or liposome.
The BT preparation is used, applied or merge with effective dose, 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 adopted (comprise in preparation and comprise or do not contain antibiotic, for example aminoglycoside antibiotics, for example amikacin); The metabolic stability of compound and action length; The condition of (plant or animal, comprise the people) experimenter or goods; The mode of using and time; BT compound wear rate in the common procedure of the activity of carrying out on experimenter or goods; And other factors.Generally speaking, treating effective daily dose is that (for the 70kg mammal) is from about 0.001mg/kg (being 0.07mg) to about 100mg/kg (being 7.0g); Preferably, the treatment effective dose is that (for the 70kg mammal) is from about 0.01mg/kg (being 7mg) to about 50mg/kg (being 3.5g); More preferably, the treatment effective dose is that (for the 70kg mammal) is from about 1mg/kg (being 70mg) to about 25mg/kg (being 1.75g).The effective dose of expection plant is low by approximately 10,20,50 or 75% or lower.
Effective dosage ranges provided herein is not intended to restrictive and represents preferred dosage range.Yet most preferred dosage will be formulated according to individual subjects, this be various equivalent modifications understanding with confirmable (referring to, for example, the editors such as Berkow, The Merck Manual, the 16th edition, Merck and Co., Rahway, N.J., 1992; The editors such as Goodman, Goodman and Gilman's The Pharmacological Basis of Therapeutics, the 10th edition, Pergamon Press, Inc., Elmsford, N.Y. (2001); Avery ' s Drug Treatment:Principles and Practice of Clinical Pharmacology and Therapeutics, the 3rd edition, ADIS Press, Ltd., Williams and Wilkins, Baltimore, MD. (1987); Ebadi, Pharmacology, Little, Brown and Co., Boston (1985); Osolci a1. edits, Remington's Pharmaceutical Sciences, the 18th edition, Mack Publishing Co., Easton, PA (1990); Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992)).
If necessary, treat required accumulated dose and can use by the multiple dose through the time or single dose for every kind.Some preferred embodiment expections every day, weekly, every 10 days, every 14 days or per longer time section single application BT preparation.Generally speaking, in different embodiments, treatment can be started by the smaller dose lower than the compound optimal dose.After this, dosage is increased by a small margin, until be issued to optimum efficiency at described environment.
bismuth-mercaptan for the protection of plant and agricultural products
Some embodiment disclosed herein relates to for the protection of plant and spends opposing to comprise biomembranous infected by microbes and the composition and the method that infect, thereby 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 with the BT composition of effective dose: (i) the prevention plant is by bacterium, fungi or viral pathogen infect, (ii) anti-bacteria, cell viability or the Growth of Cells of all cells that swim basically of fungi or viral pathogen, (iii) suppress by bacterium, the biofilm formation of fungi or viral pathogen, and (iv) anti-bacteria, basically biomembrane vigor or the biofilm development of all biomembrane form cells of fungi or viral pathogen, single suspended matter that disperses basically that wherein the BT composition comprises the particulate that contains the BT compound, described particulate has approximately 0.5 μ m to the about volume mean diameter of 10 μ m.
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 cause a disease mutation, pseudomonas syringae, xyllela fastidiosa, vine wood friend bacterium, Monilinia fructicola, Stewart's wilt bacterium, 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 at some, again further in 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 that is selected from tuberous plant, leguminous plant and grass family cereal.In some further embodiment, tuberous plant is selected from potato (potato) and sweet potato (sweet potato).
In certain embodiments, contact procedure is carried out one or many.In certain embodiments, at least one contact procedure comprises spraying, floods, applies and smears the one in plant.In certain embodiments, plant, the flowers are in blossom puts, tender shoots or growth position place or on other plant parts such as root, bulb, stem, leaf, branch, rattan, sarment, bud, flower or its part, tender shoots, fruit, seed, kind pod etc., locate or in carry out at least one contact procedure.In certain embodiments, on plant, the flowers are in blossom for the first time carries out at least one contact procedure in put 24,48 or 72 hours.In certain embodiments, the BT composition comprises and is selected from following one or more BT compound: 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 further comprises: with plant and BT composition contact procedure, simultaneously or successively and with any order, make plant and work in coordination with or the 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, penicillase resistance PCs and Aminopenicillin antibiotic.In certain embodiments, collaborative or enhancement antibiotic is to be selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
In other embodiments, be provided for therein or on it existing the method that overcomes antibiotic resistance in the plant of antibiotic resistance bacterium phytopathogen, comprise: (a) below being enough to meet under one or more condition and time, plant is contacted with the BT composition of effective dose: (i) the prevention plant is by antibiotic resistance bacterium pathogenic infection, (ii) suppress cell viability or the Growth of Cells of all cells that swim basically of antibiotic resistance bacterium pathogene, (iii) suppress the biofilm formation by antibiotic resistance bacterium pathogene, and biomembrane vigor or the biofilm development of all biomembrane form cells basically that (iv) suppress antibiotic resistance bacterium pathogene, single suspended matter that disperses basically that wherein the BT composition comprises particulate, basically single suspended matter that disperses of particulate comprises the BT compound, particulate has approximately 0.5 μ m to the about volume mean diameter of 10 μ m, and (b) and plant and BT composition contact procedure simultaneously or successively and with any order, make plant and work in coordination with or the enhancement antibiotic contacts.
the base preservative of bismuth mercaptan-(BT)
Also as mentioned above, many have antimicrobial (for example, antibacterium, antiviral, antimycotic), particularly the natural products of antibacterial properties (for example antibiotic) and synthesis of chemicals are known in the art, and by chemical constitution and anti-microbial effect, characterized at least in part, described anti-microbial effect for example kills and wounds ability (" killing " effect of microorganism, bactericidal property for example), stop or damage ability (" inhibition " effect of growth of microorganism, antibacterial character for example), perhaps disturb microbial function, for example field planting or infection site, the bacterium of exopolysaccharide secretes and/or is converted into from swimming the ability of the expansion of biomembrane colony or biofilm formation.This paper is above-mentioned, for example, and U.S.6,582,719 have discussed (comprising bismuth-mercaptan or BT compound) such as antibiotic, disinfectant, antibacterial agents, comprise the factor of the choice and operation that affects such composition, for example sterilization or antibacterial character, valid density and to the risk of toxicity of host tissue.
The mercaptan compound of the different V family metal (for example, arsenic, antimony) of above discussion bismuth mercaptan (BT) and alternative bismuth.This paper also discusses to relate to has approximately 0.5 μ m to approximately composition and the method for the favourable particles B T composition particulate of the volume mean diameter of 10 μ m.Therefore, some exemplary belongs to antimicrobial purposes described herein, be included in treatment or prevention infection and biomembranous antibiont membrane reagent in plant, described reagent is present in composition usually, said composition contains by weight a kind of or a plurality of particulate bismuth mercaptan of 0.0001% to 0.001% concentration, is preferably alkaline form.Composition can comprise BT and one or more carriers or excipient and/or can further comprise other composition such as other compatibility bactericide, and in certain preferred aspects, it comprises collaborative or enhancement antibiotic as described herein.
Some contain but in non-limiting embodiments target crop to be protected comprise for example following plant variety: cereal (for example, wheat, barley, rye, oat, rice, Chinese sorghum and relevant crop); Beet (for example, sugar beet and fodder beet); The operatic circle; Drupe and fruitlet (for example, apple, pears, plum, peach, almond, cherry, strawberry, raspberry and blackberry, blueberry); Leguminous plant (for example, soya bean, French beans, pea, soybean); Oils plant (for example, rape seed, leaf mustard, opium poppy, olive, sunflower, coconut, castor oil plant, cocoa bean, peanut); Mellon plant (for example, cucumber, custard squash, muskmelon); Fibre plant (for example, cotton, flax, hemp, jute); Citrus fruit (for example, orange, lemon, grapefruit, oranges and tangerines); Vegetables (for example, spinach, romaine lettuce, asparagus, cabbage, carrot, onion, tomato, potato, hot red pepper); Lauraceae (for example, avocado, Chinese cassia tree, camphor); And other plant, for example corn, tobacco, nut, coffee, sugarcane, tea, grape vine, lupulus, banana and natural rubber plant and ornamental plants (complex form), comprise flowering plant and by the cut-flower of its results.Therefore, by making the crop contact comprise a kind of or a plurality of composition of particles B T compound as herein provided, some embodiment for example contains prolongation, such as (coming from food, fruit, vegetables, cereal, seed etc.) cut-flower or the life of product of the target crop of the results of target crop (for example,, nutrition commercially available with respect to the upper significant prolongation things of control group statistics that does not contact this described particles B T and/or time that can use attractive in appearance).
The valid density of the T of particles B as described herein used in these and related embodiment depends on many factors, comprises the selection of mol ratio of BT, pH, temperature, BT component and the microorganism of intrusion.Validity also depends on the whether target of application-specific of the prevention of infection or the existing treatment of infecting (for example, biomembrane).Under most of condition, preventive dose meets the demands.The concentration that effectively maintains of BT may be near the MIC of maximum resistance organism.This concentration may be in the scope of 1-2 μ g/ml, but can reach 8 μ g/ml or larger at the most, and this depends on concrete particles B T compound.In an exemplary, with 5:1 mol ratio (bismuth: PTO) provide the particles B is PTO (BisPyr) that is applied to plant.In another embodiment, can be using two bismuth mercaptan BisPyr/Ery (Bis-PTO/dithioerythritol) in particulate form as providing for broad spectrum antimicrobicide.In yet another embodiment, can be used in combination to provide target and the potent protection to the infected by microbes of plant and cut-flower/tree with specific antibiotic as herein provided (preferably collaborative or enhancement antibiotic) by particles B T.Concertedness based on observing between BisEDT and gentamicin, in certain embodiments, preferably this BT-antibiotic antibiotic combinations is to apply for agricultural.
In other embodiments, the interpolation of the particles B T preparation of sodium bicarbonate (sodium bicarbonate) or other alkaline matter (for example, saleratus, calcium carbonate) can increase or strengthen the anti-microbial effect of BT.Agricultural comprises surfactant and other antimicrobial with other composition of particles B T preparation, for example, and Chlorhexidine, sanguinarine extract, metronidazole, quaternary ammonium compound (for example Cetylpyridinium Chloride), biguanides (for example CHG, Hexetidine, Octenidine, Alexidine), and halogenated bisphenol compound, for example 2, 2' di-2-ethylhexylphosphine oxide-(the chloro-6-bromophenol of 4-) or other phenol antibacterium compound, the alkyl hydroxy benzoic ether, the cation antimicrobial peptide, aminoglycoside, quinolone, Lincoln's acid amides, penicillin, cynnematin, macrolide, tetracycline and other antibiotic, Taurolidine or tauroflex, A-dec ICX, the Coleus forskohlii essential oil, silver or collargol antibacterial agent, antibacterial agent based on tin or copper, the chlorine or bromine oxide, Mai Luka oil, skin Sa grass, thyme, rosemary, Xue MingRosma rinus officinalis or other medicinal herbs extract, 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., pharmaceutically acceptable carrier, for example, starch, sucrose, water or water/pure system, DMSO etc., surfactant, for example anion, nonionic, cation and amphion or amphoteric surfactant or for example, from the saponin (, United States Patent (USP) 6,485,711) of vegetable material, buffer and salt, and other optional member that may comprise, for example, bleaching agent (such as per-compound), peroxide diphosphonic acid sylvite, effervescent system (such as the 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 additional, enhancing as described herein or synergistic these and optionally other agent combination use or in liposome or form of nanoparticles with enhanced activity with send.Some embodiment is clearly got rid of particles B T preparation, and this particles B T preparation comprises for example, liposome such as phosphatide (, phosphocholine) and/or the liposome that contains cholesterol, and some other embodiment does not limit and can comprise these and other liposome.The concrete preparation that also prepares particles B T, said preparation contains carrier, excipient or promotes adhesion preparation other additive (for example, glucose, starch, citric acid, carrier oil, emulsion, dispersant, surfactant etc.) to surface.
In the embodiment contained at other, can by plant or agricultural crops as the particles B T preparation of antibiont membrane reagent with for controlling other agent combination of biofilm development.Known, for example, between kind, quorum sensing is relevant to biofilm formation.(for example increase some reagent of colony induction signaling between LuxS dependent pathway or kind, U.S. Patent No. 7,427,408 and 6,455,031) contribute to control biomembrane, for example block compound and/or N-butyryl-L-homoserine lactone (BHL) analog of N-(3-oxo dodecanoyl)-L-homoserine lactone (OdDHL).These antibiont membrane reagents of being used in combination with particles B T described herein can be sent with for the anti-bacteria biofilm development or be used for the treatment of preformed biomembrane with blade face spraying form.In another embodiment, these antibiont membrane reagents be included in biodegradable particulate with for control discharge and/or with other antimicrobial in the liposome form.
Use to improve the antibiont membrane interaction together with the technology that therefore, particles B T as herein described can have been existed with other according to some embodiment.This particles B T can work in coordination with or strengthen the activity of the certain plants pathogene of opposing antibiotic streptomycin and/or gentamicin.Streptomycin can killing bacteria; but the propagation that can suppress them of replacing and thereby reduce the speed of field planting at the chapiter place, thereby eliminate bacterium in nectary (nectarthode) propagation subsequently (referring to, for example; Domenico etc., J Antimicrob Chemo1991; 28:801-10; The Research Advances in Antimicrob Agents Chemother2003 such as Domenico; 3:79-85).For example, by using spraying adjuvant (, the Regulaid of activator type tM) can obtain further benefit, this spraying adjuvant enough improves covering and the infiltration of streptomycin, makes this antibiotic amount that reduces safe handling.
This particles B T can be used in combination with any active component of resisting current use in agricultural and phytomicroorganism pathogene, this active component comprises those with antibiont film activity, for example oxidant, chelating agent (for example, iron chelating agent), bactericide and disinfectant.According to the disclosure, preferred combination can increase and maybe can strengthen or collaborative this antibiont membrane interaction.For example by use, give the hydrophobicity mercaptan (for example, the sulfo-chlorophenol) of the adhesion property of enhancing, 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.(for example, bismuth: the BT 1:2 mol ratio of mercaptan) also can have the adhesion property of enhancing to have net negative charge.
Can be using BT compound particulate suspended matter as aqueous formulation, as suspended matter or in the organic solvent that comprises the halogenated hydrocarbons propellant solution, dispersed oil or use as dry powder.Aqueous formulation can be by adopting the liquid dispenser atomization of waterpower or ultrasonic atomizatio.System based on propellant can be utilized suitable pressurization distributor.Dry powder can utilize the dry powder dispersal device that can effectively disperse containing the BT particulate.The granularity of expection and distribution can obtain by selecting appropriate device.
In this specification, unless the other requirement of context, word " comprises ", " comprising " and " containing " will be understood to imply the group that comprises described step or component or step or component, but not get rid of the group of any other step or component or step or component." by ... form " mean to comprise and be limited to phrase " by ... form " any content afterwards.Therefore, phrase " by ... form " to indicate listed component be essential or compulsory, and cannot have other component." substantially by ... form " mean to comprise listed any component after this phrase, and be limited to other component of not disturbing or promoting the active or effect of appointment in the disclosure of listed component.Therefore, phrase " substantially by ... form " to indicate listed component be essential or compulsory, but other component is optional and can exist or can not exist, this depends on whether they affect the active or effect of listed component.
In this specification and the appended claims, unless context is clear, indicate in addition, singulative " ", " a kind of " and " being somebody's turn to do " comprise a plurality of things that refer to.As used herein, in specific embodiments, term " about " or " approximately " are indicated add deduct 5%, 6%, 7%, 8% or 9% scope of this value before numerical value the time.Indicate add deduct 10%, 11%, 12%, 13% or 14% scope of this value when in other embodiments, term " about " or " approximately " are before numerical value.And in other embodiments, term " about " or " approximately " are indicated add deduct 15%, 16%, 17%, 18%, 19% or 20% scope of this value before numerical value the time.
List of references: Badireddy etc., Biotechnol Bioengineering2008; 99:634-43; Badireddy etc., Biomacromolecules, 2008; 9:3079-89; Bayston etc., Biomaterials2009; 30:3167-73.Codony etc., J Applied Microbiol2003; 95:288-93.Domenico etc., J Antimicrob Chemo1991; 28:801-810.Domenico etc., Antimicrob Agents Chemother1997; 41:1697-703.Domenico etc., 1999Infect Immun67:664-669.Domenico etc., Antimicrob Agents Chemother2001; 45:1417-21.Domenico etc., Research Advances in Antimicrob Agents Chemother2003; 3:79-85.Domenico etc., Peptides2004.; 25:2047-53.Domenico etc., 2005Antibiotics for Clinicians9:291-297.Dufrene, J Bacteriol2004; 186:3283-5.Eboigbodin etc., Biomacromolecules2008; 9:686-95.Feazel LM, Baumgartner LK, Peterson KL etc., Opportunistic pathogens enriched in showerhead biofilms.PNAS2009 (electronic edition before printing).Geesey GG, Lewandowski Z, Flemming H-C(edits).Biofouling and biocorrosion in industrial water systems.CRC Press, Boca Raton, FL, 1994.Huang etc., J Antimicrob Chemother1999; 44:601-5; Juhni etc., Proceedings Annual Meeting Adhesion Society2005; 28:179-181.Omoike etc., Biomacromolecules2004; 5:1219-30.Ouazzani K, Bentama J.Bio-fouling in membrane processes:micro-organism/surface interactions, hydrodynamic detachment method.Congres2008; 220:290-4.Ozdamar etc., Retina1999; 19:122-6.Piccirillo etc., J Mater Chem2009; 19:6167.Reunala etc., Curr Opin Allergy Clin Immunol2004; 4:397-401.Romo etc., Environ Progress1999; 18:107-12.Saha DC; Shahin S; Rackow EC; Astiz ME; Domenico is the 10th international conference .Inflamm.Res.Assoc. of modulation by bismuth-ethanedithiol in experimental sepsis. P.2000.Cytokine; Hot Springs, VA.Sawada etc., JPRAS1990; 43:78-82.Schultz, J Fluids Eng2004; 126:1039-47.Tiller JC, Hartmann L, Scherble J.Reloadable antimicrobial coatings based on amphiphilic silicone networks.Surface?Coatings?International?Part?B:Coaf/'ngs?Transactions2005;88:1-82。Tsuneda etc., FEMS Microbiol Lett2003; 223:287-92.Vu etc., Molecules2009; 14:2535-54.Yan etc., Ophthalmologies2008; 222:245-8.Yeo etc., Water Sci Technol2007; 55:35-42.
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Following embodiment is as way of example 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 the particulate of the synthetic schemes according to hereinafter describing for BisEDT.In order to compare, the stoichiometric ratio of the reactant based on using and bismuth and sulfur-containing compound form the known tendency of trivalent complex compound, have shown the atom ratio with respect to single bismuth atom.Numeral in bracket is the ratio (Bi for example: mercaptan 1/ mercaptan 2 of bismuth and one (or more) thiol reagent; Also referring to table 1).
1)CPD1B-1Bis-EDT(1:)BiC2H4S2
2)CPD1B-2Bis-EDT(1:5.5)BiC 3H 6S 3
3)CPD1B-3Bis-EDT(1:1.5)BiC 3H 6S 3
4) (1:1.5) BiC of CPD1CBis-EDT (solubility Bi preparation) 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 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), Shepherd Chemical Co., Cincinnati, OH, production code member 2362; δ～1.6g/mL), slowly add subsequently absolute ethyl alcohol (4L).Some white precipitates produce, but dissolved by continuing to stir.By using the 60mL syringe to add 72.19mL (0.863 mole) 1 to the 1.5L absolute ethyl alcohol, the 2-dithioglycol, then stir and prepare individually 1 in five minutes, the ethanolic solution of 2-dithioglycol (CAS540-63-6) (～1.56L ,～0.55M).Then in 5 hours, 1,2-dithioglycol/EtOH is slowly dropped to Bi (NO 3) 3/ HNO 3the aqueous solution, continue to stir and spend the night.Making the product sedimentation generated is precipitation, continues about 15 minutes, uses afterwards peristaltic pump to remove filtrate with 300mL/min.Then by the Buchner funnel at the 15-cm diameter, on meticulous filter paper, filtering and collect product, and wash three times successively subsequently the BisEDT (694.51gm/ mole) that the acquisition of take is yellow amorphous powder solid shape with ethanol, USP water and the acetone of 500-mL volume.Product is put into to 500mL amber glass bottle and under vacuum through CaCl 2dry 48 hours.Recycled materials (output～200g) give out the mercaptan characteristic odor.Crude product is dissolved in to the 750mL absolute ethyl alcohol again, stirs 30 minutes, then filter and use successively 3 * 50mL ethanol, the washing of 2 * 50mL acetone, and again with the washing of 500mL acetone.The powder of washing is again ground in 1M NaOH (500mL), filter, and with 3 * 220mL water, 2 * 50mL ethanol and the washing of 1 * 400mL acetone, to obtain the pure BisEDT of 156.74gm.The productive rate that batch obtains subsequently about 78-91% prepared in substantially the same mode.
By 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.Developed a kind of HPLC method and measured the chemical purity of BisEDT, prepared thus sample (0.5mg/mL) in DMSO.Measure λ by the DMSO solution at 190 to 600nm scanning BisEDT max.At room temperature with 1mL/min, carry out equal strength HPLC wash-out, mobile phase is acetonitrile: 0.1% formic acid in water (9:1) has (λ at 265nm max) the UV detector that detects, 2 μ L volume injected, is furnished with YMC Pack PVC Sil NP, 5 μ m, the Waters of 250 * 4.6mm internal diameter analytical column (Waters) (Millipore Corp., Milford, MA) model 2695 chromatographs, detect unimodal, the reflection chemical purity be 100 ± 0.1%.Elementary analysis is consistent with the structure of formula (I).
Identify that dry particulate matter is to estimate granularity character.In brief, by the particulate Eddy diffusion in 2%
Figure BDA00002887768301141
f-68 (BASF, Mt.Olive, NJ), suspension under standard configuration in the water-bath Ultrasound Instrument ultrasonic 10 minutes, then use Nanosizer/Zetasizer Nano-S Particle Size Analyzer (model ZEN1600 (without ζ-potential measurement ability), Malvern Instruments, Worcestershire, UK) according to the manufacturer, recommend to be analyzed.According to the combined data of twice measurement, particulate shows Unimodal Distribution, and all detectable events are at the about volume mean diameter of 0.6 micron to 4 microns (VMD), and approximately 1.3 microns there is peak VMD.By contrast, as BisEDT by existing method (Domenico etc., 1997Antimicrob.Agents Chemother.41 (8): while 1697-1703) preparing, the heterogeneous dispersion of majority of particles and have significantly larger size, got rid of their evaluations based on VMD.
Embodiment 2
The bacterium colony biological film model that chronic wounds infects:
By the BT compound, suppress
Because the bacterium existed in chronic wounds adopts biomembrane life style, use basically according to described method (Anderl etc., 2003Antimicrob Agents Chemother47:1251-56; Walters etc., 2003Antimicrob Agents Chemother47:317; Wentland etc., 1996Biotchnol.Prog.12:316; Zheng etc., 2002Antimicrob Agents Chemother46:900) the biomembrane test b T prepared is for the effect of biomembranous antibacterium cell survival.
In brief, the bacterium colony biomembrane is grown 24 hours on 10% tryptic soy agar, then transfer to the Mueller Hinton plate that contains therapeutic agent.After treatment, biomembrane is dispensed in the peptone water that contains 2%w/v glutathione (in and BT), and before the coated plate counting serial dilution to peptone water.Two kinds of bacteriums that separate from chronic wounds are utilized separately for the bacterium colony biomembrane of producing for test.These are Gram-negative bacteria strain pseudomonas aeruginosa and gram-positive methicillin resistance staphylococcus aureus (MRSA).
Basically (Anderl etc., 2003Antimicrob Agents Chemother47:1251-56 as described below; Walters etc., 2003Antimicrob Agents Chemother47:317; Wentland etc., 1996Biotchnol.Prog.12:316; Zheng etc., 2002Antimicrob Agents Chemother46:900), grown in bacterial biof iotalm bacterium colony standing microporous barrier top on agar plate.This bacterium colony biomembrane shows the many common feature of other biological film model, and for example, they are comprised of the cell of assembling in the matrix of high degree of hydration.Also as other people, report (Brown etc., J Surg Res56:562; Millward etc., 1989Microbios58:155; Sutch etc., 1995J Pharm Pharmacol47:1094; Thrower etc., 1997J Med Microbiol46:425), find that the bacterium in the bacterium colony biomembrane shows same significantly reduced antimicrobial susceptibility, this quantizes in more ripe external biological membrane reactor.The 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 the nutrients supplied under biomembrane and minimum flow velocity.Many nutrient sources, for cultivating the bacterium colony biomembrane, comprise blood agar, but it is considered to nutritional condition in analogue body.
Prepare the bacterium colony biomembrane by the planktonic bacteria liquid culture that on the polycarbonate leaching film at the 25mm diameter, inoculation 5 μ l drip.This film was exposed to ultraviolet ray 10 minutes and by sterilizing by every side before inoculation.To plant bacterium 37 ℃ of grow overnight in bacteria culture media, and be diluted under 600nm 0.1 optical density before precipitation in fresh culture on film.Then film is placed on the agar plate that contains growth medium.Then this plate is capped and is inverted in 37 ℃ of incubators.Every 24 hours, use aseptic nipper that film and bacterium colony biomembrane are transferred to new plate.The bacterium colony biomembrane usually after growth 48 hours for testing, now each film has about 10 9individual bacterium.The bacterium colony Biofilm Environment is by successfully for cultivating many single bacterial classifications and mixed bacteria biomembrane.
In order to measure the combating microorganisms agent, (for example, the BT compound, comprise the composition of BT compound; Antibiotic and BT compound-antibiotic composition) susceptibility, the bacterium colony biomembrane is transferred to the agar plate that has supplemented the agent of candidate's antimicrobial therapy.The duration that wherein is exposed to antimicrobial therapy surpasses 24 hours, and be transferred to new treatment plate by the bacterium colony biomembrane every day.In the treatment end of term, the bacterium colony biomembrane is put into to the pipe that contains the 10ml buffer solution vortex 1-2 minute to disperse biomembrane.In some cases, be necessary with the simple processed sample of Potter-Elvehjem Tissue Grinders to smash the cell aggregation thing.Then by the cell suspending liquid serial dilution that obtains coated plate with the bacterium of counting survival, it is reported as to the colony-forming units (CFU) of per unit area.Use log 10the transformation assay survival data.
Bacterial biof iotalm bacterium colony culture (pseudomonas aeruginosa, PA for every type; Methicillin resistance staphylococcus aureus, MRSA or SA), tested five kinds of antibiotic and 13 kinds of BT compounds.Comprise BT and antibiotic tobramycin, amikacin, Imipenem, Cefazolin and the Ciprofloxacin that is referred to herein as BisEDT and compound 2B, 4,5,6,8-2,9,10,11 and 15 (referring to table 1) for the antimicrobial of PA test.Comprise the BT that is referred to herein as BisEDT and compound 2B, 4,5,6,8-2,9,10 and 11 (referring to table 1) and rifamycin antibiotic is flat, Daptomycin, minocycline, ampicillin and vancomycin for the antimicrobial of SA test.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).
Under test concentrations, seven kinds of BT compounds show the remarkable effect to the PA bacteria living, and two kinds of remarkable effects that BT compound proof is survived to MRSA under test concentrations; Representational result shows, Fig. 1 all shows BT effect to bacteria living (in both cases, with respect to shown in antibiotic effect) for BisEDT and BT compound 2B (for the PA test) and Fig. 2 for BT compound 2B and 8-2 (testing for SA).Also as illustrated in fig. 1 and 2, with shown in antibiotic combinations shown in adding of BT compound cause synergy, the effect that reduces thus bacteria living with respect to independent antibiotic or separately the antibacterial action of BT compound be enhanced.In the PA survival is measured, the compound 15 that concentration is 80 μ g/mL
(Bis-EDT/2 hydroxyl, propanethiol (1:1/1)) demonstrates with using 1600 μ g/mL AMK and adds the suitable effect (not shown) of effect (Fig. 1) that 80 μ g/mL BisEDT obtain.
Embodiment 3
The drip biological film model that chronic wounds infects:
By the BT compound, suppress
The drip biomembrane represents the art-recognized authoritative model that is used to form and tests the biomembranous effect of candidate's antimicrobial compound antibacterium.The drip biomembrane above produces at the print (substrate) that goes that is placed in the drip-flow reactor passage.Many dissimilar materials can be used as the film formed substrate of bacterium living beings, comprise the ground glass microslide.Nutrient broth, by splashing near the indoor drip bio-reactor Cytology Lab that enters top, then flows along downward 10 gradients of coupongs major axis.
Biomembrane is grown in the drip bio-reactor, and be exposed to separately or with the BT compound of other antibacterial agent (comprising the BT compound) combination and/or be exposed to separately or with the Antibiotique composition of other antibacterial agent combination, or be exposed to other routine or the candidate therapeutic for chronic wounds.Therefore, identified the effect of BT compound to bacterial biof iotalm in drip-flow reactor.In drip-flow reactor, biomembrane prepares (for example, Stewart etc., 2001J Appl Microbiol.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/l NH 4nO 3, 0.25g/l KCl, 0.25g/l KH 2pO 4, 0.25g/l MgSO 4-7H 2o, supplemented adult's donor cow's serum (ph6.8) that the serum of protein is rich in the 5%v/v simulation, and the iron restrictive condition is similar in body the biofilm development condition in chronic wounds for example.This medium is (50ml/h) four coupongs that four independent parallel chambers contain of flowing through dropwise, and each measures 10cm * 1.9cm, degree of depth 1.9cm.Indoor reactor is made by polysulfone plastic.Each chamber is furnished with independent removable plastic lid, and this vinyl cover can tight seal.Biofilm reactor is put into to 37 ℃ of incubators, and the bacterial cell medium is heated through the aluminium radiator kept in incubator by making it.The method has produced the antibiotic resistance phenotype of observing in some biomembrane, simulation is hanged down the fluid shearing environment and is approached the interface feature of chronic wounds, continuous nutritional supplementation is provided simultaneously, and compatible with many analytical methods for the identification of the antibiotic scheme effect of candidate with the monitoring introducing.Drip-flow reactor is successfully for cultivating many pure and hybrid biomembranes.Biomembrane was grown 2 to 5 days usually before application of antimicrobial reagents.
In order to measure the biomembranous effect of antibiont film to growing in drip-flow reactor, (for example be corrected or be supplemented with the treatment preparation that needs through biomembranous fluid stream, one or more BT compounds and/or one or more antibiotic, or contrast, and/or other candidate agent).Flow and continue the treatment phase of regulation.Then will take out fast from reactor through the biomembrane coupongs for the treatment of, biomembrane is scraped into the beaker that contains the 10ml buffer solution.This sample uses Potter-Elvehjem Tissue Grinders rapid processing (common 30 seconds to 1 minute) with the disperse bacterial aggregation.Suspension is the microorganism to survive according to standard microorganism method counting by serial dilution coated plate.
Embodiment 4
The wound biomembrane that the keratinocyte scratch is repaired suppresses:
Suppress biomembrane by the BT compound
The present embodiment has been described the modification that the external keratinocyte of definite wound healing is scraped wound model, with reach have with biomembrane relevant wounds pathology and wound healing and particularly with acute or chronic wounds or the model that contains biomembranous wound correlation described herein.Scrape wound model according to the keratinocyte of chronic wounds biomembrane effect, the cultivation of mammal (for example people) keratinocyte and bacterial biof iotalm colony is independent indoor the carrying out that mutually fluid is communicated with, and to allow assessment, affects the effect of condition of effect of the soluble component Human Keratinocytes wound healing event of biomembrane generation.
Newborn people's foreskin cell in the vinyl disc of processing as monolayer culture, " wound " that wherein individual layer is controlled or scratch are by mechanical system (for example, by the physical damage of individual layer, for example, by with the applicable instrument acellular district of substantial linear between aseptic operation cutter, razor, cell scraper, tweezers or other instrument scraping individual layer district for example) formation.Known external keratinocyte single-layer model system responds injured event and stands cell structure and function course in the mode that stimulates the body internal injury healing.According to embodiment disclosed herein, observe the impact of the existence of bacterial biof iotalm on this process, for example, on the impact of scratch healing time, and, in these and related embodiment, also assessed the effect of the existence of selected candidate antimicrobial (for example antibiotic and antibiont film) treatment.
The injured keratinocyte individual layer of cultivating under biomembrane exists according to morphology, biochemistry, molecular genetics, stechiology and other parametric test, whether change (for example, in the mode with respect to suitable contrast statistically significant, increase or reduce) biomembranous detrimental effect with the introducing of determining the BT compound.At first wound is exposed to each independent BT compound, and is exposed to the combination of the BT compound of consideration, with the toxicity of every kind of BT compounds for treating of test before effect biomembrane affected the model wound healing process in this type for the treatment of of assessment.
In representative embodiment, three days biomembranes are incubated at and (for example remain on the above-mentioned film of organizing in culture hole, TransWell film inserts etc.) and be communicated with keratinocyte individual layer fluid, the keratinocyte individual layer is scratched to start wound healing process.The biomembrane of cultivating outside real acute or chronic wounds is considered for these and related embodiment.
Therefore, developed the vitro system to the effect of the migration of people's keratinocyte and propagation for assessment of solubility biomembrane component.This system is used dialysis membrane separating bio film and keratinocyte.Keratinocyte is cultivated (Fleckman etc., 1997J Invest.Dermatol.109:36 from newborn foreskin as previously mentioned; Piepkorn etc., 1987J Invest.Dermatol.88:215-219) and be grown to confluent monolayer on the glass cover slide.Then, keratinocyte can be scratched to produce " wound " with homogeneous width, monitors subsequently cell repair process (for example, Tao etc., 2007PLoS ONE2:e697; The 2007Eur.J Cell Biol.86:747 such as Buth; The 2000Ann.Acad.Med.Singapore29:27 such as Phan).Then artificial wound is placed in to the bottom of aseptic bilateral chamber, and uses asptic technique to assemble described chamber.Fill with keratinocyte growth medium (EpiLife) both sides of chamber, contains or do not contain antibiotic and/or bismuth-mercaptan.Nonvaccinated system is with comparing.
System is cultivated 2 hours with the microbionation of wound separation and under static conditions, so that bacterium can be attached to the surface in chamber.After the setting stage, the liquid nutrient medium chamber of being flowing in starts to remove the cell do not adhered to.Then media flow continues with the speed that minimizes the upper indoor Growth of Cells that swims, by washing the cell do not adhered to off.After the culture period of 6 to 48 hours, system (the suprabasil bacterial biof iotalm of the keratinocyte on cover glass and film) is decomposed, and takes out cover glass and analyzes.In related embodiment, biofilm was grown before assembly chamber in upper chamber.In other related embodiment, biomembrane and scratch keratinocyte individual layer cultivate separately altogether 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, for example BT compound or potential collaborative BT compound+antibiotic combinations be (for example, BT compound provided herein, the BT for example provided with particulate form and following one or more: amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin (or another kind of Lincoln's acid amides antibiotic), Daptomycin
Figure BDA00002887768301201
doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid
Figure BDA00002887768301202
minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin) effect that the keratinocyte of scratch is repaired, for example, to identify, (for example change, increasing or reduce in the statistically significant mode with respect to suitable contrast) combination of at least one index time that for example the wound reparation is carried out of scratch healing or the agent that other wound is repaired index or agent is (for example, Tao etc., 2007PLoS ONE2:e697, the 2007Eur.J Cell Biol.86:747 such as Buth, the 2000Ann.Acad.Med.Singapore29:27 such as Phan).
Embodiment 5
The wound biomembrane that the keratinocyte scratch is repaired suppresses
According to the method for describing in above-described embodiment 4, by the people's keratinocyte separated, cultivate on cover glass and scratch.Injured culture is total under the biomembranous condition of culture of cultivating and remains on the film support be communicated with the keratinocyte culture fluid in independent or existence.Then between test period, keratinocyte growth and/or migration redefine the scratch closing time interval of keratinocyte individual layer in the scraping district.Fig. 3 has described the biomembrane fluid and has been communicated with the effect of the existence of (but not being direct contact) to the healing time of scraping keratinocyte individual layer.
Therefore, expected in certain embodiments the method for identifying the material that is used for the treatment of chronic wounds, be included in and do not have under candidate's antibiont film, cultivation scratch cell (for example keratinocyte or fibroblast) individual layer under bacterial biof iotalm exists; And be evaluated at the healing index that there was not and existed lower scratch cell monolayer in candidate's antibiont film, (for example wherein promote the material of at least one healing index, the BT compound, monodispersed BT microparticle suspending liquid basically as herein described for example, separately or with the antibiotic synergistic combination, described antibiotic is following one or more for example: amikacin, ampicillin, Cefazolin, Cefepime, chloramphenicol, Ciprofloxacin, clindamycin, Daptomycin
Figure BDA00002887768301203
doxycycline, gatifloxacin, gentamicin, Imipenem, lavo-ofloxacin, Linezolid
Figure BDA00002887768301204
minocycline, NAF, paromomycin, rifampin, Sulfamethoxazole, tobramycin and vancomycin) be accredited as the material that is suitable for treating acute or chronic wounds or contains biomembranous wound.
Embodiment 6
Concertedness bismuth-mercaptan (BT)-antibiotic combinations
The present embodiment has shown the synergistic situation of one or more bismuth-mercaptan compounds with the proof of the antibiotic combination of 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 the NCCLS scheme at (the Nalge Nunc International of 96 hole tissue culturing plates, Denmark) in, meat soup dilutes to carry out (National Committee for Clinical Laboratory Standards. (1997) .Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically:Approved Standard M7-A2and Informational Supplement M100-S10.NCCLS, Wayne, PA, USA).
In brief, with the bacterial cultures that spends the night, prepare 0.5McFarland standard suspension, further dilute 1:50 (～2 * 10 in its Mueller-Hinton broth bouillon (BBL, Cockeysville, MD, USA) of regulating at cation 6cfu/mL).Add BT (as above preparation) and antibiotic with progressive concentration, keep final volume constant in 0.2mL.Culture is hatched 24 hours at 37 ℃, by using ELISA to read plate device (Biotek Instruments, Winooski, VT, USA), according to the manufacturer, recommend the absorption that is used in 630nm to assess turbidity.Minimal inhibitory concentration (MIC) is represented as and suppresses the growth lowest concentration of drug of 24 hours.Measure live bacteria count (cfu/mL) by the standard coated plate on nutrient agar.Smallest bacteria concentration (MBC) is expressed as the drug concentration that reduces initial viability 99.9% when hatching in 24 hours.
Assess the activity of antimicrobial combination by the chessboard method.According to (Eliopoulos and Moellering such as Eliopoulos, (1996) Antimicrobial combinations. is shown in Antibiotics in Laboratory Medicine (Lorian, V. edit), the 330-96 page, Williams and Wilkins, Baltimore, MD, USA), calculate FICI (FICI) and classification bacteriocidal concentration index (FBCI).Concertedness is defined as FICI or FBCI index≤0.5, during 0.5-4 without interaction, 4 o'clock antagonism (Odds, FC (2003) Synergy, antagonism, and what the chequerboard puts between them.Journal of Antimicrobial Chemotherapy52:1).The minimizing that concertedness is also antibiotic concentration >=4 times by usual definition.
The results are shown in table 2-17.
Table 2
golden yellow staphylococcus aureus-NAF resistance
Figure BDA00002887768301221
BE=0.2 μ g/ml BisEDT; Bacterial isolates is 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
Figure BDA00002887768301231
BE=0.2 μ g/ml BisEDT; Bacterial isolates is available from clinical micro-life of Winthrop university hospital
The thing laboratory, Mineola, NY.NAF is available from Sigma.
Table 4
staphylococcus aureus
rifampin/neomycin/paromomycin
Figure BDA00002887768301232
BE=0.2 μ g/ml BisEDT; Bacterial strain S2446-3 is clinical available from Winthrop university hospital
Microbiological Lab, Mineola, NY.Antibiotic is available from Sigma.
Table 5
staphylococcus epidermidis-GM resistance
Figure BDA00002887768301241
The GM=gentamicin; Bacterial strain S2400-1 is 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
the biomembrane prevention
Figure BDA00002887768301242
Data mean with μ g/ml; Bacterial strain S2400-1 is 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 mean with μ g/ml; Bacterial strain S2400-1 is 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
Figure BDA00002887768301252
Data mean with μ g/ml; Bacterial strain S2400-1 is 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
Figure BDA00002887768301261
Data mean with μ g/ml; Antibiotic is available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 10
escherichia coli-ampicillin/chlorampenicol resistant
Figure BDA00002887768301262
The AB=antibiotic; CM=chloramphenicol; The AM=ampicillin; BE=BisEDT, 0.3 μ g/ml; Bacterial strain is available from MJ doctor's Casadaban laboratory, Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL.Antibiotic is available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 11
escherichia coli-tetracycline-resistance:
doxycycline+BisEDT
Figure BDA00002887768301271
The DOX=Doxycycline; BE=BisEDT, 0.3 μ g/ml; Bacterial strain is available from I doctor's Chopra laboratory, Department of Bacteriology, The University of Bristol, Bristol, UK.Antibiotic is available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 12
pseudomonas aeruginosa-tobramycin-resistance:
the BisEDT concertedness
Agr=glucosaminide resistance; The NN=tobramycin; The PA=pseudomonas aeruginosa; BE=BisEDT, 0.3 μ g/ml; Bacterial strain is available from doctor's K.Poole laboratory, Department of Microbiology and Immunology, Queens University, Ontario, CN.Tobramycin is available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 13
burkholderia cepacia
tobramycin+BE concertedness
MIC
Figure BDA00002887768301281
The NN=tobramycin; BE=BisEDT, 0.4 μ g/ml; Bacterial strain is available from doctor's J.J.LiPuma laboratory, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI; Also has Veloira etc. 2003.Tobramycin is available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 14
burkholderia cepacia
tobramycin+BE concertedness
MBC
Figure BDA00002887768301282
The NN=tobramycin; BE=BisEDT, 0.4 μ g/ml; Bacterial strain is available from doctor's J.J.LiPuma laboratory, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI; Also has Veloira etc. 2003.Tobramycin is available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 15
the tobramycin resistant strain
MIC
The NN=tobramycin; BE=BisEDT, 0.8 μ g/ml; Lipo-BE-NN=liposome BE-NN; Bacterial strain is available from doctor's A.Omri laboratory, Department of Chemistry andBiochemistry, Laurentian University, Ontario, CN; (the M bacterial strain is the mucinoid Burkholderia cepacia; The PA=pseudomonas aeruginosa; The SA=staphylococcus aureus).Tobramycin is available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 16
the tobramycin resistant strain
MBC
Figure BDA00002887768301292
The NN=tobramycin; BE=BisEDT, 0.8 μ g/ml; Lipo-BE-NN=liposome BE-NN; Bacterial strain is available from doctor A.Omri laboratory, Department of Chemistry andBiochemistry, Laurentian University, Ontario, CN; (the M bacterial strain is the mucinoid Burkholderia cepacia; The PA=pseudomonas aeruginosa; The SA=staphylococcus aureus).Tobramycin is available from Pharmacy of Winthrop university hospital, Mineola, NY.
Table 17
bisEDT-PTO concertedness
Figure BDA00002887768301301
BE=BisEDT; The NaPYR=pyrithione zinc; Chemicals is available from Sigma-Aldrich; The concertedness overstriking.Shown in bacterial isolates from American type culture collection (ATCC, Manassas, VA).
Embodiment 7
Comparative bismuth-mercaptan (BT) and antibiotic antagonism comprise the effect of gram-positive bacteria and the Gram-negative bacteria of antibiotic resistance bacteria strain
In the present embodiment, assessed BisEDT and compared the external activity of agent for a plurality of clinical separation strains of the gram-positive bacteria of being responsible for Skin and soft tissue infection and Gram-negative bacteria.
Materials and methods.Test compounds and test concentrations scope are as follows: BisEDT (Domenico etc., 1997; Domenico etc., Antimicrob.Agents Chemother.45 (5): 1417-1421. and embodiment 1), 16-0.015 μ g/mL; Linezolid (ChemPacifica Inc., #35710), 64-0.06 μ g/mL; Daptomycin (Cubist Pharmaceuticals#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 (United States Pharmacopeia, NJ, #1337809) 16-0.015 μ g/mL and 8-0.008 μ g/mL; Ciprofloxacin (United States Pharmacopeia, #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 specimen are dissolved in DMSO; Gentamicin is dissolved in water.With 40 times, to maximum concentration, in test board, prepared by stoste.The final concentration of DMSO in test macro is 2.5%.
Microorganism.Test microbes is available from following clinical labororatory: CHP, Clarian Health Partners, Indianapolis, IN; UCLA, University of California Los Angeles Medical Center, Los Angeles, CA; GR Micro, London, UK; PHRI TB Center, Public Health Research Institute Tuberculosis Center, New York, NY; ATCC, American type culture collection, Manassas, VA; Mt Sinai Hosp., Mount Sinai Hospital, New York, NY; UCSF, University of California San Francisco General Hospital, San Francisco, CA; Bronson Hospital, Bronson Methodist Hospital, Kalamazoo, MI; The quality control separated strain is available from American type culture collection (ATCC, Manassas, VA).Microorganism line on the agar medium of applicable microorganism is separately separated.By swab picking colony put into the suitable meat soup that contains cryoprotector and suspend from separating plate.Suspension is divided into equal portions and enters the low temperature phial and remain on-80 ℃.Abbreviation: BisEDT, bismuth-1,2-dithioglycol; LZD, Linezolid; DAP, Daptomycin; VA, vancomycin; CAZ, cefotaxime; IPM, Imipenem; CIP, Ciprofloxacin; GM, gentamicin; MSSA, the methicillin-sensitivity staphylococcus aureus; CLSI QC, Clinical and Laboratory Standards Institute quality control bacterial strain; MRSA, methicillin resistance staphylococcus aureus; CA-MRSA, group acquired methicillin resistance staphylococcus aureus; MSSE, the methicillin-sensitivity Staphylococcus epidermidis; MRSE, methicillin resistance Staphylococcus epidermidis; VSE, vancomycin susceptibility enterococcus.
Separated strain is rule to appropriate culture medium from cryovial: trypticase soy agar (Becton-Dickinson, Sparks, MD) for most of microorganism, perhaps the trypticase soy agar adds 5% Blood In Sheep (Cleveland Scientific, Bath, OH) for streptococcus.By plate in 35 overnight incubation.Comprise the quality control microorganism.The medium of measuring for MIC is Mueller Hinton II meat soup (MHB II-Becton Dickinson, #212322), for most of microorganism.MHB II has supplemented the 2% horse blood (Cleveland Scientific lot number H13913) dissolved to adapt to the growth of micrococcus scarlatinae and Streptococcusagalactiae.Medium prepares to offset to each micro-dilution plate hole with 102.5% normal weight and adds the dilution that 5 μ L drug solutions are produced.In addition, in order to test Daptomycin, culture media supplemented extra 25mg/L Ca 2+.
The MIC assay method is followed program (the Clinical and Laboratory Standards Institute.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically that Clinical and Laboratory Standards Institute describes; Approved Standard-7th edition.Clinical and Laboratory Standards Institute file M7-A7[ISBN1-56238-587-9] .Clinical and Laboratory Standards Institute, 940West Valley Road, Suite1400, Wayne, Pennsylvania19087-1898USA, 2006) and adopt the automatic fluid operator to carry out serial dilution and liquid transfer.The automatic fluid operator comprises Multidrop384 (Labsystems, Helsinki, Finland), Biomek2000 and Multimek96 (Beckman Coulter, Fullerton CA).The hole of the 2-12 row of the standard 96 micro-dilution plates in hole (Falcon3918) is filled 150 μ l DMSO or water, for the gentamicin on Multidrop384.Medicine (300 μ l) is dispensed in these plates and suitably the 1st of row the is listed as.These will become motherboard, therefrom prepare test board (daughter board).Biomek2000 has completed in mother matrix through the 11st transfer be listed as.In daughter board the 12nd row the Kong Buhan medicine and be the growth of microorganism control wells.Use Multidrop384 to load the suitable test media (above-mentioned) of 185 μ l for daughter board.Prepared by daughter board, the separately respective aperture of Multimek96 instrument from each hole transferase 45 μ l drug solution of motherboard to each daughter board in single step on the Multimek96 instrument.
The standardization kind mycorhiza of each microorganism is according to CLSI method preparation (ISBN1-56238-587-9, the same quoting).In MHB, prepared by suspension, to equal the turbidity of 0.5McFarland standard.Suspension is diluted to 1:9 in the meat soup that is applicable to microorganism.The kind bacterium of each microorganism is dispersed to the aseptic reservoir (Beckman Coulter) of longitudinal subdivision, and uses Biomek2000 inoculation plate.Daughter board is inverted and is placed on the Biomek2000 working surface, makes inoculation drug concentration from low to high carry out.Biomek2000 sends 10 μ l standardization kind bacterium into each hole.This causes about 5 * 105 colony-forming units in final cell concentration position/mL in daughter board.Therefore, the Kongzui of daughter board contains 185 μ l meat soups, 5 μ l drug solutions and 10 μ l bacterium kind bacterium eventually.By plate three floor heights that superpose, uppermost plate covers with lid, puts into plastic sack, and hatches about 18 hours 35 for most of separated strains.By streptococcus plate reading after hatching 20 hours.Use the plate visualizer to watch microplate from bottom.For every 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 that suppresses visible growth of microorganism.
Result.All marketed drug are soluble under all test concentrations in broth bouillon.BisEDT shows traces of precipitated when 32 μ g/mL, but the MIC reading is unaffected, because the inhibition concentration of all test microbes is far below this concentration.Measure day at each, suitable quality control bacterial strain is included in MIC mensuration.Optionally, the MIC value obtained from these bacterial strains with for the disclosed quality control clearance of each agent (Clinical and Laboratory Standards Institute.Performance Standards for Antimicrobial Susceptibility Testing; Eighteenth Informational Supplement.CLSI file M100-S18[ISBN1-56238-653-0] .Clinical and Laboratory Standards Institute, 940West Valley Road, Suite1400, Wayne, Pennsylvania19087-1898USA, 2008) compare.
Measure day at each, suitable quality control bacterial strain is included in MIC mensuration.Optionally, the MIC value obtained from three bacterial strains with for the disclosed quality control clearance of each agent (Clinical and Laboratory Standards Institute.Performance Standards for Antimicrobial Susceptibility Testing; Eighteenth InformationalSupplement.CLSI file M100-S18[ISBN1-56238-653-0]) compare.Wherein disclose in 141 values of quality control bacterial strain of quality control clearance, 140 (99.3%) in specified scope.An exception is Imipenem and staphylococcus aureus 29213, one, takes turns and produces a value (≤0.008 μ g/mL), and this is the dilution lower than disclosed QC scope.This takes turns all other quality control results in the quality control clearance of appointment.
The BisEDT proof has powerful activity for methicillin-sensitivity staphylococcus aureus (MSSA), the acquired MRSA of methicillin resistance staphylococcus aureus (MRSA) and group (CA-MRSA), suppress all test strain when 1 μ g/mL or lower concentration, wherein the MIC90 value for all three microorganisms groups is 0.5 μ g/mL.BisEDT shows the activity that is greater than Linezolid and vancomycin, and is equal to the activity of Daptomycin.Imipenem aspect anti-MSSA than BisEDT more effectively (MIC90=0.03 μ g/mL).Yet MRSA and CAMRSA be to the Imipenem resistance, and BisEDT has proved and activity to being equal to shown in MSSA.BisEDT is to methicillin-sensitivity and methicillin resistance Staphylococcus epidermidis (MSSE and MRSE) high activity, and the MIC90 value is respectively 0.12 μ g/mL and 0.25 μ g/mL.BisEDT any other test agent aspect 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 susceptibility enterococcus faecalis (VSEfc) aspect and Daptomycin, vancomycin and Imipenem are equal to, and the MIC90 value is 2 μ g/ml.Obviously, BisEDT is the most activated anti-vancocin resistance enterococcus faecalis (VREfc) agent of test, and the MIC90 value is 1 μ g/mL.
BisEDT has activity to anti-vancocin susceptibility Enterococcus faecium (VSEfm) utmost point, and the MIC90 value is 2 μ g/mL; Its activity is equal to or is similar to Daptomycin and than the high dilution factor of the activity of vancomycin.BisEDT and Linezolid are the most activated anti-Enterococcus faecium (VREfm) agent of test, show separately the MIC90 value of 2 μ g/mL.The activity of the anti-micrococcus scarlatinae of BisEDT (the MIC90 value is 0.5 μ g/mL) is equal to vancomycin, is greater than Linezolid and is slightly less than Daptomycin and cefotaxime.This compound has suppressed 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 of wherein observing is 16 μ g/mL.The all test substances of the specific activity of BisEDT except gentamicin are all low.
BisEDT and the activity that relatively agent resists included Gram-negative bacteria show to resist the BisEDT effect (the MIC90 value is 2 μ g/mL) of Acinetobacter baumannii, make 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 strains.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 has also proved the activity of antagonism pneumobacillus, and the MIC90 value is 8 μ g/mL, this equates Imipenem.This is the microorganism group of height antibiotic resistance for the relative high MIC90 value indication that Imipenem, cefotaxime, Ciprofloxacin and gentamicin show.BisEDT is the most effective resisting pseudomonas aeruginosa agent in test compounds, and the MIC90 value is 4 μ g/mL.For this test separated strain group, exist comparing the high-level resistance of agent.
In a word, the BisEDT show needle, to representing the wide spectrum effect of a plurality of clinical separation strains of a plurality of kinds, comprises usually and infects relevant kind to acute in the people with chronic skin and skin texture.BisEDT and the crucial relatively activity of agent are assessed for 723 clinical separation strains of gram-positive bacteria and Gram-negative bacteria.The BT compound has proved broad spectrum activity, and, for the many test microbes in this research, BisEDT is the most effective in test compounds aspect antibacterial activity.BisEDT antagonism MSSA, MRSA, CA-MRSA, MSSE, MRSE and micrococcus scarlatinae are the most effective, and wherein the MIC90 value is 0.5 μ g/mL or lower.Also proved the powerful activity to VSEfc, VREfc, VSEfm, VREfm, Acinetobacter baumannii, Escherichia coli and pseudomonas aeruginosa, wherein the MIC90 value is in 1-4 μ g/mL scope.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 shows that particulate bismuth-mercaptan (BT) promotes antibacterial activity by enhancing and/or cooperative interaction.
When treatment is infected, the main deterioration factor is that resistance appears in bacterial antibiotic.Methicillin resistance in Staphylococcus epidermidis (MRSE) and staphylococcus aureus (MRSA) has in fact reflected Multidrug resistance, makes these pathogene be difficult to eradicate.Yet, from the bacterial strain of hundreds of tests, do not have staphylococcus to show the resistance to BT.In addition, inferior (subMIC) concentration that suppresses has reduced some important antibiotic resistances.
staphylococcus aureus.Illustrate (Fig. 4) of the sensibilization of the antibiotic of subMIC bismuth dithioglycol (BisEDT) to MRSA-again is provided, show some type antibiotic, 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.
The antibiotic that uses BisEDT some and the subMIC level to combine carries out diluting antimicrobial Study of Sensitivity (table 18) for the meat soup of 12 kinds of MRSA bacterial strains.In particular organisms film medium (BHIG/X), measure biomembrane prevention concentration (BPC) and minimal inhibitory concentration (MIC) both.Reduce MIC and the BPC of gentamicin and Cefazolin by subMIC BisEDT (BisEDT MIC, 0.2-0.4 μ g/ml), but not below the susceptibility flex point.The MRSA susceptibility of subMIC BisEDT Enhanced MR SA to the gatifloxacin close to the susceptibility flex point and Cefepime.These bacterial strains are to the vancomycin sensitivity, but all the more so when having subMIC BisEDT.Usually, reduce MIC and BPC2 to 5 times with subMIC BisEDT.
Table 18.
the antimicrobial acivity of BT-antibiotic composition to MRSA
Figure BDA00002887768301371
12 kinds of MRSA clinical isolates are grown in to BHIG/X and be exposed in the antibiotic of the serial dilution that has 0-0.1 μ g/mlBisEDT.The MIC that the μ g/ml of take calculates and BPC are the mean value ± standard deviation from least three tests.Right-hand column is listed the standard MIC of antibiotics sensitivity (S) and resistance (R)
The meat soup dilution of Cefepime resistance MRSA separated strain studies show that in table 19.0.1 the Cefepime of 11 that the BisEDT of μ g/ml strengthens in 12 separated strains significantly suppresses active.In this particular studies, data show the concertedness (FIC<0.5) of many separated strains between BisEDT and Cefepime at susceptibility flex point place.
Table 19
cefepime resistance MRSA is by the BisEDT sensitization
Figure BDA00002887768301381
The susceptibility 48h of the Cefepime that under 37 ℃, MRSA pair of 12 Cefepime resistance of test and subMIC BisEDT combine in the BHIG/X of XPS medium.
The table 20 that the results are shown in celbenin or gentamicin combination research.Reduce celbenin with the BisEDT (0.2 μ g/ml) of celbenin combination the MIC90 of MRSA is reached to (FIC, 0.74) more than 4 times.Reduce gentamicin with the BisEDT of gentamicin combination the MIC90 of MRSA is surpassed to 10 times (FIC, 0.6).BT has reversed the resistance [Domenico etc., 2002] of the gentamicin resistance separated strain of whole four kinds of tests to clinical respective concentration.Basically reduce the MIC of these antimicrobials, particularly gentamicin.For the meat soup of these researchs, be the trypticase soybean broth (TSB) that contains 2% glucose, the result of its demonstration to see the similar of result in the Mueller-Hinton II meat soup that has added 1% sheep blood.
Table 20
mRSA: celbenin or gentamicin+BisEDT concertedness
Figure BDA00002887768301391
NAF or GM, μ g/ml; 0.2 the BE of μ g/ml
staphylococcus epidermidis.the existence of BisEDT promotes most of antibiotic activity.About BPC, when combining with BisEDT, clindamycin and gatifloxacin show significantly the antibiont film activity (Fig. 5) stronger to Staphylococcus epidermidis.With the statement of different term, while having subMIC BisEDT, for the BPC of clindamycin, gatifloxacin and gentamicin, reduce respectively 50 times, 10 times and 4 times.
Notice for minocycline, vancomycin and Cefazolin and prevent only moderate reduction in concentration (BPC) at biomembrane, and remain unaffected at 0.05 μ g/ml BisEDT rifampin and celbenin.Do not detect biomembrane at 0.1 μ g/ml BisEDT, no matter whether adopt antibiotic, show not have antagonism to occur.This BisEDT concentration for Staphylococcus epidermidis close to MIC[Domenico etc., 2003] (referring to Fig. 5).
About growth inhibition, while having 0.1 μ g/ml (0.5 μ Μ) BisEDT, in the antibiotic of 8 tests, there are 7 to strengthen significantly antagonism Staphylococcus epidermidis (Fig. 6).The most obvious for clindamycin and gentamicin MIC variation, be secondly vancomycin, Cefazolin, minocycline, gatifloxacin and celbenin, rifampin is unaffected.In the antibiotic that this bacterial strain is resistance to it (NC, CZ, GM, CM), only the resistance of Cefazolin is reversed to clinical respective horizontal by BisEDT.
Antibiotic and subMIC BisEDT for the great majority test reduce slightly to the staphylococcic minimum bactericidal concentration of epidermis (MBC).Gentamicin shows that large MBC 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 maintenance is substantially constant.Clindamycin is bacteriostatic agent, and this illustrates that it lacks bactericidal activity.The Cefazolin resistance is reversed [Domenico etc., 2003] for MBC.These effects are accumulated.
The synergistic effect (table 21) that in vivo also demonstrates antimicrobial at the graft infection rat model.The BisEDT level that is low to moderate 0.1 μ g/ml can promote to prevent anti-Staphylococcus epidermidis biomembrane 7 days.
As table 21 is summarized, with 0.1 μ g/ml BisEDT, 10 μ g/ml RIP and 10 μ g/ml rifampins dipping implant, the rat of implanted s.c. alone or in combination.The use tuberculin syringe will be with 2 * 10 7the physiological solution that cfu/ml contains MS and MR bacterial strain (1ml) is inoculated into graft surface.All grafts in transplanting, in the time of latter 7 days, be moved out of and in sterile saline solution ultrasonic 5 minutes to remove the bacterium of adhesion.Obtain the quantitative of bacterium alive by cultivate dilution on the blood agar plate.Detectable limit is approximately 10cfu/cm 2.
Table 21
staphylococcus epidermidis in the anti-graft infection model of RIP, BT and rifampin
aeach group has 15 animals; MS, methicillin-sensitivity Staphylococcus epidermidis; MR, methicillin resistance Staphylococcus epidermidis
bby 0.1mg/l BT, 10mg/l RIP, the impregnated terylene graft of 10mg/l rifampin segment
cstatistically significant when comparing with MR with control group MS
dstatistically significant when comparing with the MS3 group
estatistically significant when comparing with the MR3 group with MR1, MR2
gram-negative bacteria.The activity of tobramycin antagonism pseudomonas aeruginosa strengthens several times (table 22) with subMICBisEDT.In these trials, more properly MIC is defined as to IC 24.
Table 22
tobramycin resistance pseudomonas aeruginosa: BisEDT effect
Figure BDA00002887768301421
When having tobramycin (NN) and BisEDT (BE:0.33 μ g/ml), the resistant strain of pseudomonas aeruginosa is incubated to Mueller-Hinton II meat soup at 37 ℃.MIC is determined as to the antibiotic concentration that stops 24 ± 1h growth.
0.4 μ g/ml BisEDT makes in 10 separated strains 7 to tobramycin resistance Burkholderia cepacia tobramycin responsive (mean F IC:0.48), and reduces MIC 90reach 10 times (table 23).Reduce significantly MIC and MBC to reach the level [Veloira etc., 2003] of opposing 50 clinical Burkholderia cepacia separated strains with subMIC BisEDT.BisEDT and the tobramycin high Collaboration opposing pseudomonas aeruginosa of liposome form have been proved.(Halwani etc., 2008; Halwani etc., 2009).
Table 23
tobramycin and BisEDT antagonism Burkholderia cepacia
Figure BDA00002887768301431
athree bacterial strains that will be suppressed by the BisEDT of 0.4 μ g/ml are got rid of from further research.FIC index≤0.5 means concertedness: FICI > 0.5 and<1.0 expression enhancings.
By adding subMIC BisEDT, make chloramphenicol and ampicillin resistance Escherichia coli to these medicaments insensitives (table 24).
Table 24
chloramphenicol/ampicillin resistance Escherichia coli: BisEDT effect
Figure BDA00002887768301432
Exist alone or in combination under chloramphenicol (CM) or ampicillin (AMP) and BisEDT (BE:0.33 μ g/ml) colibacillary resistant strain in 37 ℃ are incubated at Mueller-HintonII meat soup.MIC is determined as to the antibiotic concentration that suppresses long-living 24 ± 1h.
By adding subMIC BisEDT (table 25), make the tetracyclin resistance Escherichia coli to the Doxycycline sensitivity.The concertedness of described combination show needle to TET M and TET D bacterial strain (FIC≤0.5), have the summation action for TET A and TET B bacterial strain.
Table 25
tetracyclin resistance Escherichia coli: BisEDT effect
Figure BDA00002887768301441
In under having alone or in combination Doxycycline (DOX) and BisEDT (BE:0.33 μ g/ml), 37 ℃ of Escherichia coli resistant strains being incubated to Mueller-Hinton II meat soup.MIC is determined as to the antibiotic concentration that suppresses growth 24 ± 1h.
list of references:
Domenico?P,R?O'Leary,BA?Cunha.1992.Differential?effect?of?bismuth?and?salicylate?compounds?on?antibiotic?sensitivity?of?Pseudomonas?aeruginosa.EurJ?Clin?Microbiol?Infec?Dis11:170-175;Domenico?P,D?Parikh,BA?Cunha.1994.Bismuth?modulation?of?antibiotic?activity?against?gastrointestinal?bacterial?pathogens.Med?Microbiol?Lett3:114-119;Domenico?P,Kazzaz?JA,Davis?JM,Niederman?MS.2002.Subinhibitory?bismuth?ethanedithiol(BisEDT)sensitizes?resistant?Staphylococcus?aureus?to?nafcillin?or?gentamicin.Annual?Meeting,ASM,Salt?Lake?City,UT;Domenico?P,Kazzaz?JA,Davis?JM.2003.Combating?antibiotic?resistance?with?bismuth-thiols.Research?Advances?in?Antimicrob?Agents?Chemother3:79-85;Domenico?P,EGurzenda,A?Giacometti,O?Cirioni,R?Ghiselli,F?Orlando,M?Korem,V?Saba,G?Scalise,N?Balaban.2004.BisEDT?and?RIP?act?in?synergy?to?prevent?graft?infections?by?resistant?staphylococci.Peptides25:2047-2053;Halwani?M,Blomme?S,Suntres?ZE,Alipour?M,Azghani?AO,Kumar?A,Omri?A.2008.Liposomal?bismuth-ethanedithiol?formulation?enhances?antimicrobial?activity?of?tobramycin.Intl?J?Pharmaceut358:278-84;Halwani?M,Hebert?S,Suntres?ZE,Lafrenie?RM,Azghani?AO,Omri?A.2009.Bismuth-thiol?incorporation?enhances?biological?activities?of?liposomal?tobramycin?against?bacterial?biofilm?and?quorum?sensing?molecules?production?by?Pseudomonas?aeruginosa.Int?J?Pharmaceut373:141-6;Veloira?WG,Gurzenda?EM,Domenico?P,Davis?JM,Kazzaz?JA.2003.Synergy?of?tobramycin?and?bismuth?thiols?against?Burkholderia?cepacia.J?Antimicrob?Chemother52:915-919.
Embodiment 9
Particles B T-antibiotic strengthens and synergistic activity
The present embodiment show particulate bismuth mercaptan BisEDT by with promote antibacterial activity for the organic concrete antibiotic enhancing of concrete microorganism target and/or cooperative interaction.For one point data separately, show according to the method for using in embodiment 8 combination in generation table 26 basically.
Table 26
fICI value for single-point BisEDT-antibiotic composition
SA, staphylococcus aureus; MRSA, methicillin resistance staphylococcus aureus; EFc, enterococcus faecalis; SP, streptococcus pneumonia; PRSP, the penicillin resistance streptococcus pneumonia; 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 prepared as mentioned above by test and four kinds of Bis-EDT analogs and anti-some Gram-negative pathogens.Measure the concertedness (FICI≤0.5) of utilizing FIC (FIC) and FIC index (FICI), strengthen (0.5<FICI≤1.0), Antagonism (FICI > 4.0) and indifference (1.0<FICI≤4.0) (Eliopoulos G and R Moellering.1991.Antimicrobial combinations.In Antibiotics in Laboratory Medicine by improved General Purpose Laboratory method; the 3rd edition; V Lorian. edits Williams and Wilkins; Baltimore; MD, the 432-492 page; Odds, 2003J.Antimicrob.Chemother.52 (1): 1).Use checkerboard measure the FIC index and adopt in this research.
Table 27
fractions tested
Figure BDA00002887768301471
The stoste of all test article is prepared as to the 40 * final goal concentration in appropriate solvent.In all test article solution under these conditions.The MIC value of each reagent that final drug concentration in the FIC analysis plates is set as comprising to each test microbes, unless bacterial strain is to the test agent complete resistance.The concentration range of test is shown in table 27.The test organism is original is accepted in clinical source, or from the biological product of Unite States Standard collecting center.During reception, separator is scoring on tryptic soy agar II (TSA).Clone and prepare cell suspending liquid in comprising the suitable meat soup growth medium of cryoprotector from these plate results.Then freezing equal portions thing under-80 ℃.The freezing seed of microorganism to be tested in given analysis is thawed, separator is scoring on the TSA plate, and hatches under 35 ℃.The all microorganisms of test in Mueller Hinton II meat soup (Becton Dickinson, lot number 9044411).Prepare meat soup with 1.05 * normal weight/volume, thereby compensate the medicine of 5% volume in the final test plate.
Use the meat soup microdilution of aerobic bacteria to measure in advance minimal inhibitory concentration (MIC) value (Clinical and Laboratory Standards Institute (CLSI) .Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-the 8th edition.CLSI file M07-A8[ISBN1-56238-689-1] .Clinical and Laboratory Standards Institute, 940West Valley Road, Suite1400, Wayne, Pennsylvania19087-1898USA, 2009).
The meat soup microdilution of describing before using (Sweeney etc., 2003Antimicrob.Agents Chemother.47 (6): 1902-1906) measure the FIC value.For preparing test board, use automated fluid processor (Multidrop384, Labsystems, Helsinki, Finland; Biomek2000and Multimek96, Beckman Coulter, Fullerton CA) carry out serial dilution and liquid shifts.
Use Multidrop384 in the 2-12 row, the suitable solvent of 150 μ L is inserted in the appropriate well of the micro-dilution plate in standard 96-hole (Falcon3918).Each second testing drug of 300 microlitres is added in each hole of plate the 1st row.For the drug regimen plate, prepare the medicine " motherboard " that continuous drug dilution is provided with these plates.Come to shift each second drug solution (40 *) of 150 μ L from the 1st hole be listed as of motherboard with Biomek2000, and carry out 11 2 times of serial dilutions.Use the multichannel pipette, manually by the motherboard serial dilution from the top to bottom of Bis-EDT (and analog).Combine two motherboards (for each second medicine and for Bis-EDT (or analog)) with formation " checkerboard " pattern by shifting equal-volume (using the multichannel pipette) to the drug regimen plate.The serial dilution of capable and 12 each the self-contained independent a kind of reagent measured for MIC of row of H.
Use Multidrop384 in " daughter board " the 180 μ L test media of packing into, then, in independent step, use Multimek96 to shift 10 μ L drug solutions from each hole of drug regimen motherboard to daughter board separately corresponding hole.Finally, inoculate daughter board by test microbes.The standardized kind of bacterium for preparing each microorganism according to disclosed guide (CLSI, 2009).For all separators, the kind bacterium of each microorganism is distributed to the aseptic storage center of being cut apart by length (Beckman Coulter), and inoculates plate with Biomek2000.Instrument send standardized kind of bacterium of 10 μ L to each hole to produce about 5 * 10 in daughter board 5the final cell concentration of colony-forming units/mL.
Produce the test lattice in creating 8 * 12 checkerboards, wherein with the drug concentration that changes (the 12nd row and H are capable) and each compound of combined test recently separately.All microorganism sheetpiles are folded three height, on top board, with covering, put into plastic sack, and hatch about 20 hours at 35 ℃.After hatching, remove microplate and use ScienceWare plate reader to observe from bottom from incubator.The hole of the MIC (H is capable) of the medicine 1 of reading card prepared by mark, the MIC of medicine 2 (12 row) and growth-non-growth interface.
Use the MIC of Excel program independent compound 1 according to the MIC/ of the compound 1 of following formula mensuration FIC:(combination)+(MIC of the compound 2 that the MIC/ of the compound 2 of combination is independent).By independent FIC passing type: (FIC 1+ FIC 2+ ... FIC n)/n calculates the FICI of checkerboard, wherein the quantity in the single hole of every block of plate of n=calculating FICs.Produce in the situation of underproof MIC result the MIC value during the height concentration of next is calculated as FIC at single reagent.
Particles B isEDT, four kinds of particles B T analogs and all other reagent (with the combination of reagent) in all final test concentration, be soluble.MIC and the FICI value measured are shown in following table.
Table 28
minimal inhibitory concentration and FIC result for MB-1B-3 and Piperacillin gather
Figure BDA00002887768301501
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 29
for the minimal inhibitory concentration of MB-1B-3 and AZT and FIC result gather
Figure BDA00002887768301502
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 30
gathering of the minimal inhibitory concentration of MB-15 and Piperacillin and FIC result
Figure BDA00002887768301511
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 31
gathering of the minimal inhibitory concentration of MB-15 and AZT and FIC result
Figure BDA00002887768301512
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 32
gathering of the minimal inhibitory concentration of MB-8-2 and Piperacillin and FIC result
Figure BDA00002887768301521
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 33
gathering of the minimal inhibitory concentration of MB-8-2 and AZT and FIC result
1mIC, minimal inhibitory concentration
2flCI, FICI
Table 34
gathering of the minimal inhibitory concentration of MB-11 and Piperacillin and FIC result
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 35
gathering of the minimal inhibitory concentration of MB-11 and AZT and FIC result
Figure BDA00002887768301532
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 36
gathering of the minimal inhibitory concentration of MB-2B and Piperacillin and FIC result
11mIC, minimal inhibitory concentration
2fICI, FICI
Table 37
gathering of the minimal inhibitory concentration of MB-2B and AZT and FIC result
Figure BDA00002887768301542
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 38
gathering of the minimal inhibitory concentration of MB-1B-3 and cefotaxime and FIC result
Figure BDA00002887768301551
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 39
gathering of the minimal inhibitory concentration of MB-1B-3 and Cefepime and FIC result
Figure BDA00002887768301552
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 40
gathering of the minimal inhibitory concentration of MB-15 and cefotaxime and FIC result
Figure BDA00002887768301561
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 41
gathering of the minimal inhibitory concentration of MB-15 and Cefepime and FIC result
Figure BDA00002887768301562
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 42
gathering of the minimal inhibitory concentration of MB-8-2 and cefotaxime and FIC result
Figure BDA00002887768301571
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 43
gathering of the minimal inhibitory concentration of MB-8-2 and Cefepime and FIC result
Figure BDA00002887768301572
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 44
gathering of the minimal inhibitory concentration of MB-11 and cefotaxime and FIC result
Figure BDA00002887768301581
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 45
gathering of the minimal inhibitory concentration of MB-11 and Cefepime and FIC result
Figure BDA00002887768301582
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 46
gathering of the minimal inhibitory concentration of MB-2B and cefotaxime and FIC result
Figure BDA00002887768301591
1mIC, minimal inhibitory concentration
2fICI, FICI
Table 47
gathering of the minimal inhibitory concentration of MB-2B and Cefepime and FIC result
Figure BDA00002887768301592
1mIC, minimal inhibitory concentration
2fICI, FICI
Embodiment 11
The effect of bismuth mercaptan to the critical infection in damaged of rat femur
The current standard of open fracture nursing is flushing, debridement and antibiotic; Its objective is that the bacterial loads reduced in wound is to the degree infected does not occur.Although these treatments are arranged, for open tibial fracture, infect and still worsen the severity that reaches 75%.What is interesting is, even usually by Gram-negative bacteria, cause early infection, also can be infected to Gram-positive due to the late period that relates to healing problem and excision and infect, usually 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) that will kill the similar microorganism in medium.
The purpose of this research is measure BT or whether will fall the infection in oligosaprobic open fracture model independently or with antibiotic.The rat femur critical defective model polluted is good Acceptance Model for the described experiment of the present embodiment.This model is provided for more various potential treatments and reduction is infected and/or improved the standardized model of the effect of curing.
Table 1) and CPD-11 (bismuth pyrithione/dithioglycol: be table 1) to have shown two kinds of BIS-BiS analogs resisting the bacterium potential that in vitro biomembrane is concealed, although activity profile is different from Bis-EDT compound (CPD) CPD-8-2 (bismuth pyrithione/succinimide mercaptans:.
When with not with polymethyl methacrylate (PMMA) adhesive pearl medium in tobramycin and vancomycin while using, three kinds of BT preparations, Bis-EDT, CPD-11 and CPD-8-2 (referring to table 1) show the inhibitory action to sv staphylococcus aureus.By the production of three kinds of particles B T preparations, it is useful hydrogel gel form 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 the wound profile, need to after application, not remove.
Use two treatment groups (treatment arm): in first group, use separately BT; In second group, use BT and systemic antibiotics (ABx).
(a) BT is independent.
Cultivate latter six hours with staphylococcus aureus, remove wound, insert in breach with normal saline washing and by 1ml BT gel.
(b) BT and systemic antibiotics (ABx).
Cultivate latter six hours with staphylococcus aureus, remove wound, insert in breach with normal saline washing and by the BT gel of 1ml interpolation.The antibiotic used is for being equivalent to 5mgKg -1the Cefazolin of dosage, damage is by by twice hypodermic injection every day totally 3 days.Use immediately the first dosage before removing.Data in the past show that this dosage will cause bacteria levels to be reduced to ≈ 10 by ≈ 106 4therefore, still allow the dependent interaction of different B T to be measured.
(c) contrast
Cultivate latter six hours with staphylococcus aureus, with salt solution, remove and irrigate.Also with Cefazolin, treat in the manner described above control-animal.
Program:
Carry out the in vivo program of Damage of Rats model as described in Chen etc.(2002J.Orthop.Res.20:142;2005J.Orthop.Res.23:816;2006J.Bone?Joint?Surg.Am.88:1510;2007J.Orthop.Trauma21:693)。By rat anesthesia and make arrangements for surgery.Expose femur backbone's front Outboard Sections by the 3cm cut channel.Periosteum and appended muscle are peeled off from bone.To gather acetyl substrate (27 * 4 * 4mm) is put on the anterolateral surface of femur.The preboring orifice plate is to accept the wire kirschner wire of 0.9mm diameter.Form the matrix of these plates to be applicable to femur backbone's profile.Use plate as template, pilot hole to be drilled through to two shells of femur, and the wire kirschner wire is inserted through to plate and femur.To remove guide as bone from the otch of plate 6mm.Produce defect with little reciprocating saw, simultaneously cooling by organizing to make great efforts the prevention fire damage by continuous flushing.
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: the Bis-EDT gel; The MB-11 gel; The MB-8-2 gel; Bis-EDT Ning Jiao & Abx; MB-11 Ning Jiao & Abx; MB-8-2 Ning Jiao & Abx; Contrast (Abx is independent).
Perform the operation and anaesthetize animal in latter 14 days, bone and hardware are sent to microbiological analysis, the results are shown in Fig. 7.
Based on efficiency analysis, every group of 10 animal will provide 80% effect to detect between treatment and control group 25% difference.The expection standard deviation of this support 35% and 0.05 α.
As shown in Figure 7, strengthened the infection of staphylococcus aureus of antibacterial activity with the bone that reduces damage with the Cefazolin of Bis-EDT, MB-11 and MB-8-2 combination with respect to Cefazolin or independent Bis compound.Compare with independent Cefazolin, with the Cefazolin of MB-11 and MB-8-2 combination, show that the antibacterial activity strengthened is to reduce the infection of staphylococcus aureus detected on hardware.As if Bis-EDT does not affect the activity of Cefazolin in this.
Embodiment 12
Bismuth-containing compound is resisted halobiontic activity
This embodiment describes the antimicrobial acivity of bismuth-containing compound.The conventional method of implementing by those skilled in the art is measured the MIC value of three kinds of different marine bacterias of three kinds of bismuth-containing compound opposings such as bismuth dimercaprol dimercaptopropanol (BisBAL), bismuth dimercapto toluene (BisTOL) and bismuth dithioglycol (BisEDT).Data are shown in following table:
Embodiment 13
Bismuth-containing compound adheres to the effect of behavior to barnacle
Compound, BisBAL and BisTOL are included in determination method and kentrogon are adhered to the inhibition activity of behavior to measure each compound.Method is carried out according to the technology of this area practice.BisBAL has the EC of 1.6ppm 50(producing 50% concentration of adhering to inhibition), and BisTOL has the EC of 15.4ppm 50.In another experiment, BisEDT directly is dissolved in natural sea-water or at first is dissolved in DMSO, then be diluted in natural sea-water.EC 50measured value has significant difference.When directly being dissolved in seawater, BisEDT has the EC of 1.5ppm 50, and, when at first being dissolved in DMSO, it has the EC of 2.1ppm 50.Commercially available insecticide, the EC of SEANINE211 50for 0.5ppm.
Embodiment 14
The impact that bismuth-containing compound adheres to marine alga
Measure three kinds of impacts that bismuth-containing compound adheres to marine alga such as bismuth dimercaprol dimercaptopropanol (BisBAL), bismuth dimercapto toluene (BisTOL) and bismuth dithioglycol (BisEDT), particularly each compound suppresses the ability that Enteromorpha spore (Enteromorpha spore) germinates.Each compound of test under 0.001,0.01,0.1,1.0 and 10.0 μ g/ml.BisEDT is compounds effective, under 1 μ g/ml BisEDT, suppresses approximately 50% marine alga spore population and germinates, and, under 10 μ g/ml, suppress approximately 75% marine alga spore-germination.The BisBAL of 10 milligrams/ml and BisTOL do not have inhibitory action to the spore-germination of this specific marine alga kind at the most.
Embodiment 15
The impact that bismuth-containing compound adheres to marine alga
The technology of implementing according to this area is measured the growth of three kinds of bismuth-containing compounds such as bismuth dimercaprol dimercaptopropanol (BisBAL), bismuth dimercapto toluene (BisTOL) and bismuth dithioglycol (BisEDT) to marine diatom.Adhere to (diatom/visual field) that suppresses marine diatom by the concentration (0.001,0.01,0.1,1.0 and 10.0 μ g/ml) that increases respectively three kinds of compounds.Under 0.1 μ g/ml, each compound shows and suppresses active; BisEDT is the most active, and it shows approximately 100% inhibition.Under 0.1 μ g/ml, BisTOL and BisBAL show separately approximately 30% marine diatom and adhere to.
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Above-mentioned various embodiments capable of being combined are to provide other embodiments.By reference to its integral body by this specification, relate to and/or the application data page in list all United States Patent (USP)s,
U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and non-patent openly are incorporated to this paper.If need, can adopt various patents, application and disclosed design to come the each side of revision for execution scheme so that other other embodiments to be provided.
Can carry out these and other change to embodiment according to above-mentioned detailed description.Usually, in following claims, the term used should not be construed as claim is limited to disclosed specific embodiments in specification and claim, and should be interpreted as comprising all possible embodiment together with the whole equivalency range with this claim defined.Therefore, claim is not limited by disclosure.

Claims (35)

1. the method for directed toward bacteria, fungi or viral pathogen protective plant, it comprises:
Bismuth-mercaptan (BT) composition that makes described plant and effective dose one or more condition below being enough to meet contacts with under the time:
(i) prevent described plant to be infected by described bacterium, fungi or viral pathogen,
(ii) suppress cell viability or the Growth of Cells of all cells that swim basically of described bacterium, fungi or viral pathogen,
(iii) suppress the biofilm formation by described bacterium, fungi or viral pathogen, and
(iv) suppress biomembrane vigor or the biofilm development of all biomembrane form cells basically of described bacterium, fungi or viral pathogen,
Single suspended matter that disperses basically that wherein said BT composition comprises particulate, single suspended matter that disperses basically of described particulate comprises the BT compound, and described particulate has approximately 0.4 μ m to the about volume mean diameter of 10 μ m.
2. method according to claim 1, wherein said bacterial pathogens comprises the 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 cause a disease mutation, pseudomonas syringae, xyllela fastidiosa, vine wood friend bacterium, Monilinia fructicola, Stewart's wilt bacterium, 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, nectarine tree, Japanese plum, apricot.
9. method according to claim 6, wherein said food crops is the Banana tree of Musa.
10. method according to claim 6, wherein said food crops is the plant that is selected from tuberous plant, leguminous plant and grass family cereal.
11. method according to claim 10, wherein said tuberous plant is selected from potato (potato) and sweet potato (sweet potato).
12. method according to claim 1, wherein said contact procedure is carried out one or many.
13. method according to claim 12, wherein at least one contact procedure comprises spraying, floods, applies and smears the one in described plant.
14. method according to claim 12, wherein described plant, the flowers are in blossom puts, tender shoots or growth position place carry out at least one contact procedure.
15. method according to claim 12, wherein on described plant, the flowers are in blossom for the first time carries out at least one contact procedure in put 24,48 or 72 hours.
16. method according to claim 1, wherein said BT composition comprises and is selected from following one or more BT compound: 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.
17. method according to claim 1, wherein said bacterial pathogens shows antibiotic resistance.
18. according to the described method of any one in claim 1-17, it further comprises with described plant and described BT composition contact procedure simultaneously or successively and with any order, makes described plant and works in coordination with or the enhancement antibiotic contacts.
19. method according to claim 18, wherein said collaborative or enhancement antibiotic comprises and is selected from following antibiotic: aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, penicillase resistance PCs and Aminopenicillin antibiotic.
20. method according to claim 19, wherein said collaborative or enhancement antibiotic is to be selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
21. one kind for therein or exist the plant of antibiotic resistance bacterium phytopathogen to overcome the method for antibiotic resistance on it, it comprises:
(a) one or more condition and make the BT composition of described plant contact effective dose under the time below being enough to meet:
(i) prevent described plant by described antibiotic resistance bacterium pathogenic infection,
(ii) suppress cell viability or the Growth of Cells of all cells that swim basically of antibiotic resistance bacterium pathogene,
(iii) suppress the biofilm formation by described antibiotic resistance bacterium pathogene, and
(iv) suppress biomembrane vigor or the biofilm development of all biomembrane form cells basically of described antibiotic resistance bacterium pathogene,
Single suspended matter that disperses basically that wherein said BT composition comprises particulate, single suspended matter that disperses basically of described particulate comprises the BT compound, and described particulate has approximately 0.5 μ m to the about volume mean diameter of 10 μ m; And
(b) with described plant and described BT composition contact procedure simultaneously or successively and with any order, make described plant and work in coordination with or the enhancement antibiotic contacts.
22. according to the described method of any one in claim 1-21, wherein said bismuth-composition of mercaptans comprises a plurality of particulates, described a plurality of particulate comprises bismuth-mercaptan (BT) compound, basically all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m, and produce by the process comprised the following steps:
(a) in the condition that is enough to obtain the solution be substantially free of solids of sedimentation with mix under the time: (i) comprise bi concns at least 50mM bismuth salt and not containing the acidic aqueous solution of hydrophily, polarity or organic solubilized agent, be enough to obtain with (ii) and comprise by volume the approximately ethanol of the amount of the mixture of 25% ethanol; With
(b) be enough to form under the condition and time of the precipitation that comprises the particulate that contains described BT compound, to adding the ethanolic solution that comprises containing the compound of mercaptan in the mixture of (a) to obtain reaction solution, the wherein said compound containing mercaptan in described reaction solution to exist to the mol ratio of about 3:1 with respect to the about 1:3 of bismuth.
23. method according to claim 22, wherein said bismuth salt is Bi (NO 3) 3.
24. method according to claim 22, wherein said acidic aqueous solution comprises at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth by weight.
25. method according to claim 22, wherein said 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.
26. method according to claim 22, 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; 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) 3the SH[t-butanethiol]); Amyl hydrosulfide (C 5h 11the SH[amyl mercaptan]); Coacetylase; Lipoamide; Glutathione; Cysteine; Cystine; 2 mercapto ethanol; Dithiothreitol (DTT); Dithioerythritol; The 2-sulfydryl indole; TGase; (11-sulfydryl undecyl) six (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol); (11-sulfydryl undecyl) four (ethylene glycol) functionalized golden nanometer particle; 1,1', 4', 1 " terphenyl-4-mercaptan; 1,11-hendecane, two mercaptan; 1,16-hexadecane, two mercaptan; Technical grade 1, the 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; Hot two mercaptan of 1,8-; 1,9-mercaptan in the ninth of the ten Heavenly Stems two; Adamantane mercaptan; The l-butyl mercaptan; The l-decyl mercaptan; The l-dodecyl mercaptans; The l-heptanthiol; Pure l-heptanthiol; 1-hexadecane mercaptan; The l-hexyl mercaptan; L-sulfydryl-(triethylene glycol); 1-sulfydryl-functionalized golden nanometer particle of (triethylene glycol) methyl ether; 1-sulfydryl-2-propyl alcohol; L-mercaptan in the ninth of the ten Heavenly Stems; The l-octadecanethiol; The l-spicy thioalcohol; The 1-spicy thioalcohol; 1-pentadecane mercaptan; The 1-amyl hydrosulfide; The 1-propanethiol; 1-tetradecane mercaptan; Pure 1-tetradecane mercaptan; 1-hendecane mercaptan; 11-(1H-pyrroles-1-yl) hendecane-1-mercaptan; 11-amino-1-hendecane mercaptides hydrochlorate; The bromo-1-hendecane of 11-mercaptan; 11-sulfydryl-1-tip-nip; 11-sulfydryl-1-tip-nip; 11-sulfydryl hendecanoic acid; 11-sulfydryl hendecanoic acid; 11-sulfydryl undecyl trifluoroacetate; 11-sulfydryl undecyl phosphoric acid; 12-sulfydryl dodecylic acid; 12-sulfydryl dodecylic acid; 15-sulfydryl pentadecanoic acid; 16-sulfydryl hexadecanoic acid; 16-sulfydryl hexadecanoic acid; 1H, 1H, 2H, 2H-perfluor decyl mercaptan; 2,2 '-(ethylenedioxy) diethyl mercaptan; 2,3-succinimide mercaptans; The 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, the fluoro-1-hexyl mercaptan of 6-nine; 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; The 3-mercaptopropionic acid; The silica gel that 3-sulfydryl propyl group 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; The 6-mercaptohexanoic acid; 8-sulfydryl-1-octanol; The 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) list-11-(acetyl group sulfenyl) undecyl ether; Mercapto succinic acid; The 3-mercapto-propionate; NanoTether BPA-HH; NanoThinks tM18; NanoThinks tM8; NanoThinks tMaCID11; NanoThinks tMaCID16; NanoThinks tMaLCO11; NanoThinks tMtHIO8; The golden nanometer particle that spicy thioalcohol is functionalized; The average M of PEG bis-mercaptan n8,000; PEG bis-mercaptan molar average molecular weight 1,500; The average molar average molecular weight 3,400 of PEG bis-mercaptan; S-(11-bromo-n-11 base) thiacetate; S-(4-cyano group butyl) thiacetate; Benzenethiol; Triethylene glycol list-11-sulfydryl undecyl ether; Trimethylolpropane tris (3-mercaptopropionic acid ester); [11-(methyl carbonyl sulfenyl) undecyl] four (ethylene glycol); Between carborane-9-mercaptan; Para-terpheny base-4,4 " bis-mercaptan; Tertiary lauryl mercaptan; And tertiary nonyl mercaptan.
27. according to the described method of any one in claim 1-21, wherein said bacterial pathogens comprise 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) be selected from following bacterial pathogens: staphylococcus aureus (S.aureus), MRSA (methicillin resistance staphylococcus aureus), Staphylococcus epidermidis, MRSE (methicillin resistance Staphylococcus epidermidis), Much's bacillus, mycobacterium avium, pseudomonas aeruginosa, the drug resistance pseudomonas aeruginosa, Escherichia coli, enterotoxigenic E.Coli, enterohemorrhagic Escherichia coli, Klebsiella Pneumoniae, clostridium difficile, helicobacter pylori, legionella pneumophila, enterococcus faecalis, the methicillin-sensitivity enterococcus faecalis, enterobacter cloacae, salmonella typhimurium, proteus vulgaris, YE, comma bacillus, shigella flexneri, vancomycin resistance enterococcus (VRE), Burkholderia cepacia complex, soil Lafranchise Salmonella, bacillus anthracis, yersinia pestis, pseudomonas aeruginosa, streptococcus pneumonia, the penicillin resistance streptococcus pneumonia, Escherichia coli, Burkholderia cepacia, bite burkholderia more, smegmatis mycobacterium and Acinetobacter baumannii.
28. according to the described method of any one in claim 1-21, it comprises with described plant and described BT composition contact procedure simultaneously or successively and with any order, makes described plant and (i) work in coordination with antibiotic and contacts with at least one in (ii) cooperative antimicrobial efficacy enhancement antibiotic.
29. method according to claim 28, 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, penicillase resistance PCs and Aminopenicillin antibiotic.
30. method according to claim 29, wherein said collaborative antibiotic or described cooperative antimicrobial efficacy enhancement antibiotic are to be selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
31. one kind for therein or exist the plant of the bacterial pathogens of antibiotic resistance to overcome the method for antibiotic resistance on it, it comprises:
Be enough to meet under following one or more condition and time, making the described plant while or at least one can strengthen or contact with the synergistic antibiotic of described at least one BT composition with (2) successively and with (1) at least one bismuth-mercaptan (BT) composition of any order and effective dose:
(i) prevent described plant to be infected by described bacterial pathogens,
(ii) suppress cell viability or the Growth of Cells of all cells that swim basically of described bacterial pathogens,
(iii) suppress the biofilm formation by described bacterial pathogens, and
(iv) suppress biomembrane vigor or the biofilm development of all biomembrane form cells basically of described bacterial pathogens,
Wherein said BT composition comprises a plurality of particulates that comprise bismuth-mercaptan (BT) compound, and all described particulates have approximately 0.4 μ m to the about volume mean diameter of 5 μ m basically; Thereby and overcome at the lip-deep antibiotic resistance of described epithelial tissue.
32. method according to claim 31, wherein said bacterial pathogens shows being selected from following antibiotic resistance: methicillin, vancomycin, NAF, gentamicin, ampicillin, chloramphenicol, Doxycycline, tobramycin, clindamycin and gatifloxacin.
33. method according to claim 31, wherein said BT composition comprises and is selected from following one or more BT compound: 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.
34. method according to claim 33, wherein said collaborative or enhancement antibiotic comprises and is selected from following antibiotic: clindamycin, gatifloxacin, aminoglycoside antibiotics, carbapenem antibiotic, cephalosporins, fluoroquinolone antibiotics, penicillase resistance PCs and Aminopenicillin antibiotic.
35. method according to claim 34, wherein said collaborative or enhancement antibiotic is to be selected from following aminoglycoside antibiotics: amikacin, Arbekacin, gentamicin, kanamycin, neomycin, Netilmicin, paromomycin, red streptomycin, streptomycin, tobramycin and apramycin.
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